Clark, L.B. et al. Cellular and molecular characterization of the scurfy mouse mutant. J. Immunol. 162, 2546-2554

Oak Ridge National Laboratory, Oak Ridge, Florida, United States
The Journal of Immunology (Impact Factor: 4.92). 04/1999; 162(5):2546-54.
Source: PubMed


Mice hemizygous (Xsf/Y) for the X-linked mutation scurfy (sf) develop a severe and rapidly fatal lymphoproliferative disease mediated by CD4+CD8- T lymphocytes. We have undertaken phenotypic and functional studies to more accurately identify the immunologic pathway(s) affected by this important mutation. Flow cytometric analyses of lymphoid cell populations reveal that scurfy syndrome is characterized by changes in several phenotypic parameters, including an increase in Mac-1+ cells and a decrease in B220+ cells, changes that may result from the production of extremely high levels of the cytokine granulocyte-macrophage CSF by scurfy T cells. Scurfy T cells also exhibit strong up-regulation of cell surface Ags indicative of in vivo activation, including CD69, CD25, CD80, and CD86. Both scurfy and normal T cells are responsive to two distinct signals provided by the TCR and by ligation of CD28; scurfy cells, however, are hyperresponsive to TCR ligation and exhibit a decreased requirement for costimulation through CD28 relative to normal controls. This hypersensitivity may result, in part, from increased costimulation through B7-1 and B7-2, whose expression is up-regulated on scurfy T cells. Although the specific defect leading to this hyperactivation has not been identified, we also demonstrate that scurfy T cells are less sensitive than normal controls to inhibitors of tyrosine kinases such as genistein and herbimycin A, and the immunosuppressant cyclosporin A. One interpretation of our data would suggest that the scurfy mutation results in a defect, which interferes with the normal down-regulation of T cell activation.

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    • "There was a failure to withdraw the patient's corticosteroids , and he became steroid-dependant at a low dose (0.1 mg/kg/day). It is important to underline that newer regimes, including tacrolimus, as it has been suggested by Clark et al. [13], and sirolimus (selectively targeting T effector cells and not interfering with the function of T regulatory cells), have been shown to provide better remission rates and less side effects [14]. In our, patient, an attempt was made to introduce sirolimus, but the patient experienced too many adverse effects (arthralgia, asthenia and cutaneous eruption) and tacrolimus was not tried. "
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    ABSTRACT: We report here on the clinical, histological and immunological findings regarding a patient with immunodysregulation polyendocrinopathy enteropathy X-linked syndrome who was treated for the first 21years with a combination of immunosuppressant agents (IS). The potential modalities of care and treatment options in this rare and severe immune-mediated disorder are discussed. So, long-term outcome for IPEX patients can be obtained with immunosuppressive treatment, which is important since the outcome of haematopoietic stem cell transplantation for this population is variable. Copyright © 2015. Published by Elsevier Masson SAS.
    Full-text · Article · May 2015 · Gastroentérologie Clinique et Biologique
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    • "Scurfy (Sf) mice develop a fatal multi-organ autoimmune syndrome due to a spontaneous loss-of-function mutation in the gene encoding Foxp3 and a concomitant genetic deficit of functional Treg cells (Brunkow et al., 2001; Fontenot et al., 2003). Early studies in this mouse model indicated a decrease in the proportions of splenic B220+ cells that coincided with an increase of Mac-1+ cells (Clark et al., 1999). This appeared consistent with systemically elevated GM-CSF levels in Sf mice (Kanangat et al., 1996) and the notion that GM-CSF administration inhibits B lymphopoiesis in normal mice (Dorshkind, 1991). "
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    ABSTRACT: The role of Foxp3-expressing regulatory T (T(reg)) cells in tolerance and autoimmunity is well-established. However, although of considerable clinical interest, the role of T(reg) cells in the regulation of hematopoietic homeostasis remains poorly understood. Thus, we analysed B and T lymphopoiesis in the scurfy (Sf) mouse model of T(reg) cell deficiency. In these experiments, the near-complete block of B lymphopoiesis in the BM of adolescent Sf mice was attributed to autoimmune T cells. We could exclude a constitutive lympho-hematopoietic defect or a B cell-intrinsic function of Foxp3. Efficient B cell development in the BM early in ontogeny and pronounced extramedullary B lymphopoietic activity resulted in a peripheral pool of mature B cells in adolescent Sf mice. However, marginal zone B and B-1a cells were absent throughout ontogeny. Developmental B lymphopoietic defects largely correlated with defective thymopoiesis. Importantly, neonatal adoptive T(reg) cell therapy suppressed exacerbated production of inflammatory cytokines and restored thymopoiesis but was ineffective in recovering defective B lymphopoiesis, probably due to a failure to compensate production of stroma cell-derived IL-7 and CXCL12. Our observations on autoimmune-mediated incapacitation of the BM environment in Foxp3-deficient mice will have direct implications for the rational design of BM transplantation protocols for patients with severe genetic deficiencies in functional Foxp3(+) T(reg) cells.
    Full-text · Article · Jun 2012 · Frontiers in Immunology
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    • "Another example of induced EH is the increased myelopoiesis found in many organs of FoxP3-null scurfy mice. Scurfy mice display increased CD11b+ myeloid cells in the spleen and the liver, which is consistent with increased expression of GM-CSF and IL-3.29 In scurfy mice, T cells producing GM-CSF and IL-3 are overly activated in the absence of FoxP3+ T cells, driving excessive EH in the spleen and liver. "
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    ABSTRACT: Extramedullary hematopoiesis (EH) is defined as hematopoiesis occurring in organs outside of the bone marrow; it occurs in diverse conditions, including fetal development, normal immune responses, and pathological circumstances. During fetal development, before formation of mature marrow, EH occurs in the yolk sac, fetal liver, and spleen. EH also occurs during active immune responses to pathogens. Most frequently, this response occurs in the spleen and liver for the production of antigen-presenting cells and phagocytes. EH also occurs when the marrow becomes inhabitable for stem and progenitor cells in certain pathological conditions, including myelofibrosis, where marrow cells are replaced with collagenous connective tissue fibers. Thus, EH occurs either actively or passively in response to diverse changes in the hematopoietic environment. This article reviews the key features and regulators of the major types of EH.
    Preview · Article · Mar 2010 · Hematology Research and Reviews
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