ABSTRACT
The study of human autoimmune disease has been greatly facilitated by clear parallels between the murine and human immune systems, which allow us to draw relevant conclusions concerning human immunity and tolerance from murine knockout and transgenic models (1,2). However, in spite of similarities between the two immune systems, there are also differences that need to be recognized. The first is that the human VH germline repertoire is more limited than the murine, with only 39-51 expressed VH gene segments (3,4). Perhaps to compensate for this, there appears to be greater complexity in CDRH3, with wide variation in length and composition (5,6). Maturation of the humoral response by somatic mutation, antigen selection and isotype switch leads to high affinity antibodies, some of which are likely able to mediate autoimmune disease. In terms of following these processes at the V-gene level, studies in humans have the advantage in that the VH, D, JH, VL and JL gene segments have been fully documented (3,4,7-13), making it possible to investigate bias in variable domain gene segment usage in health and autoimmune disease. We are also able to assess the nature and level of somatic mutations. The combination of observations in mouse and human are generating new concepts that should help our understanding of autoimmune disease and perhaps lead to new approaches to treatment.
