classical pathway

**Initiation:** C1q (part of the C1 complex: C1q + 2 C1r + 2 C1s) binds the Fc region of antigen-bound IgM (best activator; one pentamer is enough) or IgG (subclasses IgG1, IgG2, IgG3; needs two or more adjacent IgG molecules). Other triggers include C-reactive protein bound to pathogens, apoptotic cells, and some viruses and bacteria.

**Cascade:** 1. C1q binding activates C1r, which cleaves and activates C1s (a serine protease). 2. C1s cleaves C4 into C4a and C4b, then cleaves C2 into C2a and C2b. 3. C4b and C2a form the **C3 convertase (C4b2a)**. 4. C3 convertase cleaves C3 into C3a and C3b. 5. C3b binds C4b2a to form the **C5 convertase (C4b2a3b)**, which cleaves C5 into C5a and C5b. 6. C5b recruits C6, C7, C8, and multiple C9 to form the **MAC (C5b-9)**, which lyses cells, especially Neisseria.

**Effector functions:** - C3b: opsonization (the most important opsonin, along with IgG). - C3a, C4a, C5a: anaphylatoxins that cause mast cell degranulation and increased vascular permeability. C5a is also a potent neutrophil chemoattractant. - MAC: cytolysis. - C3b and C4b also help clear immune complexes.

**Regulation:** - **C1 esterase inhibitor (C1 INH)** inactivates C1r and C1s. It also inhibits kallikrein and factor XIIa. - **Decay-accelerating factor (DAF, CD55)** and **CD59** (which blocks MAC formation) are GPI-anchored. They are deficient in paroxysmal nocturnal hemoglobinuria (PNH) because of a PIGA mutation, which causes complement-mediated hemolysis. - Factor I, factor H, and membrane cofactor protein (MCP, CD46) degrade C3b and C4b.

**Clinical associations (high-yield):** - **Hereditary angioedema:** C1 INH deficiency (autosomal dominant). Low C4 (even between attacks), with normal C3. Causes episodic non-pitting, non-pruritic swelling without urticaria from excess bradykinin. ACE inhibitors are contraindicated. Treat acute attacks with C1 INH concentrate, icatibant (bradykinin receptor antagonist), or ecallantide (kallikrein inhibitor). - **Early classical pathway deficiencies (C1q, C2, C4):** Strongly predispose to SLE and SLE-like disease, because impaired clearance of immune complexes and apoptotic debris increases autoantigen exposure. They also cause recurrent pyogenic (encapsulated organism) infections. C2 deficiency is the most common. - **Terminal complement deficiencies (C5-C9):** Recurrent Neisseria infections (meningococcemia, disseminated gonococcal infection). - **C3 deficiency:** Severe recurrent pyogenic sinus and respiratory infections, plus increased risk of type III hypersensitivity (immune complex) disease. - **Type II and III hypersensitivity:** Classical pathway activation causes tissue damage. Examples are transfusion reactions (acute hemolytic reaction, ABO incompatibility), autoimmune hemolytic anemia (warm IgG, cold IgM), serum sickness, post-streptococcal glomerulonephritis, and lupus nephritis. - **Complement levels:** Low C3 and C4 (and often low CH50) in active SLE, reflecting classical pathway consumption. In post-streptococcal GN, C3 is low but C4 is usually normal, which suggests alternative pathway activation. - **Eculizumab** (anti-C5) is used for PNH and atypical HUS, and carries an increased risk of Neisseria infection, so patients need meningococcal vaccination.

**Comparison with other pathways:** - **Alternative pathway:** Spontaneous C3 hydrolysis, stabilized on microbial surfaces by properdin (factor P) and factors B and D. Convertase is C3bBb. It is part of innate immunity and is not antibody-dependent. - **Lectin pathway:** MBL (mannose-binding lectin) binds mannose on microbes and activates MASP-1 and MASP-2, which cleave C4 and C2. It converges with the classical pathway at C4b2a.

**Mnemonic:** Classical = "GM makes classic cars" (IgG and IgM). The order of the classical pathway is **1, 4, 2, 3, 5** (C1, C4, C2, C3, C5), not numerical order.