Clinical Immunology

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.

1. Innate and Adaptive Immunity

PAMPs/DAMPs PRRs Complement Cytokines T Cells B Cells Antibodies MHC

Innate Immunity Overview
  • 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.
Complement System
  • 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.
Phagocytes and Innate Effector Cells
  • 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 and Mast Cells: Degranulation (histamine, heparin, tryptase, leukotrienes) - allergic reactions, anaphylaxis.
Cytokines and Chemokines
  • 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.
Adaptive Immunity: T Cells
  • T-cell development: Bone marrow -> thymus.
  • Positive and 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.
Adaptive Immunity: B Cells and Antibodies
  • 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 and Antigen Presentation
  • 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).
High-Yield Pearls
  • Three complement pathways converge on C3. Classical = C1qrs -> C4 -> C2. Alternative = spontaneous C3(H2O) + Factor B/D. Lectin = MBL + MASP.
  • Th1 fights intracellular pathogens; Th2 fights helminths and drives allergy; Th17 fights extracellular bacteria/fungi.
  • Treg (FoxP3) essential for self-tolerance. IPEX syndrome = FoxP3 mutation -> multi-organ autoimmunity.
  • MHC I presents endogenous antigen to CD8 T cells; MHC II presents exogenous antigen to CD4 T cells.
  • IgG crosses placenta. IgA is dimeric for mucosal surfaces. IgM is first Ab in primary response.
  • AIRE mutation -> APECED (APS-1): candidiasis, hypoparathyroidism, adrenal insufficiency.
Red Flags
  • Neisseria infections suggest terminal complement deficiency (C5-9). Check CH50.
  • Recurrent sinopulmonary infections + low IgG/A/M = CVID. Check immunoglobulins, vaccine responses.
  • SCID: presents in infancy with failure to thrive, severe infections, absent T cells. No live vaccines.
  • Checkpoint inhibitor toxicity can cause autoimmune-like reactions in any organ (colitis, pneumonitis, myocarditis).
  • Hyper-IgM syndrome: normal/high IgM with low IgG/A/E = CD40L defect (X-linked).

2. Hypersensitivity Reactions

Type I (IgE) Type II (Ab-Mediated) Type III (Immune Complex) Type IV (Delayed) Type V (Stimulatory)

Type I: IgE-Mediated (Immediate Hypersensitivity)
  • 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).
Type II: Antibody-Mediated (Cytotoxic)
  • 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).
Type III: Immune Complex-Mediated
  • 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).
Type IV: Delayed-Type (T-Cell Mediated)
  • 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).
Type V: Stimulatory
  • 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.
High-Yield Pearls
  • Type I = IgE + mast cells (anaphylaxis, allergic rhinitis, asthma, food allergy). Epinephrine first-line for anaphylaxis.
  • Type II = IgG/IgM against cell surface antigens (AIHA, Goodpasture, MG, ITP, Graves Type V). Direct Coombs for AIHA.
  • Type III = immune complex deposition (SLE, PSGN, serum sickness, cryoglobulinemia). Low complement C3/C4 in active SLE.
  • Type IV = T-cell mediated (contact dermatitis, PPD, MS, T1D, GvHD, Crohn's). No antibodies involved.
  • Type V = stimulatory antibodies (Graves TSI). Functional activation, not cell destruction.
  • Anaphylaxis: IM epinephrine (0.3-0.5mg, anterolateral thigh) first-line. Delay is fatal.
Red Flags
  • Anaphylaxis: IM epinephrine immediately. Do not rely on antihistamines alone. Biphasic reaction in 20%.
  • SJS/TEN: drug hypersensitivity. Stop all suspect drugs. Life-threatening.
  • DRESS Syndrome: fever, rash, eosinophilia, lymphadenopathy, organ involvement.
  • Acute interstitial nephritis (drug-induced): NSAIDs, penicillin, PPI. Fever, rash, eosinophiluria.
  • Serum sickness: 7-14 days after biologic therapy. Urticaria, arthralgia, fever.

3. Autoimmunity and Tolerance

Central Tolerance Peripheral Tolerance Breakdown Mechanisms Autoantibodies Connective Tissue Disease

Central Tolerance
  • 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.
Peripheral Tolerance
  • 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).
Breakdown Mechanisms
  • 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.
Major Autoimmune Diseases
  • 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).
Key Autoantibodies
  • 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.
High-Yield Pearls
  • ANA positive in 95% of SLE. ENA panel for sub-typing.
  • Anti-dsDNA correlates with SLE disease activity and lupus nephritis.
  • Anti-CCP more specific than RF for RA.
  • Drug-induced lupus: hydralazine, procainamide, isoniazid. Anti-histone+. Resolves on withdrawal.
  • HLA-B27: ankylosing spondylitis, reactive arthritis, psoriatic arthritis, IBD, uveitis.
Red Flags
  • Lupus nephritis: Class III/IV requires aggressive immunosuppression (steroids + MMF or cyclophosphamide).
  • Scleroderma renal crisis: abrupt HTN + AKI. ACEi lifesaving. Avoid high-dose steroids.
  • SLE + thrombosis + pregnancy loss = antiphospholipid syndrome. Triple therapy in pregnancy.
  • ANCA vasculitis with RPGN or pulmonary hemorrhage: emergency. Pulse steroids + rituximab/cyclophosphamide.
  • Anti-Jo-1 + antisynthetase syndrome: high risk of rapidly progressive ILD.

4. Immunodeficiency

Primary Secondary SCID CVID DiGeorge XLA CGD HIV/AIDS Diagnosis

T-Cell and Combined Immunodeficiencies
  • 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+ ( 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.
B-Cell and Antibody Deficiencies
  • XLA (Bruton): BTK mutation.
  • Recurrent sinopulmonary bacteria starting ~6mo.
  • Absent B cells (CD19+ 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.
Phagocyte Defects
  • 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.
HIV/AIDS
  • 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 Diagnosis: 4th-gen Ag/Ab combo -> confirmatory differentiation assay. ART: NRTI (tenofovir/emtricitabine) + INSTI (dolutegravir, bictegravir). U=U. OI Prophylaxis: CD4 IRIS: Do not stop ART.
  • Treat OI. Steroids if severe.
Secondary Immunodeficiency
  • 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.
High-Yield Pearls
  • SCID: absent T cells, TRECs absent. Emergency HSCT. No live vaccines.
  • DiGeorge: 22q11.2 deletion. CATCH-22.
  • XLA: recurrent sinopulmonary bacteria after 6mo. Absent B cells. IVIG.
  • CVID: low IgG + IgA, poor vaccine responses. Autoimmune + infectious complications. IVIG.
  • CGD: catalase-positive infections. DHR test. TMP-SMX + IFN-γ.
  • HIV: CD4 < 200 = PCP prophylaxis. U=U on ART. Check resistance test before ART.
Red Flags
  • SCID: NO live vaccines (MMR, rotavirus, BCG) -> fatal disseminated infection.
  • CVID + granulomatous disease: IVIG is treatment. Steroids may worsen infection risk.
  • Hyper-IgM: Cryptosporidium -> sclerosing cholangitis. Avoid contaminated water.
  • OPSI: fever + hypotension in splenectomized patient = emergency. Ceftriaxone + vancomycin.
  • HIV PrEP: tenofovir/emtricitabine daily. Check Cr, HBV serology. HIV test q3mo.

5. Transplant Immunology

HLA Matching Crossmatch PRA Rejection Types GvHD Immunosuppression Tolerance

HLA Matching and Antibody Screening
  • 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).
Types of Rejection
  • 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.
Graft-Versus-Host Disease (GvHD)
  • Acute GvHD ( 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.
Immunosuppressive Medications
  • 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.
High-Yield Pearls
  • Hyperacute rejection: preformed antibodies, minutes, irreversible. Prevented by ABO compatibility + negative crossmatch.
  • Acute TCMR: days-weeks. Pulse steroids, ATG for steroid-resistant.
  • Chronic rejection: fibrosis, transplant glomerulopathy. Poor response to treatment.
  • Tacrolimus trough 5-10 ng/mL (maintenance). Monitor levels.
  • GvHD prophylaxis: CNI + MTX/MMF. PTCy for haploidentical.
  • Belatacept: avoid in EBV-seronegative (PTLD risk).
Red Flags
  • Transplant + fever + rising Cr: rule out rejection, CMV, BK virus. Biopsy often needed.
  • CMV: D+/R- highest risk. Prophylaxis with valganciclovir.
  • BK polyomavirus nephropathy: BK viremia + rising Cr. Reduce immunosuppression.
  • CNI neurotoxicity: PRES (headache, seizure, vision changes, HTN). Reduce/stop CNI.
  • PTLD: EBV-driven. Reduce immunosuppression, rituximab.

6. Tumor Immunology

Immunoediting Tumor Antigens Evasion Checkpoint Inhibitors CAR-T BiTEs Vaccines

Cancer Immunoediting (Three E's)
  • 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.
Tumor Antigens and Evasion
  • 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).
Checkpoint Inhibitors
  • 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.
CAR-T Cells
  • 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 and Other Immunotherapies
  • 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.
High-Yield Pearls
  • Checkpoint inhibitors: anti-PD-1 (pembrolizumab, nivolumab), anti-PD-L1 (atezolizumab), anti-CTLA-4 (ipilimumab).
  • CAR-T: CD19 for B-ALL/DLBCL, BCMA for myeloma. CRS managed with tocilizumab.
  • MSI-high tumors respond to pembrolizumab regardless of tissue origin.
  • irAEs: hold ICI, give steroids. Infliximab for colitis.
  • Neoantigen load correlates with checkpoint response.
Red Flags
  • Checkpoint inhibitor myocarditis: rare but ~50% mortality. High-dose steroids, hold ICIs.
  • CAR-T CRS Grade 3-4: vasopressors, mechanical ventilation. Tocilizumab + steroids. ICU.
  • ICANS: aphasia, seizure, cerebral edema. Neuro assessment. Steroids.
  • ICI-induced colitis: check C. diff. Colonoscopy. Steroids, infliximab if refractory.

7. Vaccination

Active vs Passive Types Adjuvants Herd Immunity Schedule Specific Vaccines

Vaccine Types
  • 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 Immunization and Adjuvants
  • 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%).
Immunization Schedule (CDC/ACIP)
  • 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 Travel: Yellow fever, typhoid, cholera, rabies, JEV, MenACWY (Hajj).
Key Specific Vaccines
  • 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).
High-Yield Pearls
  • Live vaccines: MMR, varicella, zoster (live), rotavirus, BCG, yellow fever. CI in pregnancy and immunodeficiency.
  • Conjugate vaccines (PCV, Hib, MenACWY) work in infants. Polysaccharide (PPSV23) does not.
  • Shingrix (recombinant) > Zostavax (live) for shingles. 50+.
  • HPV vaccine prevents cervical cancer. Start age 9-12.
  • MMR CI: pregnancy, immunodeficiency (CD4 < 200), recent IVIG.
Red Flags
  • Anaphylaxis to vaccine component: CI to subsequent doses. Epinephrine at vaccination sites.
  • GBS within 6wk of influenza/tetanus vaccine: caution with future doses.
  • BCG in immunocompromised: fatal disseminated BCG-itis.
  • MMR + pregnancy: live virus. Avoid pregnancy 4wk after MMR.
  • Egg allergy no longer CI for influenza vaccine (except severe anaphylaxis with ICU).

8. Allergic and Atopic Disease

Allergic Rhinitis Asthma Atopic Dermatitis Food Allergy Urticaria Drug Allergy Anaphylaxis

Allergic Rhinitis and Asthma
  • 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 and Food Allergy
  • 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, Angioedema, Drug and Venom Allergy
  • Urticaria: Wheals. Acute ( = 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, 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.
High-Yield Pearls
  • Anaphylaxis: IM epinephrine is first-line. Do NOT delay. Antihistamines are adjunctive only.
  • Intranasal corticosteroids are first-line for allergic rhinitis.
  • AERD: asthma + nasal polyps + NSAID sensitivity. Avoid NSAIDs.
  • Dupilumab approved for AD, asthma, EoE, nasal polyps, prurigo nodularis.
  • Penicillin allergy: > 95% are not truly allergic on skin testing.
  • Chronic urticaria: H1 antihistamines up to 4x dose. Omalizumab for refractory.
Red Flags
  • Anaphylaxis: do NOT give oral antihistamines alone. IM epinephrine first. Biphasic in 20%.
  • SJS/TEN: stop all suspect drugs. ICU burn unit.
  • DRESS: fever, rash, eosinophilia, organ involvement. Stop culprit. Steroids.
  • Angioedema without urticaria + abdominal pain + FHx = HAE. Does NOT respond to antihistamines/epinephrine. Icatibant, ecallantide, C1-INH.
  • Latex allergy: HCW, spina bifida, multiple surgeries. Anaphylaxis risk. Latex-free equipment.

9. Complement and Inflammatory Disorders

Complement Deficiencies HAE PNH aHUS Cryoglobulinemia FMF Autoinflammatory Syndromes

Complement Deficiencies
  • 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.
Hereditary Angioedema (HAE)
  • 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 and aHUS
  • 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 and Autoinflammatory Syndromes
  • 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.
High-Yield Pearls
  • Terminal complement deficiency (C5-9): recurrent Neisseria. Vaccinate + prophylaxis.
  • HAE: bradykinin-mediated, no urticaria. Does NOT respond to antihistamines/epinephrine. Icatibant, ecallantide, C1-INH.
  • PNH: dark morning urine, thrombosis. Eculizumab/ravulizumab. Vaccinate for Neisseria.
  • aHUS: TMA + normal ADAMTS13 + no STEC. Eculizumab lifesaving.
  • FMF: colchicine first-line (prevents amyloidosis). IL-1i for refractory.
  • Cryoglobulinemia: HCV-associated. Treat DAA + rituximab.
Red Flags
  • HAE laryngeal edema: airway emergency. Icatibant or C1-INH immediately. Prepare for intubation.
  • PNH with thrombosis: start eculizumab + anticoagulation. High mortality without treatment.
  • aHUS: rapid diagnosis critical. Eculizumab. Plasma exchange as bridge.
  • Meningococcus on eculizumab: breakthrough despite vaccination. High suspicion.
  • Colchicine overdose: GI, multi-organ failure. Do not exceed 1.2mg/d in renal impairment.

10. Immunodiagnostics

ELISA Flow Cytometry Western Blot Immunofluorescence Coombs SPEP HLA Typing ANA Patterns

Immunoassays
  • 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.
Flow Cytometry and Immunophenotyping
  • 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 PNH: FLAER/CD55/CD59 on granulocytes/monocytes. FACS: Cell sorting.
  • Intracellular staining: Cytokines, phospho-flow.
Serum Protein and Autoantibody Testing
  • 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 and Functional Assays
  • 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.
High-Yield Pearls
  • ANA: 95% sensitive for SLE. Not specific. Patterns guide ENA testing.
  • ENAs: anti-dsDNA (SLE nephritis), anti-Sm (specific SLE), anti-Ro (neonatal lupus), anti-Jo-1 (myositis + ILD), anti-Scl-70 (diffuse scleroderma).
  • ANCA: PR3 = c-ANCA (GPA), MPO = p-ANCA (MPA, EGPA). IF + ELISA both needed.
  • DAT+ = IgG or C3 on RBCs (AIHA). IAT+ = anti-RBC in serum.
  • Flow cytometry: immunophenotyping for leukemia/lymphoma, CD4 count, PNH.
  • HLA typing: NGS for HSCT matching. Single antigen beads for DSA detection.
Red Flags
  • SPEP with M-spike + unexplained anemia/renal failure/bone pain = multiple myeloma until proven otherwise. Send IFE, FLC, skeletal survey.
  • DAT+ AIHA: rule out underlying SLE, CLL, drugs (methyldopa, penicillin, cephalosporins).
  • Low CH50 + low C3 + low C4 = classical pathway consumption (SLE, cryoglobulinemia).
  • Isolated low C4 = cryoglobulinemia (mixed).
  • Positive ANA + negative ENAs + no clinical features = may be false positive. Do not over-diagnose SLE.

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