Table VIII.
Complement deficiencies
| Disease | Functional Defect | Associated Features | Inheritance | Gene Defects |
|---|---|---|---|---|
| C1q deficiency | -Absent C hemolytic activity, Defective MAC * -Faulty dissolution of immune complexes -Faulty clearance of apoptotic cells |
SLE–like syndrome, rheumatoid disease, infections | AR | C1q |
| C1r deficiency* | -Absent C hemolytic activity, Defective MAC -Faulty dissolution of immune complexes |
SLE–like syndrome, rheumatoid disease, infections | AR | C1r* |
| C1s deficiency | -Absent C hemolytic activity | SLE-like syndrome; multiple autoimmune diseases | AR | C1s* |
| C4 deficiency | -Absent C hemolytic activity, Defective MAC -Faulty dissolution of immune complexes -Defective humoral immune response |
SLE–like syndrome, rheumatoid disease, infections | AR | C4A and C4B§ |
| C2 deficiency ** | -Absent C hemolytic activity, Defective MAC -Faulty dissolution of immune complexes |
SLE–like syndrome, vasculitis, polymyositis, pyogenic infections | AR | C2** |
| C3 deficiency | -Absent C hemolytic activity, Defective MAC -Defective Bactericidal activity -Defective humoral immune response |
Recurrent pyogenic infections | AR | C3 |
| C5 deficiency | -Absent C hemolytic activity, Defective MAC -Defective Bactericidal activity |
Neisserial infections, SLE | AR | C5 |
| C6 deficiency | -Absent C hemolytic activity, Defective MAC -Defective Bactericidal activity |
Neisserial infections, SLE | AR | C6 |
| C7 deficiency | -Absent C hemolytic activity, Defective MAC -Defective Bactericidal activity |
Neisserial infections, SLE, vasculitis | AR | C7 |
| C8a deficiency *** | -Absent C hemolytic activity, Defective MAC -Defective Bactericidal activity |
Neisserial infections, SLE | AR | C8α |
| C8b deficiency | -Absent C hemolytic activity, Defective MAC -Defective Bactericidal activity |
Neisserial infections, SLE | AR | C8β |
| C9 deficiency | -Reduced C hemolytic activity, Defective MAC -Defective Bactericidal activity |
Neisserial infections**** | AR | C9 |
| C1 inhibitor deficiency | -Spontaneous activation of the complement pathway with consumption of C4/C2 -Spontaneous activation of the contact system with generation of bradykinin from high molecular weight kininogen |
Hereditary angioedema | AD | C1 inhibitor |
| Factor I deficiency | -Spontaneous activation of the alternative complement pathway with consumption of C3 | Recurrent pyogenic infections, glomerulonephritis, hemolytic-uremic syndrome | AR | Factor I |
| Factor H deficiency | -Spontaneous activation of the alternative complement pathway with consumption of C3 | Hemolytic-uremic syndrome, membranoproliferative glomerulonephritis | AR | Factor H |
| Factor D deficiency | -Absent hemolytic activity by the alternate pathway | Neisserial infection | AR | Factor D |
| Properdin deficiency | -Absent hemolytic activity by the alternate pathway | Neisserial infection | XL | Properdin |
| MBP deficiency ***** | -Defective mannose recognition -Defective hemolytic activity by the lectin pathway. |
Pyogenic infections with very low penetrance mostly asymptamatic | AR | MBP ***** |
| MASP2 deficiency****** | -Absent hemolytic activity by the lectin pathway | SLE syndrome, pyogenic infection | AR | MASP2 |
| Complement Receptor 3 (CR3) deficiency | -see LAD1 in Table V, above | AR | INTGB2 | |
| Membrane Cofactor Protein (CD46) deficiency | -Inhibitor of complement alternate pathway, decreased C3b binding | Glomerulonephritis, atypical hemolytic uremic syndrome | AD | MCP |
| Membrane Attack Complex Inhibitor (CD59) deficiency | -Erythrocytes highly susceptible to complement-mediated lysis | Hemolytic anemia, thrombosis | AR | CD59 |
| Paroxysmal nocturnal hemoglobinuria | -Complement-mediated hemolysis | Recurrent hemolysis | Acquired X-linked mutation | PIGA |
The C1r and C1s genes are located within 9.5 kb of each other. In many cases of C1r deficiency, C1s is also deficient.
Gene duplication has resulted in two active C4A genes located within 10 kb. C4 deficiency requires abnormalities in both genes, usually the result of deletions.
Type 1 C2 deficiency is in linkage disequilibrium with HLA-A25, B18 and -DR2 and complotype, SO42 (slow variant of Factor B, absent C2, type 4 C4A, type 2 C4B) and is common in Caucasians (about 1 per 10,000). It results from a 28-bp deletion resulting in a premature stop codon in the C2 gene; C2 mRNA is not produced. Type 2 C2 deficiency is very rare and involves amino acid substitutions which result in C2 secretory block.
C8alpha deficiency is always associated with C8gamma deficiency. The gene encoding C8gamma maps to chromosome 9 and is normal. C8gamma is covalently bound to C8alpha.
Association is weaker than with C5, C6, C7 and C8 deficiencies. C9 deficiency occurs in about 1 per 1,000 Japanese.
Population studies reveal no detectable increase in infections in MBP deficient adults.
A single patient.
Abbreviations: MAC= Membrane attack complex SLE: systemic lupus erythematosus; MBP: Mannose binding Protein; MASP-2: MBP associated serine protease 2.