Lymphocyte-Dependent and Th2 Cytokine-Associated Colitis in Mice Deficient in Wiskott-Aldrich Syndrome Protein

doi:10.1053/j.gastro.2007.07.010

Gastroenterology

Volume 133, Issue 4, October 2007, Pages 1188-1197

https://doi.org/10.1053/j.gastro.2007.07.010 Get rights and content

Background & Aims: Controversy exists as to whether patients with inflammatory bowel disease have an underlying immunodeficiency. We have focused on a murine model of the Wiskott-Aldrich syndrome, an immunodeficiency in which autoimmunity can manifest in the form of an inflammatory bowel disease-like illness. Wiskott-Aldrich syndrome protein (WASP) deficiency in mice results in similar clinical features. Herein, we characterized the colitis in WASP-deficient mice. Methods: WASP-deficient mice were followed clinically and histologically. Immunologic studies were performed to determine the pathogenic cell population(s), the predominant cytokine expression pattern, and the role of cytokine(s) in colitis pathogenesis. Results: All WASP-deficient mice develop colitis by 6 months of age. Lymphocytes are required for disease induction, and CD4⁺ T cells from WASP-deficient mice are sufficient to induce disease in lymphocyte-deficient hosts. Lamina propria preparations from WASP-deficient mice demonstrated elevations in interferon-γ, interleukin (IL)-4, and IL-13 levels but decreased IL-6 and no difference in IL-17 expression in comparison with wild-type controls. Treatment with neutralizing antibody to IL-4, but not to interferon-γ, abrogated colitis development. However, mice deficient in both WASP and IL-4 showed no difference in histologic colitis scores at 24 weeks of age compared with WASP-deficient mice. Conclusions: These results demonstrate a critical role for lymphocytes and a relative T helper 2 cytokine predominance in the colitis associated with WASP-deficient mice. This is the only model of colitis with elevated T helper 2 cytokines and aberrant natural regulatory T cell function and is unique in having a human disease counterpart with similar defects.

Section snippets

Mice

WKO mice were generated on a 129 SvEv background.²⁴ Wild-type (WT) and RAG-2 KO mice on a 129 SvEv background were obtained from Taconic Farms, Inc (Hudson, NY). WASP/RAG double KO (WRDKO) mice were generated by crossing WKO mice with RAG-2 KO mice. WASP/IL-4 double KO mice were generated by crossing WKO mice with IL-4 KO mice (C57BL/6 background) and backcrossed onto 129 SvEv background for 5 generations. Mice were maintained in specific pathogen-free animal facilities at Massachusetts General

WKO Mice Develop an IBD-Like Disease Limited to the Colon by 4 Months of Age

Our initial studies of WKO mice revealed frequent signs of colitis, including wasting; rectal prolapse; diarrhea; and, sometimes, early death.²⁴ In the current study, we characterized, in detail, the colonic inflammation of WKO mice.

Gross examination of the gastrointestinal tract demonstrated a normal small intestine but a substantial thickening of the colon (Figure 1A,upper left panel) throughout its entire length. Some mice developed rectal prolapse. Severe disease was often associated with

Discussion

Murine models of IBD have permitted intense investigation into the pathogenesis of mucosal inflammation.3, 4, 5 The colitis observed in WKO mice is unique because of both the presence of disease in human patients with the same genetic defect and the relative Th2 cytokine skewing. WKO mice develop spontaneous colitis starting at 3 months of age, with 100% of mice affected by 6 months of age. The disease is progressive, eventually leading to early death in most cases. A similar observation of

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In WASp-deficient T cells, normal F-actin formation and/or polarization to the immunological synapse has been reported in several reports [59,86], which can be explained by the compensatory role of other NPFs. However, WAS T cells still display functional deficits contributing to clinical manifestations indicating the imbalance of Th1-Th2 immunity like hyper immunoglobulin E and autoimmune colitis [87], which implies the nonnegligible role of WASp in cytoskeleton-independent cellular processes. It has been shown that WKO T cells have reduced IL-2 production both in human and mice model and that the role WASp plays in this process is independent of its role in the IS formation [59].
Wiskott-Aldrich syndrome (WAS) is a form of primary immunodeficiency (PIDs) resulting from mutations of the gene that encodes Wiskott-Aldrich syndrome protein (WASp). WASp is the first identified and most widely studied protein belonging to the actin nucleation-promoting factor family and plays significant role in integrating and transforming signals from critical receptors on the cell surface to actin remodeling. WASp functions in immune defense and homeostasis through the regulation of actin cytoskeleton-dependent cellular processes as well as processes uncoupled with actin polymerization like nuclear transcription programs. In this article, we review the mechanisms of WASp activation through an understanding of its structure. We further discuss the role of WASp in adaptive immunity, paying special attention to some recent findings on the crucial role of WASp in the formation of immunological synapse, the regulation of T follicular helper (Tfh) cells and in the prevention of autoimmunity.
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Immunoglobulin E–mediated food allergy is rapidly developing into a global health problem. Publicly available therapeutic intervention strategies are currently restricted to allergen avoidance and emergency treatments. To gain a better understanding of the disease pathophysiology so that new therapies can be developed, major research efforts have been put into studying food allergy in mice. Animal models should reflect the human pathology as closely as possible to allow for a rapid translation of basic science observations to the bedside. In this regard, experimental models of food allergy provide significant challenges for research because of discrepancies between the presentation of disease in humans and mice. The goal of this review is to give a summary of commonly used murine disease models and to discuss how they relate to the human condition. We will focus on epicutaneous sensitization models, on mouse strains that sensitize spontaneously to food as seen in humans, and on models in humanized animals. In summary, expanding the research toolbox of experimental food allergy provides an important step toward closing gaps in our understanding of the derailing immune mechanism that underlies the human disease. The availability of additional experimental models will provide exciting opportunities to discover new intervention points for the treatment of food allergies. (Cell Mol Gastroenterol Hepatol 2018;x:x)
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Laboratory studies in these patients may show thrombocytopenia, low IgM levels, low marginal B cells, and lymphopenia.90 Nguyen et al91 identified that intestinal inflammation in WASP-deficient mice was critically dependent upon inflammatory T cells, which may result from impaired development of regulatory T cells (Tregs) in the thymus and periphery.92 Surprisingly, these defects are likely occurring in a cell-extrinsic manner, as the absence of WASP in cells of the innate immune system directly contributed to the development of inflammatory T-cell responses in mice.93
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Supported by NIH grants HL59561 and AI50950 (to S.B.S.), DK47677 (to A.K.B), DK55678 (to C.N.), DK64351 (to A.M.), and DK64289 and DK74454 (to E.M.); German Research Council grants (DFG), Fritz-Thyssen-Foundation and the Henkel-Foundation grants (to C.K.); postdoctoral support from the SICPA Foundation and Lausanne University Hospital (to M.H.M.); AGA Student Research Fellowship Award and predoctoral and postdoctoral support from an NIH Training Grant (T32DK007191; to D.N.); CAPES grant (to V. C-d-A.); and Broad Medical Foundation grants (to E.M and A.M).

There is no conflict of interest to disclose.

¹: M.H.M. and V. C-d-A. contributed equally to the manuscript.

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Basic–alimentary tractLymphocyte-Dependent and Th2 Cytokine-Associated Colitis in Mice Deficient in Wiskott-Aldrich Syndrome Protein

Section snippets

Mice

WKO Mice Develop an IBD-Like Disease Limited to the Colon by 4 Months of Age

Discussion

Immunity

Immunity

Immunity

Gastroenterology

Gastroenterology

Clin Immunol

Blood

Gastroenterology

Blood

Innate immunity in the pathogenesis and therapy of IBD

J Gastroenterol

Past and current theories of etiology of IBD: toothpaste, worms, and refrigerators

J Clin Gastroenterol

The immunology of mucosal models of inflammation

Annu Rev Immunol

Immune networks in animal models of inflammatory bowel disease

Inflamm Bowel Dis

Experimental models of inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota

Immunol Rev

IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis

J Exp Med

IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6

J Clin Invest

Critical role of IL-17 receptor signaling in acute TNBS-induced colitis

Inflamm Bowel Dis

Interleukin-23 drives innate and T cell-mediated intestinal inflammation

J Exp Med

Antibodies to interleukin 12 abrogate established experimental colitis in mice

J Exp Med

IL-12, but not IFN-γ, plays a major role in sustaining the chronic phase of colitis in IL-10-deficient mice

J Immunol

Cytokine imbalance and autoantibody production in T cell receptor-α mutant mice with inflammatory bowel disease

J Exp Med

Basic–alimentary tract
Lymphocyte-Dependent and Th2 Cytokine-Associated Colitis in Mice Deficient in Wiskott-Aldrich Syndrome Protein