Complement, Cytokines, Interferons & CD Markers — USMLE Step 1 Notes

Complement: activation pathways

• Classical pathway: triggered by antigen-bound IgG or IgM (C1q binds the antibody). Mnemonic: GM makes classic cars (IgG, IgM).
• Alternative pathway: triggered directly by microbial surfaces (endotoxin/LPS, polysaccharides); antibody-independent.
• Lectin (MBL) pathway: mannose-binding lectin binds mannose on microbial surfaces.
• All three converge on C3 convertase (cleaves C3 → C3a + C3b), then C5 convertase (cleaves C5 → C5a + C5b), leading to the membrane attack complex (C5b-C9).

Complement functions

• Opsonisation: C3b is the main opsonin, coating microbes for phagocytosis (the spleen is key for this).
• Membrane attack complex (C5b-9): lyses cells, especially Neisseria.
• Anaphylatoxins: C3a, C4a and C5a trigger inflammation and mast-cell degranulation; C5a is also a neutrophil chemoattractant.
• Clears immune complexes and apoptotic cells.

Complement protein deficiencies

• Early components (C1, C2, C4): impaired immune-complex clearance → SLE-like autoimmunity and pyogenic (encapsulated-organism) infections. C2 deficiency is the commonest complement deficiency.
• C3 deficiency: severe recurrent pyogenic infections (loss of the main opsonin) and immune-complex disease.
• Terminal components (C5-C9, the MAC): recurrent Neisseria infections (meningococcus, gonococcus).

Complement regulatory-protein disorders

• C1 esterase inhibitor deficiency → hereditary angioedema: uncontrolled C1 activation raises bradykinin, causing recurrent non-pitting angioedema of the face, airway and bowel without urticaria. ACE inhibitors are contraindicated (they raise bradykinin). Treat with C1-inhibitor concentrate, a bradykinin-receptor antagonist (icatibant) or a kallikrein inhibitor (ecallantide); danazol for prophylaxis.
• DAF (CD55) and CD59 deficiency → paroxysmal nocturnal haemoglobinuria: a PIGA mutation removes the GPI anchor for CD55/CD59, so red cells lose protection from complement and undergo intravascular haemolysis (haemoglobinuria, thrombosis, pancytopenia). Treated with the anti-C5 antibody eculizumab (vaccinate against meningococcus first).

Complement testing (CH50 / AH50)

• CH50: screens the classical pathway (C1-C9); low with classical/terminal-component deficiencies.
• AH50: screens the alternative pathway.
• Pattern reading: low CH50 + normal AH50 → a classical-specific defect (C1, C2, C4); both low → a shared/terminal component (C3, C5-9).

Important cytokines

• From macrophages (acute inflammation) — "Hot T-bone stEAk": IL-1 (fever, endothelial activation), IL-6 (fever, acute-phase proteins), IL-8 (neutrophil chemotaxis), IL-12 (drives Th1/NK), and TNF-alpha (fever, cachexia, vascular leak; mediates septic shock and granuloma maintenance).
• From all T cells: IL-2 (T-cell growth/proliferation) and IL-3 (bone-marrow stem-cell growth, like GM-CSF).
• From Th1 cells: interferon-gamma (activates macrophages and Th1, promotes class switch to opsonising IgG, inhibits Th2).
• From Th2 cells: IL-4 (B-cell growth, IgE/IgG class switch), IL-5 (eosinophils, IgA switch), IL-10 (anti-inflammatory, inhibits Th1 — also from Tregs), IL-13 (IgE, mucus).
• Pathophysiology: TNF-alpha and IL-1/IL-6 drive sepsis, cachexia and rheumatoid inflammation (targets of biologic therapy); excess IL-6 drives cytokine-release syndrome.

Interferons

• Type I — IFN-alpha and IFN-beta: made by virus-infected cells; induce an antiviral state in neighbouring cells (halt protein synthesis, degrade viral RNA) and boost MHC I and NK activity.
• Type II — IFN-gamma: from Th1/NK cells; activates macrophages (as above).
• Clinical use: IFN-alpha for chronic hepatitis B/C, some leukaemias/lymphomas and Kaposi sarcoma; IFN-beta for relapsing multiple sclerosis; IFN-gamma for chronic granulomatous disease.
• Adverse effects: flu-like symptoms, fatigue, bone-marrow suppression (cytopenias) and depression/neuropsychiatric effects.

Cell-surface (CD) markers

• All T cells: CD3 (part of the TCR complex), CD2, CD28 (costimulation receptor).
• Helper T cells: CD4 (binds MHC II); also CD40L on activation. HIV infects CD4 cells.
• Cytotoxic T cells: CD8 (binds MHC I).
• Regulatory T cells: CD4, CD25 and the master gene FOXP3.
• B cells: CD19, CD20, CD21 (CD21 is the EBV/complement C3d receptor), plus MHC II and surface immunoglobulin. CD20 is the target of rituximab.
• NK cells: CD16 (Fc receptor for ADCC) and CD56.
• Macrophages: CD14 (LPS receptor), CD40, MHC II, Fc and C3b receptors.
• Haematopoietic stem cells: CD34.

Active vs passive immunity

• Active immunity: the host makes its own antibody after exposure to antigen (natural infection or vaccination). Slow onset but long-lasting with memory.
• Passive immunity: preformed antibody is given (or transferred). Fast onset but short-lived, with no memory. Examples: maternal IgG across the placenta and secretory IgA in breast milk; IVIG; and post-exposure antitoxins/immunoglobulin for tetanus, rabies, hepatitis B, botulism, diphtheria and varicella ("To Rally Big Doctors, Bring Antibodies").

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