Hereditary deficiency of the fifth component of complement in man. I. Clinical, immunochemical, and family studies.

Abstract

A B S T R A C T The first recognized human kindred with hereditary deficiency of the fifth component of complement (C5) is described. The proband, a 20-year-old black female with systemic lupus erythematosus since age 11, lacked serum hemolytic complement activity, even during remission. C5 was undetectable in her serum by both immunodiffusion and hemolytic assays. Other complement components were normal during remission of lupus, but C1, C4, C2, and C3 levels fell during exacerbations.A younger half-sister, who had no underlying disease, was also found to lack immunochemically detectable C5. By hemolytic assay, she exhibited 1-2% of the normal serum C5 level and normal concentrations of other complement components. C5 levels of other family members were either normal or approximately half-normal, consistent with autosomal codominant inheritance of the gene determining C5 deficiency.Normal hemolytic titers were restored to both homozygous C5-deficient (CSD) sera by addition of highly purified human C5. In specific C5 titrations, however, it was noted that when limited amounts of C5 were assayed in the presence of low dilutions of either C5D serum, curving rather than linear dose-response plots were consistently obtained, suggesting some inhibitory effect. Further studies suggested that low dilutions of C5D serum contain a factor (or factors) interfering at some step in the hemolytic assay of C5, rather than a true C5 inhibitor or inactivator.

Severe infectious diseases of childhood as monogenic inborn errors of immunity

“…Likewise, defective factor D activity was first reported in a sporadic case of meningitis in 1989 (35), and the first causal mutation for this condition was described a decade later. C5 and C9 defects were first identified in 1976 and 1981, in a lupus patient and a healthy individual, respectively (36,37). Such defects then were detected in sporadic cases of Neisseria disease in 1979 and 1989 (38,39), leading to the discovery of C5 and C9 mutations.…”

Inherited incomplete deficiency of the fourth component of complement (C4) determined by a gene not linked to human histocompatibility leukocyte antigens.

“…Her erythrocytes were positive for Rodgers and Chido antigens. 22 (18) and for C3 through C9 by the methods of Nelson et al (19), as modified by Rosenfeld et al (20). Hemolytic titrations of Cl and C4 were also performed on mixtures of normal human serum and serum from the proband drawn during a period of inactive disease.…”

Genetic control of the eighth component of complement.

“…Concordant inheritance of polymorphism of C6 and C7 and of a combined defect of C6 and C7 in families suggests the linkage of C6 and C7 (9,25). Studies of the polymorphism of C4 and the C4-deficiency state have led to the conclusion that C4 is linked to HLA (5-7, 26, 27) and corresponding studies of the relevant proteins that C3 (28), C5 (29,30), C6 (31,32), and C7 (33,34,10) are not closely linked to HLA. Two studies of the relationship of C8 deficiency to HLA in large families have been described (35,13).…”

“…The (36) contained _20 ng/ml of C3 (37). Serum from a homozygous C5-deficient person (29,30) Isoelectricfocusing in thin-layer polyacrylamide gel. The method of Awdeh et al (43), modified as described previously (3), was used.…”