ovalbumin and Primary-Immunodeficiency-Diseases

CXCR4 plays a central role in B cell immune response, notably by promoting plasma cell (PC) migration and maintenance in the bone marrow (BM). Gain-of-function mutations in CXCR4 affecting receptor desensitization have been reported in the rare immunodeficiency called WHIM syndrome (WS). Despite lymphopenia, patients mount an immune response but fail to maintain it over time. Using a knockin mouse model phenocopying WS, we showed that, counter-intuitively, a gain of Cxcr4 function inhibited the maintenance of antibody titers after immunization. Although the Cxcr4 mutation intrinsically and locally promoted germinal center response and PC differentiation, antigen-specific PCs were barely detected in the BM, a defect mirrored by early accumulation of immature plasmablasts potentially occupying the survival niches for long-lived PCs. Therefore, fine-tuning of Cxcr4 desensitization is critically required for efficient PC differentiation and maintenance, and absence of such a regulatory process may account for the defective humoral immunity observed in WS patients.

Topics: Animals; Antibodies; B-Lymphocyte Subsets; Bone Marrow; Cell Differentiation; Cell Movement; Desensitization, Immunologic; Disease Models, Animal; Gene Expression; Gene Knock-In Techniques; Germinal Center; Haptens; Hemocyanins; Humans; Immunity, Humoral; Immunization; Immunologic Deficiency Syndromes; Mice; Mice, Transgenic; Ovalbumin; Plasma Cells; Primary Immunodeficiency Diseases; Receptors, CXCR4; Signal Transduction; Warts

The murine intestinal nematode Heligmosomoides polygyrus exerts multiple immunomodulatory effects in the host, including the suppression of allergic inflammation in mice sensitized to allergen presented with alum adjuvant. Similar suppression is attained by co-administration of H. polygyrus excretory/secretory products (HES) with the sensitizing dose of ovalbumin (OVA) in alum. We investigated the mechanism of suppression by HES in this model, and found it was maintained in MyD88xTRIF-deficient mice, implying no role for helminth- or host-derived TLR ligands, or IL-1 family cytokines that signal in a MyD88- or TRIF-dependent manner. We also found suppression was unchanged in µMT mice, which lack B2 B cells, and that suppression was not abrogated when regulatory T cells were depleted in Foxp3.LuciDTR-4 mice. However, reduced IL-5 production was seen in the first 12 h after injection of OVA-alum when HES was co-administered, associated with reduced activation of IL-5(+) and IL-13(+) group 2 innate lymphoid cells. Thus, the suppressive effects of HES on alum-mediated OVA sensitization are reflected in the very earliest innate response to allergen exposure in vivo.

Topics: Adaptor Proteins, Vesicular Transport; Adjuvants, Immunologic; Alum Compounds; Animals; B-Lymphocytes, Regulatory; Hypersensitivity; Immunologic Deficiency Syndromes; Lymphocytes; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Nematospiroides dubius; Ovalbumin; Primary Immunodeficiency Diseases; Signal Transduction; T-Lymphocytes, Regulatory