Carolyn M. Giles

EXTENDED MHC HAPLOTYPES IN 21-HYDROXYLASE-DEFICIENCY CONGENITAL ADRENAL HYPERPLASIA: SHARED GENOTYPES IN UNRELATED PATIENTS

HLA, complement, and glyoxalase I alleles were studied in 29 families in which at least one member has classical 21-hydroxylase-deficiency congenital adrenal hyperplasia. A rare complement allele, C4B*31, was found in over 20% of the haplotypes defined in these families and was always part of the complement haplotype BF*F, C2*C, C4A*Q0, C4B*31 (abbreviated FCO,31). The haplotype containing this rare set of complement alleles always carried the rare HLA allele, HLA-Bw47, usually carried HLA-A3, and almost always had the alleles HLA-Cw6, HLA-DR7, and the glyoxalase I (GLO) allele GLO1. Thus over 20% of the haplotypes in the population studied contained all or almost all of the rare extended haplotype HLA-(A3), Bw47, Cw6,DR7, FCO,31, GLO 1. 3 other haplotypes were each found twice in unrelated patients concordant for their disease phenotype and ethnic background. Extended MHC haplotypes may be markers for different genetic mutations causing 21-hydroxylase deficiency.

Genetics of human C4 polymorphism: detection and segregation of rare and duplicated haplotypes.

Applying a combined technology for the detection of allotypec variation of the fourth component of human complement (C4), including immunofixation with anti-C4 and C4-dependent lysis after agarose electrophoresis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis of C4 to separate the C4A and B α-chains, and the determination of Rodgers (Rg) and Chido (Ch) determinants of C4 in serum and at the blotted C4 α-chains, we detected rare human C4 allotypes and studied the genetic linkage. Partial inhibitors (p. i.) of anti-Rg and anti-Ch sera were found; the C4A51 allotype characterized as Rg p. i. and the C4A1 and C4B51 allotypes as Ch p. i. were genetically inherited. The C4A1 allotype has a unique Rg- Ch+ C4A α-chain. Duplicated C4A loci, A*3, A*2, and A*5, A*2 were both associated with a C4BQO and the HLA haplotype A3-Cw4-Bw35-DR1. These additions to the already known extensive C4 polymorphism may help to sort out their significance for the biological functions of human C4.

Anti-Sda, a New Blood Group Antibody

Over a period of years, the sera of a number of unrelated persons have been shown to possess an iso-antibody capable of reacting with the majority of red cell samples of adult Caucasians. The strength of the reaction varies widely among individual cell samples, the first strong reactor being a volunteer donor, S. S. and with his permission the antigen has been named after him. The antigen is to be called Sda and if it is not shown to be related to any known blood group system, then the system to which it belongs will be called ‘Sid’. The agglutination of Sd(a+) red cells is characterised by the appearance of well-defined agglutinates among a large number of free cells as shown in Plate I.

Antigenic determinants expressed by human C4 allotypes; a study of 325 families provides evidence for the structural antigenic model

The antigenic determinants of human C4 have been defined by human IgG antisera, Rodgers (Rg) and Chido (Ch), in hemagglutination-inhibition assays (HAI). Eight (2 Rg and 6 Ch) are of high frequency, > 90% , and 1, WH, is of low frequency, 15 %. The phenotypic combinations are complex; generally, C4A expresses Rg, and C4B has Ch, but reverse antigenicities have been established both by HAI and by sequence data of selected C4 allotypes. A study of 325 families provides data on the antigenic expression of each C4 allotype and demonstrates strong associations. A structural model for the antigenic determinants of C4 proteins has been proposed and is completely supported by the family material. Of the 16 possible antigenic combinations for C4 proteins, only 3 are undetected. A new Ch combination has been recorded in two French families. The reported sequence variation within the C4d region can account for the antigenic determinants but leaves the location of electrophoretic variation in C4 still unclear.

Apparent depression of antigens of the Kell blood group system associated with autoimmune acquired haemolytic anaemia.

Abstract. A case is reported of a young male patient who developed autoimmune haemolytic anaemia. During the acute phase, anti‐Kpb was detected in his serum and his antigens of the Kell system were markedly depressed. On remission, the antibody disappeared and the Kell antigens were normally expressed.

Three Chido determinants detected on the B5Rg+ allotype of human C4: Their expression in Ch-typed donors and families

A study was made of polyspecific human allo-anti-C4, anti-Chido (Ch), which reacts with determinants usually located on C4B protein. Some anti-Ch reagents are capable of reacting with Ch- red cells coated with C4 from Ch:-1,-2,-3 donors. A complex serologic pattern demonstrated three more Ch determinants, Ch4, Ch5, and Ch6, which were detected by haemagglutination-inhibition tests. All Ch:1,2,3 samples were Ch:4,5,6 but samples lacking one or more of the Ch1,Ch2,Ch3 series of determinants also lacked some of the new determinants. MHC typed families demonstrated the inheritance of the new determinants as part of the Ch haplotype, and associations with C4 allotypes and haplotypes have been established. Ch4 always associates with C4B protein. Ch5 and Ch6, normally detected on C4B protein, were detected in several individuals who lacked C4B (BQO allotypes) and were therefore presumed in these instances to be located on the accompanying C4A protein.

‘Partial Inhibition’ of Anti-Rg and Anti-Ch Reagents

Abstract. Many examples of anti‐Rg (Rodgers) and anti‐Ch (Chido) have been studied by titration‐inhibition to assess their ability to detect partial inhibition (p.i.). Generally, anti‐Rg distinguishes the inhibition type Rg+ from Rg(+) (p.i.) and Rg–, whereas anti‐Ch distinguishes Ch– from Ch+ and Ch(+) (p.i.). Serological procedures for the detection of p.i. in random samples and the results of typing one family, apparently giving anomalous results, are discussed.

Partial C4 Deficiency in Subacute Sclerosing Panencephalitis

In an immunogenetic study, 23 subacute sclerosing panencephalitis (SSPE) patients and their families were studied for the HLA region markers HLA-A, B, C, DR, BF, C2, C4A, C4B, GLO I, and PGM3. In addition, C3, C4, and factor B serum levels were determined. A highly significant association of C4A*QO with SSPE was found. Furthermore, two rare haplotypes, C4A*QOB*9QO, two C4ACh+ allotypes, and four Ch partial inhibitors were detected, which possibly impair the function of the C4 molecules. HLA-DR5 was increased. In addition, a number of rare HLA-A, C, B, DR haplotypes were observed. It is postulated that rare C4 molecular deficiency might be a predisposing factor in the pathogenesis of SSPE.

A British Family Possessing two Variants of the MNSs Blood Group System, Mv and a New Class Within the Miltenberger Complex

Abstract. A naturally‐occurring anti‐Mv was identified. The family of the Mv propositus was studied and shown to contain another variant of the MNSs blood group system. A weak N antigen was associated with a reaction with anti‐Hil, part of the Miltenberger complex. A new class (V) was revealed which is Vw(‐) Mi(a‐) Mur(‐) Hil(+).

A new genetic variant for Chido

A new and distinct partial inhibition pattern was observed for Chido during routine typing; it is found in 3% of random samples, shows recessive inheritance and is linked to HLA. Polyspecificity in anti‐Ch reagents, selected to detect partial inhibition, is demonstrated.