Core Science

Immunology

Innate and adaptive immunity, complement, antibodies, T-cell and B-cell development, hypersensitivity, immunodeficiency, autoimmunity, transplant immunology, and every immune mechanism, receptor, and clinical application across the full scope of medical immunology.

01 Overview & Significance

Immunology is the study of the immune system — the network of cells, tissues, organs, and soluble mediators that defend the body against infection and aberrant cells while maintaining tolerance to self. It integrates molecular biology, cell biology, genetics, and clinical medicine, and underpins understanding of infectious disease, autoimmunity, allergy, cancer, transplantation, and immunodeficiency. On USMLE Step 1, immunology accounts for approximately 9–15% of questions, making it one of the highest-yield foundational disciplines.

Why This Matters

Every physician encounters immunologic disease daily — from anaphylaxis to autoimmune disorders to organ rejection. A solid immunologic foundation enables you to understand why vaccines work, why transplant patients need immunosuppression, why HIV destroys immunity, and how checkpoint inhibitors fight cancer. Immunology is the key that unlocks rational clinical reasoning across every specialty.

Scope of Medical Immunology

Domain	Key Topics
Innate Immunity	Barriers, complement, phagocytes, pattern recognition receptors, NK cells
Adaptive Immunity	T cells, B cells, antibodies, MHC, antigen processing, immunologic memory
Hypersensitivity	Types I–IV reactions, allergy, anaphylaxis, serum sickness
Immunodeficiency	Primary (SCID, Bruton, DiGeorge) and acquired (HIV/AIDS)
Autoimmunity	SLE, RA, type 1 DM, Hashimoto, Graves, MS, autoantibodies
Transplant Immunology	Rejection types, HLA matching, GvHD, immunosuppressant drugs
Tumor Immunology	Immune surveillance, checkpoint inhibitors, CAR-T therapy
Vaccination	Live vs. inactivated, adjuvants, herd immunity, mRNA vaccines

Historical Milestones

Year	Milestone	Significance
1796	Jenner — cowpox vaccination	First deliberate immunization; foundation of vaccinology
1880s	Pasteur — attenuated vaccines (anthrax, rabies)	Demonstrated that weakened pathogens confer immunity
1890	von Behring & Kitasato — antitoxin therapy	Discovery of humoral immunity (serum-mediated protection)
1901	Landsteiner — ABO blood groups	Basis of transfusion medicine and understanding of alloimmunity
1953	Grubb, Grubb & Grubb — agammaglobulinemia described	First primary immunodeficiency characterized
1957	Burnet — clonal selection theory	Each lymphocyte bears a unique receptor; antigen selects responding clone
1975	Köhler & Milstein — monoclonal antibody technology	Hybridoma technology revolutionized diagnostics and therapeutics
2018	Allison & Honjo — Nobel Prize for checkpoint inhibitors	CTLA-4 and PD-1 blockade transformed cancer immunotherapy

When approaching an immunology question, first determine whether the problem involves innate vs. adaptive immunity, humoral vs. cell-mediated responses, and whether the pathology represents too much immune activity (autoimmunity/hypersensitivity) or too little (immunodeficiency).

02 Core Principles & Key Terminology

Fundamental Organizing Concepts

Concept	Definition
Innate immunity	Rapid, non-specific, no memory; present at birth; uses germline-encoded receptors
Adaptive immunity	Slow onset (days), highly specific, generates memory; requires antigen exposure; uses somatically recombined receptors (TCR, BCR)
Humoral immunity	B-cell/antibody-mediated; defends against extracellular pathogens and toxins
Cell-mediated immunity	T-cell-mediated; defends against intracellular pathogens, tumors, transplants
Active immunity	Host generates own immune response (natural infection or vaccination); long-lasting
Passive immunity	Preformed antibodies transferred (maternal IgG, IVIg, antiserum); immediate but transient
Antigen	Any molecule recognized by the adaptive immune system; epitope = the specific region bound by antibody or TCR
Immunogen	An antigen capable of eliciting an immune response (all immunogens are antigens, but not all antigens are immunogens — e.g., haptens)
Hapten	Small molecule that is antigenic but not immunogenic alone; must bind a carrier protein to elicit a response (e.g., penicillin, poison ivy urushiol)
Adjuvant	Substance that enhances the immune response to a co-administered antigen (e.g., alum, MF59)

Key Abbreviations

Abbreviation	Meaning
APC	Antigen-presenting cell (dendritic cell, macrophage, B cell)
TCR	T-cell receptor (recognizes peptide–MHC complex)
BCR	B-cell receptor (membrane-bound immunoglobulin)
MHC	Major histocompatibility complex (HLA in humans)
Ig	Immunoglobulin (IgG, IgA, IgM, IgE, IgD)
PAMP	Pathogen-associated molecular pattern
PRR	Pattern recognition receptor (TLR, NLR, RLR, CLR)
MAC	Membrane attack complex (C5b–C9)
DAMP	Damage-associated molecular pattern (released from injured host cells)

Innate vs. Adaptive Immunity: Detailed Comparison

Feature	Innate Immunity	Adaptive Immunity
Onset	Immediate (minutes–hours)	Delayed (days–weeks on first exposure)
Specificity	Broad (recognizes general molecular patterns)	Highly specific (recognizes unique epitopes)
Memory	No classical memory (some “trained immunity” in monocytes/NK cells)	Robust immunologic memory (faster, stronger on re-exposure)
Receptors	Germline-encoded, limited diversity (PRRs: TLRs, NLRs, CLRs)	Somatically recombined, vast diversity (TCR: ~10¹⁵; BCR: ~10¹¹)
Key cells	Neutrophils, macrophages, dendritic cells, NK cells, mast cells, eosinophils, basophils	T cells (CD4+, CD8+), B cells, plasma cells
Soluble mediators	Complement, cytokines, antimicrobial peptides, acute-phase proteins	Antibodies, cytokines
Self/non-self discrimination	Recognizes PAMPs (absent in host); DAMPs (host damage signals)	Clonal selection + central/peripheral tolerance mechanisms
Germ-line encoded?	Yes (fixed receptor repertoire)	No (generated by VDJ recombination; RAG-1/RAG-2 dependent)

The distinction between active and passive immunity is a perennial board favorite. Maternal IgG crossing the placenta is passive immunity (the infant did not generate the antibodies). Vaccination is active immunity (the host mounts its own response). Passive immunity provides immediate protection but fades; active immunity takes time but produces lasting memory. “Trained immunity” is a recently described phenomenon in which innate cells (monocytes, NK cells) exhibit enhanced responses after prior stimulation — mediated by epigenetic reprogramming rather than receptor recombination. BCG vaccination may enhance innate immunity through trained immunity.

03 Cells of the Immune System

Myeloid Lineage

Cell	Key Markers	Function
Neutrophil	CD66b; multilobed nucleus	First responder; phagocytosis; NETs (neutrophil extracellular traps); most abundant WBC (60–70%)
Monocyte / Macrophage	CD14, CD16; kidney-shaped nucleus	Phagocytosis, antigen presentation (MHC II), cytokine secretion; tissue-specific names (Kupffer cells in liver, microglia in CNS, alveolar macrophages in lung)
Dendritic cell	CD11c, MHC II (high)	Most potent APC; bridges innate and adaptive immunity; captures antigen in tissues, migrates to lymph nodes to activate naïve T cells
Eosinophil	CD193 (CCR3); bilobed nucleus	Defense against helminths (parasites); major basic protein release; role in allergic inflammation
Basophil	CD123; bilobed, S-shaped nucleus	IgE-mediated reactions; release histamine and heparin; circulating counterpart of mast cells
Mast cell	CD117 (c-Kit), FcεRI	Tissue-resident; IgE cross-linking triggers degranulation (histamine, tryptase, leukotrienes); central to Type I hypersensitivity

Lymphoid Lineage

Cell	Key Markers	Function
CD4+ T cell (helper)	CD3, CD4, TCRαβ	Orchestrates immune responses; recognizes MHC II–peptide; differentiates into Th1, Th2, Th17, Treg, Tfh
CD8+ T cell (cytotoxic)	CD3, CD8, TCRαβ	Kills virus-infected and tumor cells; recognizes MHC I–peptide; releases perforin and granzymes
B cell	CD19, CD20, CD21, surface Ig	Produces antibodies; antigen presentation to T cells; differentiates into plasma cells and memory B cells
Plasma cell	CD38, CD138; eccentric nucleus, clock-face chromatin	Terminally differentiated B cell; antibody factory (secretes ~2,000 Ab molecules/second)
NK cell	CD16, CD56; no TCR	Innate lymphocyte; kills cells lacking MHC I (missing self); ADCC via FcγRIII (CD16); releases perforin and granzymes
γδ T cell	CD3, TCRγδ	Bridge innate/adaptive; recognize non-peptide antigens (phospholipids, lipids); found in epithelial surfaces

Clinical Correlation

CD4 count in HIV: Normal >500 cells/μL. AIDS defined as <200 cells/μL. Opportunistic infections correlate with CD4 thresholds: <200 = PCP, <100 = Toxoplasma/Cryptococcus, <50 = MAC/CMV.

The dendritic cell is the most powerful APC and the only cell that can activate a naïve T cell. All nucleated cells express MHC I (present endogenous peptides to CD8+), but only professional APCs (dendritic cells, macrophages, B cells) express MHC II (present exogenous peptides to CD4+).

04 Barriers & Physical Defenses

The first line of defense consists of physical, chemical, and biological barriers that prevent pathogen entry without requiring immune cell activation.

Barrier Type	Mechanism	Examples
Mechanical	Physical exclusion of pathogens	Skin (stratified squamous epithelium), mucociliary escalator, urinary flow, peristalsis, cough reflex
Chemical	Antimicrobial molecules	Stomach acid (pH 1–2), lysozyme (tears, saliva), defensins (skin, GI), lactoferrin (sequester iron), surfactant proteins A & D (lung)
Biological	Commensal flora competition	Normal flora of skin, gut, vagina compete with pathogens for nutrients and produce bacteriocins; disruption leads to opportunistic infections (e.g., C. difficile after antibiotics)

Antimicrobial Peptides

Antimicrobial peptides (AMPs) are small cationic molecules that insert into microbial membranes, disrupting their integrity. Key families include:

Peptide	Location	Function
Defensins (α and β)	α-defensins: neutrophil granules, Paneth cells (small intestine); β-defensins: epithelial surfaces (skin, respiratory, GI)	Form pores in microbial membranes; chemotactic for dendritic cells and T cells
Cathelicidin (LL-37)	Neutrophils, keratinocytes, epithelial cells	Antimicrobial; enhances TLR signaling; vitamin D upregulates expression (link between vitamin D deficiency and infection susceptibility)
Lysozyme	Tears, saliva, nasal secretions, neutrophil granules	Cleaves peptidoglycan in bacterial cell walls (more effective against Gram-positives)
Lactoferrin	Mucosal secretions, neutrophil granules, breast milk	Sequesters iron from bacteria (iron-dependent organisms); direct bactericidal activity

Patients with burns lose the skin barrier and are at extreme risk for Pseudomonas and Staphylococcus sepsis. Patients on proton pump inhibitors lose the gastric acid barrier and have increased susceptibility to enteric infections (C. difficile, Salmonella). Vitamin D deficiency impairs cathelicidin production, which may partly explain the association between low vitamin D and increased susceptibility to TB and respiratory infections.

05 Pattern Recognition & Toll-Like Receptors

Innate immune cells detect pathogens through pattern recognition receptors (PRRs) that recognize conserved microbial structures called pathogen-associated molecular patterns (PAMPs) and host-derived danger signals called damage-associated molecular patterns (DAMPs).

Major PRR Families

PRR Family	Location	Ligands	Downstream Effect
TLRs (Toll-like receptors)	Cell surface (1,2,4,5,6) or endosome (3,7,8,9)	LPS, flagellin, dsRNA, ssRNA, CpG DNA	NF-κB activation → pro-inflammatory cytokines (TNF-α, IL-1, IL-6)
NLRs (NOD-like receptors)	Cytoplasm	Peptidoglycan (NOD1/2), DAMPs (NLRP3 inflammasome)	Inflammasome assembly → caspase-1 → IL-1β and IL-18 secretion
RLRs (RIG-I-like receptors)	Cytoplasm	Viral dsRNA	Type I interferon (IFN-α/β) production
CLRs (C-type lectin receptors)	Cell surface	Mannose, β-glucan (fungi)	Phagocytosis, cytokine production
cGAS-STING	Cytoplasm	Cytosolic dsDNA	Type I interferon production

Key Toll-Like Receptors

TLR	PAMP Recognized	Pathogen
TLR-1/2	Bacterial lipopeptides	Gram-positive bacteria
TLR-3	dsRNA	Viruses (endosomal)
TLR-4	LPS (lipopolysaccharide)	Gram-negative bacteria
TLR-5	Flagellin	Flagellated bacteria
TLR-7/8	ssRNA	Viruses (endosomal)
TLR-9	Unmethylated CpG DNA	Bacteria, DNA viruses (endosomal)

NLRP3 Inflammasome

The NLRP3 inflammasome is activated by diverse danger signals (uric acid crystals in gout, cholesterol crystals in atherosclerosis, asbestos, silica). Assembly activates caspase-1, which cleaves pro-IL-1β and pro-IL-18 into active forms and triggers pyroptosis (inflammatory cell death via gasdermin D pores). Mutations causing constitutive NLRP3 activation cause cryopyrin-associated periodic syndromes (CAPS), treated with IL-1 antagonists (anakinra, canakinumab).

TLR-4 recognition of LPS is the molecular basis of Gram-negative sepsis. LPS binds MD2/TLR-4, activating NF-κB and triggering a cytokine storm (TNF-α, IL-1, IL-6). This is why Gram-negative bacteremia can rapidly progress to septic shock.

06 Complement System

The complement system is a cascade of >30 plasma proteins that enhance (“complement”) the ability of antibodies and phagocytes to clear pathogens. Its three main functions are opsonization (C3b), inflammation (C3a, C5a — anaphylatoxins), and lysis (membrane attack complex, C5b–C9).

Activation Pathways

Pathway	Trigger	Key Components	C3 Convertase
Classical	IgG or IgM–antigen complexes bind C1q	C1q, C1r, C1s, C4, C2	C4b2a
Lectin (MBL)	Mannose-binding lectin binds mannose on pathogens	MBL, MASP-1/2, C4, C2	C4b2a
Alternative	Spontaneous C3 hydrolysis (tick-over) on pathogen surfaces	C3, Factor B, Factor D, Properdin	C3bBb

All three pathways converge at C3 convertase, which cleaves C3 into C3a (anaphylatoxin) and C3b (opsonin). C3b joins the C3 convertase to form C5 convertase, which cleaves C5 into C5a (most potent anaphylatoxin and neutrophil chemoattractant) and C5b, initiating the membrane attack complex (MAC) (C5b–C6–C7–C8–C9).

Complement Functions & Key Fragments

Fragment	Function
C3b	Opsonization (binds pathogen surface, recognized by CR1 on phagocytes)
C3a, C4a, C5a	Anaphylatoxins — trigger mast cell degranulation, smooth muscle contraction, vascular permeability; C5a is the most potent
C5a	Neutrophil chemotaxis (strongest complement-derived chemoattractant)
C5b–C9 (MAC)	Forms pores in cell membranes → osmotic lysis (especially effective against Neisseria)

Complement Regulatory Proteins

Regulator	Mechanism	Clinical Relevance
Decay-accelerating factor (DAF/CD55)	Accelerates decay of C3/C5 convertases	Deficiency of DAF and CD59 (GPI-anchored) → Paroxysmal nocturnal hemoglobinuria (PNH)
CD59 (protectin)	Prevents MAC assembly on host cells
C1 esterase inhibitor (C1-INH)	Inhibits C1r/C1s (classical pathway)	Deficiency → Hereditary angioedema (excess bradykinin from unchecked complement/kinin activation)
Factor H	Cofactor for Factor I–mediated cleavage of C3b	Mutations → atypical hemolytic uremic syndrome (aHUS)

High-Yield Complement Deficiencies

C1–C4 deficiency → SLE-like syndrome (impaired immune complex clearance). C3 deficiency → severe recurrent pyogenic infections (no opsonization). C5–C9 (MAC) deficiency → recurrent Neisseria infections (meningococcal meningitis, gonococcal disease). C1-INH deficiency → hereditary angioedema. DAF/CD59 deficiency → PNH (complement-mediated hemolysis).

Complement in Disease & Therapy

Clinical Scenario	Complement Finding	Mechanism
Active SLE / PSGN / cryoglobulinemia	Low C3 and C4 (consumed)	Immune complex activation of classical pathway consumes complement
Hereditary angioedema	Low C4, low C1-INH (functional or quantitative)	Uninhibited C1 cleaves C4; bradykinin excess causes angioedema
Alternative pathway activation (e.g., aHUS, C3 GN)	Low C3, normal C4	Alternative pathway preferentially consumes C3 without affecting C4
PNH	Normal complement levels; RBCs hypersensitive to complement lysis	GPI anchor deficiency → absent DAF/CD59 on RBCs

Eculizumab (anti-C5 monoclonal antibody) blocks C5 cleavage, preventing MAC formation and C5a generation. It is used in PNH, atypical HUS, and myasthenia gravis. Patients on eculizumab must be vaccinated against Neisseria meningitidis (meningococcal vaccine) because blocking the MAC increases susceptibility to meningococcal disease.

A patient with recurrent Neisseria meningitidis infections should prompt testing for terminal complement (C5–C9) deficiency. A CH50 assay of zero suggests a complete deficiency in one of the classical/terminal pathway components. An AH50 (alternative pathway hemolytic) assay tests the alternative pathway specifically. If both CH50 and AH50 are zero, suspect a deficiency in the common terminal pathway (C3 or C5–C9).

07 Phagocytosis & Inflammation

Steps of Phagocytosis

Phagocytosis follows an orderly sequence: (1) Chemotaxis — neutrophils/macrophages migrate toward chemoattractants (C5a, IL-8/CXCL8, LTB4, bacterial peptides like fMLP); (2) Opsonization — pathogen coating with IgG (Fc receptor binding) or C3b (CR1 binding); (3) Engulfment — pseudopod extension and phagosome formation; (4) Killing — phagosome fuses with lysosome, activating oxygen-dependent and oxygen-independent mechanisms.

Microbial Killing Mechanisms

Mechanism	Key Mediators	Clinical Relevance
Oxidative burst (O₂-dependent)	NADPH oxidase → superoxide (O₂⁻) → H₂O₂ → HOCl (bleach, via myeloperoxidase)	Deficient in Chronic Granulomatous Disease (CGD) — NADPH oxidase defect; diagnosed by negative nitroblue tetrazolium (NBT) or dihydrorhodamine (DHR) test
O₂-independent	Lysozyme, lactoferrin, defensins, cathepsins, major basic protein (eosinophils)	Provide baseline killing even in anaerobic conditions
NETs (neutrophil extracellular traps)	Chromatin fibers studded with antimicrobial proteins extruded by neutrophils	Trap and kill extracellular pathogens; excessive NETosis implicated in SLE, vasculitis, thrombosis

Cardinal Signs of Inflammation

Rubor (redness), calor (heat), tumor (swelling), dolor (pain), and functio laesa (loss of function). These result from vasodilation (histamine, PGE2, NO), increased vascular permeability (histamine, C3a/C5a, leukotrienes), and leukocyte infiltration.

Key Inflammatory Mediators

Mediator	Source	Action
Histamine	Mast cells, basophils	Vasodilation, increased vascular permeability, bronchospasm
TNF-α	Macrophages	Fever, acute-phase proteins, endothelial activation, cachexia; dominant mediator in sepsis
IL-1	Macrophages	Fever (acts on hypothalamus), endothelial activation, acute-phase protein synthesis
IL-6	Macrophages, T cells	Fever, hepatic acute-phase protein synthesis (CRP, fibrinogen), B-cell differentiation
PGE₂	COX-2 in many cell types	Vasodilation, pain sensitization, fever; target of NSAIDs
LTB₄	Lipoxygenase pathway	Potent neutrophil chemoattractant
LTC₄/D₄/E₄	Mast cells, eosinophils	Bronchospasm, vasoconstriction, mucus secretion (slow-reacting substances of anaphylaxis)

Leukocyte Extravasation (Diapedesis)

Leukocytes migrate from blood to tissues through a multi-step process at postcapillary venules:

Step	Molecules Involved	Mechanism
1. Rolling	E-selectin and P-selectin (endothelium) bind sialyl-Lewis^X (leukocyte)	Loose, reversible adhesion; leukocyte rolls along endothelium
2. Activation	Chemokines (IL-8, C5a) activate leukocyte integrins	Conformational change in integrins increases binding affinity
3. Firm adhesion	Integrins (LFA-1/CD11a-CD18) bind ICAM-1; VLA-4 binds VCAM-1	Tight adhesion stops rolling; leukocyte flattens
4. Transmigration	PECAM-1 (CD31) on both leukocyte and endothelium	Leukocyte squeezes between endothelial cells into tissue

Leukocyte Adhesion Deficiency

LAD Type 1: Deficiency of CD18 (β2-integrin subunit) prevents firm adhesion → neutrophils cannot leave bloodstream → leukocytosis, absent pus formation, delayed umbilical cord separation, recurrent bacterial infections. LAD Type 2: Defect in fucose metabolism (sialyl-Lewis^X absent) → defective rolling → similar but milder phenotype.

The three endogenous pyrogens are IL-1, IL-6, and TNF-α. They stimulate PGE₂ production in the hypothalamus, resetting the thermoregulatory set point. This is why NSAIDs and acetaminophen (which inhibit COX/PGE₂) reduce fever. CGD patients have recurrent infections with catalase-positive organisms (Staph aureus, Aspergillus, Serratia, Nocardia, Burkholderia cepacia) because these organisms destroy their own H₂O₂, eliminating the substrate for the myeloperoxidase system. Mnemonic for catalase-positive organisms: “Cats Need PLACESS to Breathe” (Pseudomonas, Listeria, Aspergillus, Candida, E. coli, S. aureus, Serratia, B. cepacia).

08 T-Cell Development & Thymic Selection

T-cell precursors originate from bone marrow hematopoietic stem cells and migrate to the thymus for maturation. The thymus is most active in childhood and undergoes progressive involution after puberty, though residual function persists into adulthood.

Stages of Thymic Development

Stage	Phenotype	Location	Key Event
Double-negative (DN)	CD4− CD8−	Thymic cortex	TCR β-chain gene rearrangement (VDJ recombination via RAG-1/RAG-2); β-selection checkpoint
Double-positive (DP)	CD4+ CD8+	Thymic cortex	TCR α-chain rearrangement; now express complete αβ-TCR
Positive selection	DP → SP	Thymic cortex	Cortical epithelial cells test for MHC recognition; T cells that bind MHC with moderate affinity survive; those that fail to bind → apoptosis (death by neglect)
Negative selection	SP	Cortico-medullary junction & medulla	Medullary epithelial cells and DCs present self-antigens (driven by AIRE gene); T cells that bind self-peptide–MHC too strongly → apoptosis (clonal deletion) or Treg differentiation
Single-positive (SP)	CD4+ or CD8+	Thymic medulla	Mature, self-tolerant T cells exit to periphery

AIRE Gene & Central Tolerance

The autoimmune regulator (AIRE) transcription factor enables thymic medullary epithelial cells to express tissue-restricted antigens (e.g., insulin, thyroglobulin) so that self-reactive T cells can be deleted. AIRE mutations cause Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED / APS-1) — characterized by chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency.

Only about 2–5% of thymocytes survive both positive and negative selection. The rest die by apoptosis. This rigorous screening ensures that the T-cell repertoire is both self-MHC restricted (positive selection) and self-tolerant (negative selection).

VDJ Recombination & TCR Diversity

The T-cell receptor (TCR) is generated through somatic recombination of variable (V), diversity (D), and joining (J) gene segments. This process, mediated by RAG-1 and RAG-2 recombinases, generates enormous receptor diversity from a limited number of germline gene segments.

TCR Chain	Gene Segments	Recombination
α-chain	Vα and Jα segments	VJ recombination (similar to Ig light chain)
β-chain	Vβ, Dβ, and Jβ segments	VDJ recombination (D-J first, then V-DJ); β-selection checkpoint

Additional diversity comes from junctional diversity (imprecise joining at segment boundaries) and N-nucleotide addition by terminal deoxynucleotidyl transferase (TdT). Unlike B cells, T cells do NOT undergo somatic hypermutation — TCR diversity is generated entirely during development. The estimated TCR repertoire is >10¹⁵ unique receptors.

RAG-1 and RAG-2 (recombination-activating genes) are essential for VDJ recombination of TCR and BCR genes. Deficiency of either RAG gene causes Omenn syndrome (a form of SCID with oligoclonal T-cell expansion, erythroderma, eosinophilia, and elevated IgE). TdT is a marker of immature lymphocytes (pre-B and pre-T cells) and is used as a diagnostic marker for acute lymphoblastic leukemia (ALL).

09 MHC & Antigen Presentation

MHC Class I vs. Class II

Feature	MHC Class I	MHC Class II
Genes (HLA)	HLA-A, HLA-B, HLA-C	HLA-DP, HLA-DQ, HLA-DR
Structure	α-chain + β₂-microglobulin	α-chain + β-chain
Expression	All nucleated cells + platelets (not RBCs)	Professional APCs (dendritic cells, macrophages, B cells)
Peptide source	Endogenous (intracellular) — viral, tumor proteins	Exogenous (extracellular) — phagocytosed pathogens
Processing pathway	Proteasome → TAP transporter → ER loading	Endosome/lysosome → invariant chain (Ii) removed by cathepsin → CLIP replaced by peptide via HLA-DM
Recognized by	CD8+ cytotoxic T cells	CD4+ helper T cells
Binding groove	Closed (fits 8–10 aa peptides)	Open (fits 13–25 aa peptides)

Memory Aid

“MHC I loads from the Inside” (endogenous antigen from cytoplasm). “MHC II loads from the Outside” (exogenous antigen from endosomes). Rule of 8: MHC I × CD8 = 8. MHC II × CD4 = 8.

Antigen Processing Pathways in Detail

Step	MHC I Pathway (Endogenous)	MHC II Pathway (Exogenous)
1. Antigen source	Intracellular proteins (viral, tumor, self)	Extracellular proteins (phagocytosed, endocytosed)
2. Processing	Proteasome degrades protein into 8–10 aa peptides	Acidic proteases in endosome/lysosome generate 13–25 aa peptides
3. Transport to ER/loading	TAP transporter moves peptides into ER; peptide loaded onto MHC I–β₂m complex with help of tapasin, calreticulin, ERp57	MHC II assembled in ER with invariant chain (Ii/CD74) blocking groove; Ii degraded in endosome by cathepsin S, leaving CLIP fragment; HLA-DM catalyzes CLIP removal and peptide loading
4. Surface display	MHC I–peptide transported to cell surface via Golgi	MHC II–peptide complex transported to cell surface
5. T-cell recognition	CD8+ T cell (TCR + CD8 co-receptor)	CD4+ T cell (TCR + CD4 co-receptor)

Cross-Presentation

Cross-presentation is the ability of certain dendritic cells to load exogenous antigens onto MHC I molecules, thereby activating CD8+ T cells against extracellular pathogens and tumors. This is essential for anti-tumor and anti-viral immunity when the DC itself is not infected. Defects in cross-presentation may contribute to immune evasion by tumors.

HLA Disease Associations

HLA Allele	Associated Disease
HLA-B27	Ankylosing spondylitis, reactive arthritis, psoriatic arthritis, IBD-associated arthritis
HLA-DR2	Multiple sclerosis, SLE, Goodpasture syndrome
HLA-DR3	Type 1 diabetes mellitus, SLE, Graves disease, celiac disease
HLA-DR4	Type 1 diabetes mellitus, rheumatoid arthritis
HLA-DR5	Hashimoto thyroiditis, pernicious anemia
HLA-DQ2/DQ8	Celiac disease (DQ2 in ~95%, DQ8 in remainder)
HLA-B5801	Allopurinol hypersensitivity (screen before prescribing in certain populations)

Antigen Presentation Pathways — Special Scenarios

Scenario	Mechanism	Clinical Significance
Cross-presentation	Exogenous antigen loaded onto MHC I (by specialized dendritic cells)	Essential for anti-tumor and anti-viral CTL responses when APC is not directly infected
Cross-dressing	Transfer of intact MHC–peptide complexes from donor cells to host APCs	Contributes to allograft rejection; donor MHC transferred to recipient DCs
Autophagy-mediated presentation	Intracellular antigens delivered to MHC II compartment via autophagy	Allows MHC II presentation of cytoplasmic antigens (e.g., EBV nuclear antigens)
CD1 presentation	CD1 molecules (non-classical MHC) present lipid antigens to NKT cells and γδ T cells	Important in mycobacterial immunity (mycolic acids, lipoarabinomannan)

TAP Deficiency

TAP (transporter associated with antigen processing) is essential for loading peptides onto MHC I in the ER. TAP deficiency results in markedly reduced MHC I surface expression, leading to a clinical phenotype resembling bare lymphocyte syndrome type I: recurrent respiratory infections, bronchiectasis, and necrotizing granulomatous skin lesions. Importantly, CD8+ T cells are present but poorly functional due to inadequate MHC I–mediated positive selection.

HLA-B27 is the single highest-yield HLA association. It is present in >90% of patients with ankylosing spondylitis. The seronegative spondyloarthropathies (ankylosing spondylitis, reactive arthritis, psoriatic arthritis, enteropathic arthritis) are all HLA-B27 associated. Bare lymphocyte syndrome type II (MHC II deficiency due to transcription factor defects like CIITA) causes severe combined immunodeficiency because CD4+ T cells cannot be positively selected without MHC II.

10 CD4+ T Helper Subsets (Th1, Th2, Th17, Treg)

Naïve CD4+ T cells differentiate into distinct effector subsets depending on the cytokine milieu at the time of activation. Each subset produces a characteristic cytokine profile and drives specific immune functions.

Subset	Inducing Cytokines	Master Transcription Factor	Signature Cytokines	Function
Th1	IL-12, IFN-γ	T-bet	IFN-γ, TNF-α, IL-2	Activates macrophages (intracellular pathogens: mycobacteria, fungi); promotes cell-mediated immunity; class switch to IgG
Th2	IL-4	GATA-3	IL-4, IL-5, IL-13, IL-10	B-cell activation, class switch to IgE; eosinophil recruitment (IL-5); helminth defense; drives allergic responses
Th17	IL-6, TGF-β, IL-23	RORγt	IL-17, IL-22	Neutrophil recruitment; mucosal immunity; defense against extracellular bacteria and fungi; implicated in autoimmunity (RA, MS, psoriasis)
Treg	TGF-β, IL-2	FoxP3	IL-10, TGF-β	Suppresses immune responses; maintains self-tolerance; prevents autoimmunity
Tfh (follicular helper)	IL-6, IL-21	Bcl-6	IL-21, IL-4	Helps B cells in germinal centers; essential for affinity maturation, class switching, memory B-cell formation

Th1/Th2 Balance

Th1 and Th2 responses are mutually inhibitory. IFN-γ (Th1) suppresses Th2 differentiation, while IL-4 and IL-10 (Th2) suppress Th1. An imbalanced Th2 response drives atopic disease (asthma, eczema, allergic rhinitis). An imbalanced Th1 response drives organ-specific autoimmunity. This balance is critical for understanding why some infections (e.g., lepromatous vs. tuberculoid leprosy) produce different clinical outcomes.

T-Cell Co-stimulation & Signal Integration

Full T-cell activation requires three signals:

Signal	Interaction	Consequence of Absence
Signal 1	TCR recognizes peptide–MHC complex	No activation (antigen not recognized)
Signal 2	Co-stimulation: B7 (CD80/CD86) on APC binds CD28 on T cell	T-cell anergy (functional unresponsiveness) — basis of peripheral tolerance
Signal 3	Cytokine milieu determines T-cell differentiation (IL-12 → Th1; IL-4 → Th2; TGF-β + IL-6 → Th17)	Default or unpolarized response

Key co-stimulatory and co-inhibitory pairs:

CD28–B7: Positive co-stimulation; essential for naïve T-cell activation
CTLA-4–B7: Negative regulator; higher affinity than CD28; dampens activation (target of ipilimumab)
PD-1–PD-L1/PD-L2: Negative regulator; induces T-cell exhaustion in periphery (target of pembrolizumab, nivolumab)
CD40–CD40L: T-cell “licenses” APC; also critical for B-cell class switching (CD40L deficiency → Hyper-IgM syndrome)
ICOS–ICOS-L: Important for Tfh function in germinal centers; ICOS deficiency causes CVID-like syndrome

FoxP3 mutations cause IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) — severe multi-organ autoimmunity in males presenting in infancy with type 1 DM, eczema, and intractable diarrhea. This underscores the critical role of Tregs in self-tolerance. Abatacept (CTLA-4-Ig fusion protein) blocks B7–CD28 co-stimulation and is used in rheumatoid arthritis — it mimics CTLA-4 function to dampen T-cell activation.

11 CD8+ Cytotoxic T Cells & NK Cells

CD8+ Cytotoxic T Lymphocytes (CTLs)

CD8+ T cells recognize endogenous peptides presented on MHC I. Upon activation (requiring signal 1 = TCR–MHC I, signal 2 = co-stimulation via B7–CD28, signal 3 = cytokines like IL-2), they differentiate into effector CTLs that kill target cells through two main mechanisms:

Perforin/Granzyme pathway — Perforin creates pores in the target cell membrane; granzymes (serine proteases) enter and activate caspases, triggering apoptosis
Fas/FasL pathway — FasL (CD95L) on CTL binds Fas (CD95) on target cell, activating caspase-8 and the extrinsic apoptosis pathway

Natural Killer (NK) Cells

NK cells are innate lymphocytes (CD16+, CD56+, no TCR) that provide rapid killing of virus-infected and tumor cells without prior sensitization. NK cell activity is regulated by the balance of activating and inhibitory receptors:

Signal Type	Receptor	Ligand	Outcome
Inhibitory	KIR (killer immunoglobulin-like receptors)	MHC I on target cell	Inhibits killing (self-recognition)
Activating	NKG2D, natural cytotoxicity receptors	Stress ligands (MICA/MICB, ULBPs)	Triggers killing
Activating	FcγRIII (CD16)	IgG coating target cell	ADCC (antibody-dependent cellular cytotoxicity)

Missing-self hypothesis: NK cells kill cells that have lost MHC I expression (common in virally infected and tumor cells that downregulate MHC I to evade CTLs). Loss of the inhibitory KIR signal tips the balance toward activation → killing.

Clinical Correlation — Chédiak–Higashi Syndrome

An autosomal recessive defect in the LYST gene causes impaired lysosomal trafficking, resulting in giant granules in neutrophils and NK cells. Patients present with recurrent pyogenic infections, partial oculocutaneous albinism, peripheral neuropathy, and defective NK cell function. Peripheral blood smear shows pathognomonic giant granules in neutrophils.

Perforin/Granzyme Killing in Detail

Both CTLs and NK cells use the perforin/granzyme pathway as their primary killing mechanism. The process is highly directional:

Immune synapse formation: CTL/NK cell polarizes its microtubule-organizing center (MTOC) and lytic granules toward the target cell contact point
Perforin release: Creates pores in target cell membrane (similar to MAC); also facilitates granzyme entry via endocytosis
Granzyme B entry: Serine protease enters target cell and activates caspase cascade (caspase-3, -7) → apoptosis
Serial killing: CTLs can detach and sequentially kill multiple target cells; this is why a relatively small number of CTLs can eliminate many virus-infected cells

Familial Hemophagocytic Lymphohistiocytosis (FHL)

Genetic defects in perforin (PRF1 mutations) or granule exocytosis machinery (Munc13-4, syntaxin-11) cause inability of CTLs and NK cells to kill target cells. This leads to unchecked immune activation, massive cytokine release (“cytokine storm”), and hemophagocytosis (macrophages engulfing blood cells). Presents with fever, hepatosplenomegaly, cytopenias, hyperferritinemia (>10,000), hypertriglyceridemia, and elevated soluble IL-2R. Treatment: etoposide-based chemotherapy followed by bone marrow transplant.

NK cells are the key defense in the first 0–12 hours of viral infection (before adaptive immunity engages). Patients with NK cell deficiencies are particularly susceptible to herpesvirus infections (HSV, VZV, CMV, EBV). Type I interferons (IFN-α/β) produced by virus-infected cells activate NK cells and induce an antiviral state in neighboring cells by upregulating MHC I expression and inhibiting viral protein synthesis.

12 B-Cell Development & Activation

B cells develop in the bone marrow (hence "B") through a series of stages defined by immunoglobulin gene rearrangement status.

Stages of B-Cell Development

Stage	Ig Status	Key Event
Pro-B cell	Heavy chain VDJ rearrangement begins	RAG-1/RAG-2 mediated; D-J first, then V-DJ
Pre-B cell	μ heavy chain + surrogate light chain (pre-BCR)	Successful heavy chain rearrangement; allelic exclusion ensures one heavy chain per cell
Immature B cell	Complete IgM on surface	Light chain rearrangement (κ first, then λ if needed); negative selection against self-antigens in bone marrow
Mature naïve B cell	IgM + IgD co-expressed on surface	Exits to periphery; circulates through secondary lymphoid organs awaiting antigen encounter

B-Cell Activation

B cells can be activated via two pathways:

T-cell dependent (TD): B cell internalizes antigen via BCR, processes it, and presents peptide on MHC II to a Tfh cell. Tfh provides co-stimulation (CD40L–CD40 interaction) and cytokines (IL-4, IL-21). This drives germinal center formation, affinity maturation, isotype switching, and memory cell generation.
T-cell independent (TI): Polysaccharide antigens (e.g., bacterial capsules) cross-link multiple BCRs simultaneously, activating B cells without T-cell help. Produces mainly IgM (no isotype switching), no affinity maturation, weak memory. This is why polysaccharide vaccines (pneumococcal, meningococcal) are less effective in children <2 years old (immature marginal zone B cells).

Conjugate vaccines (e.g., PCV13, Hib, MenACWY) covalently link polysaccharide antigens to protein carriers (diphtheria toxoid, tetanus toxoid, CRM197), converting a TI response into a TD response. This enables isotype switching, affinity maturation, and immunologic memory — making them effective in infants.

13 Antibody Structure & Function

Basic Immunoglobulin Structure

Each antibody molecule consists of two identical heavy chains and two identical light chains (κ or λ), linked by disulfide bonds. Each chain has a variable (V) region (antigen binding) and constant (C) region (effector function). The Fab fragment (Fragment antigen-binding) contains the variable regions; the Fc fragment (Fragment crystallizable) contains the constant regions and mediates complement activation, opsonization, and placental transfer.

Immunoglobulin Isotypes

Isotype	Heavy Chain	Structure	Serum %	Key Functions
IgG	γ	Monomer	75–80%	Most abundant; crosses placenta (passive immunity to neonate); opsonization (FcγR); complement activation (classical); secondary immune response; ADCC
IgA	α	Dimer (secretory) or monomer (serum)	10–15%	Mucosal immunity (#1 in secretions); secretory component protects from proteolysis; present in breast milk, saliva, tears, GI/respiratory secretions; does NOT activate complement
IgM	μ	Pentamer (serum)	5–10%	First antibody produced in primary response; most efficient complement activator (one IgM pentamer can activate C1q); expressed on naïve B cells as monomer (BCR)
IgE	ε	Monomer	<0.01%	Binds FcεRI on mast cells/basophils; cross-linking triggers degranulation (Type I hypersensitivity); anti-helminth defense; elevated in atopic individuals and parasitic infections
IgD	δ	Monomer	<1%	Co-expressed with IgM on mature naïve B cells; role in B-cell activation; exact function not fully defined

Antibody Diversity Mechanisms

Mechanism	Description	When
VDJ recombination	Random selection of V, D, J gene segments (heavy chain) or V, J (light chain)	During B-cell development
Junctional diversity	Imprecise joining + N-nucleotide addition (by TdT) at VD and DJ junctions	During rearrangement
Combinatorial diversity	Random pairing of different heavy and light chains	During assembly
Somatic hypermutation	Point mutations in V regions during germinal center reaction; driven by AID (activation-induced cytidine deaminase)	After antigen exposure in germinal centers

IgG Subclasses

Subclass	% of Total IgG	Key Properties
IgG1	65%	Most abundant; activates complement; crosses placenta; opsonization
IgG2	25%	Responds to polysaccharide antigens (encapsulated bacteria); weak complement activation
IgG3	7%	Strongest complement activator of IgG subclasses; shortest half-life (~7 days vs. ~21 days for others)
IgG4	3%	Does not activate complement; associated with chronic antigen exposure; anti-inflammatory; IgG4-related disease causes fibroinflammatory lesions (autoimmune pancreatitis, retroperitoneal fibrosis)

Fc Receptors & Effector Functions

Receptor	Cells	Function
FcγRI (CD64)	Macrophages, neutrophils, dendritic cells	High-affinity IgG binding; opsonization and phagocytosis
FcγRIII (CD16)	NK cells, macrophages	Low-affinity IgG binding; mediates ADCC (antibody-dependent cellular cytotoxicity)
FcεRI	Mast cells, basophils	High-affinity IgE binding; cross-linking triggers degranulation (Type I hypersensitivity)
FcRn (neonatal Fc receptor)	Placental syncytiotrophoblast, endothelium	Transports IgG across placenta; recycles IgG (extends half-life to ~21 days)
Poly-Ig receptor	Mucosal epithelium	Transcytoses dimeric IgA (and pentameric IgM) across epithelium into lumen; cleaved to form secretory component

IgG is the only antibody that crosses the placenta (via FcRn receptor). This provides passive immunity to the newborn for approximately 6 months. IgA in breast milk provides mucosal protection to the infant GI tract. Neonatal IgM is produced by the fetus; elevated IgM at birth suggests congenital infection (ToRCHeS). IgG2 subclass deficiency predisposes to infections with encapsulated organisms because IgG2 is the primary subclass responding to polysaccharide antigens.

14 Isotype Switching & Affinity Maturation

Isotype (Class) Switching

Isotype switching changes the antibody constant region (and thus the effector function) without altering antigen specificity. It requires:

CD40L–CD40 interaction between Tfh cell and B cell (patients with CD40L deficiency → Hyper-IgM syndrome, X-linked; cannot switch from IgM)
Cytokine signals that direct which isotype: IL-4 → IgE and IgG4; IFN-γ → IgG1/IgG3; TGF-β → IgA; IL-5 → IgA
AID (activation-induced cytidine deaminase) — enzyme that initiates switch recombination at switch regions upstream of C genes. AID deficiency also causes hyper-IgM syndrome (autosomal recessive form)

Affinity Maturation

Occurs in germinal centers of secondary lymphoid organs. AID introduces somatic hypermutations in Ig variable regions. B cells with higher-affinity BCRs compete for limited antigen displayed on follicular dendritic cells (FDCs). Those with improved binding receive survival signals (selected); those with lower affinity undergo apoptosis. This iterative process progressively increases antibody affinity over the course of an immune response.

Germinal Center Anatomy

Dark zone: Rapidly proliferating centroblasts undergo somatic hypermutation (SHM). Light zone: Centrocytes are tested for antigen affinity on FDCs and receive T-cell help; those with high affinity are selected to become plasma cells or memory B cells. The germinal center reaction is the basis for affinity maturation, isotype switching, and long-lived immunologic memory.

Immunologic Memory

The germinal center reaction generates two key long-lived populations:

Cell Type	Location	Function	Duration
Memory B cells	Circulating, marginal zone, mucosal tissues	Rapidly differentiate into plasma cells upon re-exposure; already isotype-switched and affinity-matured	Decades (some lifelong)
Long-lived plasma cells	Bone marrow niches	Continuously secrete antibody without re-stimulation; maintain baseline serum antibody levels	Years to decades
Memory T cells	Circulating (T_CM) and tissue-resident (T_RM)	Rapid effector response on re-encounter; lower activation threshold; secrete cytokines faster	Decades

The secondary (anamnestic) immune response is faster (1–3 days vs. 7–10 days), stronger (higher antibody titer), predominantly IgG (class-switched), and higher affinity than the primary response. This is the immunologic basis for booster vaccinations.

Hyper-IgM syndrome (X-linked CD40L deficiency) presents with recurrent sinopulmonary infections, Pneumocystis pneumonia, and Cryptosporidium diarrhea. IgM levels are elevated or normal, but IgG, IgA, and IgE are markedly decreased because the B cell cannot perform class switching. The CD40L deficiency also impairs macrophage activation (no CD40–CD40L signal to upregulate IL-12 → impaired Th1 response), explaining susceptibility to Pneumocystis and other intracellular organisms.

15 Primary & Secondary Lymphoid Organs

Primary (Central) Lymphoid Organs

Organ	Function	Clinical Relevance
Bone marrow	Site of hematopoiesis; B-cell development and maturation; site of negative selection for B cells	Aplastic anemia, leukemia, myelodysplastic syndromes affect all blood cell lineages
Thymus	T-cell maturation, positive and negative selection; involutes after puberty (replaced by fat but retains some function)	DiGeorge syndrome (22q11.2 deletion) → thymic aplasia/hypoplasia → T-cell deficiency

Secondary (Peripheral) Lymphoid Organs

Organ	Structure & Function	Clinical Relevance
Lymph nodes	Cortex: B-cell follicles (primary = naïve; secondary = germinal centers). Paracortex: T-cell zone (contains high endothelial venules, HEVs). Medulla: medullary cords (plasma cells), medullary sinuses	Paracortex enlarges in T-cell responses (viral infections); follicular hyperplasia in B-cell responses. Paracortex absent in DiGeorge
Spleen	White pulp: PALS (T cells around central arteriole) + follicles/marginal zone (B cells). Red pulp: sinusoids, macrophages; filters blood, removes old/damaged RBCs and encapsulated organisms	Splenectomy → increased risk of infections with encapsulated organisms (SHiNE: S. pneumoniae, H. influenzae, N. meningitidis, E. coli, Salmonella); Howell-Jolly bodies on smear
MALT / GALT	Mucosal-associated lymphoid tissue; includes Peyer patches (ileum), tonsils, appendix, Waldeyer ring	IgA-secreting plasma cells in lamina propria; M cells sample luminal antigens for presentation to underlying lymphoid tissue

Lymphocyte Recirculation & Homing

Lymphocytes continuously recirculate between blood and lymphoid tissues. Naïve T cells enter lymph nodes via high endothelial venules (HEVs) using L-selectin (CD62L) and CCR7 (responds to CCL19/CCL21 chemokines produced by lymph node stroma). After activation, effector T cells downregulate L-selectin and CCR7 and upregulate tissue-specific homing receptors:

Homing Receptor	Target Tissue	Ligand on Endothelium
CLA (cutaneous lymphocyte antigen)	Skin	E-selectin on dermal vessels
α4β7 integrin	Gut (Peyer patches, lamina propria)	MAdCAM-1 on gut endothelium
VLA-4 (α4β1)	CNS (across BBB), inflamed endothelium	VCAM-1

Therapeutic Targeting of Homing

Natalizumab (anti-α4 integrin) blocks lymphocyte trafficking to CNS (used in MS) and gut (used in Crohn disease); risk of PML (JC virus) due to impaired CNS immune surveillance. Vedolizumab (anti-α4β7) selectively blocks gut homing (used in IBD) without CNS risk. Fingolimod (S1P receptor modulator) traps lymphocytes in lymph nodes (used in MS).

Post-splenectomy patients require vaccination against encapsulated organisms (pneumococcal, meningococcal, Hib) and may need lifelong penicillin prophylaxis. Howell-Jolly bodies (nuclear remnants in RBCs) on peripheral smear indicate functional asplenia. The spleen’s marginal zone B cells are critical for T-independent responses to polysaccharide antigens from encapsulated bacteria.

16 Immune Tolerance & Regulation

Central Tolerance

Occurs in primary lymphoid organs during lymphocyte development:

T cells (thymus): Negative selection deletes strongly self-reactive T cells; some become Tregs (receptor editing is less common in T cells)
B cells (bone marrow): Self-reactive immature B cells undergo receptor editing (new light chain rearrangement), clonal deletion (apoptosis), or clonal anergy (functional unresponsiveness)

Peripheral Tolerance

Mechanisms that silence self-reactive lymphocytes that escape central tolerance:

Mechanism	Description
Anergy	T cell receives signal 1 (TCR engagement) without signal 2 (B7–CD28 co-stimulation) → becomes functionally unresponsive
Regulatory T cells (Tregs)	CD4+ CD25+ FoxP3+ cells suppress autoreactive T cells via IL-10, TGF-β, CTLA-4, and direct contact inhibition
Clonal deletion	Activation-induced cell death (AICD) via Fas/FasL pathway eliminates chronically stimulated T cells
Immune checkpoint molecules	CTLA-4 (competes with CD28 for B7, higher affinity; dampens T-cell activation); PD-1 (binds PD-L1/PD-L2 on target cells; induces T-cell exhaustion)
Immune privilege	Certain sites (brain, eye anterior chamber, testes, placenta) have limited immune access via blood-tissue barriers, local immunosuppressive factors (TGF-β, FasL expression)

CTLA-4 vs. PD-1

CTLA-4 acts early (during T-cell priming in lymph nodes); outcompetes CD28 for B7 binding and delivers inhibitory signals. PD-1 acts late (in peripheral tissues); binds PD-L1 on target/tumor cells and causes T-cell exhaustion. Blocking these checkpoints with antibodies (ipilimumab = anti-CTLA-4; pembrolizumab/nivolumab = anti-PD-1) unleashes anti-tumor T-cell responses but can cause immune-related adverse events (autoimmune colitis, hepatitis, thyroiditis).

Superantigens

Superantigens are microbial proteins that bypass normal antigen processing and bind directly to the outside of MHC II and the Vβ region of the TCR, non-specifically activating a large fraction (2–20%) of all T cells simultaneously. This triggers massive cytokine release (“cytokine storm”) — TNF-α, IL-1, IL-2, IFN-γ — leading to high fever, hypotension, rash, and potentially multi-organ failure.

Superantigen	Source	Disease
TSST-1 (Toxic Shock Syndrome Toxin-1)	S. aureus	Toxic shock syndrome (tampon-associated or wound-associated)
Exotoxin A (SpeA)	S. pyogenes (Group A Strep)	Streptococcal toxic shock syndrome, scarlet fever
Staphylococcal enterotoxins (SE-A through SE-E)	S. aureus	Staphylococcal food poisoning (rapid-onset vomiting and diarrhea)

Superantigen vs. Normal Antigen Presentation

Normal antigens are processed into peptides and presented within the MHC groove to the TCR CDR3 region — activating only ~0.001% of T cells (clonal response). Superantigens bind outside the groove to the Vβ region of TCR and the lateral face of MHC II, activating all T cells sharing that Vβ type (2–20% of all T cells). This explains the massive, polyclonal T-cell activation and cytokine storm in superantigen-mediated diseases.

Defects in Fas or FasL cause Autoimmune Lymphoproliferative Syndrome (ALPS) — massive lymphadenopathy, splenomegaly, and autoimmune cytopenias due to failure of activation-induced cell death and accumulation of double-negative T cells (CD4− CD8−). Superantigen questions on boards often present as a patient with fever, hypotension, and diffuse erythematous rash (toxic shock syndrome) — the key is recognizing the mechanism of non-specific T-cell activation without antigen processing.

17 Cytokines & Signaling Networks

Major Cytokines & Their Functions

Cytokine	Main Source	Key Functions
IL-1	Macrophages	Fever, acute-phase proteins, endothelial activation; co-stimulates T cells
IL-2	Th1 cells	T-cell proliferation and survival; promotes Treg development; used therapeutically (high dose in melanoma/RCC)
IL-3	T cells	Multi-lineage hematopoietic growth factor (supports growth of all bone marrow progenitors)
IL-4	Th2 cells, mast cells	B-cell class switch to IgE and IgG4; Th2 differentiation; inhibits Th1
IL-5	Th2 cells	Eosinophil production, activation, and survival; IgA class switching
IL-6	Macrophages, Th2	Fever, acute-phase proteins (CRP), B-cell differentiation to plasma cells; Th17 differentiation
IL-8 (CXCL8)	Macrophages	Neutrophil chemotaxis (most important neutrophil chemoattractant among cytokines)
IL-10	Tregs, Th2, macrophages	Anti-inflammatory; suppresses Th1 and macrophage function; inhibits APC activity
IL-12	Dendritic cells, macrophages	Th1 differentiation; NK cell activation; induces IFN-γ production
IL-17	Th17 cells	Neutrophil recruitment; pro-inflammatory; mucosal defense; implicated in autoimmunity
IL-23	Dendritic cells, macrophages	Th17 maintenance and expansion; target in psoriasis treatment (ustekinumab targets shared p40 subunit of IL-12/23)
IFN-α/β	Virus-infected cells (all nucleated cells)	Antiviral state in neighboring cells; upregulate MHC I; activate NK cells; Type I interferons
IFN-γ	Th1, NK cells, CD8+ T cells	Macrophage activation (most potent); upregulates MHC I & II; promotes Th1; antiviral; Type II interferon
TNF-α	Macrophages, T cells	Sepsis, cachexia, endothelial activation, leukocyte recruitment; major mediator of Gram-negative shock
TGF-β	Many cell types	Anti-inflammatory; promotes Treg and Th17 differentiation (context-dependent); class switch to IgA; wound healing

Cytokine-Targeted Therapies

Anti-TNF: infliximab, adalimumab, etanercept (RA, IBD, psoriasis; risk of TB reactivation). Anti-IL-1: anakinra (gout, CAPS, Still disease). Anti-IL-6R: tocilizumab (RA, giant cell arteritis, cytokine release syndrome). Anti-IL-5: mepolizumab (eosinophilic asthma). Anti-IL-4R: dupilumab (atopic dermatitis, asthma). Anti-IL-17A: secukinumab (psoriasis, ankylosing spondylitis).

Cytokine Signaling Pathways

Pathway	Cytokines	Mechanism	Clinical Significance
JAK-STAT	Most interleukins, IFNs, growth factors	Cytokine receptor activates JAK (Janus kinase) → phosphorylates STAT → STAT dimerizes, translocates to nucleus, activates gene transcription	JAK inhibitors (tofacitinib, baricitinib, ruxolitinib) used in RA, myelofibrosis, GvHD, atopic dermatitis
NF-κB	TNF-α, IL-1, TLR ligands	Activates transcription of pro-inflammatory genes (cytokines, adhesion molecules, MHC)	Constitutive NF-κB activation in many cancers and autoimmune diseases; corticosteroids inhibit NF-κB as part of their anti-inflammatory mechanism
MAPK/ERK	Growth factors (EGF, PDGF), cytokines	RAS → RAF → MEK → ERK cascade; promotes cell proliferation and differentiation	Oncogenic RAS mutations in many cancers; MEK inhibitors (trametinib) used in melanoma
PI3K/AKT/mTOR	IL-2, growth factors	Promotes cell survival, proliferation, metabolism	Sirolimus inhibits mTOR (immunosuppression); PI3K inhibitors (idelalisib) in CLL

Chemokines & Their Receptors

Chemokine	Receptor	Function
IL-8 (CXCL8)	CXCR1, CXCR2	Neutrophil chemotaxis (acute inflammation)
CCL2 (MCP-1)	CCR2	Monocyte recruitment to inflammation sites
CCL3, CCL4, CCL5 (RANTES)	CCR5	T cell, monocyte, NK cell recruitment; CCR5 is HIV co-receptor
CXCL12 (SDF-1)	CXCR4	Hematopoietic stem cell homing to bone marrow; CXCR4 is HIV co-receptor (late)
CCL19, CCL21	CCR7	Naïve T cell and dendritic cell homing to lymph nodes (via HEVs)
CCL11 (eotaxin)	CCR3	Eosinophil recruitment (allergic inflammation, parasitic infection)

“Hot T-Bone stEAk”: IL-1 = hot (fever), IL-2 = T cells (proliferation), IL-3 = bone marrow (growth), IL-4 = IgE (class switch), IL-5 = IgA and eosinophils. This mnemonic covers the first five interleukins and their primary associations. JAK inhibitors are increasingly important in clinical practice — tofacitinib (JAK1/3) is used in RA, ulcerative colitis, and psoriatic arthritis; ruxolitinib (JAK1/2) in myelofibrosis and GvHD; baricitinib (JAK1/2) in RA and alopecia areata.

18 Hypersensitivity Type I — Immediate (IgE-Mediated)

Type I hypersensitivity is an immediate reaction (minutes) mediated by IgE antibodies bound to mast cells and basophils via FcεRI. On re-exposure, antigen cross-links surface IgE, triggering degranulation and release of preformed mediators (histamine, tryptase, heparin) and newly synthesized mediators (leukotrienes, prostaglandins, PAF, cytokines).

Phases of Type I Reaction

Phase	Timing	Mediators	Effects
Sensitization	First exposure (days–weeks)	IL-4 drives IgE class switch; IgE binds FcεRI on mast cells	No symptoms; mast cells are now “armed”
Early (immediate)	Minutes after re-exposure	Histamine, tryptase, heparin (preformed granule contents)	Vasodilation, vascular permeability, bronchospasm, mucus secretion
Late	4–8 hours	Leukotrienes (LTC4/D4/E4), prostaglandins, PAF, cytokines (IL-4, IL-5, TNF-α)	Eosinophil recruitment, persistent inflammation, tissue damage

Clinical Examples

Anaphylaxis (peanuts, bee stings, penicillin, latex), allergic asthma, allergic rhinitis (hay fever), urticaria (hives), atopic dermatitis (eczema), food allergies.

Mast Cell Mediators

Mediator	Type	Actions
Histamine	Preformed (granule)	Vasodilation (H1, H2), increased vascular permeability (H1), bronchospasm (H1), gastric acid secretion (H2), pruritus
Tryptase	Preformed (granule)	Serine protease; serum marker of mast cell degranulation (diagnostic for anaphylaxis)
Heparin	Preformed (granule)	Anticoagulant; binds to granule matrix proteoglycans
LTC₄, LTD₄, LTE₄	Newly synthesized (lipoxygenase)	Bronchoconstriction (1,000× more potent than histamine), vasoconstriction, mucus secretion; target of montelukast and zileuton
PGD₂	Newly synthesized (COX)	Vasodilation, bronchospasm, neutrophil/Th2 chemotaxis
PAF (platelet-activating factor)	Newly synthesized	Platelet aggregation, bronchospasm, hypotension; potent mediator in anaphylactic shock
TNF-α, IL-4, IL-5, IL-13	Newly synthesized (cytokines)	Late-phase inflammation, eosinophil recruitment, IgE class switching

Treatment

Anaphylaxis: Epinephrine IM (first-line, lifesaving); antihistamines (H1 and H2 blockers); corticosteroids (prevent late phase); IV fluids for hypotension. Chronic allergic disease: Antihistamines, inhaled corticosteroids, leukotriene receptor antagonists (montelukast), cromolyn (mast cell stabilizer), omalizumab (anti-IgE monoclonal antibody), allergen immunotherapy (desensitization).

Serum tryptase is the best laboratory marker for mast cell degranulation and is used to confirm anaphylaxis (elevated 1–3 hours after event). Epinephrine is ALWAYS first-line for anaphylaxis because it reverses bronchospasm (β2), increases vascular tone (α1), and suppresses further mediator release (β2 on mast cells).

19 Hypersensitivity Type II — Antibody-Mediated Cytotoxicity

Type II hypersensitivity involves IgG or IgM antibodies directed against antigens on cell surfaces or extracellular matrix. Damage occurs via complement activation (MAC lysis), opsonization and phagocytosis, or antibody-dependent cellular cytotoxicity (ADCC by NK cells).

Mechanisms & Examples

Subtype	Mechanism	Examples
Cytotoxic (cell destruction)	Antibody binds cell surface antigen → complement activation (MAC) and/or opsonization → cell lysis/phagocytosis	Autoimmune hemolytic anemia, transfusion reactions (ABO incompatibility), hemolytic disease of the newborn (Rh), ITP (anti-platelet antibodies), Goodpasture syndrome (anti-GBM)
Anti-receptor (stimulatory)	Antibody binds and activates receptor	Graves disease (anti-TSH receptor → thyroid stimulation and hyperthyroidism)
Anti-receptor (inhibitory)	Antibody binds and blocks receptor	Myasthenia gravis (anti-AChR → NMJ blockade); pernicious anemia (anti-intrinsic factor)

Type II Hypersensitivity in Blood Transfusion

Reaction	Mechanism	Timing	Features
ABO incompatibility (acute hemolytic)	Pre-existing IgM anti-A or anti-B → complement activation → intravascular hemolysis	Minutes	Fever, flank pain, hemoglobinuria, DIC, renal failure; most dangerous transfusion reaction
Rh incompatibility (delayed hemolytic)	IgG anti-D (from prior sensitization) → extravascular hemolysis in spleen	Days–weeks	Gradual Hgb drop, indirect hyperbilirubinemia, positive DAT
Hemolytic disease of newborn (erythroblastosis fetalis)	Maternal IgG anti-D crosses placenta → attacks fetal Rh+ RBCs	In utero / neonatal	Hydrops fetalis, jaundice, kernicterus; prevented by RhoGAM (anti-D Ig) at 28 weeks and within 72 hours of delivery

Goodpasture Syndrome

Anti-GBM antibodies (IgG against type IV collagen α3 chain) cause rapidly progressive glomerulonephritis and pulmonary hemorrhage. Immunofluorescence shows linear IgG deposition along the glomerular basement membrane (vs. granular “lumpy-bumpy” in Type III). Treatment: plasmapheresis (remove antibodies) + cyclophosphamide + corticosteroids.

Type II is “antibody against a fixed target.” The direct Coombs test detects antibodies already bound to RBCs (positive in autoimmune hemolytic anemia, hemolytic disease of the newborn). The indirect Coombs test detects free anti-RBC antibodies in serum (used for blood bank cross-matching).

20 Hypersensitivity Type III — Immune Complex

Type III hypersensitivity results from deposition of antigen–antibody (immune) complexes in tissues, particularly blood vessel walls, joints, and kidneys. Deposited complexes activate complement, generating C3a and C5a (recruit neutrophils) → neutrophil-mediated tissue damage via lysosomal enzyme release and reactive oxygen species.

Key Clinical Examples

Disease	Antigen Source	Clinical Features
Serum sickness	Foreign serum proteins (antithymocyte globulin, monoclonal antibodies)	Fever, urticaria, arthralgias, lymphadenopathy, proteinuria; 7–14 days after exposure
Arthus reaction	Local antigen injection in previously sensitized individual	Localized vasculitis, edema, necrosis at injection site; 4–10 hours
Polyarteritis nodosa	Hepatitis B surface antigen	Necrotizing vasculitis of medium vessels; renal, GI, peripheral nerve involvement
SLE nephritis	Anti-dsDNA immune complexes	Glomerulonephritis with granular (“lumpy-bumpy”) IF; wire-loop lesion on biopsy
Post-streptococcal GN	Streptococcal antigens	Nephritic syndrome 2–3 weeks after GAS pharyngitis; subepithelial “humps” on EM; granular IF (IgG + C3)
Hypersensitivity pneumonitis	Inhaled organic antigens (mold, bird droppings)	Farmer’s lung, bird fancier’s lung; mixed Type III and IV reaction

Pathogenesis of Immune Complex Disease

Immune complex deposition depends on the size and solubility of the complexes. Small complexes remain soluble and are cleared. Very large complexes are quickly phagocytosed. Intermediate-sized complexes are the most pathogenic — they deposit in vessel walls, glomeruli, and joints, activate complement (C3a, C5a), recruit neutrophils, and cause tissue damage via lysosomal enzyme release and reactive oxygen species. The classic triad of immune complex disease is vasculitis, glomerulonephritis, and arthritis.

Type III differs from Type II by the site of antigen: Type II involves antibodies against fixed cell-surface antigens, while Type III involves soluble circulating immune complexes that deposit in tissues. Immunofluorescence pattern distinguishes them: linear (Type II, e.g., Goodpasture) vs. granular (Type III, e.g., SLE, PSGN). Serum complement levels (C3, C4) are often decreased in active Type III disease because complement is consumed by immune complexes.

21 Hypersensitivity Type IV — Delayed-Type

Type IV hypersensitivity is the only type that is T-cell mediated (not antibody-mediated). It is “delayed” because it takes 24–72 hours to develop, requiring T-cell sensitization, migration, and cytokine-mediated tissue damage.

Subtypes of Type IV

Subtype	Effector Cells	Mechanism	Examples
IVa (contact/DTH)	CD4+ Th1 cells, macrophages	Th1 cells secrete IFN-γ → macrophage activation → granulomatous inflammation	Tuberculin (PPD) skin test, contact dermatitis (poison ivy, nickel), granulomas (TB, sarcoidosis, Crohn)
IVb (T-cell mediated cytotoxicity)	CD8+ cytotoxic T cells	Direct killing of target cells expressing foreign or altered self-antigen on MHC I	Graft rejection (acute cellular), Stevens-Johnson syndrome/TEN (drug-induced), type 1 diabetes (islet cell destruction)

Granulomatous Inflammation

Chronic Type IV response to persistent antigens leads to granuloma formation: epithelioid macrophages (activated macrophages with abundant pink cytoplasm) surrounded by a collar of lymphocytes, often with multinucleated giant cells (Langhans type = peripheral nuclei horseshoe arrangement; foreign body type = haphazard nuclei).

Disease	Granuloma Type	Key Feature
Tuberculosis	Caseating (central necrosis)	Acid-fast bacilli; Ghon complex (primary); cavitary lesions (reactivation)
Sarcoidosis	Non-caseating	Bilateral hilar lymphadenopathy; elevated ACE; hypercalcemia (1α-hydroxylase in macrophages)
Crohn disease	Non-caseating	Transmural inflammation; skip lesions; cobblestone mucosa
Fungal infections	Caseating or non-caseating	Histoplasma, Coccidioides, Blastomyces
Foreign body reaction	Foreign body type giant cells	Suture material, talc, silicone, beryllium
Cat-scratch disease	Suppurative (stellate microabscesses)	Bartonella henselae; regional lymphadenopathy

Tuberculin (PPD) Test

Intradermal injection of purified protein derivative (PPD). A positive result (induration ≥5–15 mm at 48–72 hours, depending on risk group) indicates prior sensitization to mycobacterial antigens (prior TB infection, BCG vaccination, or atypical mycobacteria). The reaction is mediated by Th1 cells and macrophages — the classic example of Type IV hypersensitivity. Anergic patients (HIV, immunosuppression) may have false-negative PPD despite active TB.

Additional Type IV Examples in Clinical Medicine

Disease / Reaction	Antigen	Mechanism
Contact dermatitis (poison ivy)	Urushiol (hapten) bound to skin proteins	Th1-mediated; epidermal Langerhans cells present antigen; rash at 24–72 hours
Contact dermatitis (nickel)	Nickel ions bind skin proteins	Th1-mediated; common cause of ear piercing dermatitis
Tuberculin (PPD) test	Mycobacterial proteins	Th1/macrophage-mediated induration at 48–72 hours
Hashimoto thyroiditis	Thyroid antigens (thyroglobulin, TPO)	CD8+ T cell destruction of thyroid follicular cells; anti-TPO and anti-thyroglobulin antibodies
Type 1 diabetes mellitus	Pancreatic β-cell antigens (GAD65, insulin, IA-2)	CD8+ T cell destruction of β-cells (insulitis); HLA-DR3/DR4 associated
Multiple sclerosis	Myelin antigens (MBP, MOG, PLP)	Th1/Th17-mediated demyelination in CNS; HLA-DR2 associated
Graft rejection (acute cellular)	Donor MHC molecules	Recipient CD4+ and CD8+ T cells attack donor tissue
Stevens-Johnson syndrome / TEN	Drug-modified self-proteins	CD8+ cytotoxic T cells and NK cells kill keratinocytes via Fas/FasL and granulysin

Contact dermatitis (poison ivy, nickel) is Type IV, not Type I. The rash appears 24–72 hours after exposure. Urushiol (poison ivy) acts as a hapten, binding skin proteins to create a neoantigen recognized by T cells. Treatment: topical/systemic corticosteroids (suppress T-cell response). Type IV is the only hypersensitivity that cannot be transferred by serum (it requires sensitized T cells, not antibodies). Patch testing is the diagnostic method for Type IV contact allergens.

22 Autoimmune Diseases & Autoantibodies

Autoimmune diseases arise from a loss of self-tolerance. They are classified as organ-specific (targeting a single organ) or systemic (affecting multiple organs).

High-Yield Autoantibody Associations

Autoantibody	Disease
Anti-dsDNA	SLE (specific; correlates with disease activity and nephritis)
Anti-Smith (anti-Sm)	SLE (most specific, but less sensitive)
ANA (antinuclear antibody)	SLE (sensitive ~95%, but not specific; also positive in RA, scleroderma, Sjögren)
Anti-histone	Drug-induced lupus (hydralazine, isoniazid, procainamide, phenytoin, minocycline)
Anti-CCP (anti-cyclic citrullinated peptide)	Rheumatoid arthritis (most specific)
Rheumatoid factor (RF)	Rheumatoid arthritis (IgM against Fc of IgG; sensitive but not specific)
Anti-centromere	Limited scleroderma (CREST syndrome)
Anti-Scl-70 (anti-topoisomerase I)	Diffuse scleroderma (systemic sclerosis)
Anti-SSA (Ro) / Anti-SSB (La)	Sjögren syndrome; neonatal lupus (anti-Ro crosses placenta → congenital heart block)
Anti-Jo-1 (anti-histidyl tRNA synthetase)	Polymyositis/dermatomyositis with ILD (antisynthetase syndrome)
Anti-U1 RNP	Mixed connective tissue disease (MCTD)
c-ANCA (anti-PR3)	Granulomatosis with polyangiitis (GPA, formerly Wegener)
p-ANCA (anti-MPO)	Microscopic polyangiitis, eosinophilic GPA (Churg–Strauss)
Anti-GBM	Goodpasture syndrome
Anti-phospholipid (anticardiolipin, anti-β2GPI, lupus anticoagulant)	Antiphospholipid syndrome (recurrent thrombosis, pregnancy loss)
Anti-TSH receptor	Graves disease (stimulating antibody)
Anti-TPO, anti-thyroglobulin	Hashimoto thyroiditis
Anti-AChR	Myasthenia gravis (~85%)
Anti-MuSK	Myasthenia gravis (AChR-negative subset)
Anti-VGCC	Lambert–Eaton myasthenic syndrome
Anti-endomysial / Anti-tTG (tissue transglutaminase)	Celiac disease
Anti-mitochondrial (AMA)	Primary biliary cholangitis (PBC)
Anti-smooth muscle (ASMA)	Autoimmune hepatitis (Type 1)

Selected Autoimmune Disease Mechanisms

Disease	Hypersensitivity Type	Mechanism	Key Features
SLE	III (immune complex), II	Anti-dsDNA/anti-Sm immune complexes deposit in kidneys, joints, skin, serosa	Malar rash, discoid rash, oral ulcers, arthritis, serositis, nephritis (wire-loop lesion), cytopenias; “full house” immunofluorescence (IgG, IgM, IgA, C3, C1q); photosensitivity
Rheumatoid arthritis	III, IV	Immune complexes (RF + IgG) in joints; Th1/Th17-mediated synovitis; pannus formation	Symmetric polyarthritis (MCP, PIP, wrist); rheumatoid nodules; swan-neck/boutonniere deformities; anti-CCP most specific
Type 1 diabetes	IV	CD8+ T cells destroy pancreatic β-cells; anti-GAD65, anti-insulin, anti-IA2 antibodies	HLA-DR3/DR4; insulitis on biopsy; presents with DKA in young patients
Multiple sclerosis	IV	Th1 and Th17 cells attack myelin in CNS; Treg dysfunction	HLA-DR2; oligoclonal bands in CSF; periventricular plaques on MRI; relapsing-remitting course most common
Graves disease	II (stimulatory)	Anti-TSH receptor antibodies (thyroid-stimulating immunoglobulins) activate TSH receptor	Hyperthyroidism, diffuse goiter, exophthalmos, pretibial myxedema
Myasthenia gravis	II (blocking)	Anti-AChR antibodies block and destroy AChR at NMJ; complement-mediated damage	Fatigable muscle weakness (ptosis, diplopia, dysphagia); thymic hyperplasia/thymoma; improves with AChE inhibitors (edrophonium, pyridostigmine)
Celiac disease	IV (and II)	Gluten (gliadin) peptides presented on HLA-DQ2/DQ8 activate Th1 cells; anti-tTG cross-links gliadin to tissue transglutaminase	Villous atrophy, crypt hyperplasia, intraepithelial lymphocytes; dermatitis herpetiformis; IgA anti-tTG and anti-endomysial antibodies

Drug-Induced Lupus

Caused by hydralazine, procainamide, isoniazid, phenytoin, minocycline, and others. Presents with arthritis, serositis, rash, and positive anti-histone antibodies (present in >95%). Unlike true SLE: renal and CNS involvement are rare, anti-dsDNA is usually negative, complement levels are normal, and symptoms resolve after drug discontinuation.

For board exams, pair each autoimmune disease with its most specific antibody. Anti-dsDNA and anti-Smith are both specific for SLE, but anti-dsDNA correlates with disease activity (especially nephritis). ANA is highly sensitive for SLE (~95%) but has poor specificity. A negative ANA essentially rules out SLE. Remember that many autoimmune diseases involve multiple hypersensitivity types simultaneously.

23 Primary Immunodeficiency Syndromes

Primary immunodeficiencies are inherited defects in immune system components. They are broadly classified by the arm of immunity affected.

B-Cell (Humoral) Deficiencies

Disorder	Defect	Presentation	Diagnosis
X-linked (Bruton) agammaglobulinemia	BTK (Bruton tyrosine kinase) mutation; no B-cell maturation past pre-B stage	Males; recurrent sinopulmonary infections after 6 months (maternal IgG wanes); absent lymph node germinal centers	Absent B cells, absent all Ig classes; no tonsils/adenoids
Common variable immunodeficiency (CVID)	Defective B-cell differentiation to plasma cells; heterogeneous genetics	Most common symptomatic primary immunodeficiency in adults; recurrent sinopulmonary infections; increased risk of autoimmunity and lymphoma	Low IgG (and often IgA); normal B-cell count; poor vaccine responses
Selective IgA deficiency	Failure of IgA-producing B cells	Most common primary immunodeficiency overall; usually asymptomatic; recurrent mucosal infections; anaphylaxis risk with IgA-containing blood products	IgA <7 mg/dL; normal IgG and IgM

T-Cell Deficiencies

Disorder	Defect	Presentation
DiGeorge syndrome	22q11.2 deletion → failure of 3rd/4th pharyngeal pouch development → thymic aplasia, parathyroid hypoplasia	T-cell deficiency (variable severity), hypocalcemia (tetany), cardiac defects (truncus arteriosus, tetralogy of Fallot), facial abnormalities; no thymic shadow on CXR
IL-12 receptor deficiency	Defective Th1 response (no IFN-γ production)	Disseminated mycobacterial and fungal infections

Combined B & T Cell Deficiencies

Disorder	Defect	Presentation
SCID (Severe Combined Immunodeficiency)	Multiple genetic causes: X-linked (IL-2R γ-chain/IL-7R defect, most common), ADA deficiency, RAG1/2 deficiency	Failure to thrive, chronic diarrhea, opportunistic infections (PCP, CMV, Candida) within first months of life; absent thymic shadow; lymphopenia; fatal without bone marrow transplant or gene therapy
Hyper-IgM syndrome	X-linked: CD40L deficiency; AR: AID deficiency	Elevated IgM, very low IgG/IgA/IgE; recurrent pyogenic and opportunistic infections (Pneumocystis, Cryptosporidium)
Wiskott–Aldrich syndrome	WASp gene mutation (X-linked); defective actin cytoskeleton reorganization	Triad: thrombocytopenia (small platelets), eczema, recurrent infections; increased risk of lymphoma and autoimmunity
Ataxia-telangiectasia	ATM gene mutation; defective DNA repair	Cerebellar ataxia, oculocutaneous telangiectasias, IgA deficiency, elevated AFP, increased lymphoma/leukemia risk; sensitivity to ionizing radiation

Phagocyte Deficiencies

Disorder	Defect	Presentation
Chronic Granulomatous Disease (CGD)	NADPH oxidase deficiency (X-linked or AR)	Recurrent infections with catalase-positive organisms (S. aureus, Aspergillus, Serratia, Nocardia, Burkholderia cepacia); granuloma formation; negative NBT/DHR test
Leukocyte Adhesion Deficiency Type 1	CD18 (integrin β2) deficiency; leukocytes cannot adhere/transmigrate	Delayed umbilical cord separation (>30 days), recurrent bacterial infections without pus formation, marked leukocytosis (neutrophils cannot leave blood)
Chédiak–Higashi syndrome	LYST gene; defective lysosomal trafficking	Giant granules in neutrophils, partial albinism, peripheral neuropathy, recurrent pyogenic infections

Infection Patterns Guide Diagnosis

B-cell/humoral defects → encapsulated bacteria (S. pneumoniae, H. influenzae), Giardia. T-cell defects → intracellular organisms (viruses, fungi, mycobacteria, Pneumocystis). Phagocyte defects → catalase-positive bacteria, fungi. Complement defects → Neisseria (terminal), SLE-like (early classical).

Additional Immunodeficiency Syndromes

Disorder	Defect	Key Features
Hyper-IgE syndrome (Job syndrome)	STAT3 mutation (AD) or DOCK8 mutation (AR)	Markedly elevated IgE (>2,000 IU/mL); recurrent staphylococcal abscesses (“cold” abscesses — lack warmth and erythema due to impaired neutrophil chemotaxis); eczema; retained primary teeth; characteristic facies; pathologic fractures; STAT3 type has no increased viral infections; DOCK8 type has severe viral skin infections
Bare lymphocyte syndrome Type II	MHC II transcription factor deficiency (CIITA, RFX5, RFXAP, RFXANK)	No MHC II expression → no CD4+ T-cell positive selection → SCID-like phenotype; severe infections in infancy
Complement deficiency (C2)	Most common complement deficiency overall	SLE-like syndrome; C2 deficiency impairs classical pathway immune complex clearance
Myeloperoxidase deficiency	MPO enzyme deficiency in neutrophils	Most common neutrophil enzyme deficiency; usually clinically silent; mild increase in Candida infections in diabetic patients; positive DHR test (NADPH oxidase intact)
IL-12 / IFN-γ axis defects	IL-12, IL-12R, IFN-γR, or STAT1 mutations	Susceptibility to mycobacterial infections (both TB and NTM); disseminated BCG infection after vaccination

Live vaccines (MMR, varicella, BCG, oral polio, rotavirus, intranasal influenza, yellow fever) are contraindicated in patients with T-cell or combined immunodeficiency — they can cause disseminated, life-threatening infection. Hyper-IgE syndrome (Job syndrome) is named for the biblical figure Job who was “smote with boils.” The “cold abscesses” lack the typical signs of inflammation because STAT3 deficiency impairs Th17 differentiation and neutrophil chemotaxis (IL-17 normally recruits neutrophils).

24 Acquired Immunodeficiency (HIV/AIDS)

Human Immunodeficiency Virus (HIV) is a lentivirus (retrovirus) that primarily infects CD4+ T cells, macrophages, and dendritic cells via the CD4 receptor and a co-receptor (CCR5 in early infection, CXCR4 in late infection). It carries reverse transcriptase, integrase, and protease — key drug targets.

HIV Immunopathogenesis

HIV causes progressive immune destruction through multiple mechanisms:

Direct cytopathic effect: Viral replication and budding kills infected CD4+ T cells
Syncytia formation: gp120/gp41 on infected cells fuses with CD4/CXCR4 on uninfected cells → multinucleated giant cells → death
Bystander apoptosis: Chronic immune activation causes apoptosis of uninfected CD4+ T cells
Immune exhaustion: Persistent antigen stimulation leads to T-cell exhaustion (PD-1, CTLA-4 upregulation)
GALT depletion: Massive early CD4+ T-cell loss in gut mucosa → increased microbial translocation → chronic systemic immune activation

Natural History

Stage	Timing	Features
Acute retroviral syndrome	2–4 weeks post-infection	Mono-like illness (fever, pharyngitis, lymphadenopathy, rash, myalgias); high viral load; p24 antigen positive; antibody may be negative (window period)
Clinical latency	Years (median ~10 years without treatment)	Asymptomatic or generalized lymphadenopathy; gradual CD4 decline (~50–80 cells/μL/year); virus replicating in lymph nodes
AIDS	CD4 <200 or AIDS-defining illness	Opportunistic infections, malignancies (Kaposi sarcoma, primary CNS lymphoma, cervical cancer), wasting

Opportunistic Infections by CD4 Count

CD4 Count	Opportunistic Infections
<500	Oral thrush (Candida), hairy leukoplakia (EBV), Kaposi sarcoma (HHV-8), TB reactivation
<200	Pneumocystis jirovecii pneumonia (PCP), disseminated histoplasmosis/coccidioidomycosis
<100	Toxoplasma encephalitis, Cryptococcal meningitis, esophageal candidiasis
<50	CMV retinitis, disseminated MAC, primary CNS lymphoma (EBV), progressive multifocal leukoencephalopathy (JC virus)

HIV Life Cycle & Drug Targets

Step	Mechanism	Drug Class (Target)
1. Attachment & entry	gp120 binds CD4, then gp41 mediates fusion via co-receptor (CCR5 or CXCR4)	Maraviroc (CCR5 antagonist); enfuvirtide (fusion inhibitor, binds gp41)
2. Reverse transcription	Viral RNA → dsDNA by reverse transcriptase	NRTIs (tenofovir, emtricitabine, zidovudine, lamivudine); NNRTIs (efavirenz, rilpivirine)
3. Integration	Viral DNA integrates into host genome via integrase	INSTIs (dolutegravir, raltegravir, bictegravir) — preferred first-line agents
4. Transcription & translation	Host machinery transcribes viral genes, translates polyproteins	No current drug targets at this step
5. Assembly & maturation	Protease cleaves polyproteins into functional viral proteins	PIs (ritonavir, darunavir, atazanavir); ritonavir used as pharmacokinetic booster (CYP3A4 inhibitor)
6. Budding	New virions bud from host cell membrane	No current drug targets at this step

Diagnosis

Fourth-generation HIV test detects both p24 antigen and HIV-1/2 antibodies (best initial test). Confirmatory: HIV-1/2 antibody differentiation assay. If antibody indeterminate: HIV-1 RNA (viral load) PCR. In neonates (maternal antibodies present): use HIV DNA PCR or RNA PCR (not antibody tests).

Treatment & Prevention

Standard ART regimen: 2 NRTIs (backbone) + 1 INSTI (preferred third agent). Goal: undetectable viral load (<50 copies/mL). PrEP (pre-exposure prophylaxis): tenofovir/emtricitabine or cabotegravir for high-risk individuals. PEP (post-exposure prophylaxis): 3-drug ART within 72 hours of exposure for 28 days.

The CCR5-Δ32 homozygous mutation confers near-complete resistance to HIV infection (receptor absent). Maraviroc (CCR5 antagonist) blocks viral entry. The “Berlin patient” and “London patient” were cured of HIV after bone marrow transplant from CCR5-Δ32 homozygous donors. Prophylaxis: start TMP-SMX when CD4 <200 (PCP), azithromycin when <50 (MAC). Immune reconstitution inflammatory syndrome (IRIS) can occur when ART is started — the recovering immune system mounts an exuberant inflammatory response against pre-existing opportunistic infections.

25 Transplant Immunology & Rejection

Types of Grafts

Graft Type	Definition	Example
Autograft	Self to self	Skin graft from thigh to face; no rejection
Isograft (syngeneic)	Identical twin to twin	No rejection (genetically identical)
Allograft	Same species, different individual	Cadaveric kidney transplant; most common clinical scenario
Xenograft	Different species	Pig heart valve in human; high rejection risk

Rejection Types

Type	Timing	Mechanism	Pathology	Treatment
Hyperacute	Minutes–hours	Preformed recipient antibodies against donor HLA or ABO antigens → complement activation → vascular thrombosis	Widespread thrombosis, graft infarction	Prevention only (crossmatch testing); graft must be removed
Acute cellular	Weeks–months	Recipient CD4+ and CD8+ T cells attack donor MHC antigens	Lymphocytic infiltration of graft (tubulitis in kidney)	Increase immunosuppression (pulse steroids, anti-thymocyte globulin)
Acute humoral (antibody-mediated)	Weeks–months	Recipient antibodies against donor HLA → complement activation in graft vessels	C4d deposition in peritubular capillaries; neutrophilic infiltrate	Plasmapheresis, IVIg, rituximab
Chronic	Months–years	Both antibody and cell-mediated; vascular intimal fibrosis (transplant vasculopathy)	Fibrosis, vascular thickening (“transplant vasculopathy”); gradual graft dysfunction	Retransplantation (irreversible)

Graft-versus-Host Disease (GvHD)

Occurs when donor T cells in the graft attack immunocompromised host tissues. Most common after bone marrow/stem cell transplant (also after non-irradiated blood transfusion to immunocompromised patient). Targets: skin (maculopapular rash), liver (jaundice, elevated LFTs), GI tract (diarrhea, abdominal pain). Acute GvHD occurs <100 days post-transplant; chronic GvHD occurs >100 days and resembles systemic sclerosis.

Immunosuppressive Agents

Drug	Mechanism	Key Side Effects
Cyclosporine	Calcineurin inhibitor (binds cyclophilin) → blocks IL-2 transcription in T cells	Nephrotoxicity, hypertension, gingival hyperplasia, hirsutism, tremor
Tacrolimus (FK506)	Calcineurin inhibitor (binds FKBP) → blocks IL-2 transcription	Nephrotoxicity, diabetes, neurotoxicity (more potent than cyclosporine)
Sirolimus (rapamycin)	mTOR inhibitor (binds FKBP) → blocks T-cell proliferation at G1→S	Hyperlipidemia, myelosuppression, poor wound healing; NOT nephrotoxic
Mycophenolate mofetil	Inosine monophosphate dehydrogenase inhibitor → blocks de novo purine synthesis in lymphocytes	GI upset, myelosuppression, teratogenicity
Azathioprine	Purine analog → inhibits DNA synthesis (prodrug → 6-mercaptopurine)	Myelosuppression; metabolized by TPMT (check before dosing); drug interaction with allopurinol
Basiliximab	Anti-IL-2R (CD25) monoclonal antibody → blocks T-cell proliferation	Generally well tolerated; used as induction therapy
Anti-thymocyte globulin (ATG)	Polyclonal antibodies against T cells → lymphocyte depletion	Cytokine release syndrome, serum sickness, myelosuppression

Immunosuppression Protocols

Transplant immunosuppression typically uses a three-drug regimen:

Induction: Anti-thymocyte globulin (ATG) or basiliximab (anti-IL-2R) given peri-operatively for intense early immunosuppression
Maintenance: Triple therapy — calcineurin inhibitor (tacrolimus preferred) + antimetabolite (mycophenolate) + low-dose corticosteroids
Rejection treatment: Pulse IV methylprednisolone for mild acute rejection; ATG or OKT3 for steroid-resistant rejection; plasmapheresis + IVIg + rituximab for antibody-mediated rejection

GvHD Prevention & Treatment

GvHD prophylaxis in bone marrow transplant: tacrolimus or cyclosporine + methotrexate or mycophenolate. T-cell depletion of the graft reduces GvHD but increases relapse risk (loss of beneficial graft-versus-leukemia/GVL effect). Acute GvHD treatment: corticosteroids first-line; ruxolitinib (JAK inhibitor) for steroid-refractory cases. The graft-versus-leukemia (GVL) effect is a beneficial consequence of donor T cells recognizing and killing residual leukemia cells — this is why complete T-cell depletion is not always desirable.

Cyclosporine and tacrolimus both inhibit calcineurin but bind different intracellular proteins (cyclophilin vs. FKBP). Sirolimus also binds FKBP but inhibits mTOR instead of calcineurin — so sirolimus is NOT a calcineurin inhibitor despite sharing the same binding protein. Sirolimus is notable for being non-nephrotoxic, making it useful when calcineurin inhibitor nephrotoxicity occurs. All transplant patients on chronic immunosuppression have increased risk of infections and malignancies (especially skin cancers, lymphoma/PTLD associated with EBV).

26 Tumor Immunology & Immunotherapy

Immune Surveillance

The immune system continuously monitors for and eliminates transformed cells via the cancer immunoediting model: (1) Elimination — immune cells (NK, CTLs) kill nascent tumor cells; (2) Equilibrium — immune pressure sculpts tumor variants; (3) Escape — tumor evades immunity through downregulation of MHC I, secretion of immunosuppressive cytokines (TGF-β, IL-10), PD-L1 expression, and recruitment of Tregs/MDSCs.

Tumor Immune Evasion Mechanisms

Mechanism	Effect
MHC I downregulation	Evades CD8+ T-cell recognition (but becomes NK cell target)
PD-L1 overexpression	Engages PD-1 on T cells → T-cell exhaustion/anergy
Treg/MDSC recruitment	Creates immunosuppressive tumor microenvironment
Antigen loss / neoantigen masking	Tumor variants lacking immunogenic antigens are selected
FasL expression on tumor	Induces apoptosis of Fas-expressing infiltrating T cells

Cancer Immunotherapy Approaches

Approach	Examples	Mechanism
Checkpoint inhibitors	Pembrolizumab, nivolumab (anti-PD-1); atezolizumab (anti-PD-L1); ipilimumab (anti-CTLA-4)	Block inhibitory signals, restoring T-cell anti-tumor activity
CAR-T cell therapy	Tisagenlecleucel (anti-CD19), axicabtagene ciloleucel	Patient’s T cells engineered to express chimeric antigen receptor targeting tumor antigen (e.g., CD19 in B-ALL); cytokine release syndrome is major adverse effect
Monoclonal antibodies	Rituximab (anti-CD20), trastuzumab (anti-HER2), cetuximab (anti-EGFR)	ADCC, complement-mediated lysis, receptor blockade
Cancer vaccines	Sipuleucel-T (prostate cancer), HPV vaccine (prevention)	Stimulate anti-tumor immune response
Cytokine therapy	High-dose IL-2 (melanoma, RCC), IFN-α (melanoma, hairy cell leukemia)	Boost T-cell and NK cell anti-tumor activity
Bispecific antibodies	Blinatumomab (anti-CD19/CD3)	Bridge T cells to tumor cells, facilitating direct killing

Tumor Antigens

Antigen Type	Description	Examples
Tumor-specific antigens (TSA)	Unique to tumor cells (neoantigens from mutations); ideal immunotherapy targets	Mutated p53, mutated RAS, BCR-ABL fusion protein
Tumor-associated antigens (TAA)	Overexpressed or aberrantly expressed normal proteins; shared with normal tissues	HER2/neu (breast), PSA (prostate), AFP (α-fetoprotein, HCC/germ cell), CEA (colorectal), CA-125 (ovarian)
Cancer-testis antigens	Normally expressed only in testes (immune-privileged site); re-expressed in tumors	MAGE, NY-ESO-1
Oncoviral antigens	Viral proteins in virus-associated cancers	EBV antigens (Burkitt lymphoma, NPC), HPV E6/E7 (cervical cancer), HHV-8 (Kaposi sarcoma)

Immune-related adverse events (irAEs) from checkpoint inhibitors mimic autoimmune diseases: colitis (anti-CTLA-4), pneumonitis, hepatitis, thyroiditis, hypophysitis, type 1 DM, and myocarditis. Treatment: corticosteroids, hold checkpoint inhibitor, and organ-specific management. The risk of irAEs is higher with combination therapy (anti-PD-1 + anti-CTLA-4). Tumors with high mutational burden (melanoma, lung cancer, MSI-high colorectal cancer) tend to respond better to checkpoint inhibitors because they generate more neoantigens for T-cell recognition.

27 Vaccination & Immunoprophylaxis

Vaccine Types

Type	Mechanism	Examples	Key Points
Live attenuated	Weakened pathogen replicates, inducing strong humoral + cellular immunity	MMR, varicella, rotavirus, BCG, oral polio (Sabin), yellow fever, intranasal influenza (FluMist)	Strongest immune response; contraindicated in immunocompromised and pregnant patients; risk of reversion to virulence (oral polio)
Inactivated (killed)	Killed pathogen; induces humoral immunity (weaker, needs boosters)	Influenza (injection), hepatitis A, rabies, IPV (Salk polio)	Safe in immunocompromised; weaker immunity requires multiple doses
Subunit / recombinant	Purified antigen component	Hepatitis B (HBsAg), HPV (L1 capsid protein), acellular pertussis, influenza (recombinant)	Cannot cause disease; requires adjuvant for adequate response
Toxoid	Inactivated toxin	Tetanus, diphtheria	Induces anti-toxin antibodies; requires boosters
Conjugate	Polysaccharide linked to protein carrier	PCV13 (pneumococcal), Hib, MenACWY	Converts T-independent to T-dependent response; effective in children <2 years
Polysaccharide	Purified capsular polysaccharide	PPSV23 (pneumococcal), MenB	T-independent response (IgM only, no memory); ineffective in <2 years
mRNA	mRNA encoding antigen delivered in lipid nanoparticles; translated by host cells	COVID-19 (Pfizer-BioNTech, Moderna)	Rapid development platform; strong humoral and cellular response; requires cold storage
Viral vector	Adenovirus vector carries gene encoding target antigen	COVID-19 (J&J/Janssen), Ebola vaccine	Pre-existing vector immunity may reduce efficacy

Key Vaccination Concepts

Herd immunity: When a sufficient proportion of the population is immune, transmission is interrupted, protecting unvaccinated individuals. Threshold varies by pathogen (measles: ~95%; polio: ~80%; influenza: ~75%).
Passive immunization: Preformed antibodies given for immediate protection. Examples: anti-D immunoglobulin (RhoGAM), rabies immunoglobulin, hepatitis B immunoglobulin (HBIG), tetanus immunoglobulin, IVIg for Kawasaki disease, palivizumab (anti-RSV) for premature infants.
Adjuvants: Substances (aluminum salts, MF59, AS01B) that enhance the immune response by activating innate immunity (PAMP mimicry), creating a depot effect, and promoting APC activation.
Primary vs. secondary immune response: Primary response is slower (7–10 days), produces mainly IgM, lower affinity. Secondary response (booster/re-exposure) is faster (1–3 days), produces mainly IgG, higher affinity (due to memory B cells and affinity maturation). This is the basis for booster vaccinations.
Immune correlates of protection: The specific immune parameter that confers protection varies by pathogen — neutralizing antibody titer (most vaccines), cell-mediated immunity (TB, some viral infections), or mucosal IgA (enteric pathogens).

Special Vaccination Considerations

Population	Consideration
Immunocompromised patients	No live vaccines; killed/subunit/toxoid vaccines are safe but may have reduced efficacy; check antibody titers post-vaccination
Pregnant women	No live vaccines (risk of fetal infection); Tdap recommended at 27–36 weeks each pregnancy (passive antibody transfer to neonate); inactivated influenza and COVID-19 vaccines recommended
Asplenic patients	Pneumococcal (PCV20 or PCV15 + PPSV23), meningococcal (MenACWY + MenB), Hib vaccines; administer ≥2 weeks before elective splenectomy if possible
Healthcare workers	Hepatitis B (check anti-HBs titer), annual influenza, Tdap booster, varicella immunity, MMR immunity
Neonates	Hepatitis B vaccine at birth; maternal antibodies provide passive protection for ~6 months; conjugate vaccines effective after 2 months

Mnemonic for live attenuated vaccines: “Live, Young, Chickens get Vaccinated with Sabin’s Measly Mumps and Rubella” (Live = live attenuated; Yellow fever; Chickenpox/Varicella; Sabin = oral polio; MMR). All are contraindicated in severe immunodeficiency and pregnancy. Killed/inactivated vaccines and subunit vaccines are generally safe in immunocompromised patients.

28 High-Yield Review

Top 30 Board-Testable Immunology Facts

MHC I presents endogenous antigen to CD8+ T cells; MHC II presents exogenous antigen to CD4+ T cells (Rule of 8).
All nucleated cells express MHC I; only professional APCs express MHC II.
IgG is the only antibody that crosses the placenta; IgA dominates mucosal immunity; IgM is the first responder and best complement activator.
Type I hypersensitivity = IgE/mast cells (anaphylaxis). Type II = IgG/IgM against cell surface (hemolysis). Type III = immune complexes (serum sickness, SLE nephritis). Type IV = T cells (PPD, contact dermatitis, transplant rejection).
Complement: Classical (antibody/C1q), Lectin (MBL/mannose), Alternative (C3 tick-over). All converge at C3.
C3b = opsonization; C3a/C5a = anaphylatoxins; C5a = neutrophil chemotaxis; C5b–C9 = MAC (lysis).
Terminal complement deficiency (C5–C9) → recurrent Neisseria infections.
C1-INH deficiency → hereditary angioedema (bradykinin-mediated).
DAF/CD59 deficiency → PNH (complement-mediated hemolysis; treat with eculizumab, anti-C5).
Bruton agammaglobulinemia: BTK mutation, no mature B cells, no Ig; X-linked; infections after 6 months.
DiGeorge: 22q11.2 deletion, thymic aplasia, T-cell deficiency, hypocalcemia, cardiac defects.
SCID: absent T cells (and often B/NK); most common = X-linked IL-2R γ-chain deficiency; fatal without BMT.
CGD: NADPH oxidase defect → no oxidative burst → catalase-positive infections; negative NBT/DHR.
Leukocyte adhesion deficiency: CD18 deficiency → delayed cord separation, no pus, leukocytosis.
Hyper-IgM: CD40L deficiency (X-linked) → no class switching → elevated IgM, low IgG/IgA/IgE.
Wiskott–Aldrich: WASp mutation → thrombocytopenia + eczema + infections (X-linked).
AIRE mutations → APECED (APS-1); FoxP3 mutations → IPEX syndrome (Treg deficiency).
HIV infects CD4+ T cells via CD4 + CCR5 (early) or CXCR4 (late); AIDS = CD4 <200.
Hyperacute rejection = preformed antibodies (minutes); Acute = T cells (weeks); Chronic = fibrosis (months–years).
GvHD: donor T cells attack host; skin, liver, GI; occurs in bone marrow transplant.
Cyclosporine and tacrolimus = calcineurin inhibitors → block IL-2; sirolimus = mTOR inhibitor (non-nephrotoxic).
Anti-dsDNA and anti-Smith are specific for SLE; ANA is sensitive but not specific.
Anti-CCP is most specific for rheumatoid arthritis; RF is sensitive but not specific.
HLA-B27 → ankylosing spondylitis and seronegative spondyloarthropathies.
HLA-DQ2/DQ8 → celiac disease.
Th1 (IFN-γ, macrophage activation); Th2 (IL-4/5/13, IgE, eosinophils); Th17 (IL-17, neutrophils).
Checkpoint inhibitors: anti-PD-1 (pembrolizumab, nivolumab), anti-CTLA-4 (ipilimumab); irAEs mimic autoimmunity.
Live vaccines contraindicated in immunocompromised and pregnant patients; conjugate vaccines work in children <2.
Positive selection (thymic cortex) = MHC restriction; Negative selection (medulla) = self-tolerance.
Somatic hypermutation (AID) and affinity maturation occur in germinal centers; class switching requires CD40L-CD40 interaction.

Quick-Reference: Immunodeficiency Diagnostic Clues

Finding	Think
Absent B cells, no Ig	Bruton (XLA)
No thymic shadow, hypocalcemia	DiGeorge
Negative NBT/DHR test	CGD
Giant granules in neutrophils	Chédiak–Higashi
Delayed cord separation, no pus	LAD type 1
Eczema + thrombocytopenia + infections (male)	Wiskott–Aldrich
Ataxia + telangiectasias + elevated AFP	Ataxia-telangiectasia
Elevated IgM, low IgG/A/E	Hyper-IgM syndrome
Severe infections in first months, lymphopenia	SCID
Recurrent sinopulmonary infections in adult, low IgG	CVID
Anaphylaxis to blood products, IgA <7	Selective IgA deficiency
Cold abscesses, very high IgE, eczema, retained teeth	Hyper-IgE (Job) syndrome
Recurrent Neisseria meningitis	Terminal complement (C5–C9) deficiency
Angioedema without urticaria, low C4	Hereditary angioedema (C1-INH deficiency)

High-Yield CD Markers

CD Marker	Cell / Function	Board Association
CD3	All mature T cells (TCR complex signaling)	Pan-T-cell marker; OKT3 (muromonab) target
CD4	Helper T cells; MHC II co-receptor	HIV receptor; CD4 count stages AIDS
CD8	Cytotoxic T cells; MHC I co-receptor	Kills virus-infected and tumor cells
CD16/CD56	NK cells	ADCC (CD16 = FcγRIII); CD56 = NK marker
CD19/CD20	B cells	Rituximab (anti-CD20); CD19 = CAR-T target in B-ALL
CD21	B cells (complement receptor CR2)	EBV receptor (EBV tropism for B cells)
CD25	IL-2Rα (activated T cells, Tregs)	Basiliximab target; elevated soluble IL-2R in HLH
CD28	T-cell co-stimulatory receptor (binds B7)	Abatacept (CTLA-4-Ig) blocks this pathway
CD40	APCs, B cells	CD40L deficiency → Hyper-IgM syndrome
CD80/86 (B7)	APCs (co-stimulatory ligand)	Binds CD28 (activation) or CTLA-4 (inhibition)
CD95 (Fas)	Apoptosis receptor on many cells	Fas mutations → ALPS
CD117 (c-Kit)	Mast cells, hematopoietic progenitors	Mastocytosis; imatinib target in c-Kit+ GIST

Laboratory Tests in Immunology

Test	What It Measures	Clinical Use
Flow cytometry (FACS)	Cell surface markers (CD counts)	CD4 count in HIV; T/B/NK cell enumeration in immunodeficiency; leukemia/lymphoma immunophenotyping
Serum immunoglobulin levels	IgG, IgA, IgM, IgE quantitation	Hypogammaglobulinemia (Bruton, CVID), elevated IgE (atopy, parasites, Hyper-IgE syndrome)
Complement levels (CH50, C3, C4)	Functional complement activity	CH50 = 0 suggests complete deficiency; low C3/C4 in active SLE, PSGN; low C4 with normal C3 in hereditary angioedema
NBT / DHR test	Neutrophil oxidative burst	Negative/absent in CGD (NADPH oxidase deficiency)
Direct Coombs test (DAT)	Antibodies bound to patient RBCs	Autoimmune hemolytic anemia, hemolytic disease of newborn, drug-induced hemolysis
Indirect Coombs test	Free anti-RBC antibodies in serum	Blood bank cross-matching; antibody identification
ANA (antinuclear antibody)	Antibodies against nuclear components	Screening for SLE and other connective tissue diseases; patterns (homogeneous, speckled, nucleolar, centromere) suggest specific diagnoses
Skin prick test	IgE-mediated reactivity to specific allergens	Wheal-and-flare response within 15–20 minutes confirms Type I hypersensitivity
Mixed lymphocyte reaction (MLR)	T-cell reactivity to donor HLA	Pre-transplant assessment of donor-recipient compatibility

Hypersensitivity Quick-Reference Summary

Type	Mediator	Timing	Mechanism	Classic Examples
I	IgE	Minutes	Mast cell degranulation	Anaphylaxis, asthma, allergic rhinitis
II	IgG, IgM	Hours	Cell-surface antibodies → complement, ADCC, receptor dysfunction	AIHA, Goodpasture, Graves, MG
III	IgG (immune complexes)	Hours–days	Complex deposition → complement → neutrophilic inflammation	SLE nephritis, serum sickness, PSGN
IV	T cells	24–72 hours	Th1/macrophage activation or CD8+ cytotoxicity	PPD, contact dermatitis, graft rejection, TB granulomas

Exam Strategy: For immunology questions, use a systematic approach: (1) Identify the arm of immunity involved (innate vs. adaptive, humoral vs. cellular). (2) Determine if the problem is too much immune activity (hypersensitivity/autoimmunity) or too little (immunodeficiency). (3) Match the clinical pattern to the mechanism. (4) Recall the specific molecular defect, diagnostic test, and treatment. Most immunology board questions test pattern recognition — learn the classic presentations cold. For hypersensitivity questions, timing is the biggest clue: minutes = Type I, hours = Type II/III, days = Type IV. For immunodeficiency questions, the type of infection points to the defective component: encapsulated bacteria = humoral, intracellular organisms = cellular, catalase-positive = phagocyte.