Comprehensive study resource covering innate and adaptive immunity, hypersensitivity, autoimmunity, immunodeficiency, transplant and tumor immunology, vaccination, allergic disease, complement disorders, immunodiagnostics, and immunopharmacology. Every concept, every pathway, every therapy you need to know.
PAMPs/DAMPs • PRRs • Complement • Cytokines • T Cells • B Cells • Antibodies • MHC
First line: Physical barriers (skin, mucous membranes), antimicrobial peptides (defensins, cathelicidins), complement, natural killer (NK) cells, phagocytes (neutrophils, macrophages, dendritic cells). PAMPs (Pathogen-Associated Molecular Patterns): Conserved microbial molecules — LPS (Gram-neg), lipoteichoic acid (Gram-pos), flagellin, peptidoglycan, zymosan (fungi), dsRNA (viruses), CpG DNA. DAMPs (Danger-Associated Molecular Patterns): Host molecules released during tissue injury — HMGB1, ATP, uric acid, S100 proteins, heat shock proteins, DNA, RNA. PRRs (Pattern Recognition Receptors): Found on/in innate immune cells. TLRs (Toll-like receptors): TLR1/2/6 (lipoproteins), TLR3 (dsRNA), TLR4 (LPS), TLR5 (flagellin), TLR7/8 (ssRNA), TLR9 (CpG DNA). NLRs (NOD-like receptors): NOD1/NOD2 (peptidoglycan fragments), NLRP3 (inflammasome — activates caspase-1 — IL-1β, IL-18). RLRs (RIG-I-like receptors): RIG-I, MDA5 (cytoplasmic viral RNA). CLRs (C-type lectin receptors): Dectin-1 (β-glucan), DC-SIGN.
Three activation pathways: Classical: IgM/IgG immune complexes — C1qrs — C4 — C2 — C3 convertase (C4b2a). Alternative: Spontaneous C3 hydrolysis (C3(H2O)) — Factor B — Factor D — C3bBb (C3 convertase). Properdin stabilizes. Lectin: Mannose-binding lectin (MBL) or ficolins bind carbohydrate patterns — MASP-1/2 — C4 — C2 — same C3 convertase. Terminal pathway: C3 convertase — C3a + C3b. C5 convertase (C4b2a3b or C3bBbC3b) — C5a + C5b. C5b + C6 + C7 + C8 + multiple C9 = membrane attack complex (MAC), forming pores that lyse bacteria (especially Neisseria). Regulatory proteins: C1-INH (inhibits C1r/s, MASP), Factor H (inhibits alternative), Factor I (cleaves C3b/C4b), CD55/DAF, CD59 (blocks MAC), C4BP, vitronectin, clusterin.
Neutrophils: Most abundant WBC. First responders. Phagocytosis, degranulation, NETs. Macrophages: Tissue-resident (Kupffer cells, alveolar macrophages, microglia). M1 (pro-inflammatory) vs M2 (anti-inflammatory). Dendritic Cells (DCs): Professional APCs. Bridge innate and adaptive. NK Cells: Kill virus-infected and tumor cells (lacking MHC I). ADCC via CD16. Eosinophils: Anti-helminth, allergic inflammation (Th2, IL-5). Basophils & Mast Cells: Degranulation (histamine, heparin, tryptase, leukotrienes) — allergic reactions, anaphylaxis.
Interleukins: IL-1α/β (fever, inflammation), IL-2 (T-cell growth), IL-4 (Th2, IgE), IL-5 (eosinophil activation), IL-6 (B-cell differentiation, acute phase), IL-7 (lymphocyte development), IL-8/CXCL8 (neutrophil chemotaxis), IL-10 (anti-inflammatory, Treg), IL-12 (Th1 differentiation), IL-13 (Th2, mucus), IL-15 (NK development), IL-17A/F (Th17, neutrophil recruitment), IL-21 (Tfh), IL-22 (epithelial defense), IL-23 (Th17 maintenance). Interferons: Type I (IFN-α/β: antiviral), Type II (IFN-γ: macrophage activation), Type III (IFN-λ: mucosal antiviral). TNF superfamily: TNF-α (cachexia, fever), FasL, CD40L. TGF-β: Anti-inflammatory, Treg. Chemokines: CC (CCL2/MCP-1), CXC (CXCL8/IL-8). Acute Phase Reactants: CRP, SAA, ferritin, haptoglobin, fibrinogen, complement (C3, C4), procalcitonin.
T-cell development: Bone marrow → thymus. Positive & negative selection. AIRE drives tissue-specific antigen expression for negative selection. CD4+ (Helper) T-cell subsets: Th1 (T-bet, IFN-γ: intracellular pathogens). Th2 (GATA3, IL-4, IL-5, IL-13: helminths, allergy). Th17 (RORγt, IL-17: extracellular bacteria/fungi). Tfh (Bcl6, IL-21: germinal center). Treg (FoxP3, IL-10, TGF-β: suppression). CD8+ (Cytotoxic) T cells: Perforin/granzymes, FasL. TCR: αβ heterodimer + CD3 complex. Signal 1 (TCR:MHC-peptide), Signal 2 (CD28:CD80/86), Signal 3 (cytokine polarization). Anergy: TCR signal without costimulation.
B-cell development: Bone marrow (VDJ recombination). Immature → spleen. BCR: Membrane IgM/IgD + Igα/Igβ. Activation: TD (Tfh help: CD40:CD40L, CSR, SHM, affinity maturation) vs TI (polysaccharide). Plasma cells: Antibody factories. Memory B cells: Rapid recall. Antibodies: IgG (opsonization, complement, crosses placenta). IgA (mucosal, dimeric). IgM (pentamer, complement, primary response). IgE (mast cell degranulation, helminth). IgD (BCR). Monoclonal antibodies: -ximab (chimeric), -zumab (humanized), -umab (human).
MHC Class I (HLA-A, -B, -C): All nucleated cells. Endogenous peptides → CD8+ T cells. Proteasome, TAP1/TAP2. MHC Class II (HLA-DR, -DP, -DQ): APCs. Exogenous peptides → CD4+ T cells. Invariant chain, HLA-DM. Cross-presentation: DCs present exogenous antigen on MHC I. MHC Class III: Complement (C2, C4, Factor B), TNF. HLA polymorphism: Associated with autoimmune disease (HLA-B27 → ankylosing spondylitis, HLA-DR4 → RA, HLA-DQ2/DQ8 → celiac).
Type I (IgE) • Type II (Ab-Mediated) • Type III (Immune Complex) • Type IV (Delayed) • Type V (Stimulatory)
Mechanism: Allergen exposure → sensitization (Th2, IL-4, IgE) → mast cell/basophil FcεRI crosslinking → degranulation (histamine, tryptase, heparin) → new synthesis (leukotrienes LTC4/LTD4/LTE4, PGD2, PAF, cytokines). Immediate phase (15-30min): Histamine-mediated vasodilation, bronchoconstriction, increased vascular permeability. Late phase (6-24h): Eosinophil/neutrophil infiltration. Clinical syndromes: Anaphylaxis (systemic: urticaria, angioedema, bronchospasm, hypotension). Allergic rhinitis, asthma, food allergy, atopic dermatitis, venom allergy, drug allergy. Diagnosis: Skin prick test, serum specific IgE. Treatment: Avoidance, H1 antihistamines, intranasal corticosteroids, LTRA, omalizumab (anti-IgE), epinephrine auto-injector, immunotherapy (SCIT, SLIT).
IgG/IgM bind cell surface antigens → complement (C1q → MAC), opsonization (FcγR), ADCC (NK), antibody-mediated cellular dysfunction. AIHA: Warm (IgG, extravascular) vs Cold (IgM, intravascular, complement). Goodpasture: Anti-GBM antibodies (α3 collagen IV) → crescentic GN + pulmonary hemorrhage. Myasthenia Gravis: Anti-AChR (post-synaptic NMJ). ITP: Anti-GPIIb/IIIa. Graves (Type V): Anti-TSHR stimulatory → hyperthyroidism. Bullous pemphigoid: Anti-BP180/230. Pemphigus vulgaris: Anti-desmoglein 3 → acantholysis. Acute rheumatic fever: Molecular mimicry. Drug-induced hemolysis: Penicillin (hapten), methyldopa (autoantibody).
Antigen-antibody (IgG/IgM) complexes deposit in tissues → complement activation (C5a recruits neutrophils) → degranulation → tissue damage. Serum Sickness: Systemic immune complexes from foreign proteins (e.g., ATG, rituximab, penicillin). Fever, rash, arthralgia, lymphadenopathy, nephritis 7-14 days after exposure. Self-limited. SLE: ANA, anti-dsDNA, anti-Sm. Immune complex deposition in kidneys (lupus nephritis), skin, joints, serosa, CNS. PSGN: 2-3wk after group A Strep. Subepithelial deposits (lumpy-bumpy IF). Low C3. Arthus reaction: Local immune complex vasculitis after injection. PAN: Necrotizing vasculitis, HBV-associated. Mixed cryoglobulinemia: HCV-associated, vasculitis, purpura, GN. Hypersensitivity pneumonitis: Farmer’s lung, bird fancier’s lung (Type III + IV).
CD4+ Th1 (IFN-γ, macrophage activation) or CD8+ CTL (direct killing). Peaks 24-72h. Contact dermatitis: Poison ivy, nickel (CD8+). Topical corticosteroids. PPD (Mantoux): TB antigen, induration at 48-72h. Multiple Sclerosis: Autoimmune CNS demyelination (Th1/Th17). Type 1 Diabetes: CD8+ CTL destroy pancreatic β-cells. GvHD: Donor T cells attack recipient. RA: Th1/Th17 synovitis. Crohn’s: Th1/Th17 transmural inflammation. Granuloma formation: Chronic DTH. Caseating (TB) vs non-caseating (sarcoid, Crohn’s).
Antibodies bind and stimulate cell surface receptors. Graves disease: TSI (TSH receptor stimulatory Ig). Anti-insulin receptor: Type B insulin resistance. Note: Some classify as subset of Type II.
Central Tolerance • Peripheral Tolerance • Breakdown Mechanisms • Autoantibodies • Connective Tissue Disease
T-cell (Thymus): Positive selection (self-MHC restriction). Negative selection (AIRE-driven clonal deletion). AIRE deficiency → APECED/APS-1. B-cell (Bone Marrow): Receptor editing, clonal deletion, or anergy for self-reactive B cells.
Anergy: TCR signal without costimulation (CTLA-4). Treg: FoxP3+ (IPEX: FoxP3 mutation → multi-organ autoimmunity). Immune privilege: Eye, brain, testis, placenta (FasL, TGF-β). AICD: Fas/FasL. ALPS (Fas defect → lymphadenopathy, autoantibodies).
Molecular Mimicry: Rheumatic fever (M protein cross-reacts with myosin). GBS (Campylobacter mimics gangliosides). Epitope Spreading: Initial response spreads to new self-epitopes (SLE, MS, T1D). Bystander Activation: Local inflammation activates self-reactive cells. Polyclonal Activation: Superantigens (TSST-1, enterotoxin). EBV polyclonal B-cell activation. Loss of Treg. HLA association: HLA-DR4 (RA), HLA-B27 (SpA), HLA-DQ2/DQ8 (celiac). Sex bias: Most autoimmune diseases more common in women.
SLE: Multi-system, ANA+ (95%), anti-dsDNA, anti-Sm, anti-Ro/SSA, anti-La/SSB. Malar rash, discoid, photosensitivity, arthritis, serositis, nephritis, cytopenias. RA: RF (70-80%), anti-CCP (more specific). Synovitis, pannus, joint destruction. Extra-articular: nodules, vasculitis, Felty, Caplan. Sjögren: Sicca, anti-Ro/SSA, anti-La/SSB. Lymphoma risk (MALT). Scleroderma: Limited (CREST: Calcinosis, Raynaud, Esophageal dysmotility, Sclerodactyly, Telangiectasia; anti-centromere) vs Diffuse (anti-Scl-70). Scleroderma renal crisis (ACEi). Dermatomyositis: Anti-Jo-1 (ILD). ANCA Vasculitis: GPA (c-ANCA/PR3), MPA (p-ANCA/MPO), EGPA (p-ANCA + asthma + eosinophilia). Anti-GBM: Goodpasture (linear IF). Sarcoidosis: Non-caseating granulomas, BHL, uveitis, erythema nodosum. Elevated ACE, hypercalcemia. IBD: Crohn’s (ASCA) vs UC (pANCA).
ANA: Screening (95% SLE). Patterns: homogeneous (anti-dsDNA), speckled (ENA), nucleolar (Scl-70), centromere (CREST), peripheral (anti-dsDNA). ENAs: Anti-dsDNA (SLE, nephritis). Anti-Sm (specific SLE). Anti-Ro/SSA (SLE, Sjögren, neonatal lupus). Anti-La/SSB (Sjögren). Anti-RNP (MCTD). Anti-Jo-1 (myositis + ILD). Anti-Scl-70 (diffuse scleroderma). Anti-centromere (CREST). Anti-histone (drug-induced lupus). RF: IgM anti-IgG Fc. Not specific. Anti-CCP: Highly specific for RA. ANCA: c-ANCA/PR3 (GPA), p-ANCA/MPO (MPA, EGPA). Anti-GBM: Goodpasture. Anti-phospholipid: Lupus anticoagulant, anticardiolipin, anti-β2GP1. Triple positive = highest thrombotic risk.
Primary • Secondary • SCID • CVID • DiGeorge • XLA • CGD • HIV/AIDS • Diagnosis
SCID: Absent T cells, absent antibodies. Presents in first months with failure to thrive, severe infections (PCP, CMV, Candida). Subtypes: IL2RG (X-linked, most common), ADA deficiency, RAG1/2 (Omenn syndrome), JAK3, Artemis. Diagnosis: absent CD3+ (<300/μL), low TRECs (newborn screen). Treatment: HSCT (urgent), gene therapy (ADA, IL2RG), PEG-ADA. No live vaccines. Irradiated blood products. DiGeorge (22q11.2 deletion): Thymic aplasia + cardiac defects + hypocalcemia + dysmorphic facies + cleft palate. T-cell deficiency variable. WAS: WASP mutation. Eczema + small-platelet thrombocytopenia + recurrent infections + lymphoma risk. HSCT. Ataxia-telangiectasia: ATM mutation. Ataxia, telangiectasias, IgA deficiency, radiosensitivity, lymphoma. Elevated AFP.
XLA (Bruton): BTK mutation. Recurrent sinopulmonary bacteria starting ~6mo. Absent B cells (CD19+ <2%), pan-hypogammaglobulinemia, absent tonsils/lymph nodes. IVIG lifelong. CVID: Most common symptomatic PID. Low IgG + low IgA ± IgM, poor vaccine responses. Recurrent infections, bronchiectasis, autoimmunity (ITP, AIHA), granulomas, lymphoma risk. IVIG. Hyper-IgM: CD40L (X-linked) or CD40, AID, UNG defects. Normal/high IgM, low IgG/A/E. PCP, Cryptosporidium (sclerosing cholangitis). IVIG, HSCT. IgA deficiency: Most common (1:500). Often asymptomatic. Anaphylaxis to blood products.
CGD: NADPH oxidase defect. Catalase-positive infections (Staph, Serratia, Burkholderia, Nocardia, Aspergillus). Abscesses, granulomas. DHR flow cytometry test. Prophylaxis: TMP-SMX + itraconazole + IFN-γ. HSCT. LAD I: CD18/β2 integrin mutation. Delayed cord separation, infections without pus. High WBC. Chediak-Higashi: LYST mutation. Giant lysosomal granules, partial albinism, neuropathy, HLH.
Pathogenesis: HIV infects CD4+ T cells via CD4 + CCR5/CXCR4. Reverse transcriptase → proviral DNA → integrase → latent reservoir. Progressive CD4 depletion. Stages: Acute seroconversion (fever, pharyngitis, lymphadenopathy, rash), latency, AIDS (CD4 <200). Diagnosis: 4th-gen Ag/Ab combo → confirmatory differentiation assay. ART: NRTI (tenofovir/emtricitabine) + INSTI (dolutegravir, bictegravir). U=U. OI Prophylaxis: CD4 <200: TMP-SMX (PCP). CD4 <100: azithromycin (MAC). CD4 <50: valganciclovir (CMV). IRIS: Do not stop ART. Treat OI. Steroids if severe.
Malnutrition: Impaired T-cell function. Chemotherapy/Immunosuppressants: Corticosteroids, rituximab (B-cell depletion), alemtuzumab. Splenectomy: Encapsulated bacteria risk (S. pneumo, H. flu, N. meningitidis). OPSI. Vaccinate pre-splenectomy. Penicillin prophylaxis. Diabetes: Impaired neutrophil function. Renal failure, cirrhosis, burns. Immunosenescence: Age-related decline.
HLA Matching • Crossmatch • PRA • Rejection Types • GvHD • Immunosuppression • Tolerance
HLA (Chromosome 6p21): Class I (A, B, C: all nucleated cells). Class II (DR, DP, DQ: APCs). Highly polymorphic. PRA (Panel Reactive Antibodies): % of panel recognized by recipient serum. Sensitization from transfusion, pregnancy, prior transplant. High PRA = difficult crossmatch. DSA (Donor-Specific Antibodies): Pre-existing or de novo anti-HLA. Risk of antibody-mediated rejection. Crossmatch: CDC vs flow cytometry. Positive = hyperacute rejection risk (contraindication unless desensitization).
Hyperacute: Minutes-hours. Preformed antibodies. Irreversible. Prevention: ABO compatibility + negative crossmatch. Acute TCMR: Days-weeks. CD4+ (IFN-γ) + CD8+ CTL infiltrate. Fever, graft tenderness, rising Cr. Biopsy: tubulitis, arteritis (Banff). Treatment: pulse steroids (methylprednisolone 250-500mg x3), ATG for steroid-resistant. Acute AMR: DSA-mediated. C4d deposition, microvascular injury. Treatment: plasmapheresis, IVIG, rituximab, bortezomib, eculizumab. Chronic rejection: Months-years. IFTA, transplant glomerulopathy, arteriosclerosis, C4d+. Irreversible.
Acute GvHD (<100d): Skin (rash), liver (cholestasis), GI (diarrhea). Prophylaxis: CNI + MTX/MMF, PTCy. Treatment: steroids (methylprednisolone 1-2 mg/kg). Steroid-refractory: ruxolitinib, ATG, ECP. Chronic GvHD (>100d): Lichenoid/sclerodermatous skin, sicca, BO, GI, myositis. Treatment: steroids + CNI, rituximab, ibrutinib, ruxolitinib.
Induction: Basiliximab (anti-CD25), ATG (anti-thymocyte), alemtuzumab (anti-CD52), belatacept (CTLA4-Ig). Maintenance: CNIs (tacrolimus first-line, cyclosporine). Side effects: nephrotoxicity, HTN, neurotoxicity, DM (tacrolimus), hirsutism/gingival hyperplasia (cyclosporine). TDM required. Antiproliferatives: MMF (IMPDH inhibitor), azathioprine. mTOR inhibitors: sirolimus, everolimus. Side effects: delayed wound healing, mouth ulcers, hyperlipidemia, proteinuria, pneumonitis. Corticosteroids (low-dose maintenance). Desensitization: IVIG, rituximab, plasmapheresis, bortezomib, imlifidase.
Immunoediting • Tumor Antigens • Evasion • Checkpoint Inhibitors • CAR-T • BiTEs • Vaccines
Elimination (Surveillance): NK cells, CTLs, DCs eliminate transformed cells. Evidence: increased cancer in immunosuppressed. Equilibrium: Immune system controls tumor without elimination. Darwinian selection of less immunogenic clones. Escape: MHC I loss, PD-L1 expression, Treg/MDSC infiltration, IDO, adenosine, IL-10/TGF-β.
TSA: Mutated oncogenes (p53, RAS, BRAF V600E, EGFR vIII), fusion proteins (BCR-ABL, EML4-ALK), viral (HPV E6/E7, EBV). TAA: Cancer-testis (NY-ESO-1, MAGE-A3), differentiation (tyrosinase, gp100, HER2, CEA, AFP). Neoantigens: Personal, mutation-derived, higher load = better checkpoint response. Evasion mechanisms: MHC I loss, PD-L1/PD-1 axis, CTLA-4, Treg (CCL22/CCR4), MDSCs, IDO (tryptophan depletion), TGF-β/IL-10, adenosine (CD39/CD73 → A2A receptor), T-cell exhaustion (PD-1, TIM-3, LAG-3, TIGIT).
Anti-PD-1: Pembrolizumab (melanoma, NSCLC, HNSCC, MSI-high, etc). Nivolumab (similar). Anti-PD-L1: Atezolizumab, durvalumab, avelumab. Anti-CTLA-4: Ipilimumab (melanoma, RCC, NSCLC combo). Combination: Nivo + ipi (higher response, more irAEs). LAG-3: Relatlimab + nivolumab (melanoma). Biomarkers: PD-L1 IHC (TPS/CPS), TMB, MSI/MMR, TILs. MSI-high = tissue-agnostic pembrolizumab approval. irAEs: Colitis, hepatitis, pneumonitis, myocarditis, endocrinopathies. Management: hold ICI, corticosteroids (1-2 mg/kg prednisone), infliximab for colitis, MMF for hepatitis. Hyperprogression: ~10%, paradoxical acceleration.
Structure: scFv + transmembrane + CD3ζ + costimulatory domain (CD28 or 4-1BB). FDA-approved: Tisagenlecleucel (CD19, B-ALL, DLBCL). Axicabtagene ciloleucel (CD19, DLBCL, FL, MCL). Brexucabtagene (CD19, MCL, B-ALL). Lisocabtagene (CD19, LBCL). Idecabtagene vicleucel (BCMA, MM). Ciltacabtagene (BCMA, MM). CRS: IL-6 mediated. Tocilizumab + steroids. Grading 1-4. ICANS: Encephalopathy, aphasia, seizure, cerebral edema. Steroids, supportive. TLS: Hyperuricemia, hyperkalemia, AKI. B-cell aplasia: On-target off-tumor. IVIG.
BiTEs: Blinatumomab (CD3 x CD19, B-ALL). Teclistamab (CD3 x BCMA, MM). Mosunetuzumab/Glofitamab/Epcoritamab (CD3 x CD20, lymphoma). Cancer vaccines: Sipuleucel-T (PAP-GM-CSF, prostate cancer). Neoantigen mRNA vaccines (in trials). Oncolytic viruses: T-VEC (HSV-1 + GM-CSF, intratumoral for melanoma). Cytokines: High-dose IL-2 (melanoma, RCC). IFN-α (adjuvant). BCG: Intravesical for NMIBC.
Active vs Passive • Types • Adjuvants • Herd Immunity • Schedule • Specific Vaccines
Live attenuated: MMR, varicella, zoster (live), rotavirus, BCG, yellow fever, oral polio, nasal influenza. Contraindicated: immunodeficiency, pregnancy. Inactivated: IPV, influenza (injectable), rabies, HAV, JEV. Subunit/Recombinant: HBV, HPV, acellular pertussis. Toxoid: Tetanus, diphtheria. Conjugate: Hib, PCV13/15/20, MenACWY. Works in infants (T-dependent). mRNA: COVID-19 (Pfizer, Moderna). Lipid nanoparticle. Viral Vector: COVID-19 (J&J, AstraZeneca). VLP: HPV (Gardasil 9), HBV.
Passive: Maternal IgG (transplacental), IVIG, hyperimmune globulin (HBIG, VZIG, TIG, RIG, palivizumab). Monoclonal antibodies (nirsevimab for RSV). Adjuvants: Alum (Th2, depot). MF59 (Fluad, Th1/Th2). AS04 (alum + MPL, HBV/HPV). AS01 (MPL + QS-21, Shingrix, Mosquirix). CpG 1018 (TLR9, Heplisav-B). Matrix-M (Novavax). Herd immunity: Threshold depends on R0 (measles ~95%, polio ~80%, COVID ~70%).
Birth: HepB #1. 2mo: HepB #2, DTaP #1, IPV #1, PCV #1, Hib #1, RV #1. 4mo: DTaP #2, IPV #2, PCV #2, Hib #2, RV #2. 6mo: HepB #3, DTaP #3, IPV #3, PCV #3, Hib #3, RV #3, influenza. 12-15mo: MMR #1, varicella #1, PCV #4, Hib #4, HepA #1. 18mo: DTaP #4. 4-6y: DTaP #5, IPV #4, MMR #2, varicella #2. 11-12y: Tdap, HPV (2-3 doses), MenACWY #1, MenB. Adults: Influenza annually, Tdap x1 then Td q10yr, HPV catch-up, PCV20 (65+), Shingrix (50+), HepB (all <60), COVID-19 annual. Travel: Yellow fever, typhoid, cholera, rabies, JEV, MenACWY (Hajj).
BCG: Live M. bovis. Protects against disseminated TB in children. Contraindicated: immunodeficiency (disseminated BCG-itis). PPD+ after BCG. MMR: Live. Two doses. CI: pregnancy, immunodeficiency, recent IVIG. DTaP/Tdap: Acellular pertussis. DTaP pediatric, Tdap booster. HPV: 9-valent (Gardasil 9). L1 VLP. Prevents cervix, anus, oropharynx, penile, vulvar, vaginal cancers and warts. Age 9-26 (catch-up to 45). COVID-19: mRNA (Pfizer, Moderna), viral vector (J&J), protein subunit (Novavax). Updated annually. Pneumococcal: PCV13/15/20 (conjugate) + PPSV23 (polysaccharide) for 65+ and high-risk. Zoster: Shingrix (recombinant adjuvanted, 2 doses, 50+), superior to Zostavax. Influenza: Annual. IIV, LAIV (FluMist), high-dose (Fluzone HD, 65+), adjuvanted (Fluad).
Allergic Rhinitis • Asthma • Atopic Dermatitis • Food Allergy • Urticaria • Drug Allergy • Anaphylaxis
Allergic Rhinitis: Seasonal vs Perennial. IgE-mediated. Sneezing, rhinorrhea, congestion, pruritus, conjunctivitis. Treatment: intranasal corticosteroids (first-line), oral/intranasal H1 antihistamines, LTRA (montelukast), immunotherapy (SCIT/SLIT). Add-on: saline rinses, ipratropium. Asthma: Chronic Th2 airway inflammation + bronchial hyperresponsiveness. Atopic (allergen-triggered) vs Non-atopic. AERD (Samter triad: asthma + nasal polyps + NSAID sensitivity). Diagnosis: spirometry (reversibility ≥12%), FeNO. Treatment (GINA steps): Step 1-2: low-dose ICS-formoterol as needed (SMART). Step 3: medium-dose ICS-formoterol. Step 4: high-dose ICS-formoterol + LAMA/LTRA. Step 5: add biologics (omalizumab anti-IgE, mepolizumab/benralizumab anti-IL-5, dupilumab anti-IL-4R, tezepelumab anti-TSLP). Acute: SABA, ipratropium, systemic steroids, O2, MgSO4, NIV. Biologics: Omalizumab (allergic asthma, chronic urticaria). Mepolizumab/Benralizumab (eosinophilic asthma, ≥150 eos). Dupilumab (asthma, AD, EoE, nasal polyps, prurigo nodularis). Tezepelumab (severe asthma, phenotype-agnostic).
Atopic Dermatitis: Barrier defect (filaggrin mutation) + Th2/Th22 inflammation. Pruritus, flexural lichenification, chronic relapsing. Treatment: emollients, topical corticosteroids, topical calcineurin inhibitors (tacrolimus, pimecrolimus), crisaborole (PDE4i), dupilumab, upadacitinib/baricitinib/abrocitinib (JAKi), phototherapy, cyclosporine. Food Allergy: IgE-mediated (immediate anaphylaxis) vs Non-IgE (FPIES, EoE). Common: peanut, tree nuts, shellfish, milk, egg, soy, wheat. Diagnosis: specific IgE, skin prick, oral food challenge. Component-resolved diagnostics (Ara h 2 for peanut). Management: avoidance, epinephrine auto-injector. OIT (Palforzia for peanut). EoE: Dysphagia, food impaction. Biopsy ≥15 eos/HPF. PPI, swallowed topical steroids (fluticasone, budesonide), dietary elimination, dupilumab.
Urticaria: Wheals. Acute (<6wk) vs Chronic (≥6wk). CSU: autoimmune (anti-FcεRI). Treatment: H1 antihistamines (up to 4x), omalizumab, cyclosporine. Angioedema: Mast cell-mediated (with urticaria, responds to H1) vs Bradykinin-mediated (HAE, no urticaria, no response to antihistamines/epinephrine). Drug Allergy: β-lactams (10% report, <1% true). Penicillin skin test + oral challenge. Cephalosporin cross-reactivity low. Sulfonamides (SJS/TEN, DRESS). NSAIDs (AERD, urticaria). Chemotherapeutics. Monoclonal antibodies (infusion reactions). Desensitization: temporary tolerance, drug must be continued. Venom Allergy: Hymenoptera stings. Large local vs systemic anaphylaxis. VIT (SCIT 3-5 years). Anaphylaxis: Epinephrine IM (0.3-0.5mg, anterolateral thigh) first-line. Repeat q5-15min. ABC, O2, IV fluids, H1+H2 antihistamines, steroids. Observe 4-6h for biphasic. Discharge with epinephrine auto-injector + action plan.
Complement Deficiencies • HAE • PNH • aHUS • Cryoglobulinemia • FMF • Autoinflammatory Syndromes
Classical (C1q, C4, C2): SLE-like disease. C1q deficiency → virtually 100% SLE. C2 deficiency most common, SLE + infections. Alternative (Factor D, B, Properdin): Neisseria. Lectin (MBL, MASP-2): MBL deficiency common, mild infection risk. Terminal (C5-9): Recurrent Neisseria (no MAC). Vaccinate MenB, MenACWY. Prophylactic antibiotics. Regulatory: Factor H/I/MCP → aHUS. C1-INH → HAE. CD59 → PNH-like. Diagnosis: CH50 (screens classical/terminal), AH50 (alternative), C3, C4 levels.
AD, C1-INH deficiency (Type 1, 85%) or dysfunction (Type 2, 15%). Uncontrolled bradykinin (kallikrein → HMWK → bradykinin → B2 receptor). Recurrent subcutaneous/mucosal swelling without urticaria. Face, larynx (airway compromise), extremities, GI (pain, vomiting). Triggers: stress, trauma, surgery, estrogen, ACEi. Diagnosis: low C4, low C1-INH antigen (Type 1) or low function (Type 2). Acute: C1-INH (Berinert 20 U/kg IV), icatibant (B2 antagonist 30mg SC), ecallantide (kallikrein inhibitor 30mg SC). Prophylaxis: Danazol (androgen, increases C1-INH), lanadelumab (anti-kallikrein mAb), berotralstat (oral kallikrein inhibitor), IV C1-INH (Cinryze). Do NOT use antihistamines/epinephrine/steroids for HAE. ACEi-induced angioedema: Bradykinin-mediated. Icatibant, ecallantide, C1-INH.
PNH: PIG-A mutation → lost GPI anchors (CD55/CD59). Intravascular hemolysis (dark AM urine), thrombosis (Budd-Chiari), smooth muscle dystonia, BM failure. Diagnosis: flow cytometry (FLAER, CD55/CD59). Treatment: eculizumab/ravulizumab (anti-C5). Vaccinate for Neisseria before starting. Pegcetacoplan (C3i). Iptacopan (Factor Bi). aHUS: Uncontrolled alternative pathway (Factor H/I/MCP mutations, C3/FB gain-of-function, anti-FH Ab). TMA: MAHA (schistocytes, high LDH, low haptoglobin), thrombocytopenia, AKI. Not TTP (normal ADAMTS13) or STEC-HUS (no diarrhea). Treatment: eculizumab (first-line). Plasma exchange as bridge.
Cryoglobulinemia: Type I (monoclonal IgM/IgG: hematologic). Type II/III (mixed: monoclonal/polyclonal RF + IgG, HCV-associated). Purpura, arthralgia, neuropathy, GN, Raynaud. Low C4. RF+. Treatment: HCV DAA + rituximab for vasculitis. FMF: MEFV mutation (pyrin). Recurrent fever + serositis (peritonitis, pleuritis) + erysipelas-like rash + arthritis + AA amyloidosis. Treatment: colchicine (first-line, prevents amyloidosis). IL-1i (anakinra, canakinumab) for refractory. CAPS: NLRP3 mutation. FCAS, Muckle-Wells, CINCA/NOMID. IL-1i. PFAPA: Periodic fever in children. Steroids abort attacks. TRAPS: TNFRSF1A. Etanercept, IL-1i. HIDS/MKD: MVK mutation. Elevated IgD. SAPHO: NSAIDs, TNFi, bisphosphonates.
ELISA • Flow Cytometry • Western Blot • Immunofluorescence • Coombs • SPEP • HLA Typing • ANA Patterns
ELISA: Direct, Indirect, Sandwich, Competitive. Colorimetric/chemiluminescent detection. ELISpot: Single-cell cytokine secretion (IFN-γ for TB, vaccine immunogenicity). Western Blot: SDS-PAGE + transfer + antibody detection. Confirmatory for HIV, Lyme. IHC: Antigen detection in tissue (HER2, PD-L1, CD markers). Immunofluorescence: Direct (kidney biopsy for IgG, IgA, IgM, C3, C1q). Indirect (ANA, anti-dsDNA on Crithidia, ANCA, anti-GBM). Lateral Flow: Rapid tests (COVID-19 Ag, hCG, Strep A, HIV). RIA: Competitive binding with radio-labeled antigen. Luminex: Bead-based multiplex. Cytokines, HLA antibodies (single antigen beads for DSA). CyTOF: Mass cytometry, 40+ parameters. Deep immune profiling.
Cells in suspension, fluorochrome-conjugated antibodies, laser detection. FSC (size), SSC (granularity), fluorescence. Applications: CD4 count (HIV), leukemia/lymphoma diagnosis (CLL: CD5+, CD19+, CD23+; Burkitt: CD10+, CD19+, CD20+, Ki67 >95%; AML: CD13, CD33, CD34, CD117; ALL: CD10, CD19, CD20, TdT). MRD: Detect <0.01% leukemic cells. PNH: FLAER/CD55/CD59 on granulocytes/monocytes. FACS: Cell sorting. Intracellular staining: Cytokines, phospho-flow.
SPEP: M-spike in myeloma, MGUS, Waldenström. Immunofixation (IFE): Confirms Ig type (IgG, IgA, IgM, κ, λ). Free light chains (Freelite): κ/λ ratio. Coombs Test: DAT (direct: IgG/C3 on RBCs → AIHA). IAT (indirect: anti-RBC in serum, antibody screen/crossmatch). ANA: HEp-2 IF. Patterns: homogeneous (anti-dsDNA), speckled (ENA), nucleolar (Scl-70), centromere (CREST), peripheral (anti-dsDNA). ANCA: IF (c-ANCA cytoplasmic, p-ANCA perinuclear) + ELISA (PR3, MPO). Anti-CCP: Specific for RA. RF: IgM anti-IgG Fc. ENA panel: dsDNA, Sm, Ro, La, RNP, Jo-1, Scl-70, centromere. Anti-phospholipid: Lupus anticoagulant (dRVVT), anticardiolipin, anti-β2GP1. Quantitative Igs: IgG, IgA, IgM.
HLA Typing: PCR-SSO (Luminex beads), PCR-SSP (allele-specific primers), NGS (high-resolution, 4-field/8-field). Applications: transplant matching, disease association (B27, DR4, DQ2/DQ8). DSA screening by single antigen beads. cPRA. Cellular assays: Lymphocyte proliferation (mitogen PHA, antigen tetanus). Cytokine assays (ELISA, ELISpot, CBA). Neutrophil function: DHR flow (CGD). Complement: CH50, AH50, C3, C4, C1-INH activity. Lymphocyte subsets: CD3, CD4, CD8, CD19, CD56/16. TRECs: Newborn SCID screen. Vaccine antibody responses: Specific IgG after vaccination. Specific IgE (ImmunoCAP). Tryptase: Mastocytosis, anaphylaxis.