Complement System: Functions, Components, and Disorders, Slides of Pediatrics

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Complement Disorder

Functions of complements

• A. Host Defense
• B. Disposal of Waste
• C. Regulation of the Immune

Response

Membrane disruption

Activated complement components deposit in large numbers on microbes and unwanted materials (such as immune aggregates, apoptotic cells and necrotic tissue). This coating or "opsonization" of bacteria allows specific receptors on peripheral blood cells (especially phagocytes) to bind these ligands. In addition, activation of complement results in the formation of the membrane attack complex. This complex perturbs the bacterial cell membrane resulting in signaling events and, in organisms such as gram negative bacteria, lysis of the microbe

• Classical C
• Alternative C3bBD-C.
• MBL/ MBL-Associated Serine Protease 1- 2(MASP) C.
• Enzymatic and Non-enzymatic interactons.
• C5b,6,7,8,9 non-enzymatic interaction(change in configuration)
• C3 convertase (C4bC2b ,C3bBb)

Classical Pathway Activation

• Activating of C1(directly and indirectly).
• The classical pathway is activated when IgM or IgG antibodies bind to antigens.
• IgG subclasses 1 and 3 fix complement, while IgG4 does not. IgG2 fixes complement, although less efficiently than IgG1 and IgG
• Fc portion of the antibody-antigen complex, CRP, Mycoplasma , RNA viruses, Uric acid crystals, lipid component of endotoxins , product of tissue damage.

Alternative Pathway

• C3b
• By a form of C3 created by low-grade, spontaneous reaction of native C3 with a molecule of water, a "tickover" that occurs constantly
• If activated C3 binds to target, it can amplify using a feedback loop mechanism

Function of Individual Complements

• C2 split peptide(kenin like): post-capillary venules causing vascular permeability and edema
• C3a,C4a,C5a: (chemotaxis+ TNF and IL 1 from monocytes) all anaphylatoxin activity(mast cell binding)
• (Complement Receptor 1)Phagocytosis without C3 is inefficient

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• C3b +(C4b) fixation to immune complex permits it to adhere to Neuts and Antigen presenting cells(Macrophage,B cell and dendritic cell ). Links Innate and adaptive immune system. Also it also adheres to erythrocyte(transfer immune comples to hepatic and splenic macrophage for removal(CR1)

Alternative Pathway Components

• P (Properdin)stablizes C3bBb and prevent inactivatiob by H,I
• D cleaves B to Bb

Control mechanism

• C1 inhibitor :C1r and C1s
• C2 :short life span
• C3bBb :short life span
• Anaphylatoxin inactivator (C3a,C4a,C5a)
• Factor I inactivates C3b,C4b
• Factor H (C3b)and analogue C4 binding protien (C4b) accelerated inactivation by Factor I
• Cell membrane protein(DAF,CR1,membrane cofactor protein) disruption of C3 and C5 convertase.
• CD59(inhibits full development of membrane attacking complex)

Deficiency

• Congenital deficiency(AR) C1 to C8 (0),C9 50% level activity
• A genetic deficiency of a single component is indicated by the fixed absence ( in most cases no protein is detectable) of a single component and normal levels of all other complement components
• Hereditary Angioedema L C4 ,N C
• Classic Low C3,C4 NL Factor B
• Alternative L C3, L B,NL C

• Any disease associated with circulating immune complexes or autoantibodies of the IgG or IgM class may cause acquired hypocomplementemia.
• Inherited complement deficiencies predispose to the development of autoimmune syndromes
• Single Component: genetic multiple:activation

C2 deficiency

• Ten to 30 percent of such individuals present with an SLE-like illness
• Usually no infection, but they are prone to recurrent pyogenic infections particularly due to encapsulated bacteria
• This deficiency is also sometimes associated with IgG subclass deficiency. Other disease associations include polymyositis, glomerulonephritis, Hodgkin lymphoma, vasculitis, and Henoch-Schönlein purpura

C3 deficiency

• severe, recurrent infections with encapsulated bacteria that begins shortly after birth