3.3 Clinical Immunology & Hypersensitivity Reactions
Key Takeaways
- CD4+ T helper subsets are governed by specific transcription factors and signature cytokine profiles: Th1 (T-bet; IFN-γ), Th2 (GATA3; IL-4, IL-5, IL-13), Th17 (RORγt; IL-17, IL-22), and Treg (FOXP3; IL-10, TGF-β).
- Hereditary angioedema (HAE) is caused by C1-esterase inhibitor deficiency, leading to uninhibited plasma kallikrein activation and excessive bradykinin generation; C4 is persistently low, and attacks do not respond to adrenaline, antihistamines, or corticosteroids.
- Terminal complement pathway deficiencies (C5–C9) and treatment with eculizumab confer extreme susceptibility (> 1,000-fold) to recurrent, invasive meningococcal and gonococcal (Neisseria) infections.
- Gell & Coombs Type II hypersensitivity involves antibodies against cell-surface or tissue-fixed antigens (e.g., Goodpasture's, ITP, AIHA), whereas Type III involves vascular deposition of soluble circulating immune complexes (e.g., SLE, post-streptococcal GN, serum sickness).
- Chronic granulomatous disease (CGD) results from inherited mutations in the phagocyte NADPH oxidase complex (most commonly X-linked CYBB/gp91phox), preventing the respiratory burst; patients are uniquely susceptible to catalase-positive pathogens and are diagnosed via absent dihydrorhodamine-123 (DHR) oxidation.
Clinical immunology for MRCP(UK) Part 1 integrates lymphocyte differentiation, complement cascades, hypersensitivity reactions, and primary immunodeficiencies.
1. Cellular Immunology & Immunogenetics
CD4+ T Helper Lineages & Cytotoxic T Cells
Naive CD4+ T cells differentiate into effector lineages guided by cytokines:
| Subset | Inducing Cytokines | Master Regulator | Signature Cytokines | Target Organisms | Clinical Pathology |
|---|---|---|---|---|---|
| Th1 | IL-12, IFN-γ | T-bet | IFN-γ, IL-2 | Intracellular pathogens | Mycobacterial susceptibility |
| Th2 | IL-4 | GATA3 | IL-4, IL-5, IL-13 | Helminths, allergens | Atopic asthma, allergic eczema |
| Th17 | IL-6, IL-23 | RORγt | IL-17, IL-22 | Fungi, extracellular bacteria | Job (Hyper-IgE) syndrome (STAT3 defect) |
| Treg | TGF-β, IL-2 | FOXP3 | IL-10, TGF-β | Self-tolerance | IPEX syndrome (FOXP3 defect) |
CD8+ Cytotoxic T cells recognise 8–10 amino acid peptides on MHC Class I, inducing apoptosis via perforin pores, granzyme B (procaspase-3 activation), and FasL binding to target Fas (CD95).
B-Cell Maturation & Germinal Centres
Protein antigens require CD4+ T-cell help: B-cell CD40 binds CD40L (CD154) on follicular helper T cells. In germinal follicles, Activation-Induced Cytidine Deaminase (AID) drives somatic hypermutation (affinity maturation) and class switch recombination (exchanging Cμ for IgG, IgA, or IgE).
MHC Class I vs. II & HLA Disease Associations
- MHC Class I (HLA-A, B, C): On all nucleated cells. Heavy α chain with β₂-microglobulin. Presents endogenous peptides loaded via TAP to CD8+ T cells.
- MHC Class II (HLA-DP, DQ, DR): On APCs. α/β heterodimer presenting exogenous peptides (exchanged from CLIP by HLA-DM) to CD4+ T cells.
| HLA Allele | Disease Associations |
|---|---|
| HLA-B27 | Ankylosing spondylitis (RR > 90), Reactive, Psoriatic, Enteropathic arthritis |
| HLA-DR3 / HLA-DR4 | Type 1 diabetes (DR3/DR4 heterozygotes highest risk); SLE (DR3); Addison's |
| HLA-DR2 | Multiple sclerosis, Goodpasture's disease |
| HLA-DQ2 / HLA-DQ8 | Coeliac disease (> 95% HLA-DQ2) |
| HLA-B51 | Behçet's disease |
| HLA-B*5701 | Abacavir hypersensitivity (mandatory pre-treatment screening) |
| HLA-B*1502 | Carbamazepine Stevens-Johnson syndrome in East Asians |
2. Complement Cascade & Deficiency Syndromes
Pathways & Membrane Attack Complex (MAC)
- Classical: Antigen-bound IgM or IgG (IgG1, IgG3) binds C1q, cleaving C4 and C2 into C4b2a (C3 convertase). IgG4 does not fix complement.
- Lectin: Mannose-binding lectin activates MASP-1/2 to generate C4b2a.
- Alternative: Spontaneous C3 hydrolysis and Factor B/D generate C3bBb on microbial surfaces.
- Terminal Pathway: C3 convertases cleave C3 into C3a (anaphylatoxin) and C3b (opsonin). Addition of C3b produces C5 convertase, generating C5a (potent chemoattractant) and C5b. C5b recruits C6–C9 to assemble the MAC (C5b-9), creating lytic transmembrane pores.
Complement Deficiency States
- C1, C4, C2 Deficiencies: Impaired immune-complex clearance; >90% of C1q-deficient individuals develop severe SLE.
- C3 Deficiency: Severe recurrent pyogenic encapsulated infections (S. pneumoniae, H. influenzae).
- Terminal Deficiencies (C5–C9): Inability to form MAC. Extreme susceptibility to recurrent, invasive Neisseria infections (meningococcal meningitis). Eculizumab (anti-C5 mAb) produces identical vulnerability.
- C1-INH Deficiency (Hereditary Angioedema, HAE): Autosomal dominant loss of C1-INH causes unchecked plasma kallikrein activation, generating excessive bradykinin (not histamine). Causes recurrent non-pruritic, non-pitting oedema (face, bowel wall colic, laryngeal obstruction); no urticaria. Serum C4 is persistently low; C1q is normal. Adrenaline is ineffective; treat with C1-INH concentrate, icatibant, or ecallantide.
- Paroxysmal Nocturnal Haemoglobinuria (PNH): Somatic PIGA mutation causes absence of GPI-anchored CD55 (DAF) and CD59 (protectin), causing complement-mediated haemolysis and thrombosis. Diagnosed by flow cytometry (FLAER).
3. Gell & Coombs Classification of Hypersensitivity
| Type | Immune Mechanism | Mediators | Clinical Examples |
|---|---|---|---|
| Type I | Immediate / IgE-Mediated: Allergen cross-links specific IgE on mast cells; degranulation | Histamine, tryptase, leukotrienes (LTC₄, LTD₄) | Anaphylaxis, asthma, urticaria. Measured by mast cell tryptase (peaks 1–2 h) |
| Type II | Antibody Cytotoxic: IgG/IgM against fixed tissue/cell antigens; complement or ADCC | IgG, IgM, complement (MAC), NK cells | Goodpasture's (anti-GBM), AIHA, ITP, Myasthenia gravis, Graves' |
| Type III | Immune-Complex: Soluble antigen-antibody complexes deposit in microvasculature, activating complement | Immune complexes, C3a/C5a, neutrophils | SLE (lupus nephritis), Post-streptococcal GN, Serum sickness (fever, rash, low C3/C4) |
| Type IV | Delayed / Cell-Mediated: Sensitised T cells recruit macrophages or mediate direct lysis | CD4+ (Th1/17), CD8+ T cells, IFN-γ | Mantoux test, contact dermatitis (nickel), SJS / TEN, Coeliac disease |
4. Primary Immunodeficiency Disorders
- Severe Combined Immunodeficiency (SCID): Profound T/B cell deficiency causing failure to thrive, candidiasis, diarrhoea, and opportunistic infections (P. jirovecii). X-linked (~50%) IL2RG mutation (common γc; T⁻ B⁺ NK⁻); autosomal recessive ADA deficiency (T⁻ B⁻ NK⁻). Treatment: stem cell transplantation.
- X-Linked Agammaglobulinaemia (Bruton's XLA): BTK mutation halts B-cell development. Absent circulating B cells (CD19+, CD20+ < 1%) and marked hypogammaglobulinaemia. Presents after 6 months (waning maternal IgG) with pyogenic infections. Hallmark: absent tonsils and lymph nodes. Treatment: lifelong IVIG/SCIG.
- Common Variable Immunodeficiency (CVID): Most common symptomatic primary antibody deficiency in adults (20–40 years). Defective plasma cell differentiation causes low IgG plus low IgA/IgM and impaired vaccine responses despite normal B-cell counts. Sinopulmonary infections, Giardia, granulomas, cytopenias (ITP/AIHA), and lymphoma risk. Treatment: lifelong IVIG/SCIG.
- Selective IgA Deficiency: Most common primary immunodeficiency (~1 in 600). Undetectable IgA (< 0.07 g/L) with normal IgG/IgM. Causes mucosal infections, atopy, and coeliac disease. High risk of severe anaphylaxis to IgA-containing blood products (anti-IgA antibodies; requires washed RBCs).
- Hyper-IgM Syndrome: X-linked CD40LG (CD154) mutation prevents class switching. Normal/elevated IgM with severe IgG, IgA, and IgE deficiency. Recurrent pyogenic and opportunistic infections (Pneumocystis, Cryptosporidium).
- Chronic Granulomatous Disease (CGD): Phagocyte NADPH oxidase defect (most commonly X-linked CYBB / gp91phox) eliminates the respiratory burst. Phagocytes ingest but cannot kill catalase-positive organisms (S. aureus, Burkholderia, Serratia, Nocardia, Aspergillus). Diagnosed by absent Dihydrorhodamine-123 (DHR) oxidation on flow cytometry. Treatment: co-trimoxazole, itraconazole, IFN-γ, HSCT.
A 28-year-old man presents to the acute medical unit with acute swelling of his lips, tongue, and uvula, accompanied by severe colicky abdominal pain and vomiting. He has experienced similar episodes over the past three years, each resolving spontaneously over 48 to 72 hours. He has no associated urticaria, pruritus, or respiratory wheeze. His father died of sudden asphyxiation at age 34. On physical examination, there is marked non-pitting oedema of the lower face and lips without skin erythema. Intramuscular adrenaline, intravenous chlorphenamine, and hydrocortisone fail to halt the progression of facial swelling. Laboratory investigation during this acute attack demonstrates: C1q level normal, C4 level profoundly depressed (< 0.04 g/L; normal 0.15–0.45 g/L), C3 level normal. What is the definitive molecular mechanism responsible for this patient's presentation?
A 26-year-old woman with Systemic Lupus Erythematosus presents with worsening peripheral oedema and dark urine. Blood pressure is 164/98 mmHg. Urinalysis shows 3+ protein and 3+ blood. Serum creatinine is elevated at 178 micromol/L (50–90 micromol/L). Serum complement levels show: C3 0.32 g/L (0.90–1.80 g/L), C4 0.05 g/L (0.15–0.45 g/L). Renal biopsy confirms diffuse proliferative glomerulonephritis (ISN/RPS Class IV) with widespread subendothelial immune deposits and capillary wall 'wire-loop' lesions. According to the Gell and Coombs classification, what type of hypersensitivity reaction is primarily responsible for her renal disease?
An 8-year-old boy is evaluated following his third admission for deep-seated pyogenic infections. His medical history includes recurrent cervical lymphadenitis, a liver abscess requiring surgical drainage that cultured Staphylococcus aureus, and a previous episode of perianal abscess from which Serratia marcescens was isolated. Physical examination reveals bilateral cervical lymphadenopathy and mild hepatosplenomegaly. Flow cytometry of peripheral blood granulocytes stimulated with phorbol myristate acetate demonstrates an absence of green fluorescence following incubation with dihydrorhodamine-123 (DHR). What is the underlying biochemical defect in this patient's leukocytes?