The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease

Abstract

The immunoglobulin (IG) loci consist of repeated and highly homologous sets of genes of different types, variable (V), diversity (D) and junction (J), that rearrange in developing B cells to produce an individual's highly variable repertoire of expressed antibodies, designed to bind to a vast array of pathogens. This repeated structure makes these loci susceptible to a high frequency of insertion and deletion events through evolutionary time, and also makes them difficult to characterize at the genomic level or assay with high-throughput techniques. Given the central role of antibodies in the adaptive immune system, it is not surprising that early candidate gene approaches showed that germline polymorphisms in these regions correlated with susceptibility to both infectious and autoimmune diseases. However, more recent studies, particularly those using high-throughput genome-wide arrays, have failed to implicate these loci in disease. In this review of the IG heavy chain variable gene cluster (IGHV), we examine how poorly we understand the distribution of haplotype variation in this genomic region, and we argue that this lack of information may mask candidate loci in the IGHV gene cluster as causative factors for infectious and autoimmune diseases.

Automated analysis of high-throughput B-cell sequencing data reveals a high frequency of novel immunoglobulin V gene segment alleles

“…Subjects also differ greatly in the set of V(D)J segment alleles that they carry (6,19,21) and some V segment alleles have been associated with disease (including SLE, MS, RA, and type 1 diabetes, as summarized in ref. 5). Along with the underlying genetics of the Ig locus, properties of the expressed B-cell Ig repertoire, such as diversity, have been associated with disease and clinical status (5-10).…”

“…Although IGHV genes can be duplicated in some subjects, with IGHV1-69 being a frequent example (as reviewed in ref. 5), it is expected that each subject carries either one or two alleles of most genes. However, IMGT/HighV-QUEST assigned an average of 4.3 alleles per gene across the three subjects sequenced by 454, as shown in Table 1.…”

“…Previous studies have, for example: revealed the association of certain germline genotypes with susceptibility to such diseases as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS) (5,6); found correlations of age with a reduced Ig clonal diversity and less intense response to immune challenge (7,8); found overly expanded clones in cases of lymphoma (9,10); and discovered convergent Ig evolution across subjects in response to certain immune challenges (11,12). These repertoire-sequencing (Rep-Seq) studies have benefitted from improvements in sequencing technologies, which allow for the generation of millions of reads per run (13).…”

Antibody repertoire analysis in polygenic autoimmune diseases

“…Homozygous deletions of IGHV3‐30*01 and IGHV3‐30‐3 were found to be enriched 2·8‐fold in SLE patients with nephritis compared with ethnically matched healthy individuals, and SLE patients with these deletions exhibited higher titres of anti‐DNA antibodies 30, 31. This deletion has also been shown to be associated with susceptibility to chronic idiopathic thrombocytopaenic purpura32 and Kawasaki disease33 (reviewed in Watson et al 34…”

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

“…Each H chain gene is formed somatically and stochastically by recombination and joining of one each of the ∼55 immunoglobulin heavy chain variable (IGHV), ∼27 immunoglobulin heavy chain diversity (IGHD), and 6 immunoglobulin heavy chain joining (IGHJ) genes. Each L chain gene is similarly formed by using one of either ∼40 immunoglobulin kappa variable (IGKV) or ∼30 immunoglobulin lambda variable (IGLV) genes, recombined with one of either 5 immunoglobulin kappa joining (IGKJ) or 4 immunoglobulin lambda joining (IGLJ) genes (4). There is evidence that certain V genes are more frequently used in autoantibodies, such as IGHV1-69 (5), and certain families of V genes are overexpressed in particular diseases, e.g., Graves disease (IGHV1 family), Hashimoto disease (IGHV3 family), myasthenia gravis, chronic idiopathic thrombocytopenic purpura (IGHV3-30), and Sjogren disease (IGHV1-69 and IGHV3-7) (6).…”