Question

1.Relate biological manifestations of complement activation to generation of specific complement products.

2. Analyze lab findings and indicate disease in relation to abnormalities (complement)

Answer 1

ANSWER 1)

1. Complement system is a part of innate immune system contributing to the first-line of the host defence mechanism. Complement system is activated during pathogenic infections leading to its biological activation.
2. The complements are released into a circulatory system forming a cascade in terms of tissue stimulation to release the cascade complements.
3. Three major pathways are involved namely Classic pathway, Lectin pathway and Alternate pathway. Major effector molecules synthesized include Anaphylatoxin (C3a, C5a) , Opsonins (C3b, C3d) and MAC(terminal Membrane Attack Complex) which is associated with opsonization reaction.
4. LECTIN PATHWAY:-

• Complex of C4b, C2a and C3 convertase is formed.
• Mannose binding Lectin and their homologs namely ficolins detect the carbohydrate ligands on the surface of the bacteria leading to activation of the Lectin pathway.
• This activates MBL-associated serine proteases which cleaves the precursors C2 and C4forming C2a and C4b as final products actively involved in opsonization process for destroying microbial cells.

   5. CLASSICAL PATHWAY:-

• This pathway is different from Lectin pathway and is associated with antigen-antibody interaction to initiate complement cascade.
• Inactive C1 is being activated.
• IgG/M binds to Ciq molecule on pathogen leading to activation of C1r and C1s that cleaves C2 and C4.
• Four alternate forms are seen namely C4a, C2b, C4b, C2a.
• This initiates cleavage of C3 forming C3a and C3b associated with Anaphylatoxin synthesis.

So, basically both the pathways are associated with different biological mechanisms initiating a host response against the invading pathogenic microbe.

ANSWER 2)

1. Complement associated abnormalities are being inherited as autosomal recessive, autosomal dominant and X-linked recessive disorders.
2. Mostly the disorders are associated with malfunctioning of the Complement molecules.
3. C-1 inhibitory deficiency is an Autosomal dominant condition.
4. Pepperdine deficiency is X-linked recessive condition. It is associated with Rheumatoid disorders and Angioedema.
5. C3 deficiency or deficiency of other component of thebpathway involved in activation of C3 would result in increased susceptibility to infection with encapsulated bacteria. Defect is associated with C3b synthesis associated with opsonization.
6. C5-C9 deficiency in terms of the terminal complement system is associated with systemic neisseria infection as per test results obtained with respect to the serum bactericidal activity. This activity is affected which indicates role of the terminal complement deficiency in systemic neisseria infection.
7. Defects in classical pathway associated with formation of C1 , C4 and C2 are associated with Systemic lupus erythematosus, Vasculitis and Membranoproliferative Glomerulonephritis.

Clinical presentation Possible complement defect Proper din or membr ane attack complex (MAC) deficiency Pr oper din or MAC deficiency C3 or mannan-binding lectin (MBL) deficiency 2nd episode meningococcal disease 2nd episode gonococcal arthritis Recurrent pyogenic infections (abscesses, osteomyelitis, pneumonias) Recurrent angioedema without urticaria Late-onset angioedema with history of lymphoma/autoimmune disease Membranoproliferative glomerulonephritis Partial lipodystrophy Autoimmune condition C1 inhibitor deficiency C1 inhibit or deficiency C3 deficiency due to nephritic factor C3 deficiency due to nephritic factor Classical pathway factor (c1q, C4, C2) deficiency

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Expected result Disease state examples Mild classical normal C3, reduced C4 C1 inhibitor deficiency C2 deficiency, C4 pathway defect Severe classical reduced C3, reduced C4 SLE with nephr itis pathway defect Alternative pathway defect deficiency; SLE; many cryoglobulinemia cases reduced C3, normal C4 Factor H deficiency, factor I deficiency glomerulonephr itis, membranoproliferative glomerulonephr itis C1 inhibitor defect reduced or normal C1 Type 1 hereditary angioedema (HAE) (reduced inhibitor, reduced C4concentration), type 2 HAE (normal concentration)

This is particular data regarding association with complement defects. It is for reference.