Characteristics of IgVH genes used by human intestinal plasma cells from childhood

Plasma cells secreting immunoglobulin M (IgM) and IgA in human intestinal mucosa are the largest antibody-producing population in the human body. Despite this there have been relatively few studies of the characteristics and maturation of the genes which encode the mucosal immunoglobulins. We have previously demonstrated that intestinal plasma cells use highly mutated IgVH genes, likely to reflect germinal centre origin. Here we show that IgVH genes used by intestinal lamina propria plasma cells secreting IgM and IgA are highly mutated from childhood, with no change in the frequency of mutation through to adulthood, though IgVH genes used by IgM are significantly less mutated than those used by IgA. There was no difference between the IgA subclasses in either the frequency or distribution of mutations. The frequency of mutation in IgVH4-34 genes used by IgG was also studied in the adult biopsies, and was found to be of the same order as that observed in IgA and was significantly higher than that observed in IgM. We have identified IgM and IgA sequences which share identical CDR3 and distribution of mutations. Isotype switching may therefore occur after extensive mutation of IgM sequences, and IgM- and IgA-secreting plasma cells with the same specificity may occur within the same microenvironment. IgM should therefore be considered to be a component of secondary immune responses in the gut.