Key Facts

The immune system is divided into innate (non-specific, rapid) and adaptive (specific, slower but with memory) components. Both systems work in concert to protect against pathogens.

Epidemiology

Immune system dysfunction manifests as:

• Immunodeficiency: Increased susceptibility to infection (primary: ~1 in 1200 live births; secondary: much more common - HIV, iatrogenic)
• Autoimmunity: Affects ~5-8% of the UK population
• Hypersensitivity: Allergic disease affects ~30% of the UK population at some point
• Malignancy: Immune surveillance failure

Aetiology

Innate immunity components:

• Physical barriers (skin, mucous membranes)
• Chemical barriers (lysozyme, defensins, gastric acid)
• Cellular (neutrophils, macrophages, NK cells, mast cells, dendritic cells)
• Humoral (complement, acute phase proteins, interferons)

Adaptive immunity components:

• B lymphocytes → plasma cells → immunoglobulins
• T lymphocytes → CD4+ helper, CD8+ cytotoxic, regulatory T cells
• Antigen-presenting cells bridge innate and adaptive immunity

Pathophysiology

Immune responses are initiated by pattern recognition receptors (PRRs) including Toll-like receptors (TLRs) on innate cells, which recognise pathogen-associated molecular patterns (PAMPs). This activates inflammatory cascades and primes the adaptive immune response through antigen presentation via MHC molecules.

Immunodeficiency

• Recurrent, severe, or unusual infections
• Infections with opportunistic organisms
• Poor response to standard antimicrobial therapy
• Failure to thrive (children)

Autoimmune Disease

• Organ-specific: Type 1 diabetes, Hashimoto's, Graves', pernicious anaemia
• Systemic: SLE, rheumatoid arthritis, systemic sclerosis

Hypersensitivity

• Type I (immediate): Anaphylaxis, asthma, hay fever
• Type II (cytotoxic): Autoimmune haemolytic anaemia, Goodpasture's
• Type III (immune complex): SLE, post-streptococcal GN
• Type IV (delayed): Contact dermatitis, TB skin test

Red Flags

• Recurrent serious infections (≥2 pneumonias/year, ≥2 systemic infections)
• Unusual organisms (Pneumocystis, atypical mycobacteria)
• Family history of immunodeficiency
• Failure to thrive with recurrent infections in children

Bedside

• Clinical assessment: Lymphadenopathy, hepatosplenomegaly, skin changes, tonsil size

Bloods

• FBC with differential: Lymphopenia, neutropenia, eosinophilia
• Immunoglobulins (IgG, IgA, IgM, IgE): Quantitative levels
• Lymphocyte subsets: CD4/CD8 count (flow cytometry)
• Complement levels: C3, C4, CH50/CH100, AP50
• Autoantibodies: ANA, anti-dsDNA, ANCA, anti-CCP, RF
• CRP and ESR: Inflammatory markers

Imaging

• CXR: Thymic shadow (absent in DiGeorge), bronchiectasis
• CT chest: Bronchiectasis, lymphadenopathy, thymoma

Special Tests

• Vaccine responses: Pneumococcal antibody levels pre/post-vaccination
• Nitroblue tetrazolium (NBT) test / DHR flow cytometry: Chronic granulomatous disease
• Lymphocyte proliferation assays: T cell function
• HIV test: Secondary immunodeficiency screening
• Genetic testing: For primary immunodeficiency syndromes

Non-pharmacological

• Infection avoidance measures
• Patient education regarding signs of infection
• Medic-Alert bracelet for severe immunodeficiency
• Avoid live vaccines in immunocompromised patients

Pharmacological

• Immunoglobulin replacement: IV (0.4-0.6g/kg every 3-4 weeks) or subcutaneous for antibody deficiency
• Prophylactic antibiotics: Co-trimoxazole for Pneumocystis prophylaxis in severe T cell deficiency
• G-CSF: For severe congenital neutropenia
• Immunosuppression for autoimmunity: Corticosteroids, azathioprine, mycophenolate, rituximab, biologics
• Antihistamines/adrenaline: For allergic conditions

Surgical/Interventional

• Haematopoietic stem cell transplant: For severe primary immunodeficiency (SCID, CGD)
• Gene therapy: Emerging for specific conditions (ADA-SCID)

Referral Criteria

• Suspected primary immunodeficiency → clinical immunology
• Recurrent serious infections → infection and immunity specialist
• Suspected autoimmune disease → rheumatology or relevant organ specialist

• SCID: Fatal within first year if untreated; >90% survival with early HSCT
• Common variable immunodeficiency: Normal life expectancy with immunoglobulin replacement; increased risk of autoimmunity and lymphoma
• XLA: Good prognosis with immunoglobulin replacement
• DiGeorge syndrome: Variable - depends on severity of thymic aplasia and cardiac defects
• Autoimmune conditions: Most are chronic and require lifelong management

Immunoglobulin Summary

Complement Deficiencies