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Abstracts 115 were consistent between serum sets (9th WS and local) and within families. Five individuals were excluded as offspring of putative parents on the basis of HLA typing. Considerable polymorphism was observed at each locus with a majority of the WHO-recognized alleles represented in the parental sample, albeit at low frequency. Six parental haplotypes carried A locus alleles which were not identical to WHO-recognized specificities. All appeared to be Awl9 related specificities, one identical to the A19v specificity described in American Blacks (Ward, F.E. et al., Hum Immunol 2:255, 1981) and another (found in three families) related to AW33 and AW34. B locus alleles occurred at frequencies less than 10%. Four B locus variants were observed; all appeared distinct from WHO-recognized specificities. Bxl, a Bw6 associated specificity, occurred in three families, and was reactive with some B5-B35 CREG antibodies. Bx3, found in one family, was also B5-B35 related. Bx2 was reactive with some B7 and some Bw22 sera, while Bx4 was detected only with three local broadly reactive sera. Bw4 and Bw6 were about equally frequent in the population. Cwl and Cw8 were absent; Cw6 and Cw7 were most frequent, occurring at gene frequencies of 0.20 and 0.23, re- spectively. As has been observed for several other genetic systems (Bayoumi, R.A. et al., Am J Phys Anthropol, in press), considerable polymorphism was found for all three class I gene products in spite of a high level of consanguinity. Tribal admixture and/or a selective advantage in protecting the population against P. falciparum malaria may account for this unexpectedly high level of heterozygosity. SHARING OF HLA HAPLOTYPES BETWEEN UNRELATED PATIENTS WITH CONGEN- ITAL ADRENAL HYPERPLASIA DUE TO 21-OH DEFICIENCY. Z. Layrisse, P. Guncsler, and S. Arias; I.V.1.C., Apartado 1827, Caracas 1010 A. Venezuela As a result of HLA typing performed in 114 individuals belonging to 25 families of mixed ethnic origin with at least one affected sibling, a total of 44 pathological haplotypes and 70 healthy haplotypes were found. The group included 20 patients with the salt-wasting form and seven patients with the simply virilizing type. Out of the 38 pathological haplotypes present among the salt-wasting group, 47~: were found to share the HLA-B16 (B39 or B38) or B62 specificities; the fre- quencies of these antigens among the affected haplotypes were 29 and 18% as compared with 6 and 0% among the healthy haplotypes of the same group. Among the simply virilizing form patients, haplotypes carrying B7 were unusually frequent, 29%, as compared with 0% among the healthy haplotypes. These results are markedly different to those reported in the literature that show an association at the population level among Caucasians of HLA-Bw47 and B5 with the salt-wasting and simply virilizing forms of the disease, respectively. Further- more, three of the unrelated patients reported here were homozygous for the HLA-A, C, B, and DR loci while six others were homozygous for at least two HLA loci. Analysis of the geographical origin of the grandparents indicates clus- tering of the deficiency carrier HLA haplotypes. This observation, together with the excess of HLA homozygotes among the patients in this country, suggests that 21-OH congenital adrenal hyperplasia of both forms, salt-wasting and simply virilizing, is mostly the result of a founder effect and thus of a lower than expected number of independent mutations. HLA AND IgA DEFICIENCY IN BLOOD DONORS. Rosemarie Strothman, Jeffrey Testin, Sanking N. Chen, and Margaret J. Ball; American Red Cross Blood Services. Fort Wayne, IN Selective IgA deficiency is the most common immunodeficiency in humans. By screening 18,864 healthy blood donors, we have established a panel of 51 IgA

HLA and IgA deficiency in blood donors

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Page 1: HLA and IgA deficiency in blood donors

Abstracts 115

were consistent between serum sets (9th WS and local) and within families. Five individuals were excluded as offspring of putative parents on the basis of HLA typing. Considerable polymorphism was observed at each locus with a majority of the WHO-recognized alleles represented in the parental sample, albeit at low frequency. Six parental haplotypes carried A locus alleles which were not identical to WHO-recognized specificities. All appeared to be Awl9 related specificities, one identical to the A19v specificity described in American Blacks (Ward, F.E. et al., H u m Immunol 2:255, 1981) and another (found in three families) related to AW33 and AW34. B locus alleles occurred at frequencies less than 10%. Four B locus variants were observed; all appeared distinct from WHO-recognized specificities. Bxl , a Bw6 associated specificity, occurred in three families, and was reactive with some B5-B35 CREG antibodies. Bx3, found in one family, was also B5-B35 related. Bx2 was reactive with some B7 and some Bw22 sera, while Bx4 was detected only with three local broadly reactive sera. Bw4 and Bw6 were about equally frequent in the population. Cwl and Cw8 were absent; Cw6 and Cw7 were most frequent, occurring at gene frequencies of 0.20 and 0.23, re- spectively. As has been observed for several other genetic systems (Bayoumi, R.A. et al., Am J Phys Anthropol, in press), considerable polymorphism was found for all three class I gene products in spite of a high level of consanguinity. Tribal admixture and/or a selective advantage in protecting the population against P. falciparum malaria may account for this unexpectedly high level of heterozygosity.

SHARING OF HLA HAPLOTYPES BETWEEN UNRELATED PATIENTS WITH CONGEN- ITAL ADRENAL HYPERPLASIA DUE TO 21-OH DEFICIENCY. Z. Layrisse, P. Guncsler, and S. Arias; I.V.1.C., Apartado 1827, Caracas 1010 A. Venezuela

As a result of HLA typing performed in 114 individuals belonging to 25 families of mixed ethnic origin with at least one affected sibling, a total of 44 pathological haplotypes and 70 healthy haplotypes were found. The group included 20 patients with the salt-wasting form and seven patients with the simply virilizing type. Out of the 38 pathological haplotypes present among the salt-wasting group, 47~: were found to share the HLA-B16 (B39 or B38) or B62 specificities; the fre- quencies of these antigens among the affected haplotypes were 29 and 18% as compared with 6 and 0% among the healthy haplotypes of the same group. Among the simply virilizing form patients, haplotypes carrying B7 were unusually frequent, 29%, as compared with 0% among the healthy haplotypes. These results are markedly different to those reported in the literature that show an association at the population level among Caucasians of HLA-Bw47 and B5 with the salt-wasting and simply virilizing forms of the disease, respectively. Further- more, three of the unrelated patients reported here were homozygous for the HLA-A, C, B, and DR loci while six others were homozygous for at least two HLA loci. Analysis of the geographical origin of the grandparents indicates clus- tering of the deficiency carrier HLA haplotypes. This observation, together with the excess of HLA homozygotes among the patients in this country, suggests that 21-OH congenital adrenal hyperplasia of both forms, salt-wasting and simply virilizing, is mostly the result of a founder effect and thus of a lower than expected number of independent mutations.

HLA AND IgA DEFICIENCY IN BLOOD DONORS. Rosemarie Strothman, Jeffrey Testin, Sanking N. Chen, and Margaret J. Ball; American Red Cross Blood Services. Fort Wayne, IN

Selective IgA deficiency is the most common immunodeficiency in humans. By screening 18,864 healthy blood donors, we have established a panel of 51 IgA

Page 2: HLA and IgA deficiency in blood donors

116 Annual AACHT Meeting, 1985

deficient donors in our region, as a part of the American National Red Cross Rare Donor Registry, to provide blood products to IgA deficient patients who may experience anaphylactic reactions on exposure to human IgA. The criterion we used to define IgA deficiency was that no IgA be detectable in the serum by an Ouchterlony double diffusion assay on two consecutive donations and a con- firmative testing using the hemagglutination inhibition method with a sensitivity of 0.10 mg/dl. Thus, the incidence of IgA deficiency by this criterion in ouJ - population is 0.27% as compared to the reported range of 0.03-0.30%. Anti- IgA antibodies were present in the sera of 20 out of these 51 healthy IgA deficient blood donors. Fourteen had class-specific (react with all the IgA proteins) and six had limited-specific (react with only some of the IgA proteins) anti-lgA an- tibodies. Several recent reports indicated that IgA deficiency is associated with autoimmune disease, allergy, and possible neoplasia. Since IgA deficiency is found in many familial instances, we were interested in determining if there is an underlying genetic predisposition. We have performed HLA-A, B, C typing on the 33 unrelated healthy donors with selective IgA deficiency. Preliminary results showed a significant association with HLA A1 (p < 0.01) and B14 ~p < 0.001). The frequency of HLA A29 and B8 was also increased (p < 0.05). In addition~ a negative association with HLA A2 and B7 was found (p < 0.05). These data suggest that there is a gene within the human major histocompatibility complex that may be relevant in IgA deficiency. However, the pathogenesis of IgA de~ ficiency may be multifactorial. Studies are in progress to include family studies and HLA DR typing to determine the possible associations of HLA antigens with the extent of anti-IgA antibody formation by the IgA deficient healthy donors as well as any association with a specific immunophysiological mechanism to develop IgA deficiency by these individuals.

HUMAN IMMUNE RESPONSES TO SEQUENTIAL POLYPEPTIDES, Poly(Tyr-Ala-Glu-Gly) AND Poly(Tyr-Glu-Ala-Gly). M.M. Chan, C.A. Van Beneden, S.H. Hsu, D. Meyers, and W.B Bias; The Johns Hopkins University School of Medicine. Baltimore, MD

Polypeptides with repeating amino acid sequences have limited primary and secondary structures and, thus, possess restricted antigenic determinants. It was found that murine immune responses to the three related polypeptides, poly(Tyr~ Ala-Glu), poly(Tyr-Glu-Ala-Gly), and poly(Tyr-Ala-Glu-Gly), were controlled by at least two genes, one within the MHC and another outside the MHC. The non-MHC gene controlled the level of antibody biosynthesis to the specific antigen.

We have recently studied human in vitro lymphoproliferative responses to two sequential polypeptides, (T-G-A-Gly), and (T-A-G-Gty)n. Since these poly- peptides have very restricted antigenic determinants, the percent of responders in the general population is low. Of a 176-member panel, only 10% of subjects responded to these two antigens. Seven nuclear families and two three-generation families were tested with both antigens. Three matings between nonresponders to both antigens produced only nonresponder children. Two nuclear families and one three-generation family were informative for segregation analysis for (T-G-A-GIy).. As for (T-A-G-Gly),, only one family was informative. In these families, response phenotypes of the offspring segregated with appropriate pa- rental HLA haplotypes. However, in four of the families studied, HLA-identical sibs were found to be discordant in their responses. This suggests that human responsiveness to these molecules, as observed in the mouse, may involve in- teraction of the HLA-linked Ir genes with gene(s) outside the MHC. Studies on localization of possible non-HLA interacting gene(s) by linkage analysis with other polymorphic markers in a selected subset of families are in progress. (Supported by grant 1 R01AI17431-01A1-NIH.)