A familial dysfunction of the eighth component of complement (C8)

Abstract

A 6-year-old boy, who presented with hepatosplenomegaly, moderately elevated erythrocyte sedimentation rate, hypergammaglobulinemia, and eosinophilia, was found to have very low or undetectable serum C8 hemolytic activity. This activity was restored to normal by the addition of purified C8. Material cross-reacting antigenically with C8 was present in the serum and showed reaction of partial identity with normal C8 by immunodiffusion analysis. Similar findings were observed in an apparently healthy sibling. Further investigations on the altered C8 molecule proved its inability to induce consumption of C9 in the deficient serum following activation of the alternative pathway by inulin. Both deficient sera also contained an inhibitor, which was active only on partially purified C8 used at low concentration or on diluted normal human serum. The inhibiting activity was detected in the exclusion peak of Sephadex G-200 gel filtration and was specifically removed by an anti-human C5 antiserum. Family studies showed normal hemolytic activities and antigenic levels of C8 in both parents and three other siblings of the propositus. Linkage studies of the C8 abnormality to HLA, Bf, C3, and C7 were uninformative, whereas linkage to C6 was excluded.