RESUMEN

Neuromyelitis optica (NMO) is a rare inflammatory disorder of the central nervous system. The hallmark of NMO is the presence of specific autoantibodies directed against aquaporin 4 (AQP4-IgG). AQP4-IgG, included in diagnostic criteria, has enlarged the clinical spectrum of NMO and serves to predict relapses. Moreover AQP4-IgG has provided unprecedented insight in the immunopathology of NMO, representing a rationale for therapeutic intervention with relevant novel treatment strategies specific for NMO. However, some patients remain seronegative for AQP4-IgG despite a definite diagnosis of NMO and the use of the finest methods for antibody detection. Interestingly, seronegative NMO (NMO(neg)) patients exhibit different demographic and disease-related characteristics in comparison to seropositive patients. The recent association with autoantibodies specific for myelin oligodendrocyte glycoprotein (MOG) is the main indication that disease mechanisms might differ in NMO(pos) and NMO(neg), challenging the position of NMO(neg) patients in the spectrum of demyelinating diseases and therapeutic strategies to be adopted. Thus, a reappraisal of the NMO(neg) population is needed to improve NMO care. Here the current knowledge regarding NMO(neg) is reviewed and hypotheses on its pathogenesis are made including a comprehensive description of detection methods and the prevalence of AQP4-IgG and a review of the epidemiological, clinical and paraclinical characteristics of NMO(neg); finally an integrated view of the general pathophysiological mechanisms underlying NMO(neg) is provided.

Asunto(s)

Neuromielitis Óptica/sangre , Humanos , Neuromielitis Óptica/clasificación , Neuromielitis Óptica/epidemiología , Neuromielitis Óptica/fisiopatología

RESUMEN

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system leading to demyelination and axonal/neuronal loss. Cumulating evidence points to a key role for CD8 T cells in this disabling disease. Oligoclonal CD8 T cells reside in demyelinating plaques where they are likely to contribute to tissue destruction. Histopathological analyses and compelling observations from animal models indicate that cytotoxic CD8 T cells target neural cell populations with the potential of causing lesions reminiscent of MS. However, CD8 T cell differentiation results in several subsets of effector CD8 T cells that could be differentially implicated in the mechanisms contributing to tissue damage. Moreover CD8 regulatory T cells arise as important populations involved in restoring immune homoeostasis and in maintaining immune privileged sites. Here we examine the current literature pertaining to the role of CD8 effector and regulatory T cell subsets in the pathogenesis of MS.

Asunto(s)

Linfocitos T CD8-positivos/inmunología , Subgrupos Linfocitarios/inmunología , Esclerosis Múltiple/etiología , Esclerosis Múltiple/inmunología , Animales , Modelos Animales de Enfermedad , Humanos , Modelos Inmunológicos , Linfocitos T Reguladores/inmunología

RESUMEN

Demyelination events or multiple sclerosis following hepatitis B virus (HBV) vaccination have been reported. We therefore compared the T-cell response to HBsAg in patients with CNS demyelination following HBV vaccination and in HBV-vaccinated healthy individuals. Our data showed no differences in terms of T-cell proliferation or cytokine production between these groups and may help to allay concerns that HBV vaccination might trigger a deleterious immune response.

Asunto(s)

Sistema Nervioso Central/inmunología , Sistema Nervioso Central/patología , Enfermedades Autoinmunes Desmielinizantes SNC/inmunología , Vacunas contra Hepatitis B/efectos adversos , Vacunas contra Hepatitis B/inmunología , Hepatitis B/inmunología , Vacunación/efectos adversos , Adulto , Proliferación Celular , Citocinas/biosíntesis , Citocinas/inmunología , Citocinas/metabolismo , Enfermedades Autoinmunes Desmielinizantes SNC/etiología , Enfermedades Autoinmunes Desmielinizantes SNC/patología , Femenino , Virus de la Hepatitis B/inmunología , Humanos , Masculino , Persona de Mediana Edad , Vaina de Mielina/metabolismo , Linfocitos T/citología , Linfocitos T/inmunología , Linfocitos T/metabolismo

RESUMEN

BACKGROUND: Several studies have suggested that chronic inflammatory bowel disease may be a consequence of antigen specific recognition by appropriate T cells which expand and induce immunopathology. AIMS: We wished to investigate whether autoreactive CD4+ T cells can initiate the disease on recognition of enterocyte specific antigens directly and if induction of mucosal tolerance occurs. METHODS: Transgenic mice (VILLIN-HA) were generated that showed specific expression of haemagglutinin from influenza virus A exclusively in enterocytes of the intestinal epithelium. To investigate the impact of enterocyte specific haemagglutinin expression in an autoimmune environment, we mated VILLIN-HA mice with T cell receptor (TCR)-HA mice expressing an alpha/beta-TCR, which recognises an MHC class II restricted epitope of haemagglutinin, and analysed the HA specific T cells for induction of autoimmunity or tolerance. RESULTS: In VILLIN-HAxTCR-HA mice, incomplete central deletion of HA specific lymphocytes occurred. Peripheral HA specific lymphocytes showed an activated phenotype and increased infiltration into the intestinal mucosa, but not into other organs of double transgenic mice. Enterocyte specific lamina propria lymphocytes showed a dose dependent proliferative response on antigen stimulation whereas the proliferative capacity of intraepithelial lymphocytes was reduced. Mucosal lymphocytes from VILLIN-HAxTCR-HA mice secreted lower amounts of interferon gamma and interleukin (IL)-2 but higher levels of tumour necrosis factor alpha, monocyte chemoattractant protein 1, and IL-6. Mucosal immune reactions were accompanied by broad changes in the gene expression profile with expression of proinflammatory genes, but strikingly also a remarkable set of genes discussed in the context of peripheral induction of regulatory T cells, including IL-10, Nrp-1, and Foxp3. CONCLUSIONS: Enterocyte specific antigen expression is sufficient to trigger a specific CD4+ T cell response leading to mucosal infiltration. In our model, progression to overt clinical disease was counteracted most likely by induction of regulatory T cells.

Asunto(s)

Linfocitos T CD4-Positivos/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Mucosa Intestinal/inmunología , Animales , Autoantígenos/inmunología , Autoinmunidad/genética , Autoinmunidad/inmunología , Células Cultivadas , Citocinas/biosíntesis , Enterocitos/inmunología , Perfilación de la Expresión Génica/métodos , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Inmunidad Mucosa , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/patología , Mucosa Intestinal/patología , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos

RESUMEN

Early pathological manifestations of Crohn's disease (CD) include vascular disruption, T cell infiltration of nerve plexi, neuronal degeneration, and induction of T helper 1 cytokine responses. This study demonstrates that disruption of the enteric glial cell network in CD patients represents another early pathological feature that may be modeled after CD8(+) T cell-mediated autoimmune targeting of enteric glia in double transgenic mice. Mice expressing a viral neoself antigen in astrocytes and enteric glia were crossed with specific T cell receptor transgenic mice, resulting in apoptotic depletion of enteric glia to levels comparable in CD patients. Intestinal and mesenteric T cell infiltration, vasculitis, T helper 1 cytokine production, and fulminant bowel inflammation were characteristic hallmarks of disease progression. Immune-mediated damage to enteric glia therefore may participate in the initiation and/or the progression of human inflammatory bowel disease.

Asunto(s)

Enfermedades Autoinmunes/inmunología , Enfermedad de Crohn/inmunología , Enterocolitis/inmunología , Neuroglía/inmunología , Adolescente , Adulto , Animales , Secuencia de Bases , Linfocitos T CD8-positivos/inmunología , Estudios de Casos y Controles , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/metabolismo , Enfermedad de Crohn/etiología , Cartilla de ADN , Sistema Nervioso Entérico/inmunología , Sistema Nervioso Entérico/metabolismo , Enterocolitis/etiología , Femenino , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteína Ácida Fibrilar de la Glía/fisiología , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Glicoproteínas Hemaglutininas del Virus de la Influenza/metabolismo , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/fisiología

RESUMEN

CD8(+) T cells are important effectors, as well as regulators, of organ-specific autoimmunity. Compared with Tc1-type CD8(+) cells, Tc2 cells have impaired anti-viral and anti-tumor effector functions, although no data are yet available on their pathogenic role in autoimmunity. Our aim was to explore the role of autoreactive Tc1 and Tc2 cells in autoimmune diabetes. We set up an adoptive transfer model in which the recipients were transgenic mice expressing influenza virus hemagglutinin (HA) specifically in their pancreatic ss islet cells (rat insulin promoter-HA mice) and islet-specific Tc1 and Tc2 cells were generated in vitro from HA-specific CD8(+) cells of TCR transgenic mice (CL4-TCR mice). One million Tc1 cells, differentiated in vitro in the presence of IL-12, transferred diabetes in 100% of nonirradiated adult rat insulin promoter-HA recipients; the 50% diabetogenic dose was 5 x 10(5). Highly polarized Tc2 cells generated in the presence of IL-4, IL-10, and anti-IFN-gamma mAb had a relatively low, but definite, diabetogenic potential. Thus, 5 x 10(6) Tc2 cells caused diabetes in 6 of 18 recipients, while the same dose of naive CD8(+) cells did not cause diabetes. Looking for the cause of the different diabetogenic potential of Tc1 and Tc2 cells, we found that Tc2 cells are at least as cytotoxic as Tc1 cells but their accumulation in the pancreas is slower, a possible consequence of differential chemokine receptor expression. The diabetogenicity of autoreactive Tc2 cells, most likely caused by their cytotoxic activity, precludes their therapeutic use as regulators of autoimmunity.

Asunto(s)

Linfocitos T CD8-positivos/trasplante , Diabetes Mellitus Tipo 1/etiología , Diabetes Mellitus Tipo 1/inmunología , Epítopos de Linfocito T/inmunología , Islotes Pancreáticos/inmunología , Subgrupos de Linfocitos T/trasplante , Traslado Adoptivo , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Movimiento Celular/genética , Movimiento Celular/inmunología , Células Cultivadas , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patología , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Insulina/genética , Islotes Pancreáticos/patología , Activación de Linfocitos/genética , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Páncreas/inmunología , Páncreas/patología , Regiones Promotoras Genéticas/inmunología , Ratas , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/patología , Células Tumorales Cultivadas

RESUMEN

Astrocytes may have a role in antigen presentation in inflammatory diseases of the central nervous system (CNS) such as MS and EAE. In this study, we have assessed whether purified astrocyte cultures could stimulate naive CD4(+) or CD8(+) T-cells from TCR transgenic mice. As previously described, astrocytes sustained antigen-specific CD4(+) T-cell proliferation only in the presence of IFN-gamma, which promotes expression of both MHC class II and B7 molecules on astrocytes. In addition, we show that astrocytes also have the capacity to present antigens to naive CD8(+) T-cell and promote their proliferation. In one system, this CD8(+) T-cell proliferation was dependent on IFN-gamma-induced upregulation of B7 molecules on astrocytes. However, in a second TCR transgenic system, astrocytes could induce naive CD8(+) T-cell proliferation even in the absence of IFN-gamma. The possible implications of these findings for the pathophysiology of CNS inflammatory diseases are discussed.

Asunto(s)

Células Presentadoras de Antígenos/fisiología , Astrocitos/fisiología , Activación de Linfocitos/fisiología , Linfocitos T/fisiología , Animales , Antígenos CD/fisiología , Astrocitos/efectos de los fármacos , Antígeno B7-2 , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/fisiología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/fisiología , Células Cultivadas , Antígenos de Histocompatibilidad Clase I/inmunología , Interferón gamma/farmacología , Glicoproteínas de Membrana/fisiología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos/genética , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal

RESUMEN

There is now convincing evidence that autoreactive CD8+ T cells can contribute to the pathogenesis of organ-specific autoimmune diseases. In the non-obese diabetic mouse, there is direct evidence that beta-islet cell-specific CD8+ cytotoxic T cells have a pathogenic effect. In human diseases such as autoimmune diabetes and multiple sclerosis, indirect evidence also suggests a role for CD8+ T cells in tissue damage, although their antigen specificity is unknown. Transgenic mouse models as well as the use of knockout mice have been instrumental in the identification of the role of autoreactive CD8+ T cells. Spontaneous models of CD8+ T-cell-mediated autoimmunity generated through transgenesis should help delineate the effector mechanisms leading to tissue destruction. The study of autoreactive CD8+ T cells and the characterization of their antigenic specificity should help unravel the pathophysiology of organ-specific autoimmune diseases, help identify exacerbating foreign antigens, and allow the design of antigen-specific immunotherapy targeting the pathogenic autoreactive T cells.

Asunto(s)

Enfermedades Autoinmunes/inmunología , Linfocitos T CD8-positivos/inmunología , Animales , Enfermedades Autoinmunes/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/patología , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Humanos , Ratones , Ratones Endogámicos NOD , Ratones Transgénicos , Fenotipo

RESUMEN

Antigen-specific T cell tolerance can be induced by systemic injection of high-dose antigen. In particular, a single intravenous (i.v.) injection of influenza virus hemagglutinin peptide in HNT-TCR transgenic mice induces T cell tolerance through thymocyte apoptosis as well as anergy and deletion of peripheral CD4+ T cells. We now show that this tolerance is reversed after 8 weeks probably due to the short in vivo half-life of the peptide. Since durable tolerance is required for this strategy to be of therapeutic value, we tested whether weekly i.v. injections of peptide (up to 12 weeks) could maintain the CD4+ T cell tolerance. Each injection induces a profound deletion of thymocytes, although their level recovers before the next injection. Therefore, during the treatment period, the thymus undergoes cycles of contraction/expansion. In the periphery, the number of CD4+ T cells is stably decreased and the persisting CD4+ T cells are hyporeactive both in vitro and in vivo. This tolerance is essentially peripheral since comparable results were obtained in thymectomized HNT-TCR mice injected weekly. Our data show that stable antigen-specific tolerance can be induced by repeated i.v. injections of antigen. These findings might have implications for the treatment of T cell-mediated autoimmune diseases.

Asunto(s)

Glicoproteínas Hemaglutininas del Virus de la Influenza/administración & dosificación , Tolerancia Inmunológica , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Secuencia de Aminoácidos , Animales , Apoptosis/inmunología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Calcio/metabolismo , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Técnicas In Vitro , Inyecciones Intravenosas , Activación de Linfocitos , Depleción Linfocítica , Ratones , Ratones Transgénicos , Autotolerancia

RESUMEN

The N-terminal peptide Ac1-11 of myelin basic protein induces experimental autoimmune encephalomyelitis in H-2(u) and (H-2(u) x H-2(s)) mice but does not in H-2(s) mice. Ac1-11 binds weakly to the class II major histocompatibility complex (MHC) molecule I-Au but not at all to I-As. We have studied the interaction of Ac1-11 and I-Au as a model system for therapeutic intervention in the autoimmune response seen in experimental autoimmune encephalomyelitis. Two polymorphic residues that differ between I-Au and I-As, Y26beta and T28beta, and one conserved residue, E74beta, confer specific binding of Ac1-11 to I-Au. A fourth residue, R70beta in I-Au, affects both peptide binding and T cell recognition. These results are consistent with a model that places arginine at position five of Ac1-11 in pockets 4 and 7 of the MHC groove, which is formed in part by residues 26, 28, 70, and 74 of Abetau and places lysine at position four of Ac1-11, previously shown to be a major MHC contact, in hydrophobic pocket 6. The data indicate that the primary region of I-Au that confers specific binding of Ac1-11 lies in the center of the peptide binding groove rather than in the region that contacts the N terminus of the peptide, as has been shown for HLA DR and the homologous I-E molecules.

Asunto(s)

Encefalomielitis Autoinmune Experimental/inmunología , Antígenos HLA-DQ/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Proteína Básica de Mielina/inmunología , Secuencia de Aminoácidos , Animales , Sitios de Unión , Antígenos de Histocompatibilidad Clase II/genética , Activación de Linfocitos , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/inmunología , Unión Proteica , Linfocitos T/inmunología , Transfección

RESUMEN

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system that is of possible autoimmune origin. This article is divided into three parts, reviewing recent advances in three selected topics regarding the immunology of multiple sclerosis. The first part addresses the consequences of T cell and oligodendrocyte death in the inflammatory lesions. The second covers the recent experimental evidence favouring the involvement of infectious agents in the pathophysiology of central nervous system autoimmune diseases. The third part concerns the mode of action of interferon-beta in multiple sclerosis. These new advances have lead to a better understanding of the immunopathology of multiple sclerosis and therefore open new therapeutic possibilities.

Asunto(s)

Enfermedades del Sistema Nervioso Central/inmunología , Esclerosis Múltiple/inmunología , Muerte Celular , Infecciones del Sistema Nervioso Central/inmunología , Humanos , Interferón beta/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Oligodendroglía/patología , Proteínas Recombinantes/uso terapéutico , Linfocitos T/inmunología

RESUMEN

IDDM is a T-cell-mediated autoimmune disease in which the insulin-producing beta-cells are destroyed. The disease process is complex, involving the recognition of several beta-cell autoantigens. One of these, GAD65, appears to have a critical and not fully defined role in IDDM in humans and in the NOD mouse. We provide evidence that an ongoing diabetogenic response in NOD mice can be suppressed after intravenous administration of GAD65, but not by other beta-cell autoantigens. Furthermore, suppression of the diabetogenic response is mediated by the induction of GAD65-specific CD4+ regulatory T-cells. Finally, cytokine analysis indicates that these CD4+ regulatory T-cells have a T-helper 2 phenotype.

Asunto(s)

Autoanticuerpos/biosíntesis , Autoantígenos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Glutamato Descarboxilasa/inmunología , Linfocitos T/inmunología , Traslado Adoptivo , Animales , Autoanticuerpos/sangre , Autoantígenos/farmacología , Linfocitos T CD4-Positivos/inmunología , Diabetes Mellitus Tipo 1/patología , Glutamato Descarboxilasa/farmacología , Humanos , Islotes Pancreáticos/patología , Activación de Linfocitos , Ratones , Ratones Endogámicos NOD

RESUMEN

Repeated injections of adult mice with recombinant murine TNF prolong the survival of NZB/W F1 mice, and suppress type I insulin-dependent diabetes mellitus (IDDM) in non-obese diabetic (NOD) mice. To determine whether repeated TNF injections suppress T cell function in adult mice, we studied the responses of influenza hemagglutinin-specific T cells derived from T cell receptor (HNT-TCR) transgenic mice. Treatment of adult mice with murine TNF for 3 wk suppressed a broad range of T cell responses, including proliferation and cytokine production. Furthermore, T cell responses of HNT-TCR transgenic mice also expressing the human TNF-globin transgene were markedly reduced compared to HNT-TCR single transgenic littermates, indicating that sustained p55 TNF-R signaling is sufficient to suppress T cell function in vivo. Using a model of chronic TNF exposure in vitro, we demonstrate that (a) chronic TNF effects are dose and time dependent, (b) TNF suppresses the responses of both Th1 and Th2 T helper subsets, (c) the suppressive effects of endogenous TNF produced in T cell cultures could be reversed with neutralizing monoclonal antibodies to TNF, and (d) prolonged TNF exposure attenuates T cell receptor signaling. The finding that anti-TNF treatment in vivo enhances T cell proliferative responses and cytokine production provides evidence for a novel regulatory effect of TNF on T cells in healthy laboratory mice. These effects are more pronounced in chronic inflammatory disease. In addition, our data provide a mechanism through which prolonged TNF exposure suppresses disease in animal models of autoimmunity.

Asunto(s)

Receptores de Antígenos de Linfocitos T/fisiología , Linfocitos T/citología , Factor de Necrosis Tumoral alfa/administración & dosificación , Animales , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Calcio/fisiología , Inmunosupresores/administración & dosificación , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Interleucina-2/metabolismo , Interleucina-4/metabolismo , Ganglios Linfáticos/citología , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Receptores del Factor de Necrosis Tumoral/fisiología , Proteínas Recombinantes , Transducción de Señal/efectos de los fármacos , Células TH1/inmunología , Células Th2/inmunología

RESUMEN

The possible involvement of Fas/APO-1 (CD95) and TNF in antigen-specific AICD of thymocytes and mature T cells has been investigated. Antigenic stimulation in vivo of influenza hemagglutinin (HA)-specific TCRtg mice was used to demonstrate that the kinetics of thymocyte and peripheral CD4+ T cell deletion are similar in mice with normal (+/+) or defective Fas (lpr/lpr) background, indicating that a Fas-independent pathway(s) is responsible for the deletion of activated T cells. TCRtg-+/+ or TCRtg-lpr/lpr mice injected with murine TNF-blocking MAb (TN3) showed rapid apoptosis of thymocytes after HA stimulation, indicating that death signaling through Fas and TNF receptors is not essential for HA-induced thymocyte deletion. CDC peripheral T cells in TCRtg-lpr/lpr mice did not undergo apoptosis following injection with HA and TN3, indicating that TNF-mediated apoptosis is involved in the deletion of mature T cells after antigenic stimulation. However, apoptosis still occurred in TCRtg-+/+ mice injected with TN3, indicating that both Fas- and TNF-mediated cell death can contribute to the deletion of activated peripheral T cells.

Asunto(s)

Apoptosis/inmunología , Receptores de Antígenos de Linfocitos T/genética , Factor de Necrosis Tumoral alfa/fisiología , Receptor fas/fisiología , Secuencia de Aminoácidos , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Secuencia de Bases , Supresión Clonal/genética , Cruzamientos Genéticos , Relación Dosis-Respuesta Inmunológica , Hemaglutininas Virales/administración & dosificación , Hemaglutininas Virales/farmacología , Inmunofenotipificación , Virus de la Influenza A/inmunología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/genética , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/inmunología , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Mutación , Linfocitos T/inmunología

RESUMEN

The mechanism by which tolerance is induced via systemic administration of high doses of aqueous antigen has been analyzed by using mice transgenic for a T-cell receptor specific for the influenza virus hemagglutinin (HA) peptide comprising amino acids 126-138. After intravenous injection of 750 (but not 75) micrograms of HA peptide, a state of hyporesponsiveness was rapidly induced. In the thymus, in situ apoptosis in the cortex and at the corticomedullary junction was responsible for a synchronous and massive deletion of CD4+ CD8+ thymocytes. In secondary lymphoid organs, HA-reactive T cells were initially activated but were hyporesponsive at the single cell level. After 3 days, however, those cells were rapidly deleted, at least partially, through an apoptotic process. Therefore, both thymic and peripheral apoptosis, in addition to T-cell receptor desensitization, contribute to high-dose tolerance.

Asunto(s)

Antígenos Virales/inmunología , Apoptosis , Hemaglutininas Virales/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/biosíntesis , Linfocitos T/inmunología , Timo/inmunología , Secuencia de Aminoácidos , Animales , Antígenos Virales/administración & dosificación , Antígenos Virales/farmacología , Apoptosis/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Citometría de Flujo , Glicoproteínas Hemaglutininas del Virus de la Influenza , Hemaglutininas Virales/administración & dosificación , Hemaglutininas Virales/farmacología , Tolerancia Inmunológica , Inyecciones Intravenosas , Ganglios Linfáticos/inmunología , Depleción Linfocítica , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , Ovalbúmina/farmacología , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/farmacología , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Linfocitos T/efectos de los fármacos , Linfocitos T/fisiología , Timectomía

RESUMEN

CD4+ T cells play a key role in regulating immune system function. When these regulatory processes go awry, organ-specific autoimmune diseases may develop. Here, Roland Liblau, Steven Singer and Hugh McDevitt explore the thesis that a particular subset of CD4+ T cells, namely T helper 1 (Th1) cells, contributes to the pathogenesis of organ-specific autoimmune diseases, while another subset, Th2 cells, prevents them.

Asunto(s)

Enfermedades Autoinmunes/inmunología , Células TH1/inmunología , Células Th2/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Humanos , Ratones , Ratones Endogámicos NOD

Asunto(s)

Antígenos/inmunología , Apoptosis/inmunología , Activación de Linfocitos/inmunología , Linfocitos T/inmunología , Animales , Ratones , Ratones Transgénicos , Péptidos/inmunología , Receptores de Antígenos de Linfocitos T/genética , Timo/citología

RESUMEN

Type 1 diabetes is the result of an ongoing autoimmune response to specific proteins expressed by the insulin producing beta cells. Recently, a number of beta cell autoantigens have been identified. However, their role in mediating the diabetogenic response is not known. Here we assess the relative importance of a panel of beta cell autoantigens in the disease process. The approach was to inhibit T cell proliferation to a given autoantigen by either i.t. or i.v. injections, and then determine the effect this had on the diabetogenic response. We show that administering murine glutamic acid decarboxylase (GAD) to 3-week-old NOD females can reduce the frequency of insulitis and prevent the onset of diabetes. In contrast, carboxypeptidase H or peripherin do not induce a similar protective effect, suggesting that GAD has a critical role in the diabetogenic response. These results also suggest that GAD may provide a useful target for antigen-specific immunotherapy.

Asunto(s)

Autoantígenos/administración & dosificación , Diabetes Mellitus Tipo 1/prevención & control , Glutamato Descarboxilasa/farmacología , Islotes Pancreáticos/inmunología , Linfocitos T/inmunología , Animales , Autoanticuerpos/inmunología , Femenino , Activación de Linfocitos , Ratones , Ratones Endogámicos NOD

RESUMEN

Tumor necrosis factor (TNF) alpha is a cytokine that has potent immune regulatory functions. To assess the potential role of this cytokine in the early development of autoimmunity, we investigated the effect of TNF on the development of insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice, a spontaneous murine model for autoimmune, insulin-dependent type I diabetes. Treatment of newborn female NOD mice with TNF every other day for 3 wk, led to an earlier onset of disease (10 versus 15 wk of age in control mice) and 100% incidence before 20 wk of age (compared to 45% at 20 wk of age in control phosphate-buffered saline treated female mice). In contrast, administration of an anti-TNF monoclonal antibody, TN3.19.12, resulted in complete prevention of IDDM. In vitro proliferation assays demonstrated that mice treated with TNF developed an increased T cell response to a panel of beta cell autoantigens, whereas anti-TNF treatment resulted in unresponsiveness to the autoantigens. In addition, autoantibody responses to the panel of beta cell antigens paralleled the T cell responses. The effects mediated by TNF appear to be highly age dependent. Treatment of animals either from birth or from 2 wk of age had a similar effect. However, if treatment was initiated at 4 wk of age, TNF delayed disease onset. These data suggest that TNF has a critical role in the early development of autoimmunity towards beta-islet cells.

Asunto(s)

Autoinmunidad , Diabetes Mellitus Tipo 1/etiología , Factor de Necrosis Tumoral alfa/farmacología , Factores de Edad , Animales , Anticuerpos Monoclonales/inmunología , Diabetes Mellitus Tipo 1/inmunología , Femenino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Linfocitos T/efectos de los fármacos

RESUMEN

Susceptibility to insulin-dependent diabetes mellitus (IDDM) is greatly influenced by polymorphisms in the genes of the class II region of the human leukocyte antigen (HLA) complex. The complexity of this genetic association and the lack of a direct proof of involvement of HLA class II genes in human IDDM have continued to support speculation on a possible role of genes encoded in the close vicinity of these loci in IDDM. Because the recently discovered transporter associated with antigen processing (TAP) and large multifunctional protease (LMP) genes are encoded in the HLA class II region and are implicated in the processing of antigenic proteins for presentation by HLA class I molecules, they are additional candidates for a role in IDDM pathogenesis. We have analyzed genomic and coding sequence polymorphisms in the LMP2, TAP1, and TAP2 genes of 77 Danish IDDM patients and 102 control subjects. Although patients and control subjects did not differ in TAP1 and LMP2 alleles, we found a striking absence of the TAP2 allele B (long form) in IDDM patients. An analysis of the TAP2 alleles in individual DR types, however, revealed that this phenomenon is likely to be caused by linkage disequilibrium between the two loci. Thus, polymorphisms in the TAP and LMP genes are unlikely to be associated with IDDM.

Asunto(s)

Transportadoras de Casetes de Unión a ATP , Cisteína Endopeptidasas , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Genes MHC Clase II , Genes MHC Clase I , Complejo Mayor de Histocompatibilidad , Polimorfismo de Longitud del Fragmento de Restricción , Transportador de Casetes de Unión a ATP, Subfamilia B, Miembro 2 , Miembro 3 de la Subfamilia B de Transportadores de Casetes de Unión a ATP , Adulto , Alelos , Secuencia de Aminoácidos , Secuencia de Bases , Proteínas Portadoras/genética , Codón , Cartilla de ADN , Sondas de ADN , Femenino , Antígenos de Histocompatibilidad Clase II/genética , Humanos , Masculino , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Proteínas/genética , Valores de Referencia , Mapeo Restrictivo