🧬 Innate Immunity
Barriers & first-line defenses
Innate immunity is present from birth, acts within minutes to hours, and does not improve with repeated exposure. It relies on physical, chemical, and cellular barriers.
- Physical barriers: Skin (intact keratinized epithelium; slightly acidic pH 5.5 retards bacterial growth). Respiratory tract: mucus-coated ciliated epithelium traps and propels microbes outward; antimicrobial enzymes (lysozyme) in secretions. GI tract: gastric acid (pH 1.5–3.5) destroys most ingested pathogens; intestinal mucus and antimicrobial peptides (defensins) provide additional protection. Other: tears, saliva, breast milk contain lysozyme and lactoferrin.
- Physiologic & chemical barriers: Fever (pyrogenic cytokines IL-1, IL-6, TNF raise hypothalamic set point, inhibiting pathogen growth). Lysozyme (cleaves bacterial peptidoglycan). Defensins (pore-forming peptides in phagocytes and epithelial cells). Interferons α/β (induce an antiviral state by transiently blocking protein synthesis in neighboring cells).
💡 High‑yield: γδ T cells reside in epithelia and recognise shared microbial structures — they are considered part of the innate arm.
Innate cellular components
Neutrophils (polymorphonuclear leukocytes)
• most abundant circulating phagocyte
• short-lived, first responders (peak 6 h)
• multilobed nucleus, granules
• most abundant circulating phagocyte
• short-lived, first responders (peak 6 h)
• multilobed nucleus, granules
Monocytes / macrophages
• monocytes in blood → macrophages in tissues
• long-lived, potent phagocytes & cytokine producers
• M1 (classical, pro-inflammatory) vs M2 (anti-inflammatory, repair)
• monocytes in blood → macrophages in tissues
• long-lived, potent phagocytes & cytokine producers
• M1 (classical, pro-inflammatory) vs M2 (anti-inflammatory, repair)
Dendritic cells – professional antigen-presenting cells; bridge innate and adaptive immunity.
Mast cells – reside in skin & mucosa; activated via TLR or IgE; release histamine and inflammatory mediators.
Natural killer (NK) cells: large granular lymphocytes, CD16⁺ CD56⁺. Kill virus-infected or transformed cells via perforin/granzymes. Do not express antigen-specific receptors; rely on balance of activating (KAR) and inhibitory (KIR) signals.
Pattern recognition receptors (PRRs)
Germline-encoded receptors that recognise PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated patterns).
| Receptor family | Examples | Ligands |
|---|---|---|
| Toll-like (TLR) extracellular | TLR-4, TLR-2, TLR-5 | LPS, peptidoglycan, flagellin |
| TLR endosomal | TLR-3, TLR-7/8, TLR-9 | dsRNA, ssRNA, CpG DNA |
| NOD-like (NLR) | NOD2, NLRP3 | bacterial peptidoglycan, uric acid, ATP, ROS |
| RIG-like (RLR) | RIG-1, MDA-5 | viral RNA |
Clinical correlate: NOD2 mutations are associated with inflammatory bowel disease (IBD); defects in TLR signalling lead to recurrent bacterial infections. Gain-of-function in NLRP3 inflammasome contributes to gout, atherosclerosis, and type 2 diabetes.
Inflammasome
Multiprotein complex in myeloid cells that acts as a sensor for microbes and cellular stress. Activation of NLRP3 inflammasome → caspase-1 cleavage of pro-IL-1β and pro-IL-18 into active, pro-inflammatory cytokines.
- Triggers: microbial products, ATP, uric acid crystals, reactive oxygen species.
- Key role in sterile inflammation (e.g., gout).
Complement system
Liver-derived zymogens that amplify inflammation, opsonisation, and membrane attack. Three pathways: classical (Ab-dependent), lectin (MBL, Ab-independent), and alternative (spontaneous on microbial surfaces).
| Component | Function |
|---|---|
| C3a, C4a, C5a | anaphylatoxins (mast cell degranulation, smooth muscle contraction) |
| C5a | potent chemotactic factor for neutrophils |
| C3b | opsonin; enhances phagocytosis; clears immune complexes |
| C5b–C9 | membrane attack complex (MAC) – lysis of bacteria |
📌 USMLE: Mannose-binding lectin (MBL) pathway activates complement without antibody — part of innate immunity.
Acute inflammation & leukocyte extravasation
Triggered by tissue injury or microbial products. Four sequential steps:
- Rolling: selectins on endothelium bind mucin-like molecules on leukocytes (weak, transient).
- Activation: chemokines (IL-8), C5a, f-Met peptides bind leukocyte receptors → integrin conformational change.
- Arrest / adhesion: integrins (e.g., LFA-1) bind Ig-superfamily CAMs (ICAM-1) on endothelium – firm adhesion.
- Transmigration: leukocytes squeeze between endothelial cells into tissue.
Leukocyte adhesion deficiency (LAD): autosomal recessive defect in CD18 (β₂ integrin chain). Patients have recurrent bacterial infections, no pus formation, marked neutrophilia. Diagnosis by flow cytometry for CD18.
Phagocytosis & intracellular killing
Opsonisation by IgG or C3b increases phagocytic efficiency up to 4000‑fold.
Respiratory burst
• NADPH oxidase → superoxide (O₂⁻)
• superoxide dismutase → H₂O₂
• myeloperoxidase (MPO) → HOCl (bleach)
• NADPH oxidase → superoxide (O₂⁻)
• superoxide dismutase → H₂O₂
• myeloperoxidase (MPO) → HOCl (bleach)
Oxygen‑independent
• lysozyme, defensins, lactoferrin, hydrolytic enzymes
• lysozyme, defensins, lactoferrin, hydrolytic enzymes
Nitric oxide (NO): iNOS converts arginine to NO, potent antimicrobial.
Chronic granulomatous disease (CGD): defect in NADPH oxidase subunit → no superoxide / H₂O₂.
• Catalase‑positive organisms (S. aureus, Aspergillus, Klebsiella) survive because they destroy H₂O₂.
• Catalase‑negative bacteria supply H₂O₂ for MPO → killing occurs.
• Diagnosis: NBT test (negative in CGD) or dihydrorhodamine flow cytometry.
• Catalase‑positive organisms (S. aureus, Aspergillus, Klebsiella) survive because they destroy H₂O₂.
• Catalase‑negative bacteria supply H₂O₂ for MPO → killing occurs.
• Diagnosis: NBT test (negative in CGD) or dihydrorhodamine flow cytometry.
Phagocyte defects – high yield
| Disorder | Defect | Consequence |
|---|---|---|
| LAD (type I) | CD18 (β₂ integrin) | no adhesion / extravasation; recurrent bacterial infections, omphalitis |
| CGD | NADPH oxidase (any subunit) | no respiratory burst; recurrent catalase‑positive infections; NBT negative |
| MPO deficiency | myeloperoxidase | mild, often asymptomatic; Candida susceptibility |
💊 Treatment: CGD patients benefit from IFN‑γ (boosts macrophage activity) and prophylactic antibiotics. Bone marrow transplantation is curative for LAD.
Cytokines in innate immunity
| Cytokine | Main source | Innate actions |
|---|---|---|
| IL‑1, IL‑6, TNF‑α | macrophages | fever, acute‑phase proteins, endothelial activation, cachexia |
| IL‑8 (CXCL8) | macrophages | neutrophil chemotaxis and adhesion |
| IL‑12 | macrophages, DCs | NK cell IFN‑γ production |
| IL‑10 | macrophages, DCs | anti‑inflammatory; inhibits IL‑12, MHC class II |
| IFN‑α / β | virally infected cells | antiviral state, increased MHC I, NK activation |
| TGF‑β | macrophages, lymphocytes | anti‑inflammatory, tissue repair |
Systemic effects: IL‑1, IL‑6, TNF‑α induce fever, leukocytosis, and hepatic acute‑phase protein synthesis (CRP, serum amyloid A).
Antiviral innate response: IFN & NK
Type I interferons (IFN‑α/β)
- Produced by virus‑infected cells (and DCs, fibroblasts).
- Induce an antiviral state in neighboring cells by activating RNA endonuclease (degrades viral RNA) and phosphorylating eIF2 (inhibits protein synthesis).
- Increase MHC class I expression and activate NK cells.
Natural killer (NK) cells
- Killer activating receptors (KAR): bind stress‑induced ligands (e.g., MIC proteins) → kill.
- Killer inhibitory receptors (KIR): bind HLA‑E (which presents HLA‑A/B/C leader peptides) → inhibitory signal dominates.
- When cells lose MHC class I (viral or tumour), HLA‑E decreases → KIR signal lost → NK kills.
- ADCC: via CD16 (FcγRIII) — antibody‑coated target cells are lysed.
📌 Clinical use: IFN‑α for hepatitis B/C and hairy cell leukaemia; IFN‑β for multiple sclerosis; IFN‑γ for CGD.
🧫 Adaptive Immunity & Lymphocyte Development
Overview of adaptive immunity
B and T lymphocytes are the central players. Their receptors are generated by somatic recombination, creating a vast repertoire.
- Specificity: each lymphocyte bears a single unique receptor for a particular antigen.
- Diversity: enormous receptor repertoire (10⁹–10¹¹ possible specificities).
- Memory: upon re‑exposure, response is faster, stronger, and more effective.
- Self‑tolerance: mechanisms (central & peripheral) prevent attack on host tissues.
- Self‑limitation: after antigen clearance, effector cells contract via apoptosis, preserving resources.
Lymphocyte development
- B cells: mature in bone marrow; positive/negative selection; Ig gene rearrangements (VDJ).
- T cells: progenitors migrate to thymus; positive selection (MHC restriction), negative selection (self‑tolerance).
- Key enzymes: RAG1/2 (VDJ recombination), TdT (N‑nucleotide addition).
- Allelic exclusion: once a functional heavy (or β) chain is made, rearrangement on the other allele is silenced → one idiotype per cell.
- Combinatorial association: any heavy chain can pair with any light chain → multiplies diversity.
- Somatic hypermutation occurs in B cells after antigen stimulation (affinity maturation).
Omenn syndrome / SCID: hypomorphic RAG mutations → partial activity (Omenn: Th2 skew, rash, diarrhoea). Null RAG1/2 → complete B‑ and T‑cell deficiency (SCID).
Antigen receptors: BCR vs TCR
Mature naive lymphocytes each display a single antigen‑binding specificity (idiotype). The B‑cell receptor (BCR) is membrane‑bound immunoglobulin, while the T‑cell receptor (TCR) is a heterodimer that recognises peptide–MHC complexes.
B‑cell receptor (BCR)
- Structure: two identical heavy chains + two light chains; disulfide‑linked “Y” shape with a flexible hinge.
- Isotypes expressed: IgM and IgD (same idiotype).
- Binding: native antigens (proteins, polysaccharides, lipids) – no MHC required.
- Signalling: Igα/Igβ (CD79a/b) + co‑receptor CD19/CD21/CD81.
- Secreted form: yes, after activation → antibody.
T‑cell receptor (TCR)
- Structure: α and β glycoprotein chains; no hinge region → rigid.
- Isotypes: single (αβ) per cell.
- Binding: peptide fragments presented on MHC molecules.
- Signalling: CD3 complex (multichain).
- Secreted form: no – always membrane‑anchored.
⚡ High‑yield: CD21 (on B cells) is the EBV receptor; CD81 binds HCV and Plasmodium vivax.
| Feature | BCR | TCR |
|---|---|---|
| Molecules per lymphocyte | ~100,000 | ~100,000 |
| Idiotypes per cell | 1 | 1 |
| Isotypes co‑expressed | IgM + IgD | αβ (single) |
| Secretion | yes | no |
| Flexibility | flexible hinge | rigid |
| Signal transducers | Igα/Igβ, CD19, CD21, CD81 | CD3 |
Generation of receptor diversity
Receptor diversity arises through somatic DNA rearrangements, not from a fixed germline repertoire. Random recombination of V, D, and J segments, plus junctional diversity, creates millions of unique idiotypes.
Heavy chain (B‑cell) / β chain (T‑cell)
- V(D)J recombination: select one V, one D, one J from many germline segments.
- N‑nucleotide addition by TdT at junctions (active in B‑cell heavy chain and all TCR chains).
- RAG1/RAG2 recombinase enzymes catalyse the cuts and joins.
Light chain (B‑cell) / α chain (T‑cell)
- VJ recombination (no D segment).
- In B cells, TdT is not active during light‑chain rearrangement.
- κ or λ constant regions complete the chain.
V→D→J→+ N‑nucleotides→VDJ rearrangement
B‑lymphocyte development & selection
- Positive selection: survival signals from pre‑BCR and functional Ig.
- Negative selection (central tolerance): self‑reactive B cells are deleted (clonal deletion) or rendered anergic (high IgD, low IgM).
- Stromal cells and macrophages in the bone marrow present self‑antigens to delete high‑affinity autoreactive clones.
⚠️ Anergic B cells: express high surface IgD and are functionally unresponsive in the periphery.
- TdT – terminal deoxynucleotidyl transferase; adds N‑nucleotides; used as a marker in acute lymphoblastic leukemia (ALL).
- RAG1/RAG2 – essential for V(D)J recombination; defects cause severe combined immunodeficiency.
T‑lymphocyte development & thymic selection
Pre‑T cells migrate from bone marrow to the thymus (cortex → medulla). They undergo two selection checkpoints.
Double‑negative (DN)
- No CD4 or CD8; TCR β‑chain rearranges first.
Double‑positive (DP)
- Express CD4, CD8, and TCR αβ; located in cortex.
Positive selection
- TCR binds self‑MHC with low affinity → survival; otherwise apoptosis.
Negative selection
- High‑affinity binding to self‑peptide:MHC → apoptosis (clonal deletion) or Treg differentiation.
Lineage commitment
- TCR → class I MHC → CD8+ cytotoxic T cell.
- TCR → class II MHC → CD4+ helper T cell.
Regulatory T cells (Tregs)
- CD25+ FoxP3+; secrete IL‑10 and TGF‑β.
- Suppress self‑reactive Th1 cells; critical for peripheral tolerance.
🔥 95–99% of thymocytes die during selection – only cells with useful, non‑autoreactive TCRs exit to the periphery.
MHC (HLA) molecules – peptide presentation
MHC molecules are highly polymorphic cell‑surface glycoproteins that present peptide antigens to T cells.
Class I MHC (HLA‑A, ‑B, ‑C)
- Expressed on all nucleated cells and platelets.
- Heavy chain (α) + β2‑microglobulin (not MHC‑encoded).
- Presents intracellular (endogenous) peptides to CD8+ T cells.
Class II MHC (HLA‑DP, ‑DQ, ‑DR; also HLA‑DM chaperone)
- Expressed on professional APCs: dendritic cells, macrophages, B cells.
- α and β chains of similar length; peptide‑binding groove at N‑terminus.
- Presents extracellular (exogenous) peptides to CD4+ T cells.
🧪 HLA‑DM is not a surface molecule; it acts as a chaperone to facilitate peptide loading onto class II.
Exogenous pathway · MHC class II loading
- Invariant chain (Ii): Associates with newly synthesized MHC‑II in the ER, blocking the peptide groove and directing the complex to endosomal compartments.
- CLIP fragment: After cleavage of Ii, CLIP remains bound to the groove.
- HLA‑DM: Catalyses exchange of CLIP for antigen‑derived peptide (higher affinity).
- Stable peptide‑MHC‑II is transported to the cell surface for recognition by CD4⁺ TCR.
🔬 Key point: Without peptide, MHC‑II is unstable and degraded. HLA‑DM is essential for peptide exchange; defects cause bare lymphocyte syndrome (type II).
Endogenous pathway · MHC class I loading
- Ubiquitination targets proteins for proteasomal degradation.
- Peptides are transported by TAP (transporter associated with antigen processing) into the ER.
- Tapasin bridges TAP to empty MHC‑I, facilitating peptide loading.
- Stable peptide‑MHC‑I complexes transit to the surface via Golgi.
⚠️ Clinical correlate: TAP deficiency leads to low MHC‑I expression, impaired CD8⁺ responses, and increased susceptibility to viral infections.
Cross‑presentation (cross‑priming)
Dendritic cells can internalise infected cells (or apoptotic bodies) and present exogenous antigens on MHC‑I to CD8⁺ T cells — a bridge between innate and cytotoxic immunity.
- DC phagocytoses virus‑infected cell or tumour fragment.
- Antigens escape into cytosol or are routed to the ER via TAP‑dependent mechanisms.
- MHC‑I:peptide complexes are expressed, priming naïve CD8⁺ T cells.
- This process is augmented by CD4⁺ T‑cell help (IL‑2, CD40L).
🧠 High‑yield: Cross‑presentation is crucial for antitumour immunity and responses against viruses that do not infect DCs directly.
Th1, Th2, Th17 differentiation
Naive Th0 cells differentiate into distinct subsets based on pathogen and cytokine milieu.
| Subset | Inducers | Key cytokines | Effector functions |
|---|---|---|---|
| Th1 | Intracellular pathogens, IL‑12, IFN‑γ | IFN‑γ | Macrophage activation, IgG switching, inhibits Th2 |
| Th2 | Helminths, allergens; IL‑4 | IL‑4, IL‑5, IL‑10, IL‑13 | IgE/IgA switching, eosinophil activation, alternative macrophage |
| Th17 | Extracellular bacteria/fungi; TGF‑β + IL‑6 | IL‑17, IL‑22 | Neutrophil recruitment, antimicrobial peptides, barrier function |
Th0→IL‑12 / IFN‑γ→Th1 (T‑bet)Th0→IL‑4 (no IL‑12)→Th2 (GATA‑3)Th0→TGF‑β + IL‑6→Th17 (RORγt)
📌 Leprosy spectrum: Th1 → tuberculoid (granulomas, controlled); Th2 → lepromatous (disseminated, antibody‑mediated but non‑protective).
CTLA‑4 & immune checkpoint
CTLA‑4 (CD152): expressed on activated T cells and Tregs. It competes with CD28 for B7 binding, delivering inhibitory signals. Critical for limiting T‑cell responses and preventing autoimmunity.
Agonists
Abatacept – RA
Belatacept – renal transplant
Abatacept – RA
Belatacept – renal transplant
Antagonists
Ipilimumab – melanoma, colorectal, other cancers (enhances anti‑tumor immunity)
Ipilimumab – melanoma, colorectal, other cancers (enhances anti‑tumor immunity)
High‑yield: CTLA‑4 knockout mice develop fatal lymphoproliferation and autoimmunity.
Superantigens
Superantigens (e.g., TSST‑1, staphylococcal enterotoxins) cross‑link TCR Vβ domain with MHC class II outside the peptide groove. This activates many T‑cell clones polyclonally, causing massive IFN‑γ release and macrophage activation → cytokine storm (IL‑1, IL‑6, TNF‑α).
Clinical: Toxic shock syndrome, food poisoning.
Treg cells
- Phenotype: CD4⁺, CD25⁺, FoxP3⁺
- Secrete IL‑10 and TGF‑β → suppress Th1/Th2 responses.
- Essential for preventing autoimmunity.
Cytotoxic T lymphocytes (CTL)
CD8⁺ T cells recognize antigen on MHC class I. They require both signal 1 (TCR–MHC I) and costimulation, plus cytokines from Th cells (especially IL‑2) for proliferation and full cytotoxic function.
Effector functions: Perforin/granzyme release, Fas‑FasL, IFN‑γ.
B‑lymphocyte activation
Thymus‑independent (TI) antigens
- Lipids, polysaccharides, LPS.
- Directly activate B cells (no T‑cell help).
- Mainly IgM, no memory, weak response.
- Marginal zone B cells and B‑1 cells.
Thymus‑dependent (TD) antigens
- Protein antigens; require CD4⁺ T‑cell help.
- B cell internalizes antigen → MHC II presentation.
- B7 upregulation on B cell.
- CD40L on T cell binds CD40 on B cell → signal 2.
- Leads to germinal center formation, affinity maturation, isotype switching, and memory.
Two waves: ① early IgM plasma cells; ② germinal center cells → high‑affinity, class‑switched antibodies.
Affinity maturation & isotype switching
Affinity maturation
- Somatic hypermutation in germinal centers → point mutations in V regions.
- B cells with higher affinity outcompete for antigen → clonal selection.
- Average antibody affinity increases over time.
Isotype switching
- Heavy‑chain constant region DNA recombination (switch regions).
- Driven by cytokines from helper T cells.
- One‑way process: once switched, cannot return to IgM.
- IgM predominates in primary response; IgG/IgA/IgE in secondary.
| Cytokine | Isotype induced |
|---|---|
| IFN‑γ | IgG (opsonization, complement) |
| IL‑4 / IL‑13 | IgE (mast cell, basophil, eosinophil) |
| TGF‑β / IL‑5 | IgA (mucosal immunity) |
💡 Pearl: Isotype switching decreases avidity (Fc changes) but affinity maturation compensates via higher affinity per binding site.
🧪 Serology & Immunodiagnostics
Serology overview
foundation Serologic tests rely on the specific interaction between antibodies and antigens. These reactions occur both in vivo and in the laboratory, forming the basis for diagnosing infections, autoimmune disorders, and monitoring immune status.
Key clinical roles: detect pathogen exposure, measure vaccine response, diagnose autoimmune diseases, and monitor disease progression or treatment efficacy.
- Antibody (immunoglobulin): Y‑shaped glycoprotein produced by B cells; binds specific epitopes.
- Antigen: any molecule that can be recognized by antibodies or T‑cell receptors.
- Epitope: the precise region on an antigen recognized by an antibody.
IgM & IgG — primary vs secondary response
IgM
- First isotype produced during primary immune response.
- Pentameric structure; highly efficient at complement activation.
- clinical pearl IgM does not cross the placenta → detection in a neonate indicates in utero infection (e.g., rubella, CMV, toxoplasmosis).
- Serum IgM to hepatitis B core antigen (HBcAb) suggests acute or recent HBV infection; useful during the “window period.”
IgG
- Predominant isotype in secondary responses; high affinity.
- Crosses placenta → provides passive immunity to fetus.
- Four subclasses (IgG1–4) with different effector functions.
- Rising IgG titers (with or without IgM) indicate past infection or vaccination.
📌 High‑yield: In primary infection, IgM appears first, followed by IgG. A single high IgM titer is often diagnostic of acute infection; paired acute/convalescent IgG titers (4‑fold rise) confirm recent infection.
Idiotype · isotype · allotype
Idiotype – antigen‑binding region (variable domains). Unique to each B‑cell clone; millions of specificities. Anti‑idiotype antibodies can regulate immune responses.
Isotype – constant region of heavy chain (e.g., IgM, IgG, IgA). Determines effector function (complement fixation, opsonization, etc.).
Allotype – allelic variants of the same isotype among individuals. Minor differences in constant regions; can be immunogenic in transfused patients (e.g., type III hypersensitivity to pooled gamma globulin).
Antibody digestion: papain vs pepsin
- Papain cleaves above the hinge disulfide bonds → generates two Fab (antigen‑binding) fragments and one Fc (crystallizable) fragment.
- Pepsin cleaves below the hinge → produces a single F(ab')₂ fragment (divalent) and degrades the Fc portion.
- F(ab')₂ fragments are used in certain diagnostic assays to avoid Fc‑mediated interference.
IgG⟶Papain⟶2 Fab + FcPepsin⟶F(ab')₂ + digested Fc
Zone of equivalence & antigen‑antibody titration
Precipitation and agglutination are maximal when antigen and antibody are present in optimal proportions—equivalence. In the laboratory, titrating antigen against antibody reveals three phases:
- Antigen excess – early infection; free antigen detectable, no visible immune complexes.
- Equivalence zone – lattice formation; neither free antigen nor free antibody detected (e.g., hepatitis B “window period”).
- Antibody excess – later in infection; free antibody present, complexes form.
Clinical correlate: In HBV infection, HBsAg disappears during the window (equivalence) as HBsAb appears; this phase may be serologically “silent” for both markers.
Monoclonal vs polyclonal antibodies
- Polyclonal: derived from multiple B‑cell clones; recognize various epitopes on an antigen. Naturally produced during infection or by immunizing animals (rabbit, goat).
- Monoclonal: derived from a single clone; identical specificity for one epitope. Produced via hybridoma technology. Used in therapy (e.g., rituximab, trastuzumab) and diagnostics.
💊 Clinical pearl: Monoclonal antibodies are the backbone of many targeted cancer and autoimmune therapies; their specificity reduces off‑target effects.
Direct vs indirect serologic tests
Direct – uses known antibody to detect unknown antigen (e.g., direct fluorescent antibody for Pneumocystis, viral antigens). Rapid, qualitative, used for screening.
Indirect – uses patient serum (antibody) to detect antigen; quantifies antibody titers. More specific; serial dilutions yield titer (reciprocal of highest dilution that gives a positive reaction).
Titers are used to follow disease progression (e.g., rising IgG titer) or confirm exposure.
Agglutination & Coombs tests
Agglutination
- Particulate antigens (RBCs, latex beads) cross‑linked by antibodies → visible clumping.
- Latex agglutination: used for CSF pathogens (meningococcus, H. influenzae, pneumococcus, Cryptococcus).
- RBC agglutination: blood typing, monospot (EBV), Coombs test.
Coombs tests
- Direct Coombs: detects antibodies already bound to RBCs in vivo (e.g., Rh incompatibility, autoimmune hemolytic anemia).
- Indirect Coombs: detects free antibodies in serum (e.g., Rh‑negative mother with anti‑Rh IgG, transfusion pre‑testing).
📌 USMLE: Direct Coombs + in warm autoimmune hemolytic anemia and hemolytic disease of the newborn (RhD). Indirect Coombs used for prenatal screening and cross‑matching.
ABO blood typing
- ABO antigens are glycoproteins on RBCs and endothelial cells.
- Natural isohemagglutinins (IgM) are produced against A/B antigens not present on self (due to cross‑reaction with intestinal flora).
- ABO incompatibility → hyperacute graft rejection; ABO typing is mandatory before transplantation.
| Blood type | Antigen on RBC | Serum antibodies (IgM) |
|---|---|---|
| A | A | anti‑B |
| B | B | anti‑A |
| AB | A and B | none |
| O | none | anti‑A and anti‑B |
Labeled antibody systems
- Direct fluorescent antibody (DFA): fluorescent‑labeled antibody directly detects antigen in patient tissue (e.g., rabies, HSV, RSV).
- Indirect fluorescent antibody (IFA): patient antibody binds to fixed antigen, then detected with fluorescent anti‑human Ig. Used for autoantibodies (ANA, anti‑dsDNA).
Comparison: DFA = “antigen detection”, IFA = “antibody detection” (patient serum).
ELISA & flow cytometry (FACS)
ELISA (enzyme‑linked immunosorbent assay)
- Extremely sensitive (detects picogram amounts). Uses enzyme‑labeled antibody and chromogenic substrate → color change.
- Common application: HIV screening (p24 antigen coated plate; patient serum + enzyme‑labeled anti‑human Ig).
- Can be direct or indirect; used for hormones, drugs, tumor markers, autoantibodies.
FACS (fluorescence‑activated cell sorting)
- Analyzes and sorts cells based on surface markers using fluorescently labeled antibodies.
- Generates scatter plots; each dot represents a cell with specific fluorescence intensity and color.
- Widely used in immunophenotyping (CD4/CD8 counts, leukemia/lymphoma diagnosis).
🧬 FACS high‑yield: CD4 count by flow cytometry is essential for staging HIV; abnormal populations (e.g., light chain restriction) suggest clonal B‑cell disorders.
⚡ Hypersensitivity & Autoimmunity
Overview
Hypersensitivity refers to tissue injury caused by an exaggerated or misdirected immune response. The first encounter with an antigen sensitizes the immune system; subsequent exposure triggers a damaging reaction. The four Gell & Coombs types are classified by the effector mechanism and the type of immune response.
Key concept: autoimmune diseases occur when self‑tolerance fails. Hypersensitivity reactions can be against foreign antigens (allergy) or self‑antigens (autoimmunity).
Type I · Immediate (IgE‑mediated)
fast mast cells atopy Response within minutes of re‑exposure. Mediated by IgE bound to FcεRI on mast cells, basophils, and eosinophils.
Pathophysiology
- Sensitization: first exposure → Th2 cells produce IL‑4 and IL‑13 → B cells class‑switch to IgE.
- Effector phase: allergen cross‑links IgE on mast cells → degranulation → histamine, proteases, prostaglandins, leukotrienes.
- Late‑phase: 2–4 hours later, arachidonic acid metabolites and cytokines cause inflammation, leukocyte recruitment.
Clinical examples
- Allergic rhinitis (hay fever)
- Asthma (bronchoconstriction, mucus)
- Anaphylaxis (insect stings, drugs)
- Food allergies (urticaria, GI)
- Wheal‑and‑flare skin tests
High‑yield: systemic anaphylaxis → laryngeal edema, hypotension, bronchospasm. Immediate epinephrine is first‑line.
Allergen→Th2 → IL‑4, IL‑13→B cell IgE→Mast cell sensitization→Cross‑link → degranulation
Mediators: histamine (vasodilation, smooth muscle), heparin, prostaglandin D₂, leukotrienes C₄/D₄/E₄ (bronchospasm), LTB₄ (neutrophil chemotaxis).
Type II · Antibody‑mediated (cytotoxic / non‑cytotoxic)
IgG/IgM cell surface ECM Antibodies against cell‑surface or extracellular matrix antigens. Tissue damage localised to the antigen‑bearing tissue.
Mechanisms
- Opsonisation & complement‑mediated lysis: Fc receptor phagocytosis, MAC formation.
- Inflammatory cell recruitment: C3a, C5a, and FcγR trigger neutrophil/macrophage infiltration.
- Functional alteration: antibody binding to receptor (e.g., TSH receptor) or enzyme (e.g., AChR) alters signalling without cell death.
Cytotoxic examples
- Autoimmune hemolytic anemia (anti‑RBC)
- HDNB (Rh incompatibility)
- Goodpasture syndrome (anti‑collagen IV)
- Transfusion reactions (ABO)
Non‑cytotoxic examples
- Myasthenia gravis (anti‑AChR → muscle weakness)
- Graves disease (anti‑TSHR → hyperthyroidism)
- Pernicious anemia (anti‑intrinsic factor)
Classic HDNB: Rh‑negative mother with Rh‑positive fetus → maternal IgG crosses placenta in subsequent pregnancy → hemolysis. Prevent with RhoGAM (anti‑D) at 28 weeks and within 72h post‑partum.
Type III · Immune complex‑mediated
soluble Ag–Ab vasculitis nephritis Circulating immune complexes deposit in small vessels → complement activation, neutrophil recruitment, tissue injury. Usually systemic.
Key diseases
- SLE (dsDNA, Sm, nucleoproteins) → nephritis, arthritis, malar rash
- Post‑streptococcal glomerulonephritis (planted streptococcal Ag) → “lumpy‑bumpy” deposits
- Serum sickness (foreign proteins) → arthritis, vasculitis, nephritis
- Polyarteritis nodosa (HBV Ag) → systemic vasculitis
Pattern: immune complexes deposit where blood is filtered — glomeruli, joints, skin. “Lumpy‑bumpy” immunofluorescence.
Type IV · T‑cell mediated (delayed)
CD4+ Th1/Th17 CD8+ CTL 48–72 h No antibody involvement. Tissue damage from cytokine‑activated macrophages, neutrophils, or direct cytotoxicity.
Th1 / Th17 mediated
- Tuberculin test (PPD) – induration
- Contact dermatitis (poison ivy, nickel)
- Rheumatoid arthritis (synovial inflammation)
- Crohn disease (Th1/Th17 driven)
- Type 1 diabetes (β‑cell destruction)
CD8+ CTL mediated
- Viral infections (hepatitis)
- Graft rejection
- Some autoimmune diseases (e.g., DM1)
Clinical pearl: Type IV reactions are delayed and are often diagnosed by skin testing (PPD) or patch testing. Corticosteroids and immunosuppressants are mainstays.
Autoimmunity · pathogenesis
Autoimmunity arises from failure of central (thymus, bone marrow) and peripheral tolerance. Self‑reactive lymphocytes escape deletion and become activated.
Breakdown of tolerance
- Anergy: self‑antigen recognition without co‑stimulation → lymphocyte inactivation.
- Deletion: apoptosis via Fas/FasL or caspase pathways.
- Suppression: Treg cells secrete IL‑10, TGF‑β; high CTLA‑4 sequesters B7 (CD80/86).
- B cell tolerance: anergic B cells express high IgD, excluded from follicles → apoptosis.
Key regulators: CTLA‑4 (inhibitory), PD‑1, and Treg‑derived cytokines. Defects in these pathways are linked to autoimmunity.
Genetics & environmental triggers
HLA associations are the strongest genetic risk factors. Examples:
| Disease | HLA allele |
|---|---|
| Rheumatoid arthritis | DR4 |
| Type 1 diabetes | DR3 / DR4 |
| Ankylosing spondylitis | B27 |
| Celiac disease | DQ2 / DQ8 |
| SLE | DR2 / DR3 |
Non‑HLA genes (e.g., PTPN22, CTLA‑4, IL‑2R) also contribute. Infections (molecular mimicry) and tissue injury expose self‑antigens, driving chronic progression.
🛡️ Immunodeficiency disorders
Defects of phagocytic cells
Chronic granulomatous disease (CGD)
- Defect: NADPH oxidase deficiency (any of 4 subunits) → no superoxide / reactive oxygen species.
- Infections: catalase‑positive bacteria (Staph. aureus, Burkholderia, Serratia) & fungi (Aspergillus).
- Diagnosis: DHR (dihydrorhodamine) flow assay or NBT test.
- Treatment: prophylactic TMP‑SMX, interferon‑γ, antifungal.
Leukocyte adhesion deficiency (LAD)
- Defect: absence of CD18 (common β chain of integrins LFA‑1, Mac‑1, gp150/95).
- Features: recurrent soft‑tissue infections, delayed umbilical cord separation, failure to form pus.
- Lab: marked neutrophilia, absent CD18 on flow cytometry.
- Management: prompt antibiotics, bone marrow transplant.
Chediak‑Higashi syndrome
- Defect: LYST mutation → defective lysosomal trafficking, giant granules in leukocytes.
- Clinical: partial albinism, recurrent pyogenic infections, peripheral neuropathy, absent NK function.
- Accelerated phase: hemophagocytic lymphohistiocytosis (HLH).
Other phagocyte defects
- G6PD deficiency: impaired HMP shunt → similar to CGD (plus hemolytic anemia).
- Myeloperoxidase deficiency: mild or asymptomatic; impaired H2O2 → hypochlorite.
- Hyper‑IgE (Job) syndrome: STAT3 mutation → impaired Th17, elevated IgE, retained primary teeth, eczema, bone fractures.
📌 High‑yield: CGD → catalase‑positive organisms (because catalase destroys H2O2 that other bacteria might produce). LAD → delayed umbilical cord separation.
Defects of humoral immunity
B‑cell disorders lead to recurrent infections with encapsulated bacteria (e.g., Streptococcus pneumoniae, Haemophilus) and enteroviruses.
Bruton (X‑linked) agammaglobulinemia
- Defect: mutation in Bruton tyrosine kinase (BTK) → block at pre‑B cell stage.
- Clinical: recurrent sinopulmonary infections after 6 months (maternal IgG wanes).
- Lab: absent B cells, very low all Ig isotypes; T‑cell immunity intact.
- Treatment: IVIG replacement, antibiotics.
X‑linked hyper‑IgM syndrome
- Defect: CD40L deficiency on T cells → failure of class switching.
- Lab: high IgM, low IgG/IgA; normal B and T cell counts.
- Infections: encapsulated bacteria + opportunistic (PCP, Cryptosporidium).
- Treatment: IVIG, prophylaxis.
Selective IgA deficiency
- Most common: IgA < 7 mg/dL with normal IgG/IgM (IgE often elevated).
- Associations: atopy, autoimmune disease, GI infections.
- Caution: anaphylaxis to blood products (anti‑IgA antibodies).
- Often asymptomatic; treat infections, avoid immunoglobulin.
Common variable immunodeficiency (CVID)
- Onset: late teens – 20s; reduced IgG, IgA, and/or IgM.
- B cells present but fail to differentiate into plasma cells.
- Features: recurrent infections, autoimmune cytopenias, granulomatous disease.
- Treatment: IVIG, antibiotics.
⚠️ Transient hypogammaglobulinemia of infancy: physiologic delay in IgG production, resolves by 16–30 months. Treat only severe infections.
Complement deficiencies & regulation
Classic pathway (C1q, C1r, C1s, C4, C2)
- Presentation: immune‑complex diseases (SLE‑like), pyogenic infections.
- C2 deficiency is the most common classic pathway defect.
C3 deficiency
- Severe recurrent bacterial infections + immune‑complex disease (both pathways affected).
Terminal pathway (C5–C9)
- Recurrent meningococcal & gonococcal infections (due to loss of membrane attack complex).
- Consider in patients with recurrent Neisseria.
Regulatory defects
- C1‑INH deficiency (hereditary angioedema): overactivation of C1, C4, C2 → mucosal edema (larynx, GI), normal urticaria.
- Treatment: bradykinin antagonists, C1‑INH concentrate.
T‑cell defects & severe combined immunodeficiency
T‑cell defects have broad consequences because T cells orchestrate adaptive immunity. SCID presents within first months with failure to thrive, opportunistic infections, and absence of T cells.
DiGeorge syndrome (22q11.2 deletion)
- Defect: 3rd/4th pharyngeal pouch failure → thymic aplasia, hypoparathyroidism.
- Triad: cardiac anomalies, hypocalcemia, hypoplastic thymus.
- Immunity: low T cells (CD4+ & CD8+); B cells normal.
MHC class I deficiency (TAP defect)
- Defective peptide transport → low CD8+ T cells; recurrent viral infections.
- DTH and antibody responses are preserved.
Wiskott‑Aldrich syndrome (WAS)
- X‑linked: WASp defect → impaired actin cytoskeleton.
- Triad: eczema, thrombocytopenia, recurrent infections.
- Low IgM, elevated IgA/IgE; defective response to polysaccharides.
Ataxia‑telangiectasia
- ATM kinase defect → ataxia, telangiectasias (ocular), IgA & IgE deficiency.
- High risk of malignancy, radiosensitivity.
Severe combined immunodeficiency (SCID) variants
| Type | Defect | Key features |
|---|---|---|
| X‑linked SCID | Common γ‑chain (IL‑2,‑4,‑7,‑9,‑15 receptors) | Absent T & NK cells; B cells present but nonfunctional |
| Adenosine deaminase (ADA) deficiency | Purine metabolism → toxic dATP | SCID + neurologic abnormalities, bony abnormalities |
| RAG1/RAG2 deficiency | V(D)J recombination failure | Absent T and B cells (T− B− NK+), Omenn syndrome possible |
| Bare lymphocyte syndrome (MHC II) | Defective MHC II expression | CD4+ T‑cell deficiency, hypogammaglobulinemia, viral/fungal infections |
🧠 Clinical pearl: SCID infants often present with Pneumocystis jirovecii pneumonia, oral thrush, and chronic diarrhea. Avoid live vaccines (BCG, rotavirus, MMR).
Comparison table · high‑yield defects
| Disease | Defect | Infections / hallmark |
|---|---|---|
| CGD | NADPH oxidase | Catalase‑positive bacteria, fungi |
| LAD | CD18 integrin | Delayed cord separation, no pus |
| Bruton agammaglobulinemia | BTK | Encapsulated bacteria, enteroviruses |
| Hyper‑IgM | CD40L | Opportunistic infections + low IgG/A |
| Selective IgA deficiency | Multiple genes | Atopy, GI infections, anti‑IgA risk |
| DiGeorge | 22q11.2 | Hypocalcemia, cardiac, absent thymus |
| Wiskott‑Aldrich | WASp | Eczema, thrombocytopenia, low IgM |
| SCID (X‑linked) | γ‑chain IL‑2R | Absent T & NK, infections early |
🔹 X‑linked immunodeficiencies (males predominance): Bruton, Wiskott‑Aldrich, X‑SCID, X‑linked hyper‑IgM.
🔹 Maternal IgG protects until ~6 months; therefore, B‑cell defects often present after that age.
🔹 Encapsulated bacteria (S. pneumoniae, H. influenzae, Neisseria) → defect in antibody / complement (C3, C5–C9, B‑cell defects).
🔹 Opportunistic infections (PCP, fungi, viruses) → T‑cell defect / SCID.
🔄 Transplantation Immunology
Fundamental concepts
Transplantation refers to the transfer of cells, tissues, or organs from a donor to a recipient. The immune system’s primary role—to distinguish self from non-self—poses a major barrier, as grafts from genetically non-identical individuals are recognized as “altered self” and targeted for destruction.
Key principle: MHC (HLA) molecules are codominantly expressed. Each individual inherits one haplotype from each parent, making it nearly impossible for two unrelated people to share identical MHC alleles. This polymorphism drives allograft rejection.
Even identical twins (syngeneic) may have minor antigenic differences due to somatic mutations, though rejection is rare. In practice, all non-autologous grafts require lifelong immunosuppression to prevent rejection.
Graft types
Autograft – tissue moved within the same individual (e.g., skin grafts, saphenous vein CABG). No immunosuppression needed.
Isograft (syngeneic) – between genetically identical individuals (monozygotic twins). No rejection expected.
Allograft (allogeneic) – between genetically different members of the same species (most organ transplants). Requires immunosuppression.
Xenograft – between different species (e.g., porcine heart valves). Hyperacute rejection is common due to pre-formed antibodies.
Mechanisms of graft rejection
Recognition of alloantigens (primarily MHC molecules) triggers both cellular and humoral responses. Key players:
- CD4+ T helper cells – secrete cytokines (IL-2, IFN-γ, TNF) that activate macrophages and CD8+ T cells.
- CD8+ cytotoxic T cells – directly kill graft cells via perforin/granzyme and FasL.
- Antibodies – bind to endothelial cells, activate complement, and cause vascular damage.
Alloantigen→APC / direct presentation→T cell activation→Effector phase→Graft destruction
IFN-γ and TNF upregulate MHC class I and II on graft cells, increasing their visibility to immune effectors. This “cytokine storm” amplifies the rejection response.
Rejection timelines & patterns
| Type | Timeframe | Mechanism / pathology |
|---|---|---|
| Hyperacute | Minutes – hours | Pre-formed antibodies (anti-ABO, anti-HLA) → complement activation → thrombosis, ischemic necrosis. |
| Acute | Days – weeks | Primary cellular response: CD4+ and CD8+ T cells, alloantibodies. Reversible with immunosuppression. |
| Accelerated acute | Days | Memory T cell response (anamnestic); faster than primary acute rejection. |
| Chronic | Months – years | Chronic DTH, macrophage infiltration, intimal smooth muscle proliferation → vessel occlusion, fibrosis. |
📌 High-yield: Hyperacute rejection is prevented by cross-matching donor and recipient for pre-formed antibodies. It is rare in modern practice.
Hyperacute rejection
- Onset: within minutes to hours after revascularization.
- Pathogenesis: pre-existing antibodies (from prior transfusion, pregnancy, or transplant) bind to donor endothelial antigens → complement cascade → neutrophil infiltration, thrombosis, and hemorrhagic necrosis.
- Gross appearance: dusky, mottled organ with poor perfusion.
- Prevention: ABO-compatible donor and negative crossmatch (CDC or flow cytometry).
Acute rejection
- Onset: days to weeks post-transplant (peak at ~1 week).
- Pathology: mononuclear cell infiltrate (CD4+ & CD8+ T cells) in the interstitium and vascular endothelium. In kidney transplants: tubulitis and intimal arteritis.
- Treatment: high-dose corticosteroids, anti-thymocyte globulin, or monoclonal antibodies (OKT3, basiliximab).
- Prognosis: usually reversible if detected early; common cause of early graft loss.
Chronic rejection
- Onset: months to years; the leading cause of late graft failure.
- Pathology: concentric intimal hyperplasia (vascular smooth muscle proliferation), fibrous obliteration of arteries, interstitial fibrosis. In lung transplant: obliterative bronchiolitis.
- Risk factors: prior acute rejection episodes, inadequate immunosuppression, donor age.
- Treatment: recalcitrant to therapy; often requires retransplantation.
Graft-versus-host disease (GVHD)
Definition: A complication of bone marrow (hematopoietic stem cell) transplantation, wherein mature donor T lymphocytes attack recipient tissues that express allogeneic MHC molecules.
Clinical triad:
• Maculopapular rash (erythematous, often generalized)
• Diarrhea (secretory, often bloody)
• Jaundice / liver dysfunction (elevated bilirubin, transaminases)
• Maculopapular rash (erythematous, often generalized)
• Diarrhea (secretory, often bloody)
• Jaundice / liver dysfunction (elevated bilirubin, transaminases)
Prevention: T-cell depletion of the donor marrow (ex vivo) or post-transplant immunosuppression (methotrexate, cyclosporine, or anti-CD52 antibodies).
Acute GVHD (days to weeks) vs. chronic GVHD (months, resembles autoimmune disease with scleroderma-like features).
📌 Pearls: GVHD can occur even in HLA-identical sibling transplants due to minor histocompatibility antigens. The “graft-versus-leukemia” effect is a desirable consequence that reduces relapse.
Immunosuppressive agents
Standard protocols combine corticosteroids, calcineurin inhibitors, and antiproliferative agents. Monoclonal antibodies are increasingly used for induction and treatment of refractory rejection.
| Agent | Target / mechanism | Key notes |
|---|---|---|
| Cyclosporine / Tacrolimus | Calcineurin inhibition → ↓ IL-2 transcription | Nephrotoxic; drug interactions via CYP3A4 |
| Mycophenolate mofetil | Inhibits IMPDH → ↓ purine synthesis | GI upset, leukopenia |
| Sirolimus (rapamycin) | mTOR inhibitor → blocks IL-2 signal transduction | Interstitial pneumonitis, hyperlipidemia |
| Basiliximab / Daclizumab | Anti–IL-2 receptor (CD25) monoclonal antibody | Induction therapy; blocks T-cell proliferation |
| Muromonab (OKT3) | Anti-CD3; depletes T cells via apoptosis | First-generation; cytokine release syndrome |
| Belatacept | CTLA-4–Ig fusion protein; blocks B7:CD28 costimulation | Less nephrotoxic than calcineurin inhibitors |
| Alemtuzumab | Anti-CD52; depletes T and B cells | Profound lymphopenia; used in induction |
📋 Corticosteroids (methylprednisolone, prednisone) – broad anti-inflammatory effect via inhibition of cytokine gene transcription. First-line for acute rejection. Side effects: hyperglycemia, osteoporosis, infections.
Clinical pearls & exam tips
🔬 Diagnosis of rejection:
• Kidney: biopsy shows tubulitis, intimal arteritis (Banff classification).
• Heart: endomyocardial biopsy; cellular rejection graded by ISHLT.
• Liver: portal inflammation, bile duct damage, endothelialitis.
• Kidney: biopsy shows tubulitis, intimal arteritis (Banff classification).
• Heart: endomyocardial biopsy; cellular rejection graded by ISHLT.
• Liver: portal inflammation, bile duct damage, endothelialitis.
- Crossmatching: donor-specific antibodies are detected by complement-dependent cytotoxicity (CDC) or flow cytometry. A positive crossmatch is a contraindication to transplantation (hyperacute risk).
- Minor histocompatibility antigens: can cause rejection even in HLA-matched transplants (e.g., H-Y antigens).
- Chronic rejection is often antibody-mediated (donor-specific antibodies, C4d deposition in tissue).
- GVHD prophylaxis: T-cell depletion, post-transplant cyclophosphamide, or methotrexate + calcineurin inhibitor.
📌 USMLE high-yield:
• Hyperacute = minutes to hours, pre-formed antibodies.
• Acute = days to weeks, T-cell mediated.
• Chronic = months to years, vascular intimal hyperplasia.
• GVHD = donor T cells attacking recipient (skin, liver, GI).
• Hyperacute = minutes to hours, pre-formed antibodies.
• Acute = days to weeks, T-cell mediated.
• Chronic = months to years, vascular intimal hyperplasia.
• GVHD = donor T cells attacking recipient (skin, liver, GI).
💉 Vaccines & Immunization
Types of immunity
Active immunity
- Natural: recovery from infection → memory B/T cells
- Artificial: vaccination (attenuated, killed, toxoid, subunit, etc.)
- Long-lasting; provides memory
Passive immunity
- Natural: maternal IgG across placenta; IgA in colostrum
- Artificial: antibody preparations (e.g., antivenin, IVIG, monoclonal antibodies)
- Immediate but temporary; no memory
🧬 Key concept: Primary response: IgM → IgG, 5‑10 days lag. Secondary response: rapid (1‑3 days), high‑affinity IgG, IgA, or IgE due to memory cells.
Vaccine classes
Live attenuated – MMR, VZV, rotavirus, LAIV. Replicate in host, strong humoral + cellular immunity. Contraindicated in immunocompromised. Usually 1‑2 doses.
Killed / inactivated – Rabies, IPV, HepA. Chemically inactivated; cannot replicate. Humoral response only; requires boosters.
Toxoid – DTaP (diphtheria, tetanus). Inactivated exotoxins. Prevent disease, not infection. Induce anti‑toxin antibodies.
Polysaccharide – PPSV23 (adult). Pure capsular polysaccharide → T‑cell‑independent (IgM only, no memory).
Conjugate – PCV13, Hib, MCV4. Polysaccharide + protein carrier → T‑cell‑dependent; class switching, memory, booster response.
Component (recombinant) – HBV, HPV. Immunogenic protein produced in yeast or cell culture. Highly safe, no live component.
⚠️ Contraindication: Live vaccines (MMR, VZV, rotavirus, LAIV) are not given to severely immunocompromised patients (risk of disseminated disease).
Live non‑attenuated vaccine (unique): Enteric‑coated adenovirus types 4 & 7 (U.S. military) – causes asymptomatic intestinal infection → mucosal IgA memory; protects against aerosol pneumonia.
Passive immunotherapy
- Indications: post‑exposure prophylaxis (e.g., rabies, tetanus), snake/spider antivenin, RSV prophylaxis (palivizumab).
- Risks: Anaphylaxis (IgE against foreign proteins), serum sickness (type III hypersensitivity) from immune complexes, anti‑allotype responses (even with human Ig).
- Special consideration: IgA‑deficient patients may react to IgA in IVIG; use IgA‑depleted preparations.
🧪 Humanized monoclonal antibodies (e.g., palivizumab against RSV) are engineered to reduce immunogenicity.
Maternal antibodies & neonatal immunity
- IgG crosses placenta (active transport) → protects neonate for first few months.
- IgM does not cross; detection in newborn indicates congenital infection (e.g., TORCH).
- IgA in colostrum provides mucosal protection; infant IgA reaches ~20% of adult levels by 12 months.
- Vaccination timing: Live attenuated vaccines (MMR, VZV) are usually given after 12 months because maternal IgG can neutralize the vaccine virus. If given earlier (high‑risk situations), repeat doses are often needed.
- Infants with primary immunodeficiencies typically present after maternal IgG wanes (≈3‑6 months).
Maternal IgG→Neonatal protection (0‑6 mo)→IgG declines→Vaccination & own Ig production
Bacterial vaccines (selected)
| Organism | Vaccine | Type |
|---|---|---|
| Corynebacterium diphtheriae | DTaP (diphtheria) | Toxoid |
| Clostridium tetani | DTaP (tetanus) | Toxoid |
| Bordetella pertussis | DTaP (acellular) | Toxoid + filamentous hemagglutinin |
| Haemophilus influenzae type b | Hib | Conjugate (polysaccharide + protein) |
| Streptococcus pneumoniae | PCV13 (pediatric) / PPSV23 (adult) | Conjugate (13 serotypes) / Polysaccharide (23 serotypes) |
| Neisseria meningitidis | MCV4 | Conjugate (serogroups A, C, Y, W‑135) |
💡 High yield: Polysaccharide vaccines (PPSV23) induce IgM only and no memory; conjugate vaccines (PCV13) are T‑cell‑dependent → IgG, affinity maturation, and booster response.
Viral vaccines
| Virus | Vaccine | Type |
|---|---|---|
| Rotavirus | RV (oral) | Live attenuated |
| Polio | IPV (Salk) / OPV (Sabin) | Inactivated / Live attenuated |
| Influenza | IIV (injected) / LAIV (intranasal) | Inactivated / Live attenuated |
| Varicella zoster | VAR (chickenpox) / Zoster | Live attenuated |
| Hepatitis A | HepA | Inactivated |
| Hepatitis B | HepB | Component (recombinant HBsAg) |
| HPV | Gardasil 9 (9v) | Component (L1 protein) |
| Measles, Mumps, Rubella | MMR | Live attenuated |
🧬 HPV vaccine: 9‑valent (types 6,11,16,18,31,33,45,52,58) prevents >90% of cervical cancers. Previously quadrivalent (6,11,16,18) covered ~70%.
High‑yield USMLE facts
🔬 Primary vs secondary response
- Primary: lag 5‑10 d, low affinity IgM→IgG
- Secondary: lag 1‑3 d, high affinity IgG/IgA/IgE
🧪 Vaccine type memory
- Live & conjugate → T‑cell dependent → memory
- Polysaccharide & toxoid → variable; toxoid induces memory (protein), pure polysaccharide does not
⚠️ Common trap: DTaP contains tetanus and diphtheria toxoids and acellular pertussis components (toxoid + filamentous hemagglutinin) — it is not a live vaccine.
📅 Neonatal vaccination: Live vaccines delayed until >12 months due to maternal IgG interference. Exception: high‑risk exposure, but then boosters are required.
⚠️ Immunocompromised: Avoid live vaccines (MMR, VZV, rotavirus, LAIV, OPV, yellow fever). Killed, toxoid, subunit, and conjugate are generally safe.
✔️ Salk = inactivated polio
✔️ Sabin = live oral polio
✔️ PPSV23 = 23-valent polysaccharide (adult)
✔️ PCV13 = 13-valent conjugate (pediatric)
⚕️ Complete unabridged immunology notes · all content from provided files · arranged for video lectures