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Whither genetic analysis of human autoantibodies?

Autoantibodies are found in healthy people and in others with disease. In the latter, their high titre and characteristic fine specificity may imply that the autoantibodies are uniquely associated with the disease process. What then are the characteristics of antibodies that associate with disease and those that are seen in health? Clearly there are differences of antibody class, and in humans natural autoantibodies are predominantly ofthe IgM isotype and pathogenic autoantibodies are mostly IgG. Whilst conventional immunochemical assays, and antigen epitope analysis, can reveal differences in the fine specificity of different autoantibodies, these may tell little or nothing about the genetic origins of the antibodies under scrutiny. 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]. Its VL gene is derived from HumlLl of the VAI subgroup, also found expressed in other autoantibodies. 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 then is one of the cogent reasons for sequencing human antibody V genes: to determine if particular sets are dedicated to restricted functions. From first reasoning, however, it is hard to see that autoantigens have any common properties as a set, or that they are materially different from non-self antigens. Thus, if there is biased V gene use in autoantibodies it may be because of special temporal exposure of the immune system to autoantigens— early in ontogeny for example—and/or a selective reading of the V genes themselves at different stages of development. On the other hand, reactions with some autoantigens are technically very easy to detect, DNA being a case in point, so it is also possible that all antibodies are autoreactive, but we just do not