Production and -secretion of immunoglobulin A in the context of gastrointestinal infectious diseases

• Applicants: Dr. Verena Moos; Professor Dr. Thomas Schneider
• Subject Area: Gastroenterology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 451548000

Chronic infection of the upper gastrointestinal tract must be considered as a major problem of public health, may disturb intestinal homeostasis and are risk factors for potentially malignant or irreversible sequelae. The protection of mucosal surfaces is guaranteed by immunoglobulin (Ig) A. IgA is produced by plasma cells and subsequently transported by intestinal epithelial cells (IEC) via the polymeric-Ig-receptor (pIgR) as secretory IgA (SIgA) to the gut lumen where it enables immune-exclusion of luminal antigens. IgA-production is regulated by inducible nitrogenmonoxid (NO)-synthase (iNOS), the microbiome and Toll-like-receptors (TLR) and pIgR-expression via interferon γ (IFNγ) und tumor necrosis faktor α (TNFα). However, the complex interaction of IEC, lymphocytes and gastointestinal microbiome that is required for IgA-secretion is not completely understood, yet. We want to clarify how inadequate activation of IEC, B- and plasma cells and local SIgA secretion contribute to chronification of infections. Infections with Giardia (G.) duodenalis, Helicobacter (H.) pylori and Tropheryma (T.) whipplei, all of which affect the balance of inflammation, regulatory T cells (Treg), NO and IgA and induce epithelial barrier damage and subsequent microbial translocation, will serve as models to characterize pathomechanisms in the interaction of mucosal B-cell activation and IEC. In the context of H. pylori infection, we first described iNOS+ plasma cells in the inflamed human gastrointestinal mucosa, which are associated with the eradication of H. pylori and produce H. pylori-specific Ig, IFNγ and TNFα. These cells are absent in the duodenum of patients with Whipple's disease and giardiasis, where exceeding inflammation is absent. Since we assume that iNOS+ plasma cells promote local IgA-production and transcytosis of SIgA, we pursue two hypotheses: (I) the accumulation of specific IgA+ plasma cells correlates positively with inflammation, barrier damage and bacterial translocation and negatively with Treg and (II) TLR ligation, IFNγ and TNFα increase local pIgR expression on IEC and SIgA-transcytosis and promote B-cell activation by IEC. To this end, we want to document the affinity-maturation of the antigen-binding-sites by sequencing mucosal Ig genes and the functionality of plasma cells in the effector phase by re-expression of the respective Ig. We will characterize B-cell maturation and T-cell polarization by histology and flow cytometry in correlation with epithelial barrier damage. In human epithelial organoid cultures, the functional role of IEC in SIgA transcytosis and its modulation by pathogens, IFNγ, TNFα, TLR ligands and NO will be defined in vitro. Thus, the project will identify protective mechanisms against mucosal infections and to maintain intestinal homeostasis.

• DFG Programme: Research Grants