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3.
Arthritis Rheumatol ; 68(6): 1551-62, 2016 06.
Article in English | MEDLINE | ID: mdl-26714180

ABSTRACT

OBJECTIVE: Transforming growth factor ß (TGFß) plays a prominent role in the establishment of immunologic tolerance, and mice lacking TGFß1 die of multiorgan inflammation early in life. TGFß controls the differentiation of CD4+ lymphocytes into Treg cells or proinflammatory Th17 cells. Although this dual capacity is modulated by the presence of additional cytokines around the activated cells, TGFß also dissociates Th17/Treg cell differentiation in a dose-dependent manner by mechanisms still unknown. The purpose of this study was to explore the contribution of bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) to the modulation of TGFß activity during the differentiation of CD4+ cells and in the control of immunologic tolerance in mice with collagen-induced arthritis (CIA). METHODS: The in vitro and in vivo Treg cell and Th17 cell differentiation and the development of CIA were compared in wild-type mice and BAMBI-deficient mice. RESULTS: BAMBI was induced after activation by TGFß and fixed the appropriate intensity level of TGFß signaling in CD4+ cells. Its deficiency protected mice against the development of CIA by a Treg cell- and TGFß-dependent mechanism. Mechanistically, BAMBI was found to regulate CD25 expression and interleukin-2 (IL-2) signaling in Treg cells and in IL-2- and/or TGFß-activated CD4+ cells and modulated Treg cell and Th17 cell differentiation both in vitro and in vivo. CONCLUSION: Taken together, the results indicate that BAMBI is a component of a rheostat-like mechanism that, through the control of TGFß and IL-2 signaling strength, regulates the differentiation of CD4+ lymphocytes and the development of autoimmune arthritis.


Subject(s)
Arthritis, Experimental/immunology , Autoimmune Diseases/immunology , Bone Morphogenetic Proteins/physiology , Cell Differentiation , Interleukin-2/physiology , Membrane Proteins/physiology , T-Lymphocytes, Regulatory/physiology , Th17 Cells/physiology , Transforming Growth Factor beta/physiology , Animals , CD4-Positive T-Lymphocytes/physiology , Male , Mice , Signal Transduction
4.
Arthritis Rheum ; 65(2): 343-54, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23124840

ABSTRACT

OBJECTIVE: Despite the importance of Treg cells in the maintenance of immunologic tolerance, the mechanisms that control their generation and activity are unknown. Since the cell cycle inhibitor p27(Kip1) (p27) was involved in T cell anergy, we undertook this study to explore its role in both Treg cell processes. METHODS: The development of type II collagen-induced arthritis (CIA) and lupus-like abnormalities was compared between transgenic mice overexpressing human Bcl-2 in T cells (BCL2-TgT mice) and nontransgenic mice that were deficient or not deficient in p27. The contribution of Treg cells to disease evolution was also explored. Finally, the in vitro activity of Treg cells and their differentiation from naive CD4+ cells was compared between these strains of mice. RESULTS: BCL2-TgT mice were protected against CIA by a Treg cell-dependent mechanism. In association with this protection, the overexpression of Bcl-2 in T cells enhanced the differentiation and activity of Treg cells. Both Bcl-2 effects were independent of its antiapoptotic activity but dependent on its capacity to induce the expression of p27 that augmented the strength of transforming growth factor ß (TGFß) signaling in T cells. Accordingly, down-modulation of p27 expression in BCL2-TgT mice promoted CIA. In addition, p27 deficiency in aged C57BL/6 mice reduced the number and activity of Treg cells and induced the development of mild lupus-like abnormalities. CONCLUSION: Our results point to p27 as a critical regulator of Treg cell differentiation and function through the positive modulation of TGFß signaling strength in T cells.


Subject(s)
Arthritis, Experimental/immunology , Autoimmunity/immunology , Cell Differentiation/immunology , Cyclin-Dependent Kinase Inhibitor p27/genetics , T-Lymphocytes, Regulatory/immunology , Animals , Arthritis, Experimental/genetics , Arthritis, Experimental/metabolism , Autoimmunity/genetics , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , Cell Differentiation/genetics , Cyclin-Dependent Kinase Inhibitor p27/metabolism , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Mice , Mice, Transgenic , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Signal Transduction/genetics , Signal Transduction/immunology , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/metabolism , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/metabolism
5.
Arthritis Rheum ; 63(4): 971-80, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21225684

ABSTRACT

OBJECTIVE: To explore the bidirectional relationship between the development of rheumatoid arthritis (RA) and atherosclerosis using bovine type II collagen (CII)-immunized B10.RIII apoE(-/-) mice, a murine model of spontaneous atherosclerosis and collagen-induced arthritis (CIA). METHODS: Male B10.RIII apoE(-/-) mice and wild-type controls were immunized with 150 µg of CII emulsified in Freund's complete adjuvant (CFA). The clinical, radiologic, and histopathologic severity of CIA, the levels of circulating IgG1 and IgG2a anti-CII antibodies, the expression of proinflammatory and antiinflammatory cytokines in the joints, and the percentages of Th1, Th17, and Treg lymphocytes in the draining lymph nodes were evaluated during CIA induction. In addition, the size of atherosclerotic lesions was assessed in these mice 8 weeks after CIA induction. RESULTS: B10.RIII apoE(-/-) mice that were immunized with CII and CFA developed an exacerbated CIA that was accompanied by increased joint expression of multiple proinflammatory cytokines and by the expansion in the draining lymph nodes of Th1 and Th17 cells. In contrast, the size of vascular lesions in B10.RIII apoE(-/-) mice was not affected by the development of CIA. CONCLUSION: Our findings indicate that a deficiency in apolipoprotein E and/or its consequences in cholesterol metabolism act as accelerating factors in autoimmunity by promoting Th1 and Th17 inflammatory responses.


Subject(s)
Apolipoproteins E/deficiency , Arthritis, Experimental/metabolism , Arthritis, Experimental/pathology , Cell Proliferation , Severity of Illness Index , Th1 Cells/pathology , Th17 Cells/pathology , Animals , Antibodies/immunology , Antibodies/metabolism , Apolipoproteins E/genetics , Apolipoproteins E/metabolism , Arthritis, Experimental/physiopathology , Atherosclerosis/metabolism , Atherosclerosis/pathology , Atherosclerosis/physiopathology , Cholesterol/metabolism , Collagen/immunology , Cytokines/metabolism , Disease Models, Animal , Lymph Nodes/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , T-Lymphocytes, Regulatory/pathology
6.
J Autoimmun ; 35(4): 316-24, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20691570

ABSTRACT

Genetic abnormalities predisposing to autoimmunity generally act in a cooperative manner affecting one or several mechanisms regulating immunological tolerance. In addition, many of these genetic abnormalities are also involved in the development of lymphoproliferative diseases. In the present study, we have determined the possible cooperation between deficiencies in members of the Cip/Kip family of cell cycle regulators (p21(WAF1/Cip1) or p27(kip1)) and the overexpression of human Bcl-2 in B lymphocytes in the induction of autoimmune and lymphoproliferative diseases in non-autoimmune C57BL/6 (B6) mice. Unlike single mutant mice, B6.p21(-/-) mice transgenic for human Bcl-2 in B cells developed a lethal autoimmune syndrome characterized by the production of autoantibodies, the prominent expansion of memory B and CD4(+) T cells and the development of severe glomerular lesions resembling IgA nephropathy. Furthermore, these mice presented a high incidence of B-cell lymphoproliferative disorders. Such genetic cooperation in the induction of autoimmunity was not observed in B6.p27(-/-) mice transgenic for human Bcl-2 in B cells. Altogether, what we have demonstrated here is the existence of preferential interactions among particular regulators of the G(1)/S transition of the cell cycle and B-cell survival in the induction of systemic autoimmune and lymphoproliferative diseases.


Subject(s)
Autoimmune Lymphoproliferative Syndrome/immunology , B-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/metabolism , Lupus Erythematosus, Systemic/immunology , Proto-Oncogene Proteins c-bcl-2/metabolism , Animals , Autoantibodies/blood , Autoantibodies/immunology , Autoimmune Lymphoproliferative Syndrome/complications , Autoimmune Lymphoproliferative Syndrome/genetics , B-Lymphocytes/immunology , B-Lymphocytes/pathology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , Cyclin-Dependent Kinase Inhibitor p21/deficiency , Cyclin-Dependent Kinase Inhibitor p27/deficiency , Disease Models, Animal , Epistasis, Genetic/genetics , Epistasis, Genetic/immunology , Humans , Immunologic Memory , Kidney/immunology , Kidney/pathology , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/genetics , Mice , Mice, Inbred C57BL , Mice, Transgenic , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/immunology , Transgenes/genetics
7.
J Immunol ; 178(5): 2778-86, 2007 Mar 01.
Article in English | MEDLINE | ID: mdl-17312121

ABSTRACT

Regulation of lymphocyte survival is essential for the maintenance of lymphoid homeostasis preventing the development of autoimmune diseases. Recently, we described a systemic lupus erythematosus associated with an IgA nephropathy in autoimmune-prone (NZW x C57BL/6)F(1) overexpressing human Bcl-2 (hBcl-2) in B cells (transgenic (Tg) 1). In the present study, we analyze in detail a second line of hBcl-2 Tg mice overexpressing the transgene in all B cells and in a fraction of CD4(+) and CD8(+) T cells (Tg2). We demonstrate here that the overexpression of hBcl-2 in T cells observed in Tg2 mice is associated with a resistance to the development of lupus disease and collagen type II-induced arthritis in both (NZW x C57BL/6)F(1) and (DBA/1 x C57BL/6)F(1) Tg2 mice, respectively. The disease-protective effect observed in autoimmune-prone Tg2 mice is accompanied by an increase of peripheral CD4(+)CD25(+) hBcl-2(+) regulatory T cells (T(regs)), expressing glucocorticoid-induced TNFR, CTLA-4, and FoxP3. Furthermore, the in vivo depletion of CD4(+)CD25(+) T(regs) in (DBA/1 x C57BL/6)F(1) Tg2 mice promotes the development of a severe collagen type II-induced arthritis. Taken together, our results indicate that the overexpression of hBcl-2 in CD4(+) T cells alters the homeostatic mechanisms controlling the number of CD4(+)CD25(+) T(regs) resulting in the inhibition of autoimmune diseases.


Subject(s)
Arthritis, Experimental/immunology , Autoimmune Diseases/immunology , Autoimmunity , Proto-Oncogene Proteins c-bcl-2/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Arthritis, Experimental/pathology , Autoimmune Diseases/chemically induced , Autoimmune Diseases/pathology , Autoimmunity/genetics , B-Lymphocytes/immunology , B-Lymphocytes/pathology , Biomarkers , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , Collagen Type II/toxicity , Gene Expression , Homeostasis/immunology , Humans , Mice , Mice, Transgenic , Proto-Oncogene Proteins c-bcl-2/genetics , T-Lymphocytes, Regulatory/pathology
8.
J Immunol ; 172(11): 7177-85, 2004 Jun 01.
Article in English | MEDLINE | ID: mdl-15153542

ABSTRACT

Little is known about the pathogenic mechanisms of IgA nephropathy, despite being the most prevalent form of glomerulonephritis in humans. We report in this study that in (New Zealand White (NZW) x C57BL/6)F(1) mice predisposed to autoimmune diseases, the expression of a human bcl-2 (hbcl-2) transgene in B cells promotes a CD4-dependent lupus-like syndrome characterized by IgG and IgA hypergammaglobulinemia, autoantibody production, and the development of a fatal glomerulonephritis. Histopathological analysis of glomerular lesions reveals that the glomerulonephritis observed in these animals resembles that of human IgA nephropathy. The overexpression of Bcl-2 in B cells selectively enhances systemic IgA immune responses to T-dependent Ags. Significantly, serum IgA purified from (NZW x C57BL/6)F(1)-hbcl-2 transgenic mice, but not from nontransgenic littermates, shows reduced levels of galactosylation and sialylation and an increased ability to deposit in the glomeruli, as observed in human patients with IgA nephropathy. Our results indicate that defects in the regulation of B lymphocyte survival associated with aberrant IgA glycosylation may be critically involved in the pathogenesis of IgA nephropathy, and that (NZW x C57BL/6)F(1)-hbcl-2 Tg mice provide a new experimental model for this form of glomerulonephritis.


Subject(s)
Apoptosis , B-Lymphocytes/physiology , Glomerulonephritis, IGA/etiology , Proto-Oncogene Proteins c-bcl-2/physiology , Animals , Female , Glycosylation , Immunoglobulin A/metabolism , Lupus Erythematosus, Systemic/etiology , Mice , Mice, Inbred C57BL , Mice, Inbred NZB , Mice, Transgenic
9.
Immunology ; 109(4): 504-9, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12871216

ABSTRACT

Signalling through CD40 is essential for the development of immunoglobulin G (IgG) antibody responses, germinal centres and B-cell memory against T-dependent antigens. In addition, engagement of CD40 in B cells promotes cell survival by inducing the expression of anti-apoptotic members of the bcl-2 family of cell-death regulators. In the present study we analysed whether T-dependent immune responses can be developed in mice deficient in CD40 if the anti-apoptotic activity mediated by the engagement of CD40 in B cells is compensated by the constitutive over-expression of anti-apoptotic genes of the bcl-2 family. We showed that the over-expression of either hbcl-2 or hbcl-xL transgenes in B cells is not sufficient to restore IgG antibody responses and germinal centre formation in CD40-deficient mice. These results indicate that CD40 functions, other than those mediated through survival, are required for the establishment of T-dependent B-cell responses.


Subject(s)
B-Lymphocytes/immunology , CD40 Antigens/immunology , Genes, bcl-2/immunology , T-Lymphocytes/immunology , Animals , Apoptosis/immunology , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Gene Expression/immunology , Germinal Center/immunology , Immunity, Cellular/immunology , Immunoglobulin G/biosynthesis , Immunoglobulin M/biosynthesis , Mice , Mice, Inbred C57BL , Proto-Oncogene Proteins c-bcl-2/immunology , bcl-X Protein
10.
Nephrol Dial Transplant ; 18(5): 878-83, 2003 May.
Article in English | MEDLINE | ID: mdl-12686658

ABSTRACT

BACKGROUND: Mycophenolate mofetil (MMF) has been successfully used to improve or prevent the development of systemic lupus erythematosus (SLE) in both humans and in several lupus-prone mice. In the present study, we evaluated mechanisms through which MMF may exert its therapeutic effect on the development of systemic autoimmunity. METHODS: (NZBxNZW)F(1) female mice were continuously treated with 100 mg/kg/day (high dose) or 30 mg/kg/day (low dose) MMF beginning at 3 months of age. The development of an autoimmune syndrome was evaluated by measuring immunoglobulin (Ig) isotypes of autoantibodies and their levels, as well as by evaluating immunopathological kidney abnormalities and mortality curves. RESULTS: At both doses, MMF efficiently modulated the development of SLE. Although the higher dose of MMF directly inhibited the production of autoantibodies, 30 mg/kg/day MMF promoted qualitative but not quantitative changes in autoantibodies in (NZB x NZW)F(1) female mice. These qualitative changes were manifested as a selective reduction in total or antigen-specific IgG2a antibody levels. CONCLUSIONS: The mechanisms through which MMF controls the development of SLE in (NZB x NZW)F(1) females is highly dependent upon immunosuppressor dose. Interestingly, lower dose MMF selectively reduced IgG2a antibody levels, suggesting that this dose may modulate T(H1) CD4+ activity.


Subject(s)
Autoantibodies/biosynthesis , Lupus Erythematosus, Systemic/prevention & control , Mycophenolic Acid/analogs & derivatives , Mycophenolic Acid/pharmacology , Animals , Female , Glomerulonephritis/immunology , Glomerulonephritis/pathology , Glomerulonephritis/prevention & control , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/pharmacology , Lupus Erythematosus, Systemic/drug therapy , Lupus Erythematosus, Systemic/immunology , Lupus Nephritis/immunology , Lupus Nephritis/pathology , Lupus Nephritis/prevention & control , Mice , Mice, Inbred BALB C , Mice, Inbred NZB , Mycophenolic Acid/administration & dosage
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