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Deanna D Nguyen,
Marc-Andre Wurbel,
Jeremy A Goettel, Michelle A Eston,
Osub S Ahmed,
Romela Marin,
Elisa K Boden,
Eduardo J Villablanca,
Helena Paidassi,
Vineet Ahuja,
Hans-Christian Reinecker,
Edda Fiebiger,
Adam Lacy-Hulbert,
Bruce H Horwitz,
J Rodrigo Mora,
Scott B Snapper
[show abstract]
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ABSTRACT: Immunodeficiency and autoimmune sequelae, including colitis, develop in patients and mice deficient in Wiskott-Aldrich syndrome protein (WASP), a hematopoietic cell-specific intracellular signaling molecule that regulates the actin cytoskeleton. Development of colitis in WASP-deficient mice requires lymphocytes; transfer of T cells is sufficient to induce colitis in immunodeficient mice. We investigated the interactions between innate and adaptive immune cells in mucosal regulation during development of T cell-mediated colitis in mice with WASP-deficient cells of the innate immune system.
Naïve and/or regulatory CD4(+) T cells were transferred from 129 SvEv mice into RAG-2-deficient (RAG-2 KO) mice or mice lacking WASP and RAG-2 (WRDKO). Animals were observed for the development of colitis; effector and regulatory functions of innate immune and T cells were analyzed with in vivo and in vitro assays.
Transfer of unfractionated CD4(+) T cells induced severe colitis in WRDKO, but not RAG-2 KO, mice. Naïve wild-type T cells had higher levels of effector activity and regulatory T cells had reduced suppressive function when transferred into WRDKO mice compared with RAG-2 KO mice. Regulatory T-cell proliferation, generation, and maintenance of FoxP3 expression were reduced in WRDKO recipients and associated with reduced numbers of CD103(+) tolerogenic dendritic cells and levels of interleukin-10. Administration of interleukin-10 prevented induction of colitis following transfer of T cells into WRDKO mice.
Defective interactions between WASP-deficient innate immune cells and normal T cells disrupt mucosal regulation, potentially by altering the functions of tolerogenic dendritic cells, production of interleukin-10, and homeostasis of regulatory T cells.
Gastroenterology 06/2012; 143(3):719-29.e1-2. · 11.68 Impact Factor
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Lisa S Westerberg,
Carin Dahlberg,
Marisa Baptista,
Christopher J Moran,
Cynthia Detre,
Marton Keszei, Michelle A Eston,
Frederick W Alt,
Cox Terhorst,
Luigi D Notarangelo,
Scott B Snapper
[show abstract]
[hide abstract]
ABSTRACT: The Wiskott-Aldrich syndrome protein (WASP) is a key cytoskeletal regulator of hematopoietic cells. Although WASP-knockout (WKO) mice have aberrant B-cell cytoskeletal responses, B-cell development is relatively normal. We hypothesized that N-WASP, a ubiquitously expressed homolog of WASP, may serve some redundant functions with WASP in B cells. In the present study, we generated mice lacking WASP and N-WASP in B cells (conditional double knockout [cDKO] B cells) and show that cDKO mice had decreased numbers of follicular and marginal zone B cells in the spleen. Receptor-induced activation of cDKO B cells led to normal proliferation but a marked reduction of spreading compared with wild-type and WKO B cells. Whereas WKO B cells showed decreased migration in vitro and homing in vivo compared with wild-type cells, cDKO B cells showed an even more pronounced decrease in the migratory response in vivo. After injection of 2,4,6-trinitrophenol (TNP)-Ficoll, cDKO B cells had reduced antigen uptake in the splenic marginal zone. Despite high basal serum IgM, cDKO mice mounted a reduced immune response to the T cell-independent antigen TNP-Ficoll and to the T cell-dependent antigen TNP-keyhole limpet hemocyanin. Our results reveal that the combined activity of WASP and N-WASP is required for peripheral B-cell development and function.
Blood 03/2012; 119(17):3966-74. · 9.90 Impact Factor
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Sundaram Ramasamy,
Deanna D Nguyen, Michelle A Eston,
Sayeda Nasrin Alam,
Angela K Moss,
Farzad Ebrahimi,
Brishti Biswas,
Golam Mostafa,
Kathryn T Chen,
Kanakaraju Kaliannan, [......],
Sonoko Narisawa,
José Luis Millán,
H Shaw Warren,
Elizabeth L Hohmann,
Emiko Mizoguchi,
Hans-Christian Reinecker,
Atul K Bhan,
Scott B Snapper,
Madhu S Malo,
Richard A Hodin
[show abstract]
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ABSTRACT: The brush border enzyme intestinal alkaline phosphatase (IAP) functions as a gut mucosal defense factor and is protective against dextran sulfate sodium (DSS)-induced acute injury in rats. The present study evaluated the potential therapeutic role for orally administered calf IAP (cIAP) in two independent mouse models of chronic colitis: 1) DSS-induced chronic colitis, and 2) chronic spontaneous colitis in Wiskott-Aldrich Syndrome protein (WASP)-deficient (knockout) mice that is accelerated by irradiation.
The wildtype (WT) and IAP knockout (IAP-KO) mice received four cycles of 2% DSS ad libitum for 7 days. Each cycle was followed by a 7-day DSS-free interval during which mice received either cIAP or vehicle in the drinking water. The WASP-KO mice received either vehicle or cIAP for 6 weeks beginning on the day of irradiation.
Microscopic colitis scores of DSS-treated IAP-KO mice were higher than DSS-treated WT mice (52±3.8 versus 28.8±6.6, respectively, P<0.0001). cIAP treatment attenuated the disease in both groups (KO=30.7±6.01, WT=18.7±5.0, P<0.05). In irradiated WASP-KO mice cIAP also attenuated colitis compared to control groups (3.3±0.52 versus 6.2±0.34, respectively, P<0.001). Tissue myeloperoxidase activity and proinflammatory cytokines were significantly decreased by cIAP treatment.
Endogenous IAP appears to play a role in protecting the host against chronic colitis. Orally administered cIAP exerts a protective effect in two independent mouse models of chronic colitis and may represent a novel therapy for human IBD.
Inflammatory Bowel Diseases 02/2011; 17(2):532-42. · 4.86 Impact Factor
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PhD Sundaram Ramasamy PharmD,
Deanna D. Nguyen MD, Michelle A. Eston BA,
Sayeda Nasrin Alam MD,
Angela K. Moss MD,
Farzad Ebrahimi MD,
Brishti Biswas BS,
Golam Mostafa MD,
Kathryn T. Chen MD,
Kanakaraju Kaliannan MD, [......],
Sonoko Narisawa PhD,
José Luis Millán PhD,
H. Shaw Warren MD,
Elizabeth L. Hohmann MD,
PhD Emiko Mizoguchi MD,
Hans-Christian Reinecker MD,
Atul K. Bhan MD,
PhD Scott B. Snapper MD,
PhD Madhu S. Malo MD,
Richard A. Hodin MD
[show abstract]
[hide abstract]
ABSTRACT: Background:The brush border enzyme intestinal alkaline phosphatase (IAP) functions as a gut mucosal defense factor and is protective against dextran sulfate sodium (DSS)-induced acute injury in rats. The present study evaluated the potential therapeutic role for orally administered calf IAP (cIAP) in two independent mouse models of chronic colitis: 1) DSS-induced chronic colitis, and 2) chronic spontaneous colitis in Wiskott–Aldrich Syndrome protein (WASP)-deficient (knockout) mice that is accelerated by irradiation.Methods:The wildtype (WT) and IAP knockout (IAP-KO) mice received four cycles of 2% DSS ad libitum for 7 days. Each cycle was followed by a 7-day DSS-free interval during which mice received either cIAP or vehicle in the drinking water. The WASP-KO mice received either vehicle or cIAP for 6 weeks beginning on the day of irradiation.Results:Microscopic colitis scores of DSS-treated IAP-KO mice were higher than DSS-treated WT mice (52 ± 3.8 versus 28.8 ± 6.6, respectively, P < 0.0001). cIAP treatment attenuated the disease in both groups (KO = 30.7 ± 6.01, WT = 18.7 ± 5.0, P < 0.05). In irradiated WASP-KO mice cIAP also attenuated colitis compared to control groups (3.3 ± 0.52 versus 6.2 ± 0.34, respectively, P < 0.001). Tissue myeloperoxidase activity and proinflammatory cytokines were significantly decreased by cIAP treatment.Conclusions:Endogenous IAP appears to play a role in protecting the host against chronic colitis. Orally administered cIAP exerts a protective effect in two independent mouse models of chronic colitis and may represent a novel therapy for human IBD. (Inflamm Bowel Dis 2011)
Inflammatory Bowel Diseases 01/2011; 17(2):532 - 542. · 4.86 Impact Factor
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Lisa S Westerberg,
Parool Meelu,
Marisa Baptista, Michelle A Eston,
David A Adamovich,
Vinicius Cotta-de-Almeida,
Brian Seed,
Michael K Rosen,
Peter Vandenberghe,
Adrian J Thrasher,
Christoph Klein,
Frederick W Alt,
Scott B Snapper
[show abstract]
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ABSTRACT: X-linked neutropenia (XLN) is caused by activating mutations in the Wiskott-Aldrich syndrome protein (WASP) that result in aberrant autoinhibition. Although patients with XLN appear to have only defects in myeloid lineages, we hypothesized that activating mutations of WASP are likely to affect the immune system more broadly. We generated mouse models to assess the role of activating WASP mutations associated with XLN (XLN-WASP) in lymphocytes. XLN-WASP is expressed stably in B and T cells and induces a marked increase in polymerized actin. XLN-WASP-expressing B and T cells migrate toward chemokines but fail to adhere normally. In marked contrast to WASP-deficient cells, XLN-WASP-expressing T cells proliferate normally in response to cell-surface receptor activation. However, XLN-WASP-expressing B cells fail to proliferate and secrete lower amounts of antibodies. Moreover, XLN-WASP expression in lymphocytes results in modestly increased apoptosis associated with increased genomic instability. These data indicate that there are unique requirements for the presence and activation status of WASP in B and T cells and that WASP-activating mutations interfere with lymphocyte cell survival and genomic stability.
Journal of Experimental Medicine 06/2010; 207(6):1145-52. · 13.85 Impact Factor
