Linkage of IgA deficiency to Gm allotypes; the influence of Gm allotypes on IgA-IgG subclass deficiency

IgA deficiency (IgAD) is the most common immunodeficiency, characterized by an arrest in B cell differentiation. It has a sporadic occurrence or variable inheritance pattern, and is also linked to the HLA genes. IgA deficiency is sometimes associated with IgG subclass deficiency. In this study the Gm allotypes, as genetic characteristics of the IgG1, IgG2 and IgG3, were analysed in 83 Caucasian IgAD individuals. Half of the patients presented with IgG4 < 0·01 g/l compared with 5% (P < 0·001) in a healthy population. Three of the 83 had significantly low IgG2 and four had significantly low IgG3 levels. Gm allotype frequencies in IgAD deviated compared with a normal population. Of the 83 patients, 44 (53%) showed homozygous G2m(“,”) expression on the IgG2 locus (33% in controls, P < 0·01). In IgAD the Gm(a, g) haplotype was more frequent (43%) compared with controls (31%, P < 0·01). The Gm homozygous phenotype Gm(a', g/a', g) was most common, found in 20 of 83 patients (24%, P < 0·05) compared with controls (14%). On the other hand the Gm(f,n,b) haplotype of IgAD was rare (28%) compared with controls (45%, P < 0·001). The low IgG4, < 0·01 g/l, found in 50% of the patients, was even more frequent (56–69%) among the G2m(“,”) phenotypes. IgG subclass levels were given for different Gm phenotypes of the IgAD group and compared with controls. Significantly low IgG4 was revealed in the Gm(a,“,g/a,”,g) phenotype (P < 0·01) and significantly low IgG2 in the Gm(a,“,g/f,”,b) phenotype (P < 0·01). The Gm(a,“,g/f,”,b) phenotype contained the three patients found with IgG2 levels < - 2 s.d., and the four patients with IgG3 levels < -2 s.d. were present among those with the homozygous Gm(a,“,g/a,”,g) phenotype; both phenotypes with G2m(“,”) on the IgG2 locus. The ‘compensatory’ increase of IgG was significant for both IgG1 and IgG3 in all Gm phenotypes, but in the Gm(a,“,g/f,”,b). Thus, the susceptibility of IgAD with the additional IgG antibody deficiencies, down-regulated IgG4 and IgG2/IgG3, is associated with Gm allotypes, especially the homozygous G2m(“,”) expression on the IgG2 locus.     

Gm and Km allotypes in Charcot-Marie-Tooth disease

Gm and Km immunoglobulin allotypes were studied in 46 Caucasian patients with Charcot-Marie-Tooth disease (CMT). No significant association of Gm and Km phenotypes with CMT was found. Family studies revealed that Gm haplotypes and CMT were not inherited together, thus arguing against the involvement of immunoglobulin allotypes in CMT.     

Correlation between atopy and Gm allotypes

In 50 consecutive atopic Caucasian patients with increased IgE greater than 600 kU/l, the phenotypic Gm allotype constellation deviated from that to be expected, with significantly increased frequency of patients with the phenotype Gm(f,n,b). There was an increased frequency of the G2m(n) allotype, more frequent in patients with IgE greater than 1,000 kU/l, and in patients with IgG4 greater than 1 g/l. In patients with IgE greater than 1,000 kU/l the phenotype Gm(a,f,n,b) was significantly increased and in patients with IgG4 greater than 1 g/l the phenotype Gm(f,n,b) was significantly increased. Those atopic patients with increased IgE and increased IgG4, according to earlier studies known to have the most severe forms of the disease, were thus mainly found to have the m(f,n,b) phenotype.     

Immunoglobulin allotypes Gm and Km in hematologic malignancies

Immunoglobulin allotypes of the Gm and Km systems have been compared in patients with various forms of hematologic malignancies and healthy controls of the same ethnographic background. These comparisons found an increased frequency of the haplotype Gm and a decreased frequency of Gm in patients with Hodgkin's disease; a decreased frequency of Gm in diffuse, large-cell lymphoma patients; a decreased frequency of Gm and an increased frequency of Gm in acute myeloid leukemia patients; a decreased frequency of Gm in chronic myeloid leukemia patients, and an increased frequency of the phenotype Km(1+) in chronic lymphocytic leukemia patients. These results support previous suggestions of the involvement of immunoglobulin allotypes in the susceptibility to some forms of human hematologic malignancy.     

Gm and Km allotypes in disputed parentage.

Immunoglobulin allotyping in 925 cases of disputed paternity provided evidence of exclusion for 70 alleged fathers. Combining results from erythrocytic antigen, enzyme, and serum protein tests, 230 men were proven to be falsely accused; in 15 cases the immunoglobulin allotype provided the only evidence for exclusion, in 67 no exclusion would have been identified if testing had been limited to ABO, Rh, and MNSs. Various cases in this study illustrate the importance of using an extensive battery of immunoglobulin reagents in order maximally to exclude falsely accused men, and to identify infrequent haplotypes, which might erroneously be interpreted as indirect exclusions or may indicate a high likelihood of paternity. The problems of Gm typing of very young children are described. When child is less than 6 months of age, direct exclusions may be missed by the Gm allotypes; indirect exclusions are valid only when the phenotype differs from that of the mother. Km allotypes are not age-dependent.     

Gm allotypes in blacks with systemic lupus erythematosus

Serum samples were collected from 328 healthy American Blacks and from 61 American Blacks with systemic lupus erythematosus (SLE). Sera were typed for the Gm1,2,3,5,6,13,17, and 21 allotypes as well as for the Km(1) allotype. The frequency of Gm phenotype 1,17;5,6,13 was significantly increased in the SLE patients (p = 0.0001, RR = 3.19, EF = 0.29). Our data suggest the existence of at least two immunoglobulin allotype associated genes that somehow interact to increase susceptibility to SLE in Blacks. To our knowledge, this is the first report of an association of Gm and SLE in Blacks.     

IgG heavy chain allotypes (Gm) in autoimmune diseases.

Serum samples from 100 patients with myasthenia gravis, 322 with Graves' disease, 113 with Hashimoto's disease, 132 with systemic lupus erythematosus (SLE), 192 with insulin-dependent juvenile diabetes mellitus, 83 with Behçet's syndrome, 73 with psoriasis vulgaris, 258 with leprosy, 112 with Duchenne progressive muscular dystrophy and 343 non-related normal controls were studied for Gm allotypes. The incidence of Gm phenotypes with Gm(2) was significantly increased in patients with myasthenia gravis. Graves' disease, Hashimoto's disease, and high in SLE patients. The Gm1,2,21 haplotype was increased in patients with myasthenia gravis (chi 2 = 34 . 08, corrected P less than 0 . 001), Hashimoto's disease (chi 2 = 12 . 39, corrected P less than 0 . 05), Graves' disease (chi 2 = 8 . 65, corrected P less than 0 . 05), and SLE (chi 2 = 6 . 41, 0 . 1 greater than corrected P greater than 0 . 05). The total chi-square for the four different Gm haplotypes was significantly increased in patients with myasthenia gravis (chi 2 = 44 . 46, corrected P less than 0 . 001), SLE (chi 2 = 20 . 70, corrected P less than 0 . 005), Hashimoto's disease (chi 2 = 17 . 03, corrected P less than 0 . 025), and Graves' disease (chi 2 = 11 . 87, corrected P less than 0 . 025). Our data suggest the presence of Gm-associated pathogenic polygenes in certain autoimmune disorders.     

The association of IgG heavy-chain allotypes (Gm) with Graves' disease in Hungary

In an Eastern Hungarian population of patients, we sought to confirm an association with IgG heavy-chain allotypes (Gm) with Graves' disease. We found an increase in the phenotype fb (chi 2(1) = 4.7, p less than 0.05) among the patient group compared to controls. The influence of Ig-linked genes to Graves' disease susceptibility is, thus, dose-dependent. We found no interaction between fb homozygosity and HLA-DR3 positivity in Graves' disease susceptibility.     

Immunoglobulin concentration and Gm allotypes in a family with thirty-three cases of myotonic dystrophy

Serum IgG, IgA, and IgM concentrations were measured in 120 members of a family with 33 cases of Dystrophia myotonica (Dm) and 27 members who were "possibly affected". The Dm individuals had significantly lower serum concentrations of IgG and IgA (P<0.01), while the "possibly affected" did not differ from the matched pair controls. IgG subclass concentrations were measured and Gm and Am types determined. The lower concentration of IgA in the affected individuals was not associated with a particular Am type. The concentration of IgG3 was barely lower in the affected than in the controls (P=0.05), but there were no differences for IgGl. When IgG3 concentration was compared according to Gm haplotype, only the two affected individuals who were Gm gg had a statistically significant lower concentration than the 12 controls (P<0.02). Thus, there is no evidence that a particular subclass of IgG is being hypercatabolized in our Dm patients. A rare Gm haplotype, Gm(-, n, b) had entered the family with two brothers; it is not known whether this codes for an IgGl-IgG3 hybrid molecule or a normal IgGl molecule with an unknown Gm allele or a yl deleted Gm haplotype.     

Immunoglobulin (Gm and Km) allotypes in the Aymara of Chile and Bolivia

Immunoglobulin (Gm and Km) allotype and haplotype frequencies are presented for 1707 individuals from Northern Chile and Western Bolivia, subdividing them by ethnicity and altitude of residence. The haplotype distribution of Gm as well as Km loci in these populations suggest that in almost all of the ethnicity x altitude subdivisions of this population considerable admixture of Amerindian and Caucasian genes have occurred. The haplotype frequency heterogeneity and the analysis of departure from Hardy-Weinberg expectations demonstrate that while some local variation in haplotype frequencies at the Gm and Km loci exists in this region, there is no clear evidence suggesting that the pattern of variation is due to an adaptation to the hypoxia of altitude. We conclude that such differences in haplotype frequencies are probably due to random genetic drift and differential admixture of Amerindian and Caucasian genes that have occurred in the past.     

Association of immunoglobulin Gm allotypes with antiglomerular basement membrane antibodies and their titer

We studied the immunoglobulin Gm allotypes in 41 patients with glomerular nephritis caused by autoantibodies to glomerular basement membrane (GBM). Gm phenotypes of all 41 patients were attributable to combinations of the 3 Gm haplotypes commonly found in Caucasoid populations; identified by the allotypes Gm 1,21 (ag), Gm 1,2,21 (axg), and Gm 3,5,11 (fb). The incidence of the putative haplotype Gm 1,2,21 (axg) was greatly increased in the patients being present in 22 of 41 (56%) of patients compared to 28 of 167 controls. (P_cor = 1.5 × 10⁻⁵). The increase in Gm 1,2,21 (axg) was attributable entirely to presumed heterozygotes with the phenotype Gm 1,2,21; 3,5,11 (axg; fb), with concomitant decreases in the frequencies of patients with the phenotypes Gm 1,21 (ax) and with Gm 3,5,11 (fb). Heterozygotes at Gm loci had higher titers of anti-GBM antibodies irrespective of the presence of Gm 1,2,21 (axg). Thus genes within or closely linked to the Gm complex in addition to HLA linked genes influence susceptibility to or clinical expression of anti-GBM disease.     

The putative anti-thyrotropin receptor antibodies of Graves' disease. I. Gm allotypes

The hyperthyroidism of Graves' disease is thought to be related to antithyrotropin receptor (TSH-R) antibodies. In order to study the degree of immunogenetic homogeneity of these antibodies, we carried out Gm typing of 'receptor-purified' IgG from patients with active Graves' disease and controls. The results were compared to those of serum, total IgG and IgG which failed to attach to TSH-R. We found that in five out of seven Gm heterozygote patients studied the receptor-purified antibodies were restricted to the products of one haplotype compared to three out of five similar controls. Such eluted antibodies were biologically active. Similar results in terms of immunogenetic restriction and activity were obtained when F(ab)2 preparations were used. An unexpected finding was that sera and IgG from normal persons attached to thyroid membranes and that the attachment occurred via F(ab)2. Normal whole serum and 'receptor-purified' IgG and F(ab)2 inhibited TSH binding in the receptor assay; however, this inhibition showed no specificity for TSH-R.