Genetic analysis of the variable region genes encoding a monospecific human natural anti-DNA antibody

Abstract

SUMMARYRecent evidence suggests that natural autoantibodies may ptay an integral rote in the development of the normal immune repertoire. To explore the genetic origins of these antibodies, we have isolated and sequenced the variable (V) region genes encoding both the heavy (H) and light (L) chains of a natural anti-DNA antibody, Kim It.4. The genes appear to be derived from the VH4.t8 (subgroup VntV), JH5, Hum t LI (subgroup VAt) and JA3 germline genes. The origin of the H chain diversity gene is more obscure, being potentially derived from one or more of several germline genes, arranged in either the forward or reverse orientations. Both the Kim 11.4 VH and VL genes share significant degrees of similarity with those utilized in other autoantibodies, indicating that at least some degree of V restriction may exist in human autoreactive B cells. The pattern of nucleotide differences between the Kiml 1.4 VH and VL genes and their putative germline counterparts suggests that the Kiml 1.4 genes may have undergone somatic mutation and arisen as a result of antigen selection.

Whither genetic analysis of human autoantibodies?

“…So, sequencing the V genes of autoantibodies for a start will reveal something about their genetic origins. The approach taken in this issue by Daley and colleagues has allowed the precise description ofthe VH and VL gene sequences of a MoAb that has been derived from the tonsilar lymphocytes of a healthy child and which reacts with single stranded DNA (ssDNA) [1]. This is an example of an autoantibody coded by genes that have been shown before to code for autoantibodies; it has a VH region encoded by a gene derived from VH4.18 which is a member of the VHIV subgroup-well recognized as a family of genes especially involved in encoding autoantibodies [2].…”

“…It is often concluded (as in [1]) that there is a restriction on the use of V genes in human autoreactive B cells. In this case the germline VH and VL sequences of the original cell donor are unfortunately not available, so the extent to which the genes had mutated, an important issue in understanding natural autoantibodies, can only be estimated by comparison with other germline sequences recorded from other individuals.…”

“…This is a burning issue, especially in the area of connective tissue disease. The paper by Daley et al [1] deals with a DNA-binding antibody. Several hundred DNA-binding MoAbs have been reported, but many more must have passed without mention for they are common isolates in making hybridomas.…”