Basic immunology

Innate immunity

Innate immunity acts within minutes to hours, uses receptors fixed in the genome, and has no memory.

• Barriers and secretions: skin, mucus, cilia, gastric acid, normal flora. Lysozyme splits peptidoglycan; lactoferrin (in saliva, tears, milk and neutrophil granules) binds iron so bacteria cannot use it; defensins punch holes in membranes.
• Cells: neutrophils, macrophages, dendritic cells, mast cells, eosinophils, NK cells (kill cells that have lost MHC class I, such as virus-infected and tumour cells).
• Pattern recognition receptors such as Toll-like receptors detect microbial patterns: LPS via TLR4, flagellin via TLR5, viral nucleic acids via TLR3, 7 and 9. Signalling through NF-κB releases TNF, IL-1, IL-6 and interferons. IL-8 (CXCL8) is the main early chemokine attracting neutrophils; IL-1 and TNF cause fever.
• Complement: the classical pathway is started by antibody (IgM, IgG) on antigen; the lectin pathway by mannose-binding lectin; the alternative pathway spontaneously on microbial surfaces. All meet at C3. C3b opsonises; C3a and C5a are anaphylatoxins (C5a also attracts neutrophils); C5b–C9 forms the membrane attack complex (deficiency predisposes to recurrent Neisseria).
• C1 esterase inhibitor deficiency (hereditary angioedema): uncontrolled C1 and kallikrein activity raises bradykinin, causing recurrent swelling of lips, larynx and gut without urticaria; C4 is low; autosomal dominant.
• Acute phase proteins (CRP, fibrinogen, serum amyloid A, ferritin, hepcidin) are made by the liver under IL-6. Interferon-α and β create an antiviral state; IFN-γ activates macrophages.

Adaptive immunity

• Diversity: each lymphocyte builds its receptor by somatic V(D)J recombination (RAG enzymes) with junctional diversity, giving millions of specificities from few genes. Somatic hypermutation in germinal centres raises affinity. Class switching changes the heavy-chain constant region (IgM to IgG, IgA, IgE) but not what the antibody binds; it needs T-cell help through CD40 ligand–CD40.

Rule of 8: class I × CD8 = 8; class II × CD4 = 8. HLA typing for transplantation uses lymphocytes, which carry both classes. Flow cytometry with fluorescent anti-CD4 antibodies counts CD4 cells in HIV, whose envelope gp120 binds CD4 (with CCR5 or CXCR4 as co-receptor).

• Atypical lymphocytes in infectious mononucleosis are activated CD8 T cells reacting against EBV-infected B cells.

Antibodies

Two heavy and two light chains. The Fab (variable) region binds antigen; the Fc region decides biological activity: complement activation, binding to phagocyte Fc receptors, placental transfer.

• Secondary response: faster, larger, longer and dominated by high-affinity IgG, thanks to memory cells; the basis of boosters.

Hypersensitivity

• Allergen (venom) immunotherapy works by inducing IgG4 "blocking" antibodies that intercept allergen before it reaches IgE, plus regulatory T cells (IL-10) and a shift away from Th2.
• Hypersensitivity pneumonitis (pigeon breeder, farmer lung) is mixed type III and IV: symptoms hours after exposure, lymphocytic interstitial inflammation and poorly formed granulomas.
• Granulomas: epithelioid macrophages with Langhans giant cells (nuclei in a horseshoe at the edge) in TB; Touton giant cells (central ring of nuclei with foamy cytoplasm around) in xanthomas and xanthelasma.
• Haemolytic disease of the newborn needs a baby carrying an antigen the mother lacks. A group A Rh-positive mother with a group O Rh-negative baby has no risk.

Primary immunodeficiencies

• Patients with T-cell deficiency must receive irradiated cellular blood products to prevent transfusion-associated GVHD (rash, diarrhoea, jaundice and pancytopenia about 2 weeks later).
• Splenectomy leaves risk of overwhelming sepsis from encapsulated bacteria, chiefly Streptococcus pneumoniae.

Tolerance and autoimmunity

• Central tolerance deletes self-reactive T cells in the thymus (AIRE lets thymic cells display tissue proteins) and B cells in the marrow. Peripheral tolerance uses anergy (no CD28–B7 co-stimulation), regulatory T cells and inhibitory checkpoints (CTLA-4, PD-1).
• Triggers: HLA genes, infection with molecular mimicry (rheumatic fever), release of hidden antigens (sympathetic ophthalmia), female hormones.
• Organ-specific: Hashimoto, Graves, type 1 diabetes, pernicious anaemia, Addison, myasthenia. Systemic: SLE, RA, systemic sclerosis, Sjögren, dermatomyositis.
• Schmidt syndrome (autoimmune polyglandular syndrome type 2): Addison disease with autoimmune hypothyroidism (often type 1 diabetes). Replace steroid first: thyroxine alone speeds cortisol clearance and can precipitate adrenal crisis.

Autoantibodies and disease clues

• SLE: tissue damage is mainly immune complex (type III). Its arthritis is non-erosive (deformities are reducible, Jaccoud type) whereas RA erodes bone. Libman–Sacks endocarditis: small sterile vegetations on both surfaces of the mitral leaflets, can embolise.
• Antiphospholipid syndrome: recurrent miscarriage, venous or arterial thrombosis, with lupus anticoagulant or anticardiolipin antibodies on two occasions 12 weeks apart. The APTT is prolonged and does not correct on mixing with normal plasma (an inhibitor). Pregnancy: low-dose aspirin plus prophylactic LMWH. Long term after thrombosis, especially triple-positive arterial disease: warfarin (not DOACs).
• RA extras: rheumatoid nodules show central fibrinoid necrosis with palisading histiocytes; Felty syndrome is RA, splenomegaly and neutropenia; Caplan syndrome is RA with multiple lung nodules in coal miners.
• Dermatomyositis: heliotrope rash, Gottron papules, proximal weakness, raised CK; biopsy shows perifascicular atrophy; screen for malignancy. Polymyositis shows endomysial CD8 T cells.
• Sjögren syndrome: a new firm parotid swelling with a monoclonal band and low C4 suggests MALT (marginal zone) lymphoma.
• Giant cell arteritis: temporal headache, jaw claudication, high ESR; give high-dose steroids immediately, biopsy later, to prevent permanent blindness. Polymyalgia rheumatica responds rapidly to modest prednisolone; a poor response suggests another diagnosis.
• Polyarteritis nodosa: medium arteries, lesions at different stages, spares the lungs, renal and mesenteric microaneurysms, mononeuritis multiplex; linked with hepatitis B.
• ITP: isolated low platelets, often after a viral illness in children; in pregnancy with bleeding, give IV immunoglobulin (platelet transfusion is destroyed by the antibody).

Transplantation

• Grafts: autograft (self), isograft (identical twin, not rejected), allograft (same species), xenograft (another species).

• Graft-versus-host disease: donor T cells attack host skin, gut and liver, mainly after bone marrow transplant or non-irradiated blood in immunodeficient patients.
• Immunosuppressants: ciclosporin and tacrolimus (calcineurin inhibitors blocking IL-2; nephrotoxic), sirolimus (mTOR), azathioprine and mycophenolate, corticosteroids, basiliximab.
• After transplantation: the commonest cancer is cutaneous squamous cell carcinoma; EBV drives post-transplant lymphoproliferative disease; CMV pneumonitis (large cells with owl-eye inclusions) peaks 1–4 months after transplant.
• Amyloid stains Congo red with apple-green birefringence under polarised light.

Remember MHC I to CD8 on every nucleated cell; MHC II to CD4 on antigen-presenting cells.

Exam trap The Fc portion, not the Fab, decides what an antibody does; class switching never changes its specificity.

Exam trap Mantoux and contact dermatitis are type IV; Arthus and serum sickness are type III; low complement points to type III.

How FCPS asks about this

• Part of the antibody that fixes complement and binds phagocytes: Fc portion.
• Secondary response: faster, larger, high-affinity IgG from memory cells.
• Indurated Mantoux at 72 hours / haemorrhagic swelling after a toxoid booster: type IV / type III (Arthus).
• Most sensitive and most specific SLE tests: ANA; anti-dsDNA (tracks nephritis).
• Commonest primary immunodeficiency with transfusion anaphylaxis: selective IgA deficiency; absent B cells in a boy is Bruton; normal B cells with low Ig is CVID.
• Cells used for HLA typing and rejection within minutes: lymphocytes; hyperacute rejection from preformed antibodies.
• Recurrent miscarriage with DVT and positive lupus anticoagulant: antiphospholipid syndrome; aspirin plus LMWH in pregnancy.