Clinical Immunology — Hypersensitivity, Immunodeficiency & Transplant — USMLE Step 1 Notes

The four hypersensitivity types (ACID)

• Type I — Anaphylactic/immediate (IgE): preformed IgE on mast cells/basophils cross-links on re-exposure → immediate histamine/tryptase release (minutes). Two phases (immediate + late). Examples: anaphylaxis, allergic asthma, atopy, hay fever, food/drug allergy.
• Type II — Cytotoxic (antibody, usually IgG/IgM vs cell-surface antigen): antibody binds a fixed tissue antigen → complement lysis, opsonisation or (in some) receptor stimulation/blockade. Examples: autoimmune haemolytic anaemia, ITP, Goodpasture, rheumatic fever, pemphigus, Graves (stimulatory), myasthenia gravis (blocking), acute haemolytic transfusion reaction.
• Type III — Immune-complex (antigen-antibody complexes deposit → complement + neutrophils): Examples: SLE, post-streptococcal glomerulonephritis, serum sickness, polyarteritis nodosa, the Arthus reaction, reactive arthritis.
• Type IV — Delayed/cell-mediated (T cells, no antibody): sensitised T cells and macrophages act over 48-72h. Examples: contact dermatitis, the tuberculin (PPD) test, TB granulomas, graft rejection, graft-versus-host disease.

Pathophysiology of key hypersensitivity conditions

• Myasthenia gravis (II): antibodies against the postsynaptic acetylcholine receptor → fatigable weakness worse through the day; improves with acetylcholinesterase inhibitors; thymoma association.
• Graves disease (II, stimulatory): anti-TSH-receptor antibodies stimulate the thyroid → hyperthyroidism, goitre, ophthalmopathy.
• Allergic asthma (I): IgE-mediated mast-cell degranulation with Th2 cytokines (IL-4/5/13) → bronchospasm, eosinophilic airway inflammation, reversible obstruction.
• SLE (III): anti-dsDNA/anti-Smith immune complexes deposit in skin, joints, kidney (glomerulonephritis) → multi-system disease; low complement during flares.
• Reactive arthritis (III/HLA-B27): sterile arthritis, urethritis and conjunctivitis days-weeks after GI/GU infection ("can't see, pee or climb a tree").
• Polyarteritis nodosa (III): immune-complex medium-vessel vasculitis (hepatitis B association) → renal, GI and neurological infarcts; spares the lungs; rosary-bead aneurysms.
• Post-streptococcal glomerulonephritis (III): immune complexes deposit in glomeruli ~2 weeks after strep infection → haematuria, oedema, hypertension, low C3.
• Serum sickness (III): antibodies against a foreign protein (e.g. antitoxin, chimeric drug) form complexes ~1-2 weeks later → fever, urticaria, arthralgia, low complement.
• Arthus reaction (III, local): intradermal antigen in a pre-sensitised host → local complex deposition with oedema, haemorrhage and necrosis (e.g. at a vaccine site).
• Contact dermatitis (IV): haptens (nickel, poison ivy) sensitise T cells → delayed eczematous rash on re-exposure.
• Graft-versus-host disease (IV): donor T cells attack host tissue → rash, diarrhoea/cholestasis (skin, gut, liver).

Immunologic blood transfusion reactions

• Acute haemolytic (type II): ABO incompatibility — recipient antibodies destroy donor red cells → fever, flank pain, haemoglobinuria, DIC and shock within minutes. Usually a clerical error; stop the transfusion.
• Febrile non-haemolytic (commonest): recipient antibodies react to donor leucocyte cytokines/HLA → fever and chills without haemolysis; prevented by leucoreduction.
• Allergic/urticarial: recipient IgE against donor plasma proteins → hives/pruritus; treat with antihistamine, continue if mild.
• Anaphylactic: severe reaction classically in IgA-deficient recipients with anti-IgA antibodies → give washed/IgA-deficient products.
• TACO (transfusion-associated circulatory overload): volume overload → hypertension, dyspnoea, raised JVP, pulmonary oedema; treat with diuresis and slow transfusion.
• TRALI: donor anti-leucocyte antibodies activate recipient neutrophils in the lung → non-cardiogenic pulmonary oedema with normal filling pressures.

Autoantibodies (high-yield table)

• Myasthenia gravis: anti-acetylcholine-receptor (also anti-MuSK).
• Lambert-Eaton myasthenic syndrome: anti-presynaptic voltage-gated calcium channel (paraneoplastic, small-cell lung cancer; weakness improves with use).
• SLE: ANA (sensitive), anti-dsDNA and anti-Smith (specific), anti-phospholipid.
• Drug-induced lupus: anti-histone (hydralazine, procainamide, isoniazid).
• Rheumatoid arthritis: rheumatoid factor and anti-CCP (more specific).
• Diffuse scleroderma: anti-Scl-70 (anti-topoisomerase I); limited (CREST): anti-centromere.
• Sjogren syndrome: anti-Ro (SSA) and anti-La (SSB).
• Graves disease: anti-TSH receptor (stimulating).
• Hashimoto thyroiditis: anti-thyroid peroxidase (TPO) and anti-thyroglobulin.
• Coeliac disease: anti-tissue transglutaminase, anti-endomysial, anti-deamidated gliadin.
• Others: anti-mitochondrial (primary biliary cholangitis), anti-smooth-muscle (autoimmune hepatitis), anti-GBM (Goodpasture), c-ANCA/PR3 (granulomatosis with polyangiitis), p-ANCA/MPO (microscopic polyangiitis), anti-desmoglein (pemphigus vulgaris), anti-IF/parietal (pernicious anaemia).

Primary immunodeficiencies

• B-cell — X-linked (Bruton) agammaglobulinaemia: BTK defect → no B cells/immunoglobulin; recurrent encapsulated infections after ~6 months (maternal IgG wanes). Selective IgA deficiency: commonest PID; sinopulmonary/GI infection, transfusion anaphylaxis.
• T-cell — thymic aplasia (DiGeorge, 22q11): no thymus/parathyroids → tetany (hypocalcaemia), cardiac defects, viral/fungal infection. IL-12 receptor deficiency: impaired Th1 response → disseminated mycobacterial/fungal infection. Job (hyper-IgE) syndrome: STAT3 defect → coarse facies, retained primary teeth, cold (non-inflamed) staph abscesses, eczema, very high IgE.
• Combined (B and T) — SCID: IL-2R-gamma or adenosine-deaminase defect → failure to thrive, opportunistic/all infections; needs bone-marrow transplant. Ataxia-telangiectasia: ATM defect → cerebellar ataxia, telangiectasias, low IgA, raised AFP, cancer risk. Hyper-IgM syndrome: CD40L defect → no class switching (high IgM, low IgG/A/E). Wiskott-Aldrich: WAS defect (X-linked) → the triad of thrombocytopenia (small platelets), eczema and recurrent infection.
• Phagocyte — leukocyte adhesion deficiency type 1: LFA-1 integrin (CD18) defect → delayed cord separation, no pus, recurrent skin infections, high neutrophils. Chediak-Higashi: LYST defect → giant granules, partial albinism, neuropathy, recurrent infections. Chronic granulomatous disease: NADPH-oxidase defect → catalase-positive organism infections (Staph, Aspergillus); abnormal dihydrorhodamine/nitroblue-tetrazolium test.

Transplant rejection

• Hyperacute (minutes): preformed recipient antibodies against donor antigen → immediate graft thrombosis; graft must be removed.
• Acute (weeks-months): host T cells (cellular) +/- antibody → graft dysfunction; often reversible with increased immunosuppression.
• Chronic (months-years): vascular remodelling/fibrosis (intimal thickening) → slow, irreversible graft loss.
• Graft-versus-host disease: immunocompetent donor T cells attack host (skin rash, diarrhoea, cholestasis) — common after bone-marrow transplant; can be therapeutic (graft-versus-tumour).

Immunosuppressant pharmacology (mechanisms & targets)

• Ciclosporin (cyclosporine): binds cyclophilin, inhibits calcineurin → blocks IL-2 transcription (less T-cell activation); nephrotoxic, gum hypertrophy, hypertension.
• Tacrolimus (FK506): binds FKBP, inhibits calcineurin (more potent); nephrotoxic, neurotoxic, diabetes.
• Sirolimus (rapamycin): binds FKBP but inhibits mTOR → blocks IL-2 signal transduction/proliferation; not nephrotoxic (pairs with calcineurin inhibitors); causes hyperlipidaemia, thrombocytopenia.
• Basiliximab: monoclonal against IL-2 receptor (CD25) → blocks T-cell proliferation.
• Azathioprine: antimetabolite (purine synthesis inhibitor via 6-mercaptopurine); toxicity increased by allopurinol.
• Glucocorticoids: broadly anti-inflammatory (inhibit NF-kB, cytokines); side effects Cushingoid.
• Recombinant cytokines: erythropoietin (raises red cells in anaemia of CKD), colony-stimulating factors (G-CSF/GM-CSF) (raise neutrophils after chemotherapy), thrombopoietin/romiplostim (raise platelets), IL-2 (aldesleukin) (stimulates T/NK cells — renal cell carcinoma, melanoma), and interferons (antiviral/antitumour).

Which defence handles which microbe

• B cells / antibody: defend against encapsulated bacteria and enteroviruses; deficiency → recurrent sinopulmonary pyogenic infections.
• T cells: defend against viruses, fungi and intracellular pathogens; deficiency → opportunistic/viral/fungal infection.
• Granulocytes (neutrophils): defend against catalase-positive bacteria and fungi; deficiency/dysfunction → skin/mucosal abscesses and Aspergillus.
• Complement: early components clear immune complexes and opsonise; terminal (C5-9) lyse Neisseria — deficiency → encapsulated-organism and Neisseria infection.

High-yield revision notes; verify against a primary source before clinical use.