Inherited deficiency of C8 in a patient with recurrent meningococcal infections: Further evidence for a dysfunctional C8 molecule and nonlinkage to the HLA system

Abstract

An adult male with recurrent meningococcal infections is reported whose serum lacked functional C8 activity but possessed antigenic C8. The addition of 1500 U of purified C8/ml of serum restored hemolytic activity to normal. Four to five times more C8 was required to restore bactericidal activity than to restore hemolytic activity. Bactericidal activity could also be restored by mixing the patient's serum with a second C8-deficient serum that lacked detectable antigenic or functional C8. The patient's serum contained bactericidal antibody for groups A, B, C, and Y meningococci and specific antibody to group Y capsular polysaccharide. There was two to three times more bactericidal antibody activity in the serum than in a pool of normal sera for the infecting strain. Family studies disclosed a sibling who was HLA identical to the patient but whose serum contained normal amounts of total hemolytic and C8 functional activity.

Two types of dysfunctional eighth component of complement (C8) molecules in C8 deficiency in man. Reconstitution of normal C8 from the mixture of two abnormal C8 molecules.

“…A similar phenomenon has been reported in the reactive hemolysis system where acute phase reactant and NHS provide the source of C56 and C7, respectively (18,19). The appearance of lines of hemolysis does not contradict the conclusion of previous studies (5,6,8,9,11,13), which established the lack of hemolytic activity in these sera. This was confirmed in the present study by the absence of hemolytic rings surrounding the individual wells.…”

“…Sera from seven unrelated C8-deficient subjects were examined in this study. Detailed analysis carried out previously on each of these sera permitted the distinction between one group of four sera (group 1) with dysfunctional C8 (9,11,13) and a second group of three sera (group 2) with antigenically undetectable C8 (5,6,8). All the four sera of group 1 have been shown to contain abnormal C8 consisting only of the a-y-subunit (11,14).…”

“…These sera are thought to completely lack the C8 molecule (5)(6)(7)(8). Other patients owe their C8 deficiency to a dysfunctional C8 molecule that cross-reacts antigenically with C8 in the serum of normal individuals (9)(10)(11)(12)(13). Analysis of these dysfunctional C8 molecules has established that they lack the C8f3-chain (11,12,14).…”

Ca2+-activated K+ efflux limits complement-mediated lysis of human erythrocytes.

“…Pools ofsera were derived from blood obtained by cardiac puncture of carbon dioxide narcotized outbred Hartley guinea pigs. Human serum genetically deficient in C8 (8,9) was provided by Dr. Peter Rice, Boston University Medical School. The sera used as complement sources were aliquotted and stored at -70°C; new aliquots were used for each experiment.…”

Complement induces a transient increase in membrane permeability in unlysed erythrocytes.

“…Lysis and Na+ uptake by EA exposed to C8-deficient serum with and without the addition of isolated C8. 20 Ml of either C8 (20 U) or GBV. D2' were added to 30 ,l of C8-deficient serum.…”