This is likely to be the result of the thorough sampling of a hig

This is likely to be the result of the thorough sampling of a highly restricted portion of sequence space that is revealed by PCR amplification using a forward primer specific for IGHV6-1. MLN0128 In contrast, the relatively low proportion of clonally related sequences seen in this study suggests that the IgE response, in parasitized individuals, may be highly diverse. The varying proportions of clonally related sequences seen in association with different IgG subclasses may also point to varying levels of diversity in these responses, although analysis is confounded by the unequal numbers of different IgG subclass transcripts obtained from different individuals.

Certainly, the high proportion of clonally related IgG4 sequences suggests a lack of diversity which might be expected if this subclass response was restricted to the minor set of the most persistent antigens. Further insights into the IgE anti-parasite response come from analysis of somatic point mutations, and to better interpret our observations of mutations in IgE sequences, we amplified IgG-associated VDJ gene sequences, using IgG subclass-specific reverse PCR primers. The mean mutation levels seen in these 886 unique IgG sequences varied substantially between subclasses and correlated with the position of the constant region

genes within the constant region gene locus (IgG3 < IgG1 < IgG2 < IgG4). Although unexpected, this is in accord with the reports of low-affinity IgG3 being seen early in a response Ceritinib price [25], and high-affinity IgG4 emerging after long periods of persistent antigen stimulation [28]. These studies are consistent with the concept that B cells only switch to IgG4 after multiple rounds of cell division, during which the VDJ sequences accumulate high numbers of mutations [29]. On the other hand, it does not imply that IgG class-switching progresses inevitably by a series of sequential downstream steps, for cells

may switch to IgG4 both directly from IgM and indirectly via other constant region genes, as is also known to occur in the IgE response [30, 31]. Interestingly, despite IgE also being associated with persistent stimulation, and the IGHE gene being downstream of Fenbendazole the IGHG genes, the level of mutation in IgE sequences was similar to that of IgG1 and IgG2 sequences and was significantly less than that of IgG4 sequences. The average number of mutations seen in the IgE-associated VDJ gene sequences was 23.0, which is substantially higher than we previously reported for IgE sequences from individuals with atopic dermatitis, whose mean mutation counts were 14.7 and 15.7 [13, 27]. Higher counts have been seen in individuals with seasonal rhinitis and allergy to grass pollen [32], with a reported median count of 21. While an average of 19.

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