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1.
Dig Dis Sci ; 64(8): 2140-2146, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30788684

RESUMO

BACKGROUND: Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a group of cytoplasmic sensors that survey danger signals released by invading pathogens or damaged tissue. Mutations in the NLRP subfamily affect pro-inflammatory mediators and cause nonspecific systemic symptoms. AIMS: We sought to identify a potential genetic etiology of an inflammatory syndrome in a patient that presented with an atypical multisystem illness with carcinoid syndrome as well as atopic and autoimmune features. METHODS: Exome sequencing was performed using the Agilent SureSelect Clinical Research Exome XT kit on an Illumina HiSeq 2500. Longitudinal monitoring of pro-inflammatory cytokines was performed. RESULTS: We identified a novel variant (heterozygous c.536C > T [p.Thr179Ile]) in the NLRP12 gene in a 63-year-old woman and her daughter, who presented with an unusual clinical syndrome that differs from autoinflammatory disorders previously reported in association with the NLRP subfamily gene mutations. This NLRP12 variant was predicted to be pathogenic by functional analysis through Hidden Markov Models (FATHMM). Both the mother and the daughter had episodes of abdominal pain, fever, diarrhea, skin rash, hypothyroidism, and elevated urine 5-hydroxyindoleacetic acid (5-HIAA) levels. The proband also had elevated serum levels of pro-inflammatory (IL-1ß, IL-6, IL-12, and TNF-α), Th1 (IL-2, IFN-γ), and Th2 (IL-4, IL-5, IL-13) cytokines, but not of Th17 (IL-17) and IL-10. CONCLUSION: This report adds to the expanding spectrum of clinical manifestations attributed to the NLRP subfamily gene variants and suggests a role of NLRP12 in the regulation of multiple cytokines.


Assuntos
Doenças Autoimunes/genética , Citocinas/sangue , Mediadores da Inflamação/sangue , Peptídeos e Proteínas de Sinalização Intracelular/genética , Síndrome do Carcinoide Maligno/genética , Mutação , Doenças Autoimunes/sangue , Doenças Autoimunes/diagnóstico , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Síndrome do Carcinoide Maligno/sangue , Síndrome do Carcinoide Maligno/diagnóstico , Pessoa de Meia-Idade , Fenótipo , Regulação para Cima
2.
Arthritis Rheum ; 65(4): 1043-54, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23334904

RESUMO

OBJECTIVE: To determine the necessity for any individual BAFF receptor in the development of systemic lupus erythematosus (SLE). METHODS: Bcma-, Taci-, and Br3-null mutations were introgressed into NZM 2328 mice. NZM.Bcma-/-, NZM.Taci-/-, and NZM.Br3-/- mice were evaluated for lymphocyte phenotype and BAFF receptor expression by flow cytometry; for B cell responsiveness to BAFF by in vitro culture; for serum levels of BAFF and total IgG and IgG anti-double-stranded DNA (anti-dsDNA) by enzyme-linked immunosorbent assay; for renal immunopathology by immunofluorescence and histopathology; and for clinical disease. RESULTS: BCMA, TACI, and B lymphocyte stimulator receptor 3 (BR3) were not surface-expressed in NZM.Bcma-/-, NZM.Taci-/-, and NZM.Br3-/- mice, respectively. Transitional and follicular B cells from NZM.Br3-/- mice were much less responsive to BAFF than were the corresponding cells from wild-type, NZM.Bcma-/-, or NZM.Taci-/- mice. In comparison with wild-type mice, NZM.Bcma-/- and NZM.Taci-/- mice harbored an increased number of spleen B cells, T cells, and plasma cells, whereas serum levels of total IgG and IgG anti-dsDNA were similar to those in wild-type mice. Despite their paucity of B cells, NZM.Br3-/- mice had an increased number of T cells, and the numbers of plasma cells and levels of IgG anti-dsDNA were similar to those in wild-type mice. Serum levels of BAFF were increased in NZM.Taci-/- and NZM.Br3-/- mice but were decreased in NZM.Bcma-/- mice. Despite their phenotypic differences, NZM.Bcma-/-, NZM.Taci-/-, and NZM.Br3-/- mice had renal immunopathology and clinical disease that were at least as severe as that in wild-type mice. CONCLUSION: Any single BAFF receptor, including BR3, is dispensable for the development of SLE in NZM mice. Development of disease in NZM.Br3-/- mice demonstrates that BAFF-BCMA and/or BAFF-TACI interactions contribute to SLE, and that a profound, life-long reduction in the numbers of B cells does not guarantee protection against SLE.


Assuntos
Antígeno de Maturação de Linfócitos B/metabolismo , Subpopulações de Linfócitos B , Lúpus Eritematoso Sistêmico/metabolismo , Proteína Transmembrana Ativadora e Interagente do CAML/metabolismo , Animais , Anticorpos Antinucleares , Fator Ativador de Células B/farmacologia , Receptor do Fator Ativador de Células B/genética , Receptor do Fator Ativador de Células B/metabolismo , Antígeno de Maturação de Linfócitos B/genética , Subpopulações de Linfócitos B/citologia , Subpopulações de Linfócitos B/efeitos dos fármacos , Subpopulações de Linfócitos B/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Imunoglobulina M/imunologia , Imunoglobulina M/metabolismo , Rim/imunologia , Rim/metabolismo , Rim/patologia , Lúpus Eritematoso Sistêmico/etiologia , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Camundongos Congênicos , Proteína Transmembrana Ativadora e Interagente do CAML/genética
3.
Arthritis Rheum ; 64(5): 1610-9, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22127792

RESUMO

OBJECTIVE: To determine the role of APRIL in the development of systemic lupus erythematosus (SLE) in mice. METHODS: Wild-type (WT) NZM 2328, NZM. April(-/-) , NZM.Baff(-/-) , and NZM.Baff(-/-) .April(-/-) mice were evaluated for lymphocyte phenotype by flow cytometry, for serum total IgG and IgG autoantibody levels by enzyme-linked immunosorbent assay, for glomerular deposition of IgG and C3 by immunofluorescence, for renal changes by histopathology, and for clinical disease by laboratory assessment (severe proteinuria). RESULTS: In comparison to WT mice, NZM.April(-/-) mice harbored increased spleen B cells, T cells, and plasma cells (PCs), increased serum levels of IgG antichromatin antibodies, and decreased numbers of bone marrow (BM) PCs. Glomerular deposition of IgG and C3 was similar in NZM.April(-/-) mice and WT mice, renal changes on histopathology tended to be more severe in NZM.April(-/-) mice than in WT mice, and development of clinical disease was identical in NZM.April(-/-) mice and WT mice. BM (but not spleen) PCs and serum IgG antichromatin and anti-double-stranded DNA antibody levels were lower in NZM.Baff(-/-) .April(-/-) mice than in NZM.Baff(-/-) mice, whereas renal immunopathology in each cohort was equally mild. CONCLUSION: APRIL is dispensable for the development of full-blown SLE in NZM mice. Moreover, the elimination of both APRIL and BAFF had no discernible effect on the development of renal immunopathology or clinical disease beyond that of elimination of BAFF alone. The reduction in BM PCs in hosts doubly deficient in APRIL and BAFF beyond that in hosts deficient only in BAFF raises concern that combined antagonism of APRIL and BAFF may lead to greater immunosuppression without a concomitant increase in therapeutic efficacy.


Assuntos
Fator Ativador de Células B/deficiência , Lúpus Eritematoso Sistêmico/imunologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/deficiência , Animais , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Fator Ativador de Células B/genética , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Biomarcadores/metabolismo , Células da Medula Óssea , Complemento C3/imunologia , Complemento C3/metabolismo , Modelos Animais de Doenças , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Terapia de Imunossupressão , Glomérulos Renais/imunologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Camundongos Endogâmicos NZB , Camundongos Knockout , Plasmócitos/imunologia , Plasmócitos/metabolismo , Plasmócitos/patologia , Especificidade da Espécie , Baço/imunologia , Baço/metabolismo , Baço/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética
4.
J Immunol ; 186(8): 4984-93, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21383240

RESUMO

IFN-α is a potent activator of innate and adaptive immunity, and its administration to preautoimmune (NZB×NZW)F1 mice promotes virulent systemic lupus erythematosus (SLE) disease. Given the known contributions of B cells and BAFF to SLE, we evaluated the ability of IFN-α administration to induce disease in wild-type (WT), B cell-deficient, and BAFF-deficient NZM 2328 mice. Whereas WT mice rapidly developed proliferative glomerulonephritis, marked proteinuria, and increased mortality in response to IFN-α administration, B cell-deficient mice developed neither renal pathology nor clinical disease. Moreover, BAFF-deficient mice, despite developing limited glomerular IgG and C3 deposition, also remained free of histological glomerulonephritis and clinical disease. Strikingly, similar T cell expansion and serum IgG responses were observed in adenovirus (Adv)-IFN-treated WT and BAFF-deficient mice despite their disparate pathological and clinical responses, whereas numbers of activated B cells increased in WT mice but not in BAFF-deficient mice. Nonetheless, B cell, plasma cell, and T cell infiltration of the kidneys in Adv-IFN-treated WT mice was similar to that in WT mice treated with Adv-control. Its ability to promote SLE disease in WT mice notwithstanding, IFN-α administration failed to drive the preferential expansion of CD4(+) memory T cells that occurs during the natural course of disease, and glomerular infiltration of macrophages failed to associate with development of disease. These results collectively suggest that therapeutic targeting in SLE of BAFF and/or B cells in SLE could be successful even in states of IFN-α overexpression. Moreover, our results document important biological differences between IFN-α-driven and spontaneous natural SLE disease.


Assuntos
Fator Ativador de Células B/imunologia , Linfócitos B/imunologia , Interferon-alfa/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Adenoviridae/genética , Animais , Autoanticorpos/sangue , Autoanticorpos/imunologia , Fator Ativador de Células B/genética , Fator Ativador de Células B/metabolismo , Linfócitos B/metabolismo , Feminino , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Imuno-Histoquímica , Interferon-alfa/genética , Interferon-alfa/metabolismo , Rim/imunologia , Rim/metabolismo , Rim/patologia , Glomérulos Renais/imunologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NZB , Camundongos Endogâmicos , Camundongos Knockout , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/genética , Receptores Tipo II do Fator de Necrose Tumoral/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Tempo
5.
J Immunol ; 186(7): 4223-33, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21357255

RESUMO

Engagement of the low-affinity Ab receptor FcγRIIb downregulates B cell activation, and its dysfunction is associated with autoimmunity in mice and humans. We engineered the Fc domain of an anti-human CD19 Ab to bind FcγRIIb with high affinity, promoting the coengagement of FcγRIIb with the BCR complex. This Ab (XmAb5871) stimulated phosphorylation of the ITIM of FcγRIIb and suppressed BCR-induced calcium mobilization, proliferation, and costimulatory molecule expression of human B cells from healthy volunteers and systemic lupus erythematosus (SLE) patients, as well as B cell proliferation induced by LPS, IL-4, or BAFF. XmAb5871 suppressed humoral immunity against tetanus toxoid and reduced serum IgM, IgG, and IgE levels in SCID mice engrafted with SLE or healthy human PBMC. XmAb5871 treatment also increased survival of mice engrafted with PBMC from a unique SLE patient. Unlike anti-CD20 Ab, coengagement of FcγRIIb and BCR complex did not promote B cell depletion in human PBMC cultures or in mice. Thus, amplification of the FcγRIIb inhibitory pathway in activated B cells may represent a novel B cell-targeted immunosuppressive therapeutic approach for SLE and other autoimmune diseases that should avoid the complications associated with B cell depletion.


Assuntos
Sítios de Ligação de Anticorpos , Comunicação Celular/imunologia , Imunidade Humoral , Lúpus Eritematoso Sistêmico/imunologia , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores de IgG/metabolismo , Animais , Antígenos CD19/imunologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Subpopulações de Linfócitos B/patologia , Comunicação Celular/genética , Modelos Animais de Doenças , Feminino , Amplificação de Genes/imunologia , Células HEK293 , Humanos , Imunidade Humoral/genética , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/transplante , Lúpus Eritematoso Sistêmico/patologia , Lúpus Eritematoso Sistêmico/prevenção & controle , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos , Camundongos SCID , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/fisiologia , Receptores de IgG/deficiência , Receptores de IgG/fisiologia
6.
Cell Mol Gastroenterol Hepatol ; 16(1): 83-105, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37011811

RESUMO

BACKGROUND & AIMS: Tumor necrosis factor (TNF) superfamily member tumor necrosis factor-like protein 1A (TL1A) has been associated with the susceptibility and severity of inflammatory bowel diseases. However, the function of the tumor necrosis factor-like protein 1A and its receptor death receptor 3 (DR3) in the development of intestinal inflammation is incompletely understood. We investigated the role of DR3 expressed by intestinal epithelial cells (IECs) during intestinal homeostasis, tissue injury, and regeneration. METHODS: Clinical phenotype and histologic inflammation were assessed in C57BL/6 (wild-type), Tl1a-/- and Dr3-/- mice in dextran sulfate sodium (DSS)-induced colitis. We generated mice with an IEC-specific deletion of DR3 (Dr3ΔIEC) and assessed intestinal inflammation and epithelial barrier repair. In vivo intestinal permeability was assessed by fluorescein isothiocyanate dextran uptake. Proliferation of IECs was analyzed by bromodeoxyuridine incorporation. Expression of DR3 messenger RNA was assessed by fluorescent in situ hybridization. Small intestinal organoids were used to determine ex vivo regenerative potential. RESULTS: Dr3-/- mice developed more severe colonic inflammation than wild-type mice in DSS-induced colitis with significantly impaired IEC regeneration. Homeostatic proliferation of IECs was increased in Dr3-/- mice, but blunted during regeneration. Cellular localization and expression of the tight junction proteins Claudin-1 and zonula occludens-1 were altered, leading to increased homeostatic intestinal permeability. Dr3ΔIEC mice recapitulated the phenotype observed in Dr3-/- mice with increased intestinal permeability and IEC proliferation under homeostatic conditions and impaired tissue repair and increased bacterial translocation during DSS-induced colitis. Impaired regenerative potential and altered zonula occludens-1 localization also were observed in Dr3ΔIEC enteroids. CONCLUSIONS: Our findings establish a novel function of DR3 in IEC homeostasis and postinjury regeneration independent of its established role in innate lymphoid cells and T-helper cells.


Assuntos
Colite , Imunidade Inata , Camundongos , Animais , Hibridização in Situ Fluorescente , Mucosa Intestinal/patologia , Camundongos Endogâmicos C57BL , Linfócitos/metabolismo , Colite/patologia , Inflamação/patologia , Fatores de Necrose Tumoral/efeitos adversos , Fatores de Necrose Tumoral/genética , Fatores de Necrose Tumoral/metabolismo , Homeostase , Regeneração
7.
Arthritis Rheum ; 62(8): 2432-42, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20506216

RESUMO

OBJECTIVE: To determine whether overexpression of BAFF can promote systemic lupus erythematosus (SLE)-like autoimmunity in mice that are otherwise autoimmune-resistant. METHODS: We used class II major histocompatibility complex (MHC)-deficient C57BL/6 (B6) mice as a model of resistance to SLE and Sles1-bearing B6 mice as a model of resistance to the autoantibody-promoting capacity of the Sle1 region. We generated BAFF-transgenic (Tg) counterparts to these respective mice and evaluated lymphocyte phenotype, serologic autoimmunity, renal immunopathology, and clinical disease in the BAFF-Tg and non-Tg mouse sets. RESULTS: Although constitutive BAFF overexpression did not lead to B cell expansion in class II MHC-deficient B6 mice, it did lead to increased serum IgG autoantibody levels. Nevertheless, renal immunopathology was limited, and clinical disease did not develop. In B6 and B6.Sle1 mice, constitutive BAFF overexpression led to increased numbers of B cells and CD4+ memory cells, as well as increased serum IgG and IgA autoantibody levels. Renal immunopathology was modestly greater in BAFF-Tg mice than in their non-Tg counterparts, but again, clinical disease did not develop. Introduction of the Sles1 region into B6.Sle1.Baff mice abrogated the BAFF-driven increase in CD4+ memory cells and the Sle1-driven, but not the BAFF-driven, increase in serum IgG antichromatin levels. Renal immunopathology was substantially ameliorated. CONCLUSION: Although constitutive BAFF overexpression in otherwise autoimmune-resistant mice led to humoral autoimmunity, meaningful renal immunopathology and clinical disease did not develop. This raises the possibility that BAFF overexpression, even when present, may not necessarily drive disease in some SLE patients. This may help explain the heterogeneity of the clinical response to BAFF antagonists in human SLE.


Assuntos
Autoimunidade/genética , Fator Ativador de Células B/genética , Rim/imunologia , Lúpus Eritematoso Sistêmico/genética , Análise de Variância , Animais , Autoanticorpos/genética , Autoanticorpos/imunologia , Autoimunidade/imunologia , Fator Ativador de Células B/imunologia , Linfócitos B/imunologia , Imunofluorescência , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
8.
J Immunol ; 183(9): 6021-9, 2009 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-19812195

RESUMO

Type I IFNs are potent regulators of innate and adaptive immunity and are implicated in the pathogenesis of systemic lupus erythematosus. Here we report that clinical and pathological lupus nephritis and serum anti-nuclear Ab levels are greatly attenuated in New Zealand Mixed (NZM) 2328 mice deficient in type I IFN receptors (IFNAR). To determine whether the inflammatory environment in NZM 2328 mice leads to IFNAR-regulated changes in dendritic cells (DC), the number, activation, and function of DC subsets were compared in 2- and 5-mo-old (clinically healthy) female NZM and NZM-IFNAR(-/-) mice. Numbers of activated CD40(high) plasmacytoid DC (pDC) were significantly increased in renal lymph nodes of 2-mo-old NZM but not NZM-IFNAR(-/-) mice, suggesting an early IFNAR-dependent expansion and activation of pDC at disease sites. Relative to NZM spleens, NZM-IFNAR(-/-) spleens in 5-mo-old mice were significantly decreased in size and contained reduced numbers of conventional DC subsets, but not pDC. Splenic and renal lymph node NZM-IFNAR(-/-) DC analyzed directly ex vivo expressed significantly less CD40, CD86, and PDL1 than did NZM DC. Upon activation with synthetic TLR9 ligands in vitro, splenic NZM-IFNAR(-/-) DC produced less IL-12p40/70 and TNF-alpha than did NZM DC. The limited IFNAR(-/-) DC response to endogenous activating stimuli correlated with reduced numbers of splenic activated memory CD4(+) T cells and CD19(+) B cells in older mice. Thus, IFNAR signaling significantly increases DC numbers, acquisition of Ag presentation competence, and proinflammatory function before onset of clinically apparent lupus disease.


Assuntos
Células Dendríticas/imunologia , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/prevenção & controle , Receptor de Interferon alfa e beta/deficiência , Receptor de Interferon alfa e beta/genética , Animais , Apresentação de Antígeno/genética , Autoanticorpos/biossíntese , Contagem de Células , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Feminino , Humanos , Tolerância Imunológica/genética , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/fisiologia , Interferon-alfa/fisiologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/mortalidade , Camundongos , Camundongos Endogâmicos MRL lpr , Camundongos Endogâmicos NZB , Camundongos Knockout , Receptor de Interferon alfa e beta/fisiologia
9.
J Immunol ; 182(4): 2532-41, 2009 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-19201910

RESUMO

TNF-alpha has both proinflammatory and immunoregulatory functions. Whereas a protective role for TNF administration in systemic lupus erythematosus (SLE)-prone (New Zealand Black x New Zealand White)F(1) mice has been established, it remains uncertain whether this effect segregates at the individual TNFR. We generated SLE-prone New Zealand Mixed 2328 mice genetically deficient in TNFR1, in TNFR2, or in both receptors. Doubly-deficient mice developed accelerated pathological and clinical nephritis with elevated levels of circulating IgG anti-dsDNA autoantibodies and increased numbers of CD4(+) T lymphocytes, especially activated memory (CD44(high)CD62L(low)) CD4(+) T cells. We show that these cells expressed a Th17 gene profile, were positive for IL-17 intracellular staining by FACS, and produced exogenous IL-17 in culture. In contrast, immunological, pathological, and clinical profiles of mice deficient in either TNFR alone did not differ from those in each other or from those in wild-type controls. Thus, total ablation of TNF-alpha-mediated signaling was highly deleterious to the host in the New Zealand Mixed 2328 SLE model. These observations may have profound ramifications for the use of TNF and TNFR antagonists in human SLE and related autoimmune disorders, as well as demonstrate, for the first time, the association of the Th17 pathway with an animal model of SLE.


Assuntos
Interleucina-17/imunologia , Nefrite Lúpica/genética , Nefrite Lúpica/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/deficiência , Receptores Tipo I de Fatores de Necrose Tumoral/deficiência , Animais , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Imunofluorescência , Perfilação da Expressão Gênica , Interleucina-17/metabolismo , Nefrite Lúpica/patologia , Camundongos , Camundongos Knockout , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo II do Fator de Necrose Tumoral/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
10.
Sci Rep ; 10(1): 18189, 2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-33097818

RESUMO

Tumor necrosis factor-like cytokine 1A (TL1A, TNFSF15) is implicated in inflammatory bowel disease, modulating the location and severity of inflammation and fibrosis. TL1A expression is increased in inflamed mucosa and associated with fibrostenosing Crohn's disease. Tl1a-overexpression in mice causes spontaneous ileitis, and exacerbates induced proximal colitis and fibrosis. Intestinal fibroblasts express Death-receptor 3 (DR3; the only know receptor for TL1A) and stimulation with TL1A induces activation in vitro. However, the contribution of direct TL1A-DR3 activation on fibroblasts to fibrosis in vivo remains unknown. TL1A overexpressing naïve T cells were transferred into Rag-/- , Rag-/- mice lacking DR3 in all cell types (Rag-/-Dr3-/-), or Rag-/- mice lacking DR3 only on fibroblasts (Rag-/-Dr3∆Col1a2) to induce colitis and fibrosis, assessed by clinical disease activity index, intestinal inflammation, and collagen deposition. Rag-/- mice developed overt colitis with intestinal fibrostenosis. In contrast, Rag-/-Dr3-/- demonstrated decreased inflammation and fibrosis. Despite similar clinical disease and inflammation as Rag-/-, Rag-/-Dr3∆Col1a2 exhibited reduced intestinal fibrosis and attenuated fibroblast activation and migration. RNA-Sequencing of TL1A-stimulated fibroblasts identified Rho signal transduction as a major pathway activated by TL1A and inhibition of this pathway modulated TL1A-mediated fibroblast functions. Thus, direct TL1A signaling on fibroblasts promotes intestinal fibrosis in vivo. These results provide novel insight into profibrotic pathways mediated by TL1A paralleling its pro-inflammatory effects.


Assuntos
Enteropatias/metabolismo , Membro 25 de Receptores de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Animais , Fibroblastos/metabolismo , Fibrose/metabolismo , Camundongos , Camundongos Transgênicos , Membro 25 de Receptores de Fatores de Necrose Tumoral/genética , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética
11.
Mucosal Immunol ; 11(5): 1466-1476, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29988118

RESUMO

Tumor necrosis factor-like cytokine 1A (TL1A, TNFSF15) is implicated in inflammatory bowel disease (IBD), modulating the location and severity of intestinal inflammation and fibrosis. TL1A expression is increased in inflamed gut mucosa and associated with fibrostenosing Crohn's disease. Tl1a-overexpression in mice lead to spontaneous ileitis, and exacerbated induced proximal colitis and fibrosis. IBD is associated with shifts in the gut microbiome, but the effect of differing microbial populations and their interaction with TL1A on fibrosis has not been investigated. We demonstrate that the pro-fibrotic and inflammatory phenotype resulting from Tl1a-overexpression is abrogated in the absence of resident microbiota. To evaluate if this is due to the absence of a unique bacterial population, as opposed to any bacteria per se, we gavaged germ-free (GF) wild-type and Tl1a-transgenic (Tl1a-Tg) mice with stool from specific pathogen free (SPF) mice and a healthy human donor (Hu). Reconstitution with SPF, but not Hu microbiota, resulted in increased intestinal collagen deposition and fibroblast activation in Tl1a-Tg mice. Notably, there was reduced fibroblast migration and activation under GF conditions compared to native conditions. We then identified several candidate organisms that correlated directly with increased fibrosis in reconstituted mice and showed that these organisms directly impact fibroblast function in vitro. Thus, Tl1a-mediated intestinal fibrosis and fibroblast activation are dependent on specific microbial populations.


Assuntos
Fibrose/metabolismo , Fibrose/microbiologia , Microbioma Gastrointestinal/fisiologia , Inflamação/metabolismo , Intestinos/microbiologia , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Animais , Colite/metabolismo , Colite/microbiologia , Colágeno/metabolismo , Doença de Crohn/metabolismo , Doença de Crohn/microbiologia , Fibroblastos/metabolismo , Fibroblastos/microbiologia , Humanos , Ileíte/metabolismo , Ileíte/microbiologia , Inflamação/microbiologia , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/microbiologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
12.
United European Gastroenterol J ; 4(4): 531-40, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27536363

RESUMO

The frequency of fibrosing Crohn's disease (CD) is significant, with approximately 40% of CD patients with ileal disease developing clinically apparent strictures throughout their lifetime. Although strictures may be subdivided into fibrotic, inflammatory, or mixed forms, despite immunosuppressive therapy in CD patients in the form of steroids or immunomodulators, the frequency of fibrostenosing complications has still remained significant. A vast number of genetic and epigenetic variables are thought to contribute to fibrostenosing disease, including those that affect cytokine biology, and therefore highlight the complexity of disease, but also shed light on targetable pathways. Exclusively targeting fibrosis may be difficult, however, because of the relatively slow evolution of fibrosis in CD, and the potential adverse effects of inhibiting pathways involved in tissue repair and mucosal healing. Acknowledging these caveats, cytokine-targeted therapy has become the mainstay of treatment for many inflammatory conditions and is being evaluated for fibrotic disorders. The question of whether anti-cytokine therapy will prove useful for intestinal fibrosis is, therefore, acutely relevant. This review will highlight some of the current therapeutics targeting cytokines involved in fibrosis.

13.
Rheum Dis Clin North Am ; 38(2): 243-57, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22819082

RESUMO

Rheumatoid arthritis (RA) is the most common rheumatic disease. The genetic basis of RA is supported through the identification of more than 30 susceptibility genetic variants. Each of these genes individually makes only a slight contribution to the risk of disease. Moreover, there is significant disparity in the genetic variants associated with different RA subgroups and patient ethnicities, which emphasizes the intricate nature of the disease's pathogenesis, and the complexities involved in large-scale genetic studies. This review evaluates critically the recent literature on the genetic contribution to RA and assesses the methodology used to identify these risk alleles.


Assuntos
Artrite Reumatoide/genética , Predisposição Genética para Doença , Variação Genética , Herança Multifatorial , Artrite Reumatoide/etnologia , Etnicidade , Antígenos HLA-A/genética , Humanos , Fatores de Risco
14.
Arthritis Res Ther ; 13(4): 228, 2011 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-21745419

RESUMO

The pathogenesis of systemic lupus erythematosus (SLE) is complex, and the resulting disease manifestations are heterogeneous. Cytokine dysregulation is pervasive, and their protein and gene expression profiles may serve as markers of disease activity and severity. Importantly, biologic agents that target specific cytokines may represent novel therapies for SLE. Four cytokines (IL-6, TNFα, IFNα, and BLyS) are being evaluated as therapeutic targets in SLE. The present review will examine the roles of each of these cytokines in murine and human SLE, and will summarize results from clinical trials of agents that target these cytokines.


Assuntos
Fator Ativador de Células B/imunologia , Interferon-alfa/imunologia , Interleucina-6/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Fator Ativador de Células B/antagonistas & inibidores , Biomarcadores/análise , Ensaios Clínicos como Assunto , Citocinas/imunologia , Humanos , Interferon-alfa/antagonistas & inibidores , Interleucina-6/antagonistas & inibidores , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Fator de Necrose Tumoral alfa/antagonistas & inibidores
15.
Autoimmunity ; 43(1): 84-97, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20014977

RESUMO

It has long been known that B cells produce autoantibodies and, thereby, contribute to the pathogenesis of many autoimmune diseases. Systemic lupus erythematosus (SLE), a prototypic systemic autoimmune disorder, is characterized by high-circulating autoantibody titers and immune-complex deposition that can trigger inflammatory damage in multiple organs/organ systems. Although the interest in B cells in SLE has historically focused on their autoantibody production, we now appreciate that B cells have multiple autoantibody-independent roles in SLE as well. B cells can efficiently present antigen and activate T cells, they can augment T cell activation through co-stimulatory interactions, and they can produce numerous cytokines which affect inflammation, lymphogenesis, and immune regulation. Not surprisingly, B cells have become attractive therapeutic targets in SLE. With these points in mind, this review will focus on the autoantibody-dependent and autoantibody-independent roles for B cells in SLE and on therapeutic approaches that target B cells.


Assuntos
Autoanticorpos/imunologia , Linfócitos B/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Linfócitos T/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Modelos Animais de Doenças , Humanos , Lúpus Eritematoso Sistêmico/terapia , Camundongos
16.
Arthritis Rheum ; 60(4): 1085-95, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19333953

RESUMO

OBJECTIVE: Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disorder, with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in terms of the pathogenesis of SLE. STAT-1 and STAT-4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for involvement in SLE susceptibility. METHODS: Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 on chromosome 2 were genotyped using the Illumina platform, as part of an extensive association study in a large collection of 9,923 lupus patients and control subjects from different racial groups. DNA samples were obtained from the peripheral blood of patients with SLE and control subjects. Principal components analyses and population-based case-control association analyses were performed, and the P values, false discovery rate q values, and odds ratios with 95% confidence intervals were calculated. RESULTS: We observed strong genetic associations with SLE and multiple SNPs located within STAT4 in different ethnic groups (Fisher's combined P = 7.02 x 10(-25)). In addition to strongly confirming the previously reported association in the third intronic region of this gene, we identified additional haplotypic association across STAT4 and, in particular, a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to its proximity to STAT4. CONCLUSION: Our findings indicate that STAT4 is likely to be a crucial component in SLE pathogenesis in multiple racial groups. Knowledge of the functional effects of this association, when they are revealed, might improve our understanding of the disease and provide new therapeutic targets.


Assuntos
Lúpus Eritematoso Sistêmico/etnologia , Lúpus Eritematoso Sistêmico/genética , Grupos Raciais/estatística & dados numéricos , Fator de Transcrição STAT4/genética , Negro ou Afro-Americano/estatística & dados numéricos , Asiático/estatística & dados numéricos , Povo Asiático/estatística & dados numéricos , Feminino , Predisposição Genética para Doença/etnologia , Haplótipos , Hispânico ou Latino/estatística & dados numéricos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Fator de Transcrição STAT1/genética , Estados Unidos/epidemiologia , População Branca/estatística & dados numéricos
17.
J Immunol ; 181(1): 833-41, 2008 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-18566449

RESUMO

In otherwise non-autoimmune-prone C57BL/6 (B6) mice rendered genetically deficient in CD152 (CTLA-4), polyclonal hypergammaglobulinemia with increased levels of systemic lupus erythematosus (SLE)-associated IgG autoantibodies, glomerular IgG and C3 deposition, and interstitial nephritis all developed by 3-5 wk of age. Remarkably, superimposing genetic deficiency of BAFF (B cell-activating factor belonging to the TNF family) onto CD152 deficiency did not substantially attenuate humoral autoimmunity and immunopathology in these mice, despite the resulting marked reduction in B-lineage cells. Although superimposing a BAFF transgene (resulting in constitutive BAFF overexpression) onto CD152-deficient mice did lead to increases in B-lineage cells and serum levels of certain SLE-associated IgG autoantibodies, renal immunopathology remained largely unaffected. Taken together, these results demonstrate that global T cell dysregulation, even in an otherwise non-autoimmune-prone host, can promote systemic humoral autoimmunity and immunopathology in a BAFF-independent manner. Moreover, supraphysiologic expression of BAFF in the setting of ongoing autoimmunity does not necessarily lead to greater immunopathology. These findings may help explain the limited clinical efficacy appreciated to date of BAFF antagonists in human SLE.


Assuntos
Autoimunidade/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Linfócitos T/imunologia , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Autoanticorpos/imunologia , Fator Ativador de Células B/deficiência , Fator Ativador de Células B/genética , Fator Ativador de Células B/imunologia , Fator Ativador de Células B/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Antígeno CTLA-4 , Complemento C3/metabolismo , Hipergamaglobulinemia/imunologia , Hipergamaglobulinemia/patologia , Imunoglobulinas/imunologia , Nefropatias/genética , Nefropatias/imunologia , Nefropatias/metabolismo , Nefropatias/patologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Camundongos , Camundongos Knockout , Fenótipo , Linfócitos T/metabolismo , Fatores de Tempo
19.
Clin Immunol ; 108(3): 182-9, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-14499241

RESUMO

Microbial superantigens (SAg), including SEB and TSST-1, polyclonally activate T cells belonging to specific TCR BV families. A pathogenic role for SAg in various human diseases has been suggested, but enthusiasm for this view has been tempered by the T cell oligoclonality in these disorders. To assess whether T cell oligoclonality can emerge following protracted SAg stimulation, human PBMC were stimulated with SEB, TSST-1, or anti-CD3 mAb and maintained in culture with exogenous IL-2. Oligoclonality was appreciated by day 14 among CD4(+) and CD8(+) T cells. In addition, mice transgenic for human DR2 and DQ8 were injected weekly with SEB, and splenic CD4(+) and CD8(+) T cells were analyzed for oligoclonality. In mice that received one or three such injections, little-to-no oligoclonality was detected. In contrast, considerable oligoclonality was detected in mice that received eight weekly SEB injections. Many of these T cell oligoclones were identical to "spontaneously" arising oligoclones detected in SEB-naive mice. Thus, T cell oligoclonality can emerge following chronic SAg stimulation. In hosts who have lost tolerance to self Ag, chronic exposure to SAg may preferentially promote expansion of autoreactive T cells and facilitate development of clinical disease.


Assuntos
Toxinas Bacterianas , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Regiões Determinantes de Complementaridade/genética , Staphylococcus/imunologia , Superantígenos/imunologia , Animais , Células Cultivadas , Células Clonais , Enterotoxinas/administração & dosagem , Enterotoxinas/imunologia , Enterotoxinas/farmacologia , Feminino , Genes MHC da Classe II/genética , Antígenos HLA-DQ/genética , Antígeno HLA-DR2/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Dados de Sequência Molecular , Baço/imunologia , Superantígenos/administração & dosagem , Superantígenos/farmacologia
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