Donald Raum

Inherited deficiency of the second component of complement. Rheumatic disease associations.

The prevalence of homozygous and heterozygous deficiency of the second component of complement (C2) was determined in patients with rheumatic disease including 137 with systemic lupus erythematosus (SLE), 274 with juvenile rheumatoid arthritis, and 134 with rheumatoid arthritis. 1 C2 homozygous deficient and 19 possible heterozygous deficient individuals were identified by using both immunochemical and functional assays to determine C2 levels. Of the 20, 8 had SLE (5.9%), 10 had juvenile rheumatoid arthritis (3.7%), and 2 had rheumatoid arthritis (1.4%), the homozygous deficient individual having SLE. The prevalence of C2 deficiency in the SLE and juvenile rheumatoid arthritis patients was significantly increased (P = 0.0009 and P = 0.02, respectively) when compared with controls, 6 (1.2%) of 509 blood donors having C2 levels consistent with heterozygous deficiency. 15 of the 20 C2 deficient patients were HLA typed and found to have antigens A10(Aw25), B18, or both. The patients with C2 deficiency and SLE had earlier age of onset of disease and less antinuclear antibody when compared with the C2 normal SLE patients. 11 families of the propositi were studied and found to have one or more C2 heterozygous deficient individuals. The family members had an equal distribution of rheumatic disease and antinuclear antibody in the C2 deficient and C2 normal groups. C2 deficient individuals were found to have significantly lower levels of properdin Factor B (242 mug/ml+/-54) when compared with the non-C2 deficient family members (282 mug/ml+/-73). These data support the concept that inherited deficiency of C2 is significantly associated with both SLE and juvenile rheumatoid arthritis.

Serum Complement ‘Supergenes' of the Major Histocompatibility Complex in Man (Complotypes)

Abstract. The loci for the complement proteins C2 and BF, and the two loci for C4 arc closely linked to one another. In many hundreds of meioses no crossing over has been detected between these loci. In addition, the alleles of these four loci occur in specific combinations not predicted by their gene frequencies in much the same way as alleles of the Rh and MNS systems. These units are termed complotypes. There are 14 complotypes with frequencies in excess of 1% in our study population of normal sixth chromosomes from Caucasians. Since they are also intimately associated with HLA‐DR, complotypes may also be of importance in screening programs for transplantation.

GENETIC MARKER FOR INSULIN-DEPENDENT DIABETES MELLITUS

A rare genetic type (Bf F1) of properdin factor B is found in 22.6% of patients with insulin-dependent diabetes mellitus but in only 1.9% of the general population, yielding a relative risk of 15.0. This indicates that a genetic locus for insulin-dependent diabetes mellitus is very close on chromosome 6 to Bf, and that Bf F1 is a marker for nearly 1 out of 4 insulin-dependent diabetic patients.

Studies of hepatic synthesis in vivo of plasma proteins, including orosomucoid, transferrin, α-antitrypsin, C8, and factor B

Abstract Serum protein types were determined in eight recipients and donors in cases of hepatic homotransplantation. A change from recipient type to donor type was observed for factor B, C8, orosomucoid, haptoglobin, transferrin, α1-antitrypsin, C3 and C6, but not for Gm and Inv immunoglobulin markers. The results indicate that all the proteins studied (except immunoglobulins) are produced primarily by the liver in vivo.

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.

Extended major histocompatibility complex haplotypes in man: Role of alleles analogous to murine t mutants

Abstract Extended haplotypes involving HLA-A,B,D,DR, the complotypes, and glyoxalase I appear to occur at appreciable frequency in man and differ from population to population. We here suggest that, in addition to previously recognized mechanisms for the generation and maintenance of such haplotypes (selection for immune response or other advantageous genes, recent mutation, and others), features similar to those exhibited by murine t mutants may be important. Two such features, a positive transmission bias from the male and crossover suppression for a large segment of the human sixth chromosome, are sufficient to explain a number of phenomena and characteristics of the major histocompatibility complex in man. The presence of t -like alleles having these features provides at least partial explanations for the observed linkage disequilibria in different human populations, for much of the observed HLA allele—disease associations (including the “protective” effects of certain alleles), and for the observed higher crossover rate in females than males of genes on the short arm of the sixth chromosome. The presence of such t -like mutants at appreciable frequencies requires a reassessment of chromosomal map distances in this region and of the role of other specific known genes in the evolution of the major histocompatibility complex.

The chromosomal order of genes controlling the major histocompatibility complex, properdin factor B, and deficiency of the second component of complement.

The relationship of the genes coding for HLA to those coding for properdin Factor B allotypes and for deficiency of the second component of complement (C2) was studied in families of patients with connective tissue disorders. Patients were selected because they were heterozygous or homozygous for C2 deficiency. 12 families with 15 matings informative for C2 deficiency were found. Of 57 informative meioses, two crossovers were noted between the C2 deficiency gene and the HLA-B gene, with a recombinant fraction of 0.035. A lod score of 13 was calculated for linkage between C2 deficiency and HLA-B at a maximum likelihood value of the recombinant fraction of 0.04. 18 families with 21 informative matings for both properdin Factor B allotype and HLA-B were found. Of 72 informative meioses, three recombinants were found, giving a recombinant fraction of 0.042. A lod score of 16 between HLA-B and Factor B allotypes was calculated at a maximum likelihood value of the recombinant fraction of 0.04. A crossover was shown to have occurred between genes for Factor B and HLA-D, in which HLA-D segregared with HLA-A and B. These studies suggest that the genes for Factor B and C2 deficiency are located outside those for HLA, that the order of genese is HLA-A, -B, -D, Factor B allotype, C2 deficiency, that the genes coding for C2 deficiency and Factor B allotypes are approximately 3--5 centimorgans from the HLA-A and HLA-B loci, and that the apparent lack of recombinants between the Factor B gene and C2 deficiency gene suggests that these two genes lie in close proximity to one another.

Genetic control of the eighth component of complement.

Using isoelectric focusing in polyacrylamide gel and a hemolytic assay for development of patterns, extensive, structural polymorphism in human C8 has been delineated. Two alleles, C8A and C8B, have been identified in orientals, with gene frequencies of 0.655 and 0.345. In blacks, what appears to be a third common allele was found, so that frequencies were 0.692, 0.259, and 0.049 for C8A, C8B, and C8A1. In whites, C8A1 was rare with a frequency of 0.003, and frequencies for C8A and C8B were 0.649 and 0.349. Inheritance was autosomal codominant in family studies and the distribution of types in random unrelated populations fit the Hardy-Weinberg equilibrium in all groups. C8 allotypes have been determined for two previously studied families, each with a homozygous C8-deficient propositus. This study suggests that C8 deficiency is a silent or null allele of the C8 structural locus, and that half normal levels of C8 cannot be used as a single criterion for the establishment of heterozygous C8 deficiency. C8 allotypes, as well as 18 other autosomal markers, were also determined for 24 families. The C8 structural locus is not closely linked to these markers, including the human histocompatibility loci complex.

Complement-human histocompatibility antigen haplotypes in C2 deficiency.

C4 allotyping 13 homozygous C2-deficient individuals demonstrated 23 of 25 haplotypes to be of the relatively rare type C4A4 B2. This is of the same magnitude as the association of C2Q0 with HLA-DW2/DR2.

The location of C2, C4, and BF relative to HLA-B and HLA-D.

The loci forHLA-A, B, C, D, andDR are known to be closely linked to the structural loci for the complement components C2, BF, and the duplicated loci for C4, C4A and C4B. Conflicting evidence has been presented for the order of these genes. However, new techniques have made possible identification of markers in theHLA-D andC4 region for nearly all identified haplotypes. In our population we have confirmed fiveHLA-B-D crossovers and in each case informative allotypes of C2, BF, or C4A and C4B segregated withHLA-D orDR suggesting that the loci for these proteins lie close toHLA-D andDR. These findings may be of importance for resolving problems encountered in the assignment ofHLA-D alleles.