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"ROLE OF A2B RECEPTOR AND RESISTIN LIKE MOLECULE-£] IN THE DEVELOPMENT OF THE TYPE 2 IMMUNE RESPONSE TO THE INTESTINAL NEMATODE PARASITE HELIGMOSOMOIDES POLYGYRUS"

by
Nirav Patel
Interdisciplinary Biomedical Sciences Program
B.S. 2003, North Gujarat University
M.S. 2006, Long Island University



Thesis Advisor: William C. Gause, Ph.D.
Professor
Department of Medicine

Friday, October 19, 2012
1:15 P.M., MSB C-680


Abstract

Previous studies have suggested that resistin-like molecule beta (RELM£]) contributes to protective immunity against intestinal nematode parasites by directly interfering with adult worm feeding in the lumen. Other studies have suggested that RELM£] may also function in the mucosal milieu by regulating Th1/Th2 cytokine production. In our studies, we examined the development of the memory type 2 response to the murine intestinal nematode parasite, H. polygyrus bakeri. Mice were inoculated with H. polygyrus bakeri, drug-cleared at day 14, and several weeks later given an H. polygyrus bakeri secondary inoculation. Consistent with previous studies, adult worm burden was increased in H. polygyrus bakeri -inoculated RELM£] deficient mice compared to inoculated WT controls. Analysis of cytokine gene (RT-PCR) and protein (ELISPOT) expression in draining mesenteric lymph nodes (MLNs) showed reductions in type 2 cytokine levels in RELM£] compared to WT mice at day 7 after H. polygyrus bakeri secondary inoculation. At this time point analysis of sorted CD4+T cells showed reduced IL-4 expression in RELM£]−/− mice compared to WT mice after secondary inoculation. Also, elevations in IL-4, IL-13, and IL-5 mRNA were greatly reduced after H. polygyrus bakeri secondary inoculation in RELM£]−/− mice compared to inoculated WT controls along with Arg1, RELMÉ—, and Ym1, which are characteristically expressed by M2 cells in the small intestinal granuloma during the tissue dwelling phase. Finally, we found that exogenous addition of rRELMÉ“ stimulates CD4+ T cells to secrete type 2 cytokines but not IFN-£^ in vitro. These studies suggest that RELM£] may affect protective immunity through multiple mechanisms, including enhancement of the type 2 cytokine response.
A2B adenosine receptor (A2BAR) signaling can modulate lymphocyte function. A2BARs can control proinflammatory immune responses by enhancing IL-10 and down regulating IFN- production. A2BARs can activate mast cells to secrete IL-4, a type 2 cytokine that can trigger alternatively activated (M2) macrophages and expulsion of the intestinal nematode parasite, H. polygyrus bakeri. To examine whether A2BARs contribute to the in vivo protective type 2 immune response to helminthes, A2BAR-/- mice were infected with H. polygyrus bakeri. Worm burden and egg production were increased while serum IgE and IgG1 were reduced in A2BAR-/- mice compared to WT mice at day 14 after H. polygyrus bakeri inoculation. Worms recovered from A2BAR-/- mice at day 11 after secondary H. polygyrus bakeri inoculation exhibited higher protein and ATP levels, suggesting impaired host protective responses. Type 2 cytokine expression and M2 macrophage markers were also inhibited in small intestines and in mesenteric lymph nodes (MLN) in A2BAR-/- mice at day 11 after secondary H. polygyrus bakeri infection. Absence of A2BAR signaling reduced IL-4 but not IFN- secreting MLN CD4+T cells after secondary H. polygyrus bakeri inoculation. Eosinophil and M2 macrophage accumulation in the small intestine and increases in mucous producing intestinal epithelial cells were markedly inhibited in A2BAR-/- mice, after H. polygyrus bakeri secondary inoculation. We also found that A2BAR signaling is essential for initiation of the type 2 immune response as early as 48 hours after H. polygyrus bakeri inoculation. Thus, these studies suggest that A2BAR signaling plays an essential role in the development of the host protective type 2 immune response during helminth infection.


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