The Complement System: Pathways, Regulation, and Associated Disorders
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The document summarizes the complement system, including its three activation pathways (classical, alternative, and lectin), membrane attack complex, receptors, regulation, associated disorders, and laboratory assessment. It describes how the classical pathway is activated by antigen-antibody complexes, the alternative pathway does not require antibodies, and the lectin pathway is triggered by microbial polysaccharides binding to lectins or ficolins. Regulation is needed to prevent improper activation. Deficiencies can lead to increased infection risk or autoimmune diseases like SLE. Laboratory tests include measuring complement component levels.
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The Complement System: Pathways, Regulation, and Associated Disorders
- 1. The Complement System Puttatida Chetwong, MD.
- 2. Outline • The classical pathway • The alternative pathway • The lectin activation pathway • The membrane attack complex • Receptors and biologic functions • Regulation of complement activation • Disorders associated with complement activation/deficiency • Laboratory assessment of complement • Management of complement deficiency
- 4. Classical Pathway • Activated primarily by Ag-Ab complexes • Soluble • Fixed on the surface of cells • Deposited on extracellular matrices Ability to activate complement IgM > IgG3 > IgG1 > IgG2 - Need 1 IgM or at least 2 IgGs - Binding site: IgM – CH3 domain IgG – CH2 domain Can’t activate complement IgG4, IgA, IgE Abbas, AK. Cellular and Molecular Immunology. 9th ed. Middleton’s Allergy, 9th ed.
- 5. Classical Pathway Apoptotic cell C-reactive protein Serum amyloid P β-amyloid DNA/chromatin Cytoskeletal filaments Some pathogens Can activate the classical pathway • Persistence of apoptotic debris leads to the development of autoantibodies • C1 deficiency in humans is strongly associated with the development of systemic lupus erythematosus Middleton’s Allergy, 9th ed.
- 6. Classical Pathway: C1 complex Abbas, AK. Cellular and Molecular Immunology. 9th ed. Middleton’s Allergy, 9th ed. C1q → C1r → C1s C4 C4a + C4b
- 7. Classical Pathway C4b2a = C3 convertase Bind C3 Catalyze proteolysis C2a = large fragment C2b = small fragment Abbas, AK. Cellular and Molecular Immunology. 9th ed. Main function of classical pathway achieved: C3b has been deposited on the surface of a pathogen where it can act to enhance phagocytosis Middleton’s Allergy, 9th ed. anaphylatoxin anaphylatoxin
- 8. Classical Pathway C4a, C3a, C5a = anaphylatoxins - Induce mast cell degranulation and neutrophil aggregation Increased vascular permeability, vasodilation Most potent, most powerful chemotactic factor for neutrophils Abbas, AK. Cellular and Molecular Immunology. 9th ed. Middleton’s Allergy, 9th ed. anaphylatoxin C4b2a3b = C5 convertase
- 11. Alternative Pathway • Does not require preformed antibody • Basis of the pathway is “C3 tickover” spontaneous hydrolysis of C3 at a rate of 0.2% to 0.4% per hour Abbas, AK. Cellular and Molecular Immunology. 9th ed. Middleton’s Allergy, 9th ed. anaphylatoxin
- 12. Abbas, AK. Cellular and Molecular Immunology. 9th ed.
- 13. Alternative Pathway Even when C3b is generated by the classical or lectin pathway, it can form a complex with Bb C3 convertase Classical pathway - C4b2a Alternative pathway - C3bBb Abbas, AK. Cellular and Molecular Immunology. 9th ed. Properdin - Released by activated neutrophils - Only known positive regulator of complement
- 14. Alternative Pathway Middleton’s Allergy, 9th ed. Own cell Pathogen - Mannose - N-acetyl glucosamine - Sialic acid residue *post-cardiac bypass syndrome
- 15. Alternative Pathway anaphylatoxin anaphylatoxin C5 convertase Classical pathway - C4b2a3b Alternative Pathway - C3bBb3b or C3b2Bb Abbas, AK. Cellular and Molecular Immunology. 9th ed.
- 16. Abbas, AK. Cellular and Molecular Immunology. 9th ed.
- 17. The Lectin Activation Pathway
- 18. Lectin Activation Pathway Triggered by the binding of microbial polysaccharides to 1) circulating lectins or 2) ficolins Abbas, AK. Cellular and Molecular Immunology. 9th ed. N-terminal collagen like domain C-terminal carbohydrate recognition domain C-terminal fibrinogen- like domain N-terminal collagen like domain
- 19. MBL also binds to agalactosyl IgG with high affinity Produced at times of inflammation Activate both classical and lectin activation pathways Abbas, AK. Cellular and Molecular Immunology. 9th ed. Middleton’s Allergy, 9th ed. Lectin Activation Pathway
- 20. Abbas, AK. Cellular and Molecular Immunology. 9th ed.
- 23. Membrane Attack Complex Functions of complement system • Opsonization • Clearance of apoptotic debris • Activation of B cells and of T cells • Lysis of cells and pathogens Only function that requires terminal complements Middleton’s Allergy, 9th ed. Abbas, AK. Cellular and Molecular Immunology. 9th ed.
- 24. Abbas, AK. Cellular and Molecular Immunology. 9th ed. Membrane Attack Complex
- 25. Membrane Attack Complex Nucleated cells are resistant to lysis: 1. Because they are metabolically active, they can repair membrane damage 2. Eukaryotic cells are coated with complement regulatory proteins that inhibit completion of the lytic process Susceptible to lysis - Gram-negative bacteria - Most enveloped virus Resistant to lysis - Gram-positive bacteria Middleton’s Allergy, 9th ed.
- 26. Abbas, AK. Cellular and Molecular Immunology. 9th ed.
- 27. Receptors
- 29. Fcγ receptor of phagocyte simultaneously engaged by antibody-coated particles activate the microbicidal mechanisms of the phagocytes Binding of C3b- or C4b-coated particles to CR1 augment Abbas, AK. Cellular and Molecular Immunology. 9th ed.
- 30. Degradation by reticuloendothelial cells of liver and spleen • Immune complex clearance • Destabilization of the C3 and C5 convertase complexes • CR1-bearing cells in the bone marrow may become tolerized on exposure to apoptotic cells bound by complement → defect could lead to lupus Middleton’s Allergy, 9th ed. immune complexes are maintained in a soluble state through the binding of C3b CR1 *serum sickness
- 31. The activation threshold for B cells is dramatically lowered when both the B cell receptor and CR2 are simultaneously engaged. Patients with C3 deficiency also have compromised antibody response Middleton’s Allergy, 9th ed. Abbas, AK. Cellular and Molecular Immunology. 9th ed. B cell coreceptor complex
- 32. CD11c = marker of dendritic cells Middleton’s Allergy, 9th ed. Abbas, AK. Cellular and Molecular Immunology. 9th ed.
- 33. Anaphylatoxin receptors Expressed on mast cells, basophils, eosinophils, neutrophils, platelets, endothelial cells, and smooth muscle cells. Effects: - vasodilation - aggregation of neutrophils - stimulation of mucus release from goblet cells - activation of macrophages Middleton’s Allergy, 9th ed.
- 34. C5a receptor - Also express on hepatocytes, lung epithelium, vascular smooth muscle, umbilical cord epithelium, astrocytes, microglial cells, T cells - Superior to C3aR in terms of anaphylatoxic activity C5a - Most powerful endogenous chemotactic factor for neutrophil - Also chemotactic agent for monocyte-macrophage - Overproduction of C5a in sepsis can lead to inhibition of neutrophil function → paradoxical immunocompromise seen in sepsis Middleton’s Allergy, 9th ed.
- 35. Middleton’s Allergy, 9th ed. C1q receptors Their function appears to relate to phagocytosis and clearance of apoptotic and cell debris.
- 37. Why regulate? Unregulated complement activation would lead to - host cell lysis - inappropriate production of inflammatory mediators - aberrant B cell activation Middleton’s Allergy, 9th ed. Regulators of complement activity (RCA) cell membrane proteins - decay accelerating factor (DAF/CD55) - membrane cofactor protein (MCP/CD46) - complement receptor 1 (CR1/CD35) - complement receptor 2 (CR2/CD21) circulating plasma proteins - Factor H - C4-binding protein (C4BP) encoded by homologous genes tightly clustered on chromosome 1q3.2
- 38. Abbas, AK. Cellular and Molecular Immunology. 9th ed.
- 39. DAF MCP CR1 C4BP DAF MCP CR1 Factor H Membrane-bound Fluid-phase Dissociation of C3 convertase Mechanism:
- 40. Abbas, AK. Cellular and Molecular Immunology. 9th ed.
- 41. Inhibit MAC formation Mechanism: - CD59 - S protein - C8 binding protein Abbas, AK. Cellular and Molecular Immunology. 9th ed.
- 42. Abbas, AK. Cellular and Molecular Immunology. 9th ed.
- 43. Middleton’s Allergy, 9th ed.
- 44. Middleton’s Allergy, 9th ed. Regulation of the Classical Pathway
- 45. Middleton’s Allergy, 9th ed. Regulation of the Alternative Pathway
- 46. Regulation of the Lectin Activation Pathway Middleton’s Allergy, 9th ed.
- 47. Disorders Associated with Complement Activation
- 48. Post–cardiac bypass syndrome • Bypass circuitry is an activator surface → alternative pathway • Activate kinin system, fibrinolysis, platelet activation • Release large amounts of C5a • Neutrophils bind to C5a → form aggregates - interfere circulation - release reactive oxygen species • Results: neutropenia, thrombocytopenia, end-organ dysfunction, hypotension Middleton’s Allergy, 9th ed.
- 49. Serum sickness • When the clearance pathway is overwhelmed, immune complexes deposit on endothelial cells wherever pressure or tortuosity allows (usually skin, glomeruli, and synovium). • An urticarial or vasculitic rash often is the first sign, followed by adenopathy, fever, arthritis, and proteinuria. • Lab: hypocomplementemia secondary to consumption Patho: leukocytoclastic vasculitis with deposition of C3, IgM, and IgG Middleton’s Allergy, 9th ed.
- 50. Nephritic Factors • A group of autoantibodies against C3 and C5 convertases • Associated with lipodystrophy, membranoproliferative glomerulonephritis • C3 hypocomplementemia is present Front Immunol. 2019; 10: 886.
- 51. •Antibodies to C1q: - hypocomplementemic urticarial vasculitis - glomerulonephritis •Antibodies to factor H •Antibodies to C1 inhibitor •Local complement activation • Placenta of pregnant women with antiphospholipid Abs or Abs associated with SLE • Burn injury, pancreatitis, crush injury → activator surface Middleton’s Allergy, 9th ed. Presentations same as deficiencies
- 52. Disorders Associated with Complement Deficiencies
- 53. Middleton’s Allergy, 9th ed. X-linked AD Factor B GOF mutation associated with aHUS
- 54. C1 deficiency • Patients with C1q deficiency present almost uniformly with early-onset SLE. • Also increased risk of infection • More dramatic cutaneous and CNS manifestations • Similar autoantibody profile, anti-dsDNA less common • Less steroid-responsive Compared to typical SLE Middleton’s Allergy, 9th ed.
- 55. C4 deficiency • Partial C4 deficiency is extremely common C4A deficiency: 1-2% of general population up to 15% of patients with SLE C4B deficiency: 1-2% of general population • C4A binds protein, C4B binds carbohydrate • Complete C4 deficiency is rare 50% of patients with complete C4 deficiency have SLE Milder form of SLE Severe, early onset, anti-dsDNA less frequent Middleton’s Allergy, 9th ed.
- 56. C2 deficiency • One of the more common complement deficiencies • Most are asymptomatic • Approximately half will develop lupus • 2/3 have a history of invasive bacterial disease • Common: S. pneumoniae and H. influenzae Onset in early adulthood Cerebritis, nephritis, arthritis less common Anti-Ro Ab extremely common Anti-dsDNA infrequent Middleton’s Allergy, 9th ed.
- 57. C2 deficiency • Accelerated atherosclerosis • Role for complement cascade proteins and complement regulatory proteins in the regulation of low-density lipoprotein (LDL) and vascular injury • Likely that all patients with early complement deficiencies have a similar phenotype Middleton’s Allergy, 9th ed.
- 58. C3 deficiency • Rarest of the early component deficiency • Most severe phenotype • Membranoproliferative glomerulonephritis instead of SLE • Profound predisposition to infection • Staphylococcal abscess: inability to opsonize and generate C5a chemotactic factor • Recurrent sinopulmonary infection: compromised B cell costimulation • Systemic infection: complete failure of C3b opsonization Middleton’s Allergy, 9th ed. During infections, a vasculitic rash may appear and symptoms of serum sickness may occasionally be seen.
- 59. Mannose-binding lectin deficiency • 2-7% in general population • Mutations lead to accelerated clearance, poor function, and impaired production • Modest risk for infection Middleton’s Allergy, 9th ed.
- 60. Factor I deficiency • 1. marked susceptibility to infection due to low C3 • Clinical manifestation like C3 deficiency • Low but not absent CH50 and AH50 • Low C3 • 2. atypical HUS or MPGN II • Low or normal C3 • Normal factor I level • 3. autoinflammatory disease Middleton’s Allergy, 9th ed.
- 61. Factor H deficiency • Main phenotypes: • Infections • atypical HUS • glomerulonephritis • macular degeneration Middleton’s Allergy, 9th ed. MCP deficiency • Atypical HUS: later onset compared to Factor H or Factor I deficiency Low but not absent CH50, AH50 Low C3 Normal complement analysis Mutation analysis required
- 62. CD59 Deficiency and PHN • CD59 expresses on hematopoietic cells and endothelial cells • CD59 deficiency is associated with chronic hemolytic anemia and recurrent stroke. • PNH is caused by mutations of PIG-A → protein product required for GPI-anchored proteins • DAF, C8 binding protein and CD59 are GPI-anchored proteins that protect hematopoietic cells from complement-mediated lysis • Diagnosis by flow cytometry for CD59 or CD55 (DAF) Middleton’s Allergy, 9th ed.
- 64. Indications • Recurrent sinopulmonary infections • Recurrent sepsis or recurrent systemic infections, particularly on a background of autoimmune disease (or a family history of autoimmune disease) • Single meningococcal infection, either meningitis or meningococcemia in nonendemic area Middleton’s Allergy, 9th ed https://wwwnc.cdc.gov/travel/yellowbook/2020/travel-related-infectious-diseases/meningococcal-disease If a complement deficiency is identified, vaccinate to prevent future infection
- 65. Indications • Chronic meningococcemia • Patients with meningococcal disease with an unusual serotype (serotype X, Y, Z, W135, or 29E in the United States) • Patients with meningococcal disease on a background of a positive family history • Patients with recurrent meningococcal disease Frequency of complement deficiency 10-50% Middleton’s Allergy, 9th ed
- 66. Indications • Pediatric-onset severe SLE • Patients with clinical symptoms suggestive of SLE but with negative results on antinuclear antibody (ANA) and anti- dsDNA assays • Membranoproliferative glomerulonephritis and atypical HUS • Initial screening: CH50 assay, an AH50 assay, and factor H, factor I, factor B, and C3 levels • Flow cytometry for MCP on neutrophils if available • ADAMTS13 activity level and antifactor H antibody measures Middleton’s Allergy, 9th ed
- 67. Indications • Patients with recurrent angioedema in the absence of allergic reactions • Patients with a family history of angioedema • Patients in whom angioedema is preceded by a reticular rash • Patients who experience angioedema after trauma Initial test: C4 levels Superior strategy: C1 inhibitor antigen and functional levels Middleton’s Allergy, 9th ed
- 68. Functional Tests of Complement System • The CH50 tests the functional capability of serum complement components of the classical pathway to lyse sheep red blood cells (SRBC) pre-coated with rabbit anti-sheep red blood cell antibody (haemolysin). • The assay result reports the dilution of serum capable of lysing 50% of the sheep cells. • Similarly, rabbit red cells are used to measure the intactness of the alternative pathway (AH50). Middleton’s Allergy, 9th ed J Vis Exp. 2010; (37): 1923.
- 69. • Deficiencies of all of the cascade components (except C9) lead to a CH50 of zero or near zero • With low levels of CH50 or AH50, the assays should be repeated, because mishandling of the serum is an extremely common problem Functional Tests of Complement System Middleton’s Allergy, 9th ed
- 70. Low but not absent CH50 More common: complement consumption Less common: regulatory protein defects leading to consumption of C3 • active immune complex disease • diminished hepatic production related to liver disease • immaturity of hepatic production seen in young infants • Factor D deficiency • Factor H deficiency • Factor I deficiency Middleton’s Allergy, 9th ed
- 71. Shih, A.R. and Murali, M.R. (2015), Laboratory tests for disorders of complement and complement regulatory proteins. Am. J. Hematol., 90: 1180-1186. Cannot exclude C9, properdin, MBL, MASP-2, or ficolin deficiencies → Genetic testing - C3 - C4 - C1 inhibitor
- 73. Early Classical Complement Deficiencies • Major risks of infection: S. pneumoniae and H. influenzae → vaccination → lifelong prophylactic antibiotics • Management of cardiac risk factors due to accelerated atherosclerosis • C1q: - produced to large extent by myeloid cells → hematopoietic stem cell transplantation may be considered Middleton’s Allergy, 9th ed
- 74. C3 deficiency • Use of IVIG to compensate for compromised B cell function • Prophylactic antibiotics • MPGN in C3 deficiency responds to no specific intervention • Renal transplantation attempted – unknown recurrence risk Middleton’s Allergy, 9th ed Nayagam JS. Am J Transplant. 2020 Aug;20(8):2260-2263.
- 75. Terminal Complement Deficiencies • Vaccination every 3 years with the polysaccharide meningococcal vaccine decreases the frequency of meningococcal episodes to 20% of that for nonvaccinated individuals Middleton’s Allergy, 9th ed
- 76. HUS from Factor H, Factor I, MCP deficiency • Plasmapheresis and FFP replacement • Renal transplantation in end-stage renal disease • Indicated: MCP deficiency • Not recommended: Factor H deficiency, Factor I deficiency • Liver transplantation Middleton’s Allergy, 9th ed