VH-gene representation in autoantibodies reflects the normal human B-cell repertoire.
The recurrence in the V-gene repertoire of individual germline VH genes can now be extended from the restricted B-cell populations of the fetus, autoantibodies and B-cell malignancies to the expressed V-gene repertoire of normal adults. Why the human B cell preferentially utilizes these individual VH genes remains speculative. However, it is apparent that the population of VH genes used to encode autoantibodies reflects the normal expressed repertoire (Fig. 7). Even so, the overrepresentation of other V genes such as Dxp'1 in anti-DNA antibodies and the presence of somatic mutation in the pathogenic autoantibodies of autoimmune disease continues to suggest an antigenic influence on V-gene selection. We postulate that only a fraction of available germline V genes are utilized in the expressed repertoire, and that polyspecificity of naturally occurring antibodies and somatic mutation of CDR3 compensate for the loss of diversity entailed by the limited use of the potential repertoire. The mechanisms by which germline genes become pathogenic remains unclear but they presumably relate to mutation, loss of regulatory control or perhaps environmental factors (Isenberg et al. 1992). What then are the mechanisms which lead to escape of these VH genes from normal control? What antigenic drive if any produces anti-DNA specificity in SLE? Why indeed is the expressed repertoire using only a fraction of the available germline? To answer these questions, further study of the V-gene repertoire of selected populations of antigen-binding cells and of pathogenic IgG autoantibodies is necessary and is ongoing. The contribution of individual V genes to antigen binding and idiotype is also being dissected and promises to yield important information about the relative contribution of VH genes to autoimmunity.
Stewart
A K
AK
Department of Medicine, New England Medical Center Hospitals, Boston, Massachusetts.
Huang
C
C
Long
A A
AA
Stollar
B D
BD
Schwartz
R S
RS
D000328:Adult; D000595:Amino Acid Sequence; D001323:Autoantibodies / Q000235:genetics* / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D005333:Fetus / Q000276:immunology; D015870:Gene Expression; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005803:Genes, Immunoglobulin; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D008954:Models, Biological; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D016415:Sequence Alignment
D001323:Autoantibodies; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region