Publisher Summary The immunoglobulin classes and subclasses represent a group of structurally related proteins, and in all instances consist of two pairs of polypeptide chains held together by disulfide bridges and noncovalent forces. The immunoglobulins can be classified according to three different parameters related to different antigenic and biochemical structures: (1) heavy-chain C regions constitute the basis for the different classes and subclasses; (2.) light-chain C regions specify the types or subtypes; and (3.) variable regions of both heavy and light chains can be divided into different groups and subgroups. Immunoglobulin G is the major immunoglobulin class making up about 80% of serum immunoglobulin. There are four subclasses of immunoglobulin G that were first distinguished by antigenic differences. These also show distinct peptide and amino acid differences and differences in biological activities that are discussed in details in the chapter. Immunoglobulin A is the dominant immunoglobulin class in secretions and may be present in serum as a monomer or polymer. The antigenic properties of the immunoglobulins can be divided into three main categories: (1) antigens present in all normal sera are called “isotypes;” (2) antigens present in some but not in all normal sera and segregate as if controlled by allelic genes are called “azlotypes;” (3) antigenic properties related to one particular antibody population are called “individual specificities” or “idiotypes.”

Human immunoglobulins: classes, subclasses, genetic variants, and idiotypes.

Structure and evolution of immunoglobulins

Analysis of immunoglobulin classes, γG subgroups, and Gm genetic markers from 59 patients with various types of immune deficiencies was undertaken to assess the function of the several cistrons concerned with synthesis of gamma globulins. 13 patients including two sibling pairs were found to have γG subgroup imbalances. All of these patients had non sex-linked disease. 11 of the 13 had preponderance of the γG3 subgroup. In most instances of γG3 preponderance it was the Gm(b) type of γG3 that was selectively retained; the Gm(g) type, controlled by the allelic gene was markedly depressed but not absent in the cases where it could be studied. Other imbalances, either seen concomitantly with γG3 preponderance or independently, included predominance of the γG2 subgroup and selective absence of single γG subgroups.

One family was encountered with probable structural gene abnormalities in the autosomal Gm loci. Both parents had different abnormal gene complexes detectable by absence of specific Gm markers and the propositus received both types from the parents. Similar gene complexes have been seen previously in rare instances through population screening but only in the heterozygous state and were not associated with clinically evident hypogammaglobulinemia. Of several other families of patients with subgroup imbalance, two were informative in that structural gene defects could be excluded. Studies on 22 first degree relatives of patients with subgroup imbalances indicated that the most common abnormality detected was in γA which was absent in 3 and markedly decreased in 2 others; other abnormalities included decreased levels of specific genetic types of γG globulin. It is concluded that γG subgroup imbalances are frequently found in non sex-linked immunoglobulin deficiency disorders and in some instances may be associated with family abnormalities suggesting either regulator or structural gene defects.

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Imbalances of gamma globulin subgroups and gene defects in patients with primary hypogammaglobulinemia

. Random Dutch donors were typed for Gm markers of γ1, γ2 and γ3 heavy chains. The relatives of individuals with uncommon phenotypes were collected and typed. The uncommon gene complexes, deducted from the pedigrees, were classified into several groups according to their possible generation. It was concluded that multiple genetic events, notably recombination, although rare, occur in γ subclass cistrons.

Uncommon Gm gene complexes.

Individuals with selective absence of IgG1 and IgG2 were discovered by testing for allotypes and isotypes of the respective sub-classes. These individuals were homozygous for sub-class deleted Gm-Am haplotypes, as shown by allotype studies in two families (Gm--;..;g;A2m1/Gm--;n;b;A2m1 and Gm--;n;b;A2m1/Gm--;..;b;A2m1) and by a population study of New Guineans (Gm fa;--;b;A2m2). The individuals with IgG1 sub-class deficiency showed elevation of IgG2, IgG4 and in particular of IgG3. Gene deletion can result from unequal crossing over which renders a complementary chromosome with a duplication of a sub-class gene. In one family, duplication of gamma 3 genes was observed to have happened in one of a twin pair. Quanitation of sub-classes in families with gamma 1- and with gamma 3-duplicated haplotypes did not show increased levels of the gene involved.

W A Muir

Papers

Two unusual Gm alleles: their implications for the genetics of the Gm antigens.