Selective deficiency of immunoglobulin A2.

A case of familial selective IgA2 deficiency is described. The mother had no detectable IgA2, but a low level of IgA1. She had anti-alpha 2 antibodies of the IgG class. One of her daughters also lacked IgA2 with a normal level of IgA1. The analysis of the immunoglobulin haplotypes of the family suggested the deletion of the alpha 2-gene. In addition, the analysis of B lymphocytes of mother and daughter showed the absence of IgA2-bearing cells. Upon stimulation with pokeweed mitogen, the B cells differentiated into IgA1-containing plasma cells, but IgA2-containing cells were not found. The results suggest a defect in the generation of intraclonal B cell isotype diversity. The molecular basis of this phenomenon is unknown.

Correlation between G2m(n) immunoglobulin allotype and human antibody response and susceptibility to polysaccharide encapsulated bacteria.

To determine whether genetic factors influence the human antibody response to polysaccharides, we correlated Ig allotypes with the concentrations of antibody to 14 bacterial capsular antigens in 130 actively immunized Caucasian adults. The 88 individuals possessing G2m(n), an allotype antigen of IgG2 subclass heavy chains, had significantly higher postimmunization antibody levels to Haemophilus influenzae type b (Hib) and 8 of 11 pneumococcal types (P less than 0.05) than the 42 lacking this antigen. For Hib, pneumococcus type 14, and meningococcus group C, an increased response was observed in IgG class but not in IgM or IgA classes of antibody. The G2m(n) positive individuals also had higher preimmunization antibody levels to most polysaccharide antigens. Total IgG2 concentrations were correlated with the mean postimmunization antibody concentrations to pneumococci (P = 0.005), but this correlation was independent of G2m(n) by multiple regression analysis. To determine if the lack of G2m(n) was associated with increased susceptibility to infection, we compared the frequencies of various Ig allotypes in 98 children infected with Hib and 98 matched controls. Caucasian children with Hib infections other than epiglottitis were significantly more likely to lack the G2m(n) allotype than controls (P less than 0.05). G2m(n) negative Caucasian children less than or equal to 18 mo old have a 5.1-fold higher risk of nonepiglottitic Hib infections than G2m(n) positive children (P less than 0.01). We conclude that allotypic variants of the gamma-2 heavy chain genes, or genes in linkage equilibrium with them, exert a regulatory influence on the caucasian antibody response to a variety of immunologically distinct bacterial polysaccharide antigens. Young Caucasian children of the low responder phenotype, i.e., those lacking the G2m(n) allotype, are genetically predisposed to Hib and perhaps other bacterial infections.

Allotypic and isotypic aspects of human immunoglobulin A.

The location of isotypic, isoallotypic and allotypic determinants is reviewed in the light of data obtained when specific antisera are tested with proteolytic fragments of IgA molecules or mutants of IgA obtained from patients with alpha-heavy chain disease. Isotypic determinants are distributed throughout the alpha chain constant regions although when intact IgA proteins are used as immunogens the CH3 domain is immunodominant. Alpha 1 subclass specific isotypic determinants are present in both Fab and Fc fragments. Amino acid sequence analysis suggest that alpha 1 subclass isotypic determinants depend on substitution in the CH1, hinge and/or CH2 domain. The isoallotypic determinants nA2m(2) appears to be located on the CH1 domain and appears to require disulphide-linked alpha chains for its expression. The allotypic determinant A2m(2) appears to be located in the CH3 domain involving residues 428, 458 and/or 467. The latter residues are present in both A2m(1) and A1 proteins which indicates that for A2m(1) to be the antithetical determinant of A2m(2), the determinant formed by residues 428, 458 and/or 467 in these proteins must be influenced by subclass differences which allows its expression in A2m(1) proteins and not in A1 proteins.

Gene conversion in human immunoglobulin gamma locus shown by unusual location of IgG allotypes.

The constant region of the gamma 1, gamma 2 and gamma 3 heavy chains of the human IgG1, IgG2 and IgG3 immunoglobulins carries antigenic determinants or G1m, G2m and G3m allotypes, which are genetic markers of these subclasses. The exceptional presence on gamma 1 and gamma 2 chains of Gm allotypes usually located on the CH3 domain of gamma 3 shows an unexpected clustering of base changes and subsequent identity of short DNA sequences in the CH3 exon of the non-allelic gamma 1, gamma 2 and gamma 3 genes. Such clusters of substitutions are not easily explained on the classical basis of point mutations. A gene conversion, which substituted a segment of the gamma 1 or gamma 2 gene with the homologous region of the non-allelic gamma 3 gene, is more likely. Other examples of possible conversion involving the gamma genes are described. The conservation or the restoration of short sequences produced by the conversion events might be related to the biological properties of the constant region of the heavy chains.

Lymphoid chimerism after allogeneic bone marrow transplantation. Y-chromatin staining of peripheral T and B lymphocytes and allotyping of serum immunoglobulins.

Lymphoid cell engraftment was monitored for several years after bone marrow transplantation by Y-chromatin staining of T and B lymphocytes in the peripheral blood and/or by immunoglobulin allotyping in the serum of 20 of 52 pediatric patients grafted successively between October 1973 and October 1983. Data on 2 patients with severe combined immunodeficiency, grafted earlier in December 1968 and April 1971, are also included. These children received an allogeneic bone marrow graft for leukemia (n = 7), severe aplastic anemia (n = 11), or severe combined immunodeficiency (n = 4) and were informative for this study, because they differed from their donor by sex (n = 16) and/or by immunoglobulin phenotype (n = 13). Of 16 pairs in which the donor was of the opposite sex, 11 patients ultimately showed circulating T and B lymphocytes of donor origin after bone marrow transplantation; in the remaining 5, there was an incomplete chimerism of the circulating lymphoid cells. Of 13 pairs with a difference in immunoglobulin phenotype between donor and recipient, 8 patients exhibited donor allotypes 3 months or later after transplantation, in 3 of them together with recipient allotypes. In the remaining 5 patients, recipient allotypes were detected after transplantation, but the simultaneous presence of donor-type immunoglobulin production could not be excluded in 4. The persistence of either a split (T lineage of donor origin and B lineage of recipient origin) or mixed (T and/or B lineage of donor and recipient origin) chimerism was related to the type of disease. In 3 children circulating B cells of donor-origin did not fit with the recipient origin of the sessile immunoglobulin-secreting plasma cells. This implies that different immune compartments--e.g., bone marrow and peripheral lymphoid tissues--should be investigated following allogeneic bone marrow transplantation. A prolonged presence of recipient-type lymphoid cells increased the risk of leukemic relapse in the patients investigated.

Gm markers in celiac disease.

The association of Ig allotypes with celiac disease was analyzed in a sample of 95 Italian patients typed for HLA polymorphisms. No significant association was found for any Gm, A2m, or Km specificity when the overall sample was considered. However, significant different sex ratios were shown by patients' fnb positive and fnb negative genotypes, with a relative risk of 10.7 for this haplotype in males, suggesting that sex and Gm influence the penetrance of the HLA-linked genes. The significance of this finding is strengthened by the recent report that H-2 and Ig allotypes intervene in the genetic control of murine immune response to A-gliadin (M.F. Kagnoff, Nature 296:158, 1982).

HLA and GM in insulin-dependent diabetes in the Netherlands: report on a combined multiplex family and population study.

This report deals with the genetic factors involved in insulin-dependent diabetes mellitus (IDD) in The Netherlands. Twenty-two Dutch multiplex families with IDD were typed for HLA-A, -B, -C, and -DR antigens, for BF, C2, C4, and GLO polymorphisms, as well as for GM allotypes of immunoglobulins. In addition, 53 unrelated IDD children and 31 unrelated patients with adult onset IDD were typed for HLA-A, -B, -C, and -DR antigens. A significant heterogeneity for the frequency of HLA-DR4 related to age of onset was observed. A significant deviation of the Hardy-Weinberg equilibrium was observed for the HLA-DR locus with an excess in patients of heterozygotes HLA-DR3, -DR4.HLA-B8, and HLA-B15 were not only secondary associated, but constituted with HLA-DR3 and -DR4, respectively, a haplotype in association with IDD. Nonrandom segregation of HLA-haplotypes was observed in multiplex families exemplified by an excess of HLA-identical affected sibpairs . Cross- overs between HLA-DR and GLO identified the HLA-DR segment as mainly involved in the association with IDD. Three diabetic haplotypes were confirmed to occur frequently among affected sibs: (a) A1, B8, BFS, C2.1, C4AQO , C4B1 ,DR3, GLO2 ; (b) Aw30, Cw5 ,B18,BFF1,C2.1, C4A3 , C4BQO ,DR3, GLO2 ; (c) A2,Cw3, B15,BFS, C2.1, C4A3 , C4B3 , DR4,GLO1. The segregation of GM allotypes to affected sibpairs was not significantly different from random segregation. The main conclusions from this study are that significant heterogeneity for age of onset exists and that the data are not compatible with simple genetic models including dominant, recessive, and intermediate models of inheritance. The data do require more complex models, involving two different HLA-linked (sets of) susceptibility genes.

Linkage studies in autosomal dominant facioscapulohumeral muscular dystrophy.

Linkage studies were undertaken in 120 individuals from 10 kindreds with autosomal dominant facioscapulohumeral muscular dystrophy using 35 different marker genes. No linkage was found. The highest lod score was 1.438 for the immunoglobulin heavy chain gene cluster (IGH) at a recombination fraction of 0.2. IGH is located on the long arm of chromosome 14. Based on scores of other marker genes and on a recombination map of chromosome 14, the probability that the gene for facioscapulohumeral muscular dystrophy is located on chromosome 14 is estimated to be approximately 6%.

Antigenic analysis of the IgA component of LDH-IgA immunoglobulin complexes.

LDH-IgA complexes present in some human sera were purified by using affinity chromatography on 5'-AMP-Sepharose 4-B. The IgA component of the purified complexes was analysed in haemagglutination-inhibition tests. Antigenic determinants specific for alpha1 and alpha2 heavy chains and for kappa and lambda light chains were found. Earlier studies suggested that the IgA component is of kappa light chain type only. These different results are discussed. It is suggested that the LDH association site is located in the Fab fragment of the IgA component.

On the nature of the genes influencing the prevalence of Graves' disease.

Burnet's theory that Graves' and other autoimmune diseases are caused by forbidden clones of immunocytes, reactive against host antigens and emerging in post-natal life due to somatic events (somatic mutations of V genes and inter-clonal deletions), remains the most comprehensive and likely concept of the pathogenesis. The MHC antigens, B8 and D/DR3, have a predisposing influence of X 2.5 and X 3.7 respectively, whilst male sex has a protective influence, divided by 6. Family studies testing for associated inheritance of Graves' disease and immunoglobulin allotypes (Gm and Km), by observation of the segregation of known heterozygous allotypes and also by Penrose's sibling pair method, have failed to show involvement of immunoglobulin genes. The H gene theory, prompted by studies on the inheritance of autoimmune diseases in the New Zealand mice, postulates that germline genes influencing the prevalence of Graves' and other autoimmune diseases code for major and minor histocompatibility or other alloantigens. By deleting complementary clones, alloantigens alter the immune response repertoire of each individual and this could alter the chance of emergence of a forbidden clone by the somatic mutations and the inter-clonal deletions envisaged by Burnet and Jerne. The H gene theory is superior to the linkage disequilibrium theory in that it accounts for all the known genetic features of Graves' disease, including the female sex preponderance, which is ascribed to the effect of clonal deletions imposed by the H-Y antigen.

Immunoglobulin heavy chain haplotypes in caucasian New Zealanders.

In the course of studies on the genetic basis of autoimmune disease, immunoglobulin allotypes were measured in New Zealand people of caucasian origin. We report the observed frequencies of the various allotypes of the gamma heavy chains, together with the frequencies of the combinations observed to occur in individuals (phenotypes) and the nature and frequency of the combinations on individual chromosomes (haplotypes), as calculated by application of Kurczynski and Steinberg's computer programme MAXIM.

Genetically determined deficiencies in IgA and IgG.

Disturbance in the immune response can be caused by malfunction of T and/or B cells. Certain inborn errors such as absence of enzymes in the purine salvage pathway, may lead to severe combined immunodeficiencies or to other syndromes related to impaired immune response, that are mostly diseases of infancy. Selective immunodeficiencies in one or more immunoglobulin subclasses are less severe and occur among adults. The best known is IgA deficiency. The first case of IgG3 subclass deficiency was described in 1976 [13]. Examples of IgG1 and IgG2 deficiencies are reported in this paper. The implication of structural and of regulator genes in the various defects is discussed.

The first example of an isoallotype of human IgG located on the Fd fragment.

An isoallotype of IgG is described that is an isotype on heavy chains of IgG3 and IgG4 proteins and an allotype for IgG1 proteins, in which it is associated with Glm(f). The isoallotypic determinant is located on Fd. Binding of light chains (independent of their type) is required for its antigenic expression, since isolated heavy chains are not reactive in inhibition tests. It is suggested that the coding for the amino acid sequence related to this isoallotype was present on the ancestral gene before the duplication of subclasses. The presence in many non-human primate species proves that it is strongly conserved in evolution.