Summary of Biological Effects Mediated by Complement Products Inheritance

Effect Complement Product Meddling Common to all Pathways

Cell Lysis - C5b-9 or MAC C3 Autosomal recessive Recurrent pyogenic infection
Inflammatory Response Glomerulonephritis
Degranulation of mast cells and basophils - C3a Classical Pathway
(+) - C4a anaphylatoxins C1q Autosomal recessive Glomerulonephritis and SLE
- C5a C1r Autosomal recessive Glomerulonephritis and SLE
Degranulation of eosinophil - C3a C1s Autosomal recessive Glomerulonephritis and SLE
- C5a C4 Autosomal recessive Systemic Lupus Erythematosus
Extravasation and Chemotaxis of - C3a Scleroderma
Leukocytes at inflammatory site - C5a IgA neuropathy
- C3b67 Membranous glomerulonephritis
Aggregation of Platelets - C3a C2 Autosomal recessive Systemic Lupus Erythematosus
- C5a DLE
Inhibition of monocyte/macrophage - Bb Juvenile Rheumatoid Arthritis
migration and induction of their spreading Glomerulonephritis
Release of neutrophil from Bone Marrow - C3c Alternative Pathway
Release of hydrolytic enzymes from - C5a Factor B Autosomal recessive N. meningitidis infection
neutrophils Factor D Autosomal recessive Recurrent pyogenic infections
Increase expression of complement - C5a Properdin X-linked Recurrent pyogenic infections
receptors type 1 and 3 (CR1 and CR3) on Fulminant meningococcemia
neutrophils MB Lectin Pathway
Opsonisation of particulate antigens, - C3b MBL Autosomal dominant Recurrent infections
increasing their phagocytosis - C4b Membrane Attack Complex
C5 Autosomal recessive Recurrent disseminated nesserial infection
- iC3b
Viral neutralization - C3b Systemic Lupus Erythematosus
C6 Autosomal recessive Recurrent disseminated nesserial infection
- C5b-9 (MAC)
C7 Autosomal recessive Recurrent disseminated nesserial infection
Solubilization and clearance of immune - C3b
Reynaud’s disease
complexes
C8 Autosomal recessive Recurrent disseminated nesserial infection
(+) degranulation leads to release histamine and other mediators that induce
(B/Y chains)
contraction of smooth muscle cells and increase permeability of blood vessel
C9 Autosomal recessive None
Fluid Phase Control Proteins
Bold letters : most important in mediating indicated effect C1 Inh Autosomal dominant Hereditary angioedema
Acquired Autoimmune disease
C4bp Autosomal recessive Angioedema
Behcet-like syndrome
Factor I Autosomal recessive Recurrent pyogenic infections
Factor H Autosomal recessive Recurrent pyogenic infections
Inherited Deficiencies in Complement and Complement Related Proteins
Glomerulonephritis
Protein Pattern of Major Clinical Correlates
 Age related macular degeneration Bullous pemphigoid Normal or elevated serum complement
Cell Bound Proteins Pemphigoid gestationis Role of C5a in pathogenesis of bullous
CR1 Autosomal recessive Association between low RBC expression Cicatrical pemphigoid pemphigoid and epidermolysos bullosa
Systemic Lupus Erythematosus Epidermolysis bullosa acqusita aquisita seen
CR3 Autosomal recessive Leukocyte adhesion deficiency (LAD1) Dermatitis herpetiformis Chemoattactants for neutrophils leading to
Recurrent pyogenic infections Pemphigus vulgaris more tissue damage
Leukocytosis Hematologic Disease Neurologic Disease
Autoimmune haemolytic anemia Myasthenia gravis
DAF Acquired Paroxysmal Nocturnal Hemoglobinuria Paroxysmal cold hemoglobinuria Multiple sclerosis
CD59/HRF PNH Paroxysmal nocturnal hemoglobinuria Cerebral lupus
Gullain Barre Syndrome
Complement in Disease State Alzheimer’s disease
Rheumatologic disease
Systemic Lupus Erythematosus Reduced C3 & C4 especially in active disorders Clinically Useful Complement Inhibitors
Low C1q and C2 - Necessary to limit tissue damage
MBL deficiency CR1 Accelerates the decay of C3 and C5 convertase
Chronic Cold Agglutinin Disease Reduced erythrocyte CR1 Serves as cofactor for factor I mediated cleavage of C4b, C3b
PNH, AHA, Sjorjen syndrome and iC3b
JRA, Palidromic arthritis sCR1 Soluble recombinant form of CR1
Pseudogout, Gout Normal or elevated serum complement levels Ameliorated the disease process in several stidues
Reiter syndrome - Pig heart xenotransplantation in monkeys
Gonoccocal arthritis - Alveolitis in pulmonary arthus reaction model
Hereditary Angioedema Type 1 : reduced level or functional antigenic - Ischemia or reperfusion myocardial tissue injury
C1 inhibitor - Demyelination in allergic encephalomyelitis in rats
Type II : normal levels of C1 inhibitor but with - Glomerulonephritis
reduced or absent activity Has entered phase I clinical trials in patients with myocardial
Infectious Disease infarcts and burn induced ADRS
Gram negative septicaemia Low C3
Pyogenic infections Ab to C5 Allows the blocking of complement activation without release of
HBsAG + infections Early fall in C3 C5a and deposition of C5b-9
N. gonorrhoeae infection Deficiency of Membrane Attack Complex and
N. meningitidis infection Properdin Ab to C5 Research
Renal Disease - Interferes with hyperacute rejection of porcine organs
Glomerulonephritis Deposition of C3 or other complements within in in-vitro perfusion systems
or near the glomerular basement membrane - Prevents onset of arthritis in mouse model of collagen
Membranoproliferative Very low C3
induced arthritis
Glomerulonephritis type II C3 nephritic factor (C3NeF or NF3) stabilizes
- Reduced glomerulonephritis in mouse model of SLE
the alternative pathway C3 convertase
- Reduce infarct size in rat models of myocardial
Dermatologic Diseases
ischemia or reperfusion injury
 Clinical trials factor
- Reduces myocardial damage in patients undergoing PNH - CD55
cardiopulmonary bypass surgery - CD59 (flow cytometry)
IVIG Idiopathic thrombocytopenic purpura, Kawasaki disease,
Guillain-Barre syndrome, Myasthenia gravis
Complement Activation of ELISA Results Using Peripheral Blood in Screening
May prevent complement mediated tissue damage by
Suspected Complement Deficiency
interacting directly with C1 or by preventing C4 from binding to
Impaired Function or ELISA ACTIVITY
target cell
Deficiency
C1 inhibitor Septic shock
Complement Classical Pathway Alternative Lectin Pathway
Reperfusion injury
Component Pathway
Hyperacute transplant rejections C1q, C1r, C1s Low Normal Normal
Paroxysmal nocturnal hemoglobinuria C4, C2 Low Normal Low
MBL, MASP Normal Normal Low
B, D, P Normal Low Normal
Complement Deficiency-Related Disease State and Recommended Analysis on
Peripheral Blood C3, C5, C6, C7, C8, C9 Low Low Low
Disease Complement Analysis
Recurrent bacterial - CH50 - C3a/C3d
CH50 and AH50 Interpretation
infections - AH50 - C5-C9 Neisseria
Test Results Interpretation
- WiELISA - Properdin Neisseria CH50 very low or zero Missing C1q, C1r, C1s, C2, or C4
- C3 - MBL Neisseria AH50 normal
Systemic Lupus - CH50 CH50 normal Missing properdin, or (very rarely)
Erythematosus - C4 (C4a/C4b) AH50 very low or zero factor B or factor D
- C3a/C3d CH50 very low or zero Missing C3, C5, C6, C7, C8, or C9
- Anti-C1q autoantibodies AH50 very low or zero
Angioedema - C1 inhibitor antigenic assay Late components low Missing factor H or factor I
- C4 and C1q (especially C3)
- Acquired anti-C1q autoantibody CH50 and AH50 low
aHUS - CH50 - Factor H
- AH50 - Factor B
- C3 - Factor I
- C3a/C3d - Anti-factor H antibody
- C3 nephritic
factor
MPGN - CH50 - Factor H
- AH50 - Factor I
- C3 - Anti-factor H antibody
- C3a/C3d
- C3 nephritic