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1.
Cells ; 13(12)2024 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-38920670

RESUMEN

Proinflammatory T-lymphocytes recruited into the brain and spinal cord mediate multiple sclerosis (MS) and currently there is no cure for MS. IFN-γ-producing Th1 cells induce ascending paralysis in the spinal cord while IL-17-producing Th17 cells mediate cerebellar ataxia. STAT1 and STAT3 are required for Th1 and Th17 development, respectively, and the simultaneous targeting of STAT1 and STAT3 pathways is therefore a potential therapeutic strategy for suppressing disease in the spinal cord and brain. However, the pharmacological targeting of STAT1 and STAT3 presents significant challenges because of their intracellular localization. We have developed a STAT-specific single-domain nanobody (SBT-100) derived from camelids that targets conserved residues in Src homolog 2 (SH2) domains of STAT1 and STAT3. This study investigated whether SBT-100 could suppress experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We show that SBT-100 ameliorates encephalomyelitis through suppressing the expansion of Th17 and Th1 cells in the brain and spinal cord. Adoptive transfer experiments revealed that lymphocytes from SBT-100-treated EAE mice have reduced capacity to induce EAE, indicating that the immunosuppressive effects derived from the direct suppression of encephalitogenic T-cells. The small size of SBT-100 makes this STAT-specific nanobody a promising immunotherapy for CNS autoimmune diseases, including multiple sclerosis.


Asunto(s)
Encefalomielitis Autoinmune Experimental , Anticuerpos de Dominio Único , Células Th17 , Animales , Femenino , Ratones , Camélidos del Nuevo Mundo , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/terapia , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Anticuerpos de Dominio Único/farmacología , Anticuerpos de Dominio Único/inmunología , Anticuerpos de Dominio Único/uso terapéutico , Médula Espinal/patología , Médula Espinal/efectos de los fármacos , Médula Espinal/inmunología , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT3/metabolismo , Células TH1/inmunología , Células TH1/efectos de los fármacos , Células Th17/inmunología , Células Th17/efectos de los fármacos
2.
Front Immunol ; 14: 1071162, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37334383

RESUMEN

Introduction: IL-27 is a heterodimeric cytokine composed of Ebi3 and IL-27p28 and can exert proinflammatory or immune suppressive effects depending on the physiological context. Ebi3 does not contain membrane-anchoring motifs, suggesting that it is a secreted protein while IL-27p28 is poorly secreted. How IL-27p28 and Ebi3 dimerize in-vivo to form biologically active IL-27 is unknown. Major impediment to clinical use of IL-27 derives from difficulty of determining exact amount of bioavailable heterodimeric IL-27 needed for therapy. Methods: To understand how IL-27 mediates immune suppression, we characterized an innate IL-27-producing B-1a regulatory B cell population (i27-Breg) and mechanisms i27-Bregs utilize to suppress neuroinflammation in mouse model of uveitis. We also investigated biosynthesis of IL-27 and i27-Breg immunobiology by FACS, immunohistochemical and confocal microscopy. Results: Contrary to prevailing view that IL-27 is a soluble cytokine, we show that i27-Bregs express membrane-bound IL-27. Immunohistochemical and confocal analyses co-localized expression of IL-27p28 at the plasma membrane in association with CD81 tetraspanin, a BCR-coreceptor protein and revealed that IL-27p28 is a transmembrane protein in B cells. Most surprising, we found that i27-Bregs secrete IL-27-containing exosomes (i27-exosomes) and adoptive transfer of i27-exosomes suppressed uveitis by antagonizing Th1/Th17 cells, up-regulating inhibitory-receptors associated with T-cell exhaustion while inducing Treg expansion. Discussion: Use of i27-exosomes thus obviates the IL-27 dosing problem, making it possible to determine bioavailable heterodimeric IL-27 needed for therapy. Moreover, as exosomes readily cross the blood-retina-barrier and no adverse effects were observed in mice treated with i27-exosome, results of this study suggest that i27-exosomes might be a promising therapeutic approach for CNS autoimmune diseases.


Asunto(s)
Enfermedades Autoinmunes , Exosomas , Interleucina-27 , Uveítis , Ratones , Animales , Exosomas/metabolismo , Células TH1
3.
Int J Mol Sci ; 23(15)2022 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-35897732

RESUMEN

Interleukin-27 is constitutively secreted by microglia in the retina or brain, and upregulation of IL-27 during neuroinflammation suppresses encephalomyelitis and autoimmune uveitis. However, while IL-35 is structurally and functionally similar to IL-27, the intrinsic roles of IL-35 in CNS tissues are unknown. Thus, we generated IL-35/YFP-knock-in reporter mice (p35-KI) and demonstrated that photoreceptor neurons constitutively secrete IL-35, which might protect the retina from persistent low-grade inflammation that can impair photoreceptor functions. Furthermore, the p35-KI mouse, which is hemizygous at the il12a locus, develops more severe uveitis because of reduced IL-35 expression. Interestingly, onset and exacerbation of uveitis in p35-KI mice caused by extravasation of proinflammatory Th1/Th17 lymphocytes into the retina were preceded by a dramatic decrease of IL-35, attributable to massive death of photoreceptor cells. Thus, while inflammation-induced death of photoreceptors and loss of protective effects of IL-35 exacerbated uveitis, our data also suggest that constitutive production of IL-35 in the retina might have housekeeping functions that promote sterilization immunity in the neuroretina and maintain ocular immune privilege.


Asunto(s)
Enfermedades Autoinmunes , Interleucinas , Uveítis , Animales , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Privilegio Inmunológico , Inflamación/metabolismo , Interleucina-27/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Ratones , Ratones Endogámicos C57BL , Células Fotorreceptoras/metabolismo , Retina/metabolismo , Células Th17 , Uveítis/metabolismo
4.
Proc Natl Acad Sci U S A ; 118(47)2021 11 23.
Artículo en Inglés | MEDLINE | ID: mdl-34782464

RESUMEN

Regulatory B cells (Breg cells) that secrete IL-10 or IL-35 (i35-Breg) play key roles in regulating immunity in tumor microenvironment or during autoimmune and infectious diseases. Thus, loss of Breg function is implicated in development of autoimmune diseases while aberrant elevation of Breg prevents sterilizing immunity, exacerbates infectious diseases, and promotes cancer metastasis. Breg cells identified thus far are largely antigen-specific and derive mainly from B2-lymphocyte lineage. Here, we describe an innate-like IL-27-producing natural regulatory B-1a cell (i27-Breg) in peritoneal cavity and human umbilical cord blood. i27-Bregs accumulate in CNS and lymphoid tissues during neuroinflammation and confers protection against CNS autoimmune disease. i27-Breg immunotherapy ameliorated encephalomyelitis and uveitis through up-regulation of inhibitory receptors (Lag3, PD-1), suppression of Th17/Th1 responses, and propagating inhibitory signals that convert conventional B cells to regulatory lymphocytes that secrete IL-10 and/or IL-35 in eye, brain, or spinal cord. Furthermore, i27-Breg proliferates in vivo and sustains IL-27 secretion in CNS and lymphoid tissues, a therapeutic advantage over administering biologics (IL-10, IL-35) that are rapidly cleared in vivo. Mutant mice lacking irf4 in B cells exhibit exaggerated increase of i27-Bregs with few i35-Bregs, while mice with loss of irf8 in B cells have abundance of i35-Bregs but defective in generating i27-Bregs, identifying IRF8/BATF and IRF4/BATF axis in skewing B cell differentiation toward i27-Breg and i35-Breg developmental programs, respectively. Consistent with its developmental origin, disease suppression by innate i27-Bregs is neither antigen-specific nor disease-specific, suggesting that i27-Breg would be effective immunotherapy for a wide spectrum of autoimmune diseases.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Enfermedades del Sistema Nervioso Central/inmunología , Interleucina-27/metabolismo , Enfermedades Neuroinflamatorias/inmunología , Animales , Linfocitos B Reguladores/inmunología , Diferenciación Celular , Encefalitis , Factores Reguladores del Interferón , Interleucina-10 , Ratones , Uveítis/inmunología
5.
Front Immunol ; 12: 724609, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34603297

RESUMEN

STAT3 activates transcription of genes that regulate cell growth, differentiation, and survival of mammalian cells. Genetic deletion of Stat3 in T cells has been shown to abrogate Th17 differentiation, suggesting that STAT3 is a potential therapeutic target for Th17-mediated diseases. However, a major impediment to therapeutic targeting of intracellular proteins such as STAT3 is the lack of efficient methods for delivering STAT3 inhibitors into cells. In this study, we developed a novel antibody (SBT-100) comprised of the variable (V) region of a STAT3-specific heavy chain molecule and demonstrate that this 15 kDa STAT3-specific nanobody enters human and mouse cells, and induced suppression of STAT3 activation and lymphocyte proliferation in a concentration-dependent manner. To investigate whether SBT-100 would be effective in suppressing inflammation in vivo, we induced experimental autoimmune uveitis (EAU) in C57BL/6J mice by active immunization with peptide from the ocular autoantigen, interphotoreceptor retinoid binding protein (IRBP651-670). Analysis of the retina by fundoscopy, histological examination, or optical coherence tomography showed that treatment of the mice with SBT-100 suppressed uveitis by inhibiting expansion of pathogenic Th17 cells that mediate EAU. Electroretinographic (ERG) recordings of dark and light adapted a- and b-waves showed that SBT-100 treatment rescued mice from developing significant visual impairment observed in untreated EAU mice. Adoptive transfer of activated IRBP-specific T cells from untreated EAU mice induced EAU, while EAU was significantly attenuated in mice that received IRBP-specific T cells from SBT-100 treated mice. Taken together, these results demonstrate efficacy of SBT-100 in mice and suggests its therapeutic potential for human autoimmune diseases.


Asunto(s)
Enfermedades Autoinmunes/prevención & control , Factor de Transcripción STAT3/inmunología , Células Th17/inmunología , Uveítis/prevención & control , Traslado Adoptivo , Animales , Autoantígenos/inmunología , Autoantígenos/metabolismo , Enfermedades Autoinmunes/inmunología , Proliferación Celular/efectos de los fármacos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Electrorretinografía , Proteínas del Ojo/inmunología , Proteínas del Ojo/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Proteínas de Unión al Retinol/inmunología , Proteínas de Unión al Retinol/metabolismo , Factor de Transcripción STAT3/metabolismo , Células Th17/patología , Uveítis/inmunología
6.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-33803441

RESUMEN

Interferon regulatory factor-4 (IRF4) and IRF8 regulate differentiation, growth and functions of lymphoid and myeloid cells. Targeted deletion of irf8 in T cells (CD4-IRF8KO) has been shown to exacerbate colitis and experimental autoimmune uveitis (EAU), a mouse model of human uveitis. We therefore generated mice lacking irf4 in T cells (CD4-IRF4KO) and investigated whether expression of IRF4 by T cells is also required for regulating T cells that suppress autoimmune diseases. Surprisingly, we found that CD4-IRF4KO mice are resistant to EAU. Suppression of EAU derived in part from inhibiting pathogenic responses of Th17 cells while inducing expansion of regulatory lymphocytes that secrete IL-10 and/or IL-35 in the eye and peripheral lymphoid tissues. Furthermore, CD4-IRF4KO T cells exhibit alterations in cell metabolism and are defective in the expression of two Ikaros zinc-finger (IKZF) transcription factors (Ikaros, Aiolos) that are required for lymphocyte differentiation, metabolism and cell-fate decisions. Thus, synergistic effects of IRF4 and IkZFs might induce metabolic reprogramming of differentiating lymphocytes and thereby dynamically regulate relative abundance of T and B lymphocyte subsets that mediate immunopathogenic mechanisms during uveitis. Moreover, the diametrically opposite effects of IRF4 and IRF8 during EAU suggests that intrinsic function of IRF4 in T cells might be activating proinflammatory responses while IRF8 promotes expansion of immune-suppressive mechanisms.


Asunto(s)
Enfermedades Autoinmunes , Linfocitos T CD4-Positivos , Diferenciación Celular , Eliminación de Gen , Factores Reguladores del Interferón/deficiencia , Transcripción Genética/inmunología , Uveítis , Animales , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/patología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Factores Reguladores del Interferón/inmunología , Factores Reguladores del Interferón/metabolismo , Ratones , Ratones Noqueados , Uveítis/genética , Uveítis/inmunología , Uveítis/metabolismo , Uveítis/patología
7.
Sci Rep ; 10(1): 16188, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-33004854

RESUMEN

STAT3 transcription factor induces differentiation of naïve T cells into Th17 cells and loss of STAT3 in T cell prevents development of CNS autoimmune diseases. However, function of STAT3 in the B lymphocyte subset is not well understood. In this study, we have generated mice lacking STAT3 in CD19+ B cells (CD19-STAT3KO) and investigated intrinsic and extrinsic functions of STAT3 in B cells and its potential role in resistance or pathogenesis of organ-specific autoimmune diseases. We show that STAT3 regulates metabolic mechanisms in B cells with implications for bioenergetic and metabolic pathways that control cellular homeostasis in B cells. Thus, loss of STAT3 in CD19-STAT3KO cells perturbed growth and apoptosis by inducing rapid entry of B cells into the S-phase of the cell cycle, decreasing expression of cyclin-dependent kinase inhibitors and upregulating pro-apoptotic proteins. We further show that the CD19-STAT3KO mice develop severe experimental autoimmune uveitis (EAU), an animal model of human uveitis. Exacerbated uveitis in CD19-STAT3KO mice derived in part from enhanced expression of costimulatory molecules on B cells, marked increase of Th17 responses and increased recruitment of granulocytes into the neuroretina. The enhanced autoimmunity upon deletion of STAT3 in B cells is also recapitulated in experimental autoimmune encephalitis, a mouse model of multiple sclerosis and thus support our conclusion that STAT3 deletion in B cells enhanced inflammation and the effects observed are not model specific. Our data further indicate that STAT3 pathway modulates interactions between B and T cells during EAU resulting in alteration of lymphocyte repertoire by increasing levels of autoreactive pathogenic T cells while suppressing development and/or expansion of immune-suppressive lymphocytes (Bregs and Tregs). Taken together, STAT3 exerts diametrically opposite effects in lymphocytes, with loss of STAT3 in B cells exacerbating uveitis whereas Stat3 deletion in T cells confers protection.


Asunto(s)
Enfermedades Autoinmunes/patología , Linfocitos B Reguladores/inmunología , Factor de Transcripción STAT3/fisiología , Linfocitos T Reguladores/inmunología , Células TH1/inmunología , Células Th17/inmunología , Uveítis/patología , Animales , Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/metabolismo , Diferenciación Celular , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Retina/inmunología , Retina/patología , Uveítis/etiología , Uveítis/metabolismo
8.
Adv Exp Med Biol ; 1185: 353-358, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31884637

RESUMEN

Neurotrophic factors can promote the survival of degenerating retinal cells through the activation of STAT3 pathway. Thus, augmenting STAT3 activation in the retina has been proposed as potential therapy for retinal dystrophies. On the other hand, aberrant activation of STAT3 pathway is oncogenic and implicated in diverse human diseases. Furthermore, the STAT3/SOCS3 axis has been shown to induce the degradation of rhodopsin during retinal inflammation. In this study, we generated and used mice with constitutive activation of STAT3 pathway in the retina to evaluate the safety and consequences of enhancing STAT3 activities in the retina as a potential treatment for retinal degenerative diseases. We show that long-term activation of the STAT3 pathway can induce retinal degenerative changes and also exacerbate uveitis and other intraocular inflammatory diseases. Mechanisms underlying the development of vision impairment in the STAT3c-Tg mice derived in part from STAT3-mediated inhibition of rhodopsin and overexpression of SOCS3 in the retina. These results suggest that much caution should be exercised in the use of STAT3 augmentation therapy for retinal dystrophies.


Asunto(s)
Envejecimiento , Retina/patología , Degeneración Retiniana/patología , Factor de Transcripción STAT3/metabolismo , Animales , Ratones , Ratones Endogámicos C57BL , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Proteínas Supresoras de la Señalización de Citocinas , Uveítis/patología
9.
J Leukoc Biol ; 104(6): 1147-1157, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30117603

RESUMEN

IL-10 and IL-35 suppress excessive immune responses and therapeutic strategies are being developed to increase their levels in autoimmune diseases. In this study, we sought to identify major cell types that produce both cytokines in-vivo and to characterize mechanisms that regulate their production. Experimental autoimmune uveitis (EAU) is a CNS autoimmune disease that serves as model of human uveitis. We induced EAU in C57BL/6J mice and investigated whether T cells, B lymphocytes, or myeloid cells are the major producers of IL-10 or IL-35 in blood, lymph nodes (LNs), spleen, and at the site of ocular inflammation, the neuroretina. Analysis of these tissues identified B cells as the major producers of IL-10 and IL-35 in-vivo. Compared to regulatory T cells (Tregs), IL-10- or IL-35-producing regulatory B cells (Bregs) are substantially expanded in blood, LNs, spleen, and retina of mice with EAU. We performed EMSA and chromatin immunoprecipitation (ChIP) assays on activated B cells stimulated with IL-35 or TLR agonists. We found that BATF, IFN regulatory factor (IRF)-4, and IRF-8 transcription factors were recruited and bound to AP1-IRF-composite elements (AICEs) of il12a, ebi3, and/or il10 loci, suggesting their involvement in regulating IL-10 and IL-35 transcriptional programs of B cells. Showing that B cells are major source of IL-10 and IL-35 in-vivo and identifying transcription factors that contribute to IL-10 and IL-35 expression in the activated B-cell, suggest that the BATF/IRF-4/IRF-8 axis can be exploited therapeutically to regulate physiological levels of IL-10/IL-35-Bregs and that adoptive transfer of autologous Bregs might be an effective therapy for autoimmune and neurodegenerative diseases.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Linfocitos B Reguladores/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/fisiología , Factores Reguladores del Interferón/fisiología , Interleucina-10/genética , Subunidad p35 de la Interleucina-12/genética , Interleucinas/biosíntesis , Antígenos de Histocompatibilidad Menor/genética , Receptores de Citocinas/genética , Uveítis/inmunología , Animales , Enfermedades Autoinmunes/metabolismo , Femenino , Interleucina-10/biosíntesis , Subunidad p35 de la Interleucina-12/biosíntesis , Interleucinas/agonistas , Interleucinas/genética , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Distribución Aleatoria , Retina/inmunología , Retina/metabolismo , Retina/patología , Linfocitos T Reguladores/inmunología , Transcripción Genética , Uveítis/metabolismo
10.
J Exp Med ; 215(4): 1079-1090, 2018 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-29490936

RESUMEN

Appropriate regulation of IL-17 production in the host can mean the difference between effective control of pathogens and uncontrolled inflammation that causes tissue damage. Investigation of conventional CD4+ T cells (Th17 cells) has yielded invaluable insights into IL-17 function and its regulation. More recently, we and others reported production of IL-17 from innate αß+ T cell populations, which was shown to occur primarily via IL-23R signaling through the transcription factor STAT-3. In our current study, we identify promyelocytic leukemia zinc finger (PLZF)-expressing iNKT, CD4-/CD8+, and CD4-/CD8- (DN) αß+T cells, which produce IL-17 in response to TCR and IL-1 receptor ligation independently of STAT-3 signaling. Notably, this noncanonical pathway of IL-17 production may be important in mucosal defense and is by itself sufficient to control pathogenic Staphylococcus aureus infection at the ocular surface.


Asunto(s)
Infecciones del Ojo/inmunología , Infecciones del Ojo/patología , Inmunidad Innata , Interleucina-17/biosíntesis , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Factor de Transcripción STAT3/metabolismo , Animales , Memoria Inmunológica , Interleucinas/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Membrana Mucosa/inmunología , Membrana Mucosa/microbiología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Fosforilación , Proteína de la Leucemia Promielocítica con Dedos de Zinc/metabolismo , Transducción de Señal , Staphylococcus aureus/fisiología , Linfocitos T/metabolismo , Células Th17/metabolismo , Timo/metabolismo
11.
Front Immunol ; 8: 1258, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29051763

RESUMEN

Multiple sclerosis (MS) is an inflammatory demyelinating disease in which cytokines produced by immune cells that infiltrate the brain and spinal cord play a central role. We show here that the IL-12p35, the alpha subunit of IL-12 or IL-35 cytokine, might be an effective biologic for suppressing neuroinflammatory responses and ameliorating the pathology of experimental autoimmune encephalomyelitis (EAE), the mouse model of human MS. We further show that IL-12p35 conferred protection from neuropathy by inhibiting the expansion of pathogenic Th17 and Th1 cells and inhibiting trafficking of inflammatory cells into the brain and spinal cord. In addition, in vitro exposure of encephalitogenic cells to IL-12p35 suppressed their capacity to induce EAE by adoptive transfer. Importantly, the IL-12p35-mediated expansion of Treg and Breg cells and its amelioration of EAE correlated with inhibition of cytokine-induced activation of STAT1/STAT3 pathways. Moreover, IL-12p35 inhibited lymphocyte proliferation by suppressing the expressions of cell-cycle regulatory proteins. Taken together, these results suggest that IL-12p35 can be exploited as a novel biologic for treating central nervous system autoimmune diseases and offers the promise of ex vivo production of large amounts of Tregs and Bregs for immunotherapy.

12.
Nat Commun ; 8(1): 719, 2017 09 28.
Artículo en Inglés | MEDLINE | ID: mdl-28959012

RESUMEN

Interleukin 35 (IL-35) is a heterodimeric cytokine composed of IL-12p35 and Ebi3 subunits. IL-35 suppresses autoimmune diseases while preventing host defense to infection and promoting tumor growth and metastasis by converting resting B and T cells into IL-10-producing and IL-35-producing regulatory B (Breg) and T (Treg) cells. Despite sharing the IL-12p35 subunit, IL-12 (IL-12p35/IL-12p40) promotes inflammatory responses whereas IL-35 (IL-12p35/Ebi3) induces regulatory responses, suggesting that IL-12p35 may have unknown intrinsic immune-regulatory functions regulated by its heterodimeric partner. Here we show that the IL-12p35 subunit has immunoregulatory functions hitherto attributed to IL-35. IL-12p35 suppresses lymphocyte proliferation, induces expansion of IL-10-expressing and IL-35-expressing B cells and ameliorates autoimmune uveitis in mice by antagonizing pathogenic Th17 responses. Recapitulation of essential immunosuppressive activities of IL-35 indicates that IL-12p35 may be utilized for in vivo expansion of Breg cells and autologous Breg cell immunotherapy. Furthermore, our uveitis data suggest that intrinsic immunoregulatory activities of other single chain IL-12 subunits might be exploited to treat other autoimmune diseases.IL-12p35 is common to IL-35 and IL-12, which have opposing effects on inflammation. Here the authors show that the IL-12p35 subunit induces regulatory B cells and can be used therapeutically to limit autoimmune uveitis in mice.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Linfocitos B Reguladores/metabolismo , Interleucina-10/metabolismo , Subunidad p35 de la Interleucina-12/metabolismo , Animales , Proliferación Celular , Terapia de Inmunosupresión , Subunidad beta 2 del Receptor de Interleucina-12/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Multimerización de Proteína , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Uveítis/inmunología , Uveítis/patología
13.
Mediators Inflamm ; 2016: 2939370, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27703302

RESUMEN

Uveitis is a potentially sight-threatening disease characterized by repeated cycles of remission and recurrent inflammation. The JAK/STAT pathway regulates the differentiation of pathogenic Th1 and Th17 cells that mediate uveitis. A SOCS1 mimetic peptide (SOCS1-KIR) that inhibits JAK2/STAT1 pathways has recently been shown to suppress experimental autoimmune uveitis (EAU). However, it is not clear whether SOCS1-KIR ameliorated uveitis by targeting JAK/STAT pathways of pathogenic lymphocytes or via inhibition of macrophages and antigen-presenting cells that also enter the retina during EAU. To further investigate mechanisms that mediate SOCS1-KIR effects and evaluate the efficacy of SOCS1-KIR as an investigational drug for chronic uveitis, we induced EAU in rats by adoptive transfer of uveitogenic T-cells and monitored disease progression and severity by slit-lamp microscopy, histology, and optical coherence tomography. Topical administration of SOCS1-KIR ameliorated acute and chronic posterior uveitis by inhibiting Th17 cells and the recruitment of inflammatory cells into retina while promoting expansion of IL-10-producing Tregs. We further show that SOCS1-KIR conferred protection of resident retinal cells that play critical role in vision from cytotoxic effects of inflammatory cytokines by downregulating proapoptotic genes. Thus, SOCS1-KIR suppresses uveitis and confers neuroprotective effects and might be exploited as a noninvasive treatment for chronic uveitis.


Asunto(s)
Péptidos/uso terapéutico , Proteína 1 Supresora de la Señalización de Citocinas/química , Uveítis/tratamiento farmacológico , Animales , Células Presentadoras de Antígenos/efectos de los fármacos , Células Presentadoras de Antígenos/metabolismo , Biomimética , Enfermedad Crónica , Citometría de Flujo , Janus Quinasa 2/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Péptidos/química , Ratas , Factor de Transcripción STAT1/metabolismo , Células Th17/efectos de los fármacos , Células Th17/metabolismo
14.
PLoS One ; 11(5): e0155420, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27171004

RESUMEN

Interferon Regulatory Factor-8 (IRF8) is constitutively expressed in monocytes and B cell lineages and plays important roles in immunity to pathogens and cancer. Although IRF8 expression is induced in activated T cells, the functional relevance of IRF8 in T cell-mediated immunity is not well understood. In this study, we used mice with targeted deletion of Irf8 in T-cells (IRF8KO) to investigate the role of IRF8 in T cell-mediated responses during herpes simplex virus 1 (HSV-1) infection of the eye. In contrast to wild type mice, HSV-1-infected IRF8KO mice mounted a more robust anti-HSV-1 immune response, which included marked expansion of HSV-1-specific CD8+ T cells, increased infiltration of inflammatory cells into the cornea and trigeminal ganglia (TG) and enhanced elimination of virus within the trigeminal ganglion. However, the consequence of the enhanced immunological response was the development of ocular inflammation, limbitis, and neutrophilic infiltration into the cornea of HSV-1-infected IRF8KO mice. Surprisingly, we observed a marked increase in virus-specific memory precursor effector cells (MPEC) in IRF8KO mice, suggesting that IRF8 might play a role in regulating the differentiation of effector CD8+ T cells to the memory phenotype. Together, our data suggest that IRF8 might play a role in restraining excess lymphocyte proliferation. Thus, modulating IRF8 levels in T cells can be exploited therapeutically to prevent immune-mediated ocular pathology during autoimmune and infectious diseases of the eye.


Asunto(s)
Linfocitos T CD8-positivos/patología , Ojo/patología , Ojo/virología , Herpes Simple/inmunología , Herpes Simple/virología , Herpesvirus Humano 1/fisiología , Factores Reguladores del Interferón/metabolismo , Activación de Linfocitos/inmunología , Traslado Adoptivo , Animales , Antígenos Virales/inmunología , Linfocitos T CD8-positivos/inmunología , Proliferación Celular , Memoria Inmunológica , Inflamación/complicaciones , Inflamación/inmunología , Inflamación/patología , Integrinas/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Receptores de Quimiocina/metabolismo , Carga Viral
15.
Cytokine Growth Factor Rev ; 26(5): 587-93, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26279360

RESUMEN

Cytokines coordinate the activities of innate and adaptive immune systems and the Interleukin 12 (IL-12) family of cytokines has emerged as critical regulators of immunity in infectious and autoimmune diseases. While some members (IL-12 and IL-23) are associated with the pathogenesis of chronic inflammatory diseases, others (IL-27 and IL-35) mitigate autoimmune diseases. Unlike IL-12, IL-23 and IL-27 that are produced mainly by antigen presenting cells, IL-35 is predominantly secreted by regulatory B (i35-Bregs) and T (iTR35) cells. The discovery that IL-35 can induce the conversion or expansion of lymphocytes to regulatory B and T cells has considerable implications for therapeutic use of autologous regulatory B and T cells in human diseases. Although our current understanding of the immunobiology of IL-35 or its subunits (p35 and Ebi3) is still rudimentary, our goal in this review is to summarize what we know about this enigmatic cytokine and its potential clinical use, particularly in the treatment of CNS autoimmune diseases.


Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Linfocitos B Reguladores/inmunología , Interleucinas/inmunología , Linfocitos T Reguladores/inmunología , Animales , Enfermedades Autoinmunes del Sistema Nervioso/patología , Linfocitos B Reguladores/patología , Humanos , Linfocitos T Reguladores/patología
16.
J Immunol ; 195(4): 1480-8, 2015 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-26163590

RESUMEN

IFN regulatory factor 8 (IRF8) is constitutively expressed in monocytes and B cells and plays a critical role in the functional maturation of microglia cells. It is induced in T cells following Ag stimulation, but its functions are less well understood. However, recent studies in mice with T cell-specific Irf8 disruption under direction of the Lck promoter (LCK-IRF8KO) suggest that IRF8 directs a silencing program for Th17 differentiation, and IL-17 production is markedly increased in IRF8-deficient T cells. Paradoxically, loss of IRF8 in T cells has no effect on the development or severity of experimental autoimmune encephalomyelitis (EAE), although exacerbating colitis in a mouse colitis model. In contrast, mice with a macrophage/microglia-specific Irf8 disruption are resistant to EAE, further confounding our understanding of the roles of IRF8 in host immunity and autoimmunity. To clarify the role of IRF8 in autoimmune diseases, we have generated two mouse strains with targeted deletion of Irf8 in retinal cells, including microglial cells and a third mouse strain with targeted Irf8 deletion in T cells under direction of the nonpromiscuous, CD4 promoter (CD4-IRF8KO). In contrast to the report that IRF8 deletion in T cells has no effect on EAE, experimental autoimmune uveitis is exacerbated in CD4-IRF8KO mice and disease enhancement correlates with significant expansion of Th17 cells and a reduction in T regulatory cells. In contrast to CD4-IRF8KO mice, Irf8 deletion in retinal cells confers protection from uveitis, underscoring divergent and tissue-specific roles of IRF8 in host immunity. These results raise a cautionary note in the context of therapeutic targeting of IRF8.


Asunto(s)
Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Factores Reguladores del Interferón/genética , Uveítis/genética , Uveítis/inmunología , Animales , Enfermedades Autoinmunes/diagnóstico , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Electrorretinografía , Eliminación de Gen , Mediadores de Inflamación/metabolismo , Factores Reguladores del Interferón/deficiencia , Factores Reguladores del Interferón/metabolismo , Ratones , Ratones Noqueados , Microglía/inmunología , Microglía/metabolismo , Retina/inmunología , Retina/metabolismo , Retina/patología , Neuronas Retinianas/inmunología , Neuronas Retinianas/metabolismo , Índice de Severidad de la Enfermedad , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Uveítis/diagnóstico
17.
J Autoimmun ; 62: 31-8, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26094775

RESUMEN

Uveitis is a diverse group of potentially sight-threatening intraocular inflammatory diseases and pathology derives from sustained production of pro-inflammatory cytokines in the optical axis. Although topical or systemic steroids are effective therapies, their adverse effects preclude prolonged usage and are impetus for seeking alternative immunosuppressive agents, particularly for patients with refractory uveitis. In this study, we synthesized a 16 amino acid membrane-penetrating lipophilic suppressor of cytokine signaling 1 peptide (SOCS1-KIR) that inhibits JAK/STAT signaling pathways and show that it suppresses and ameliorates experimental autoimmune uveitis (EAU), the mouse model of human uveitis. Fundus images, histological and optical coherence tomography analysis of eyes showed significant suppression of clinical disease, with average clinical score of 0.5 compared to 2.0 observed in control mice treated with scrambled peptide. We further show that SOCS1-KIR conferred protection from ocular pathology by inhibiting the expansion of pathogenic Th17 cells and inhibiting trafficking of inflammatory cells into the neuroretina during EAU. Dark-adapted scotopic and photopic electroretinograms further reveal that SOCS1-KIR prevented decrement of retinal function, underscoring potential neuroprotective effects of SOCS1-KIR in uveitis. Importantly, SOCS1-KIR is non-toxic, suggesting that topical administration of SOCS1-Mimetics can be exploited as a non-invasive treatment for uveitis and for limiting cytokine-mediated pathology in other ocular inflammatory diseases including scleritis.


Asunto(s)
Antiinflamatorios/administración & dosificación , Péptidos/administración & dosificación , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Uveítis/inmunología , Uveítis/metabolismo , Administración Tópica , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Angiografía con Fluoresceína , Inmunidad , Ratones , Retina/inmunología , Retina/metabolismo , Retina/patología , Proteína 1 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/química , Linfocitos T/inmunología , Linfocitos T/metabolismo , Uveítis/tratamiento farmacológico , Uveítis/patología
18.
Crit Rev Immunol ; 35(1): 49-57, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25746047

RESUMEN

Neuroinflammation contributes to neuronal deficits in neurodegenerative CNS (central nervous system) autoimmune diseases, such as multiple sclerosis and uveitis. The major goal of most treatment modalities for CNS autoimmune diseases is to limit inflammatory responses in the CNS; immune-suppressive drugs are the therapy of choice. However, lifelong immunosuppression increases the occurrence of infections, nephrotoxicity, malignancies, cataractogenesis, and glaucoma, which can greatly impair quality of life for the patient. Biologics that target pathogenic T cells is an alternative approach that is gaining wide acceptance as indicated by the popularity of a variety of Food and Drug Administration (FDA)-approved anti-inflammatory compounds and humanized antibodies such as Zenapax, Etanercept, Remicade, anti-ICAM, rapamycin, or tacrolimus. B cells are also potential therapeutic targets because they provide costimulatory signals that activate pathogenic T cells and secrete cytokines that promote autoimmune pathology. B cells also produce autoreactive antibodies implicated in several organ-specific and systemic autoimmune diseases including lupus erythematosus, Graves' disease, and Hashimoto's thyroiditis. On the other hand, recent studies have led to the discovery of several regulatory B-cell (Breg) populations that suppress immune responses and autoimmune diseases. In this review, we present a brief overview of Breg phenotypes and in particular, the newly discovered IL35-producing regulatory B cell (i35-Breg). We discuss the critical roles played by i35-Bregs in regulating autoimmune diseases and the potential use of adoptive Breg therapy in CNS autoimmune diseases.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Subgrupos de Linfocitos B/inmunología , Linfocitos B Reguladores/inmunología , Enfermedades del Sistema Nervioso Central/inmunología , Inmunoterapia Adoptiva , Interleucinas/metabolismo , Animales , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/terapia , Linfocitos B Reguladores/trasplante , Enfermedades del Sistema Nervioso Central/terapia , Humanos , Inflamación Neurogénica
19.
Inflammation ; 38(2): 555-65, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24993154

RESUMEN

Immunological responses to pathogens are stringently regulated in the eye to prevent excessive inflammation that damage ocular tissues and compromise vision. Suppressors of cytokine signaling (SOCS) regulate intensity/duration of inflammatory responses. We have used SOCS1-deficient mice and retina-specific SOCS1 transgenic rats to investigate roles of SOCS1 in ocular herpes simplex virus (HSV-1) infection and non-infectious uveitis. We also genetically engineered cell-penetrating SOCS proteins (membrane-translocating sequence (MTS)-SOCS1, MTS-SOCS3) and examined whether they can be used to inhibit inflammatory cytokines. Overexpression of SOCS1 in transgenic rat eyes attenuated ocular HSV-1 infection while SOCS1-deficient mice developed severe non-infectious anterior uveitis, suggesting that SOCS1 may contribute to mechanism of ocular immune privilege by regulating trafficking of inflammatory cells into ocular tissues. Furthermore, MTS-SOCS1 inhibited IFN-γ-induced signal transducers and activators of transcription 1 (STAT1) activation by macrophages while MTS-SOCS3 suppressed expansion of pathogenic Th17 cells that mediate uveitis, indicating that MTS-SOCS proteins maybe used to treat ocular inflammatory diseases of infectious or autoimmune etiology.


Asunto(s)
Infecciones Virales del Ojo/inmunología , Herpes Simple/inmunología , Factor de Transcripción STAT1/genética , Proteínas Supresoras de la Señalización de Citocinas/genética , Uveítis Anterior/inmunología , Animales , Endotoxinas , Infecciones Virales del Ojo/microbiología , Infecciones Virales del Ojo/virología , Herpes Simple/virología , Herpesvirus Humano 1/inmunología , Interferón gamma/inmunología , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratas , Infecciones por Salmonella/inmunología , Infecciones por Salmonella/microbiología , Salmonella typhimurium/inmunología , Salmonella typhimurium/patogenicidad , Transducción de Señal/inmunología , Proteína 1 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/biosíntesis , Células Th17/inmunología , Uveítis Anterior/microbiología , Uveítis Anterior/virología
20.
PLoS One ; 9(4): e95900, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24780906

RESUMEN

Age-related macular degeneration (AMD) is a common yet complex retinal degeneration that causes irreversible central blindness in the elderly. Pathology is widely believed to follow loss of retinal pigment epithelium (RPE) and photoreceptor degeneration. Here we report aberrant expression of interleukin-17A (IL17A) and the receptor IL17RC in the macula of AMD patients. In vitro, IL17A induces RPE cell death characterized by the accumulation of cytoplasmic lipids and autophagosomes with subsequent activation of pro-apoptotic Caspase-3 and Caspase-9. This pathology is reduced by siRNA knockdown of IL17RC. IL17-dependent retinal degeneration in a mouse model of focal retinal degeneration can be prevented by gene therapy with adeno-associated virus vector encoding soluble IL17 receptor. This intervention rescues RPE and photoreceptors in a MAPK-dependent process. The IL17 pathway plays a key role in RPE and photoreceptor degeneration and could hold therapeutic potential in AMD.


Asunto(s)
Citocinas/antagonistas & inhibidores , Interleucina-17/toxicidad , Degeneración Macular/prevención & control , Receptores de Interleucina-17/genética , Retina/efectos de los fármacos , Transfección , Dependovirus/genética , Vectores Genéticos , Humanos , Degeneración Macular/genética
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