HYPERMUTATION, DIVERSITY AND DISSEMINATION OF HUMAN INTESTINAL LAMINAPROPRIA PLASMA-CELLS

In this work we have microdissected lamina propria plasma cells and us ed polymerase chain reaction and sequencing to investigate immunoglobu lin (Ig) gene rearrangements and mutations in human intestine. In addi tion, specific primers were designed for individual Ig gene rearrangem ents to analyze the distribution of related B cell and plasma cell clo nes at different sites along the bowel. Confirming our earlier work, i ntestinal IgV(H) genes were highly mutated in plasma cells from older individuals (> 30 years). IgV(H) genes were significantly less mutated in samples taken from patients aged 11-30 years, and there were fewer mutations again in samples from young children (< 11 years). In age-m atched specimens the number of mutations was equivalent in the duodenu m and colon. Using complementarity-determining region 3 primers to amp lify specific Ig gene rearrangements, evidence was also found for the existence of related lamina propria plasma cells along the small bowel and colon, although these were quite scarse. In addition, analysis of the numbers of related clones in a random sampling from discrete area s of lamina propria indicates that the local population is diverse. Th ese results suggest that the highly mutated IgV(H) genes in adult inte stinal plasma cells are a consequence of chronic antigen exposure with age. Duodenal plasma cells are as highly mutated as colonic plasma ce lls, despite the fact that the upper bowel has no indigenous microbial flora (the stimulus for intestinal plasma cells). They also show that the plasma cell population is diverse and can be widely disseminated along the bowel.