T Cell-Dependent Maturation of Pathogen-Specific Igs in the Antrum of Chronically Helicobacter pylori-Infected Patients.

Mucosal plasma cells (PC) and Ig production are essential to fend pathogens and to maintain mucosal homeostasis. In human Helicobacter pylori infection, mucosal PC express inducible NO synthase (iNOS), which positively correlates with clearance of experimental human infection. To characterize Ig genes and specificities of antral mucosal iNOS+ and iNOS- PC in H. pylori infection, we sequenced rearranged Ig genes from single cell-sorted PC from biopsy specimens of chronically infected patients and analyzed them with respect to their molecular features. The binding specificity of individual PC's Ig was determined following recombinant expression. We identified high rates of somatic hypermutations, especially targeting RGYW/WRCY hotspot motifs in the individual Ig genes, indicating T cell-dependent maturation. For seven of 14 recombinantly expressed Ig, Ag specificity could be determined. Two clones reacted to H. pylori proteins, and five were found to be polyreactive against LPSs, dsDNA, and ssDNA. All specific Ig originated from iNOS+ PC. H. pylori-specific Ig are encoded by V and J family genes previously shown to be also used in rearranged Ig loci of MALT B cell lymphomas. In summary, mucosal iNOS+ PC producing H. pylori-specific Ig accumulate in infection and appear to be a product of T cell-dependent B cell maturation. Moreover, the Ig's molecular features partly resembled that of MALT B cell lymphoma Ig genes, suggestive of a mechanism in which a progressive molecular evolution of pathogen-specific B cells to MALT B cell lymphoma occurs.