Human immunoglobulin allotypes

More than twenty recombinant monoclonal antibodies are approved as therapeutics. Almost all of these are based on the whole IgG isotype format, but vary in the origin of the variable regions between mouse (chimeric), humanized mouse and fully human sequences; all of those with whole IgG format employ human constant region sequences. Currently, the opposing merits of the four IgG subclasses are considered with respect to the in vivo biological activities considered to be appropriate to the disease indication being treated. Human heavy chain genes also exhibit extensive structural polymorphism(s) and, being closely linked, are inherited as a haplotype. Polymorphisms (allotypes) within the IgG isotype were originally discovered and described using serological reagents derived from humans; demonstrating that allotypic variants can be immunogenic and provoke antibody responses as a result of allo-immunisation. The serologically defined allotypes differ widely within and between population groups; therefore, a mAb of a given allotype will, inevitably, be delivered to a cohort of patients homozygous for the alternative allotype. This publication reviews the serologically defined human IgG allotypes and considers the potential for allotype differences to contribute to or potentiate immunogenicity.     

Possible existence of autoantibodies against immunoglobulin allotypes in normal rabbits, and their relation to the expression of these allotypes

The concentration of a3 allotype was increased in the serum of heterozygous a1 a3 rabbits which received antiidiotypic antibodies against anti-a3 antibodies in the perinatal period. This is explained by the normal presence of anti-a3 autoantibodies which control the expression of a3 allotype in heterozygous a1 a3 rabbits under physiological conditions.     

Molecular basis of the allelic inheritance of rabbit immunoglobulin VH allotypes: implications for the generation of antibody diversity

Rabbits are unique in that their immunoglobulin VH regions bear allotypic markers encoded by allelic genes. The presence of these markers on most serum immunoglobulins is difficult to explain, as the germline contains several hundred VH genes. We cloned VH genes from normal rabbits of the VHa allotypes a1, a2, and a3 and from a mutant a2 rabbit, Alicia, which expresses almost no a2 allotype. The D-proximal VH gene VH1 of normal rabbits encoded prototype a1, a2, or a3 allotype VH regions in a1, a2, or a3 rabbits, respectively; VH1 was shown to be preferentially utilized in leukemic rabbit B cells. This VH1 gene was deleted from the germline of the Alicia rabbit. These data suggest that the allelic inheritance of a allotypes results from preferential utilization of VH1 in VDJ rearrangements. We suggest that antibody diversity in rabbit primarily results from somatic hypermutation and gene conversion.     

Gm and Km immunoglobulin allotypes in Sicily

The aim of this study was to evaluate the intra- and inter-population variability of the Gm/Km system in the Madonie Mountains, one of the main geographical barriers in north-central Sicily. We analysed 392 samples: 145 from Alia, 128 from Valledolmo, 25 from Cerda and 94 from Palermo. Serum samples were tested for G1m (1,2,3,17), G2m (23), G3m (5,6,10,11,13,14,15,16,21,24,28) and Km (1) allotypes by the standard agglutination-inhibition method. We found the typical genetic patterns of populations in peripheral areas of the Mediterranean basin, with a high frequency of haplotypes Gm5*;3;23 and Gm5*;3;... The frequency of Gm21,28;1,17;... (about 16%) is rather high compared with other southern areas. Of great importance is the presence of the common African haplotype Gm 5*;1,17;..., ranging in frequency from 1.56% at Valledolmo to 5.5% at Alia. The presence of this haplotype suggests past contacts with peoples from North Africa. The introduction of African markers could be due to the Phoenician colonization at the end of the 2nd millennium b.c. or to the more recent Arab conquest (8th–9th centuries a.d.).     

Association between immunoglobulin allotypes and pulmonary tuberculosis

In a sample of n = 133 non-related patients suffering from pulmonary tuberculosis, Gm and Km typings have been carried out and compared with healthy controls from the same geographical area. All the Gm allotypes tested were found to be more preponderant in the patients than in the healthy controls and these differences were found to be statistically significant for Gm (1) and Gm (5) only and not for the other immunoglobulin allotypes e.g. Gm (2). The frequency of Km (1) was lower and that of Km (3) was higher in the patients than in the controls. These differences were, however, statistically not significant.     

Evolution of immunoglobulin allotypes and phylogeny of apes

Serum samples from 72 Pan troglodytes, 5 Pan paniscus, 22 Gorilla gorilla, 23 Pongo pygmaeus abelii, 5 Pongo pygmaeus pygmaeus, 2 hybrids P.p. abelii X P.p. pygmaeus and 13 Hylobates lar were tested for Gm(1, 2, 3, 5, 6, 10, 11, 13, 14, 15, 16, 17, 21, 24, 28), Km(1) and Bm(1, 2, 3, 4, 5, 6, 7, 8) immunoglobulin allotypes by the classical hemagglutination inhibition method. The distribution of the various alleles and phenotypes makes it possible to distinguish each species or subspecies. Common chimpanzees have the richest polymorphism. Pygmy chimpanzees share common phenotypes with gorillas. Bornean and Sumatran orangutans have their own patterns of polymorphism, as do gibbons. Our principal component plot and dendrogram are compatible with the traditional classification of Hominoidea [e.g. Simpson, Bull. Am. Mus. nat. Hist. 85: 1-350, 1945] in 3 families: Hominidae, Pongidae and Hylobatidae.     

Genetic control of immunoglobulin allotypes in the fowl

Eight immunoglobulin allotypic specificities have been identified in the fowl by isoimmunization. Aa1 and Aa2 are controlled as codominants at the a locus, Ab1 and Ab2 at the b locus, and Ac1, Ac2, Ac3, and Ac4 at the c locus. Column chromatography and ultracentrifugation indicate that the specificities at the a locus are located on molecules corresponding to IgG with sedimentation coefficients 7 S. Immunoelectrophoresis results also indicate that we are dealing with an immunoglobulin G molecule. Further tests are underway to resolve this beyond doubt.Journal Paper No. 5405 of the Iowa Agricultural and Home Economics Experiment Station, Ames, Iowa. Project 1039. Supported in part by National Science Foundation Grants GB 318 and GB 4450.     

Genetic nomenclature for chicken immunoglobulin allotypes: An extensive survey of inbred lines and antisera

Based on a survey of 36 inbred and 8 partially inbred chicken lines and outbred jungle fowl, and with 29 alloantisera generated in different laboratories, 13 7S Ig and 5 IgM allotypes were designated and a new system of nomenclature for chicken Ig polymorphisms was developed. The survey also revealed considerable genetic polymorphism in the structural gene(s) (G-1) responsible for the production of 7S Ig H chains. IgM H chains, encoded by theM-1 locus were less polymorphic. NineG-1 and fourM-1 gene alleles were delineated in highly inbred lines by the formation of unique combinations ofG-1 orM-1 specificities. Five additionalG-1 alleles were found in chicken lines and jungle fowl segregating for allotypes. Thirty-three percent of theG-1M-1 haplotypes theoretically expected, were detected in inbred lines.     

Characteristics of Mongoloid populations based on the human immunoglobulin allotypes

Since the discovery of Gm ab3st haplotype which characterizes Mongoloid populations in 1966, the distribution of the genetic markers of immunoglobulins (Gm) among the Mongoloid populations scattered from Southeast Asia through East Asia to South America has been investigated and concluded as follows: 1) Mongoloid populations characterized by the four Gm haplotypes, ag, axg, ab3st and afb 1b3 are divided into two groups on the basis of analysis of genetic distances based on the Gm haplotype frequencies: one is a southern group characterized by a remarkably high frequency of Gm afb 1b3 and a low frequency of Gm ag and the other is a northern group characterized by a high frequency of Gm a and an extremely low frequency of Gm afb 1b3. 2) Populations in China, mainly Han including minority nationalities, show remarkable heterogeneities from north to south, in sharp contrast to Korean and Japanese populations showing homogeneities, respectively. The center of dispersion of the Gm afb 1b3 characterizing southern Mongoloids must exist in Guangxi and Yunnan area in the southwest China. 3) The Gm ab3st gene found in the highest incidence among the north Baikal Buriats flows in all directions. The gene, however, shows precipitous drop which occur from mainland China to Southeast Asia and from North to South-America, although the Gm ab3st gene is still found in high incidences among Eskimos, Yakuts, Tibetans, Olunchuns, Koreans, Japanese and Ainus. On the other hand, the gene is introduced into Huis, Uighurs, Indians, Iranians and far Hungarians.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunoelectron microscopic localization of idiotypes and allotypes on immunoglobulin molecules

We have developed a novel approach to the analysis of antigenic (allotypic and idiotypic) determinants on intact immunoglobulin molecules. Immune complexes composed of IgG in combination with anti-idiotype or anti-allotype antibody were "visualized" by transmission electron microscopy. Individual Fab fragments of anti-idiotype or anti-allotype antibody, when bound to the IgG, altered the "Y" configuration in a reproducible and interpretable manner. Anti-idiotype antibody (either as Fab or IgG) bound to the terminus of the presumed V region of the IgG molecule, thus extending the apparent length of the Fab arms. Analysis of a rabbit VH framework allotype (a1) revealed that the determinant(s) is (are) located on the lateral portion of the V region of IgG. Binding of the anti-a1 Fab fragments was always at approximately right angles to the axis of the Fab arms of IgG. Fab antibody to the rabbit kappa light chain (b4) allotype bound to the lateral portion of the terminal half of the IgG Fab arms. This technique should be of value in localizing less well defined immunoglobulin determinants.     

Structural and genetic analysis of four chicken 7S immunoglobulin allotypes

Four 7S immunoglobulin allotypic specificities in three inbred chicken lines were demonstrated in two immunoglobulin regions, probably associated with the heavy chains. Two specificities were associated with papain-produced Fab fragments, most likely the Fd fragment since they were not demonstrated on the 17S immunoglobulin. The other allotypes were detected only on intact 7S immunoglobulin and were undetectable on the Fab and Fc fragments; therefore, they probably were associated with a region of the heavy chain sensitive to papain digestion. Among F₂ hybrids, these specificities segregated in a manner statistically indistinguishable from that expected of three codominant alleles at an autosomal locus. This locus was not closely associated with any of five chicken blood group loci.     

Distribution of immunoglobulin allotypes among local populations of Kenya olive baboons

In this paper we report on the distributions of immunoglobulin allotypes among 564 olive baboons collected at six localities in Kenya. The sample localities and sizes are 1) Lake Magadi, N = 107; 2) Nanyuki, N = 77; 3) Lake Baringo, N = 55; 4) Mosiro, N = 132; 5) Isiolo, N = 36; 6) Gilgil, N = 157. Gm allotypes 1, 10, 13, 15, and 17 are polymorphic among these samples. Gm(11) and Km(3) were present in all samples, and Gm(2,3,5,6,14,16,21,24,26) and Km(1) were absent from all samples. The proportions of individuals positive for polymorphic allotypes varied substantially between different local samples, as did the arrays and estimated frequencies of haplotypes. Allotype frequencies in local samples do not appear to be simply related to either geographic location or habitat characteristics of the localities. Our data suggest that much of the geographic variability in Kenya olive baboon populations occurs between populations separated by small geographic distances.     

Gm and Km immunoglobulin allotypes in Reindeer Chukchi and Siberian Eskimos

Summary Blood samples from 403 Reindeer Chukchi of inland Chukotka, and 100 samples from Chaplin Eskimos of the Chukot Peninsula were tested for G1m (z,a,x,f), G2m (n), G3m (g,b0,b1,b3,b5,s,t), and Km (1) allotypic determinants. An apparent affinity between the Chukchi and the Eskimos could be inferred from similar frequencies of the two common haplotypes, Gm^za;g and Gm^za;bst, and from very similar frequencies of the Km¹ allele. However, none of the Eskimos had Gm^zax;g, though it occurred at a low or moderate frequency in the five Chukchi populations studied. It is assumed that Chukchi can be distinguished from adjoining Eskimos by the same G1m (x) outlier, that has been considered as a taxonomic marker useful in differentiating between Eskimos and American Indians. Comparison of North Asian and North American populations with respect to the array and frequencies of Gm haplotypes and the Km¹ allele, supports the hypothesis of a nonrandom distribution of the Gm^za;bst and Km¹ on both sides of the Bering Strait.