0 mutations. This broad similarity in the extent of mutations between IgG sequences from PNG villagers and sequences from urban residents of developed nations is surprising. It might be expected that mutation numbers would reflect an individual’s history of antigen exposure. Individuals from developed nations could therefore be expected to have substantially fewer mutations than individuals who have lived in the less hygienic circumstances of the developing world. Our observation may be explained by recent studies of HM781-36B in vivo the memory response. It has been shown that in a recall response, IgG+ memory cells rapidly give rise to plasma cells, but IgM+ memory cells re-enter the germinal centre reaction [33].

As CD27+ IgM+ memory cells carry few mutations in their immunoglobulin

genes [34, 35], the extent of mutations generated in the germinal centre reaction of a recall response is likely to be little different from that seen as a result of the earlier exposure to the antigen. Repeated exposure to common microbial antigens, which is a likely feature of village life in developing countries, would therefore be likely to lead to a relatively slow rise in mean mutation levels with age. As expected, many IgG sequences displayed a significantly higher proportion of replacement mutations within the CDRs than is seen in a model of random mutation. This can be taken as evidence that antigen selection guided the evolution of these sequences. The percentage of such sequences ranged between 22% (IgG3) and 39% (IgG2). The majority of sequences do not show evidence of antigen selection. This is not because most Cisplatin nmr IgG sequences develop in the absence of antigen selection, but rather it likely reflects the underlying random nature of the mutational process, which makes it impossible

to see clear evidence of antigen selection in more than a fraction of all selected sequences. In contrast to the IgG sequences, only 12% of IgE sequences showed evidence of antigen selection. This is in line with previous observations of allergic IgE sequences. We and others have reported an absence of antigen selection, and therefore presumably the absence of affinity maturation in allergic IgE sequences [13, 36, 37]. Kerzel et al. [14] recently used the same kind of comparison with a random model of mutation in a study of antigen selection and mutations in allergic IgE sequences. In their study, a different probability of mutation much was used, as different definitions of the CDRs were also used. The use of these different definitions and probabilities do not alter the conclusions of the present analysis. The relative lack of antigen selection in the evolution of IgE sequences in parasitized individuals could be the result of early departure of IgE-committed cells from the germinal centre reaction and the continuing accumulating of mutations at other sites where follicular dendritic cells and follicular helper T cells, that are essential to the antigen selection process, are absent [6, 38].