RESUMEN
BACKGROUND AND PURPOSE: Antibodies to myelin oligodendrocyte glycoprotein (MOG) have been identified in both children and adults with demyelination, with a strong association with bilateral or recurrent optic neuritis (ON). However, the full clinical spectrum of this newly described condition is unknown. We sought to describe non-ON inflammatory ophthalmological presentations such as uveitis and optic perineuritis in the context of MOG antibody seropositivity. METHODS: Using a live cell-based assay analysed by flow cytometry, we identified seropositive patients referred for MOG antibody testing in Australasia between 2014 and 2017. We identified four MOG antibody-positive patients with non-ON inflammatory ophthalmological presentations and present their detailed clinical information in this case series. RESULTS: Three patients had uveitis either in association with, or remote from, ON. One patient had optic perineuritis and peripheral ulcerative keratitis. We describe the presentation, examination, investigation findings and clinical course of these four patients. CONCLUSIONS: Recognition of these novel clinical associations may expand the clinical spectrum of MOG antibody-associated presentations. An expedited diagnosis may guide the management of these complex patients.
Asunto(s)
Autoanticuerpos/inmunología , Glicoproteína Mielina-Oligodendrócito/inmunología , Neuritis Óptica/diagnóstico , Uveítis/diagnóstico , Adulto , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuritis Óptica/inmunología , Uveítis/inmunologíaRESUMEN
OBJECTIVE: To study the longitudinal dynamics of anti-myelin oligodendrocyte glycoprotein (MOG) autoantibodies in childhood demyelinating diseases. METHODS: We addressed the kinetics of anti-MOG immunoglobulins in a prospective study comprising 77 pediatric patients. This was supplemented by a cross-sectional study analyzing 126 pediatric patients with acute demyelination and 62 adult patients with multiple sclerosis (MS). MOG-transfected cells were used for detection of antibodies by flow cytometry. RESULTS: Twenty-five children who were anti-MOG immunoglobulin (Ig) positive at disease onset were followed for up to 5 years. Anti-MOG antibodies rapidly and continuously declined in all 16 monophasic patients with acute disseminated encephalomyelitis and in one patient with clinically isolated syndrome. In contrast, in 6 of 8 patients (75%) eventually diagnosed with childhood MS, the antibodies to MOG persisted with fluctuations showing a second increase during an observation period of up to 5 years. Antibodies to MOG were mainly IgG 1 and their binding was largely blocked by pathogenic anti-MOG antibodies derived from a spontaneous animal model of autoimmune encephalitis. The cross-sectional part of our study elaborated that anti-MOG Ig was present in about 25% of children with acute demyelination, but in none of the pediatric or adult controls. Sera from 4/62 (6%) adult patients with MS had anti-MOG IgG at low levels. CONCLUSIONS: The persistence or disappearance of antibodies to MOG may have prognostic relevance for acute childhood demyelination.
Asunto(s)
Autoanticuerpos/análisis , Encefalomielitis Aguda Diseminada/inmunología , Glicoproteína Asociada a Mielina/inmunología , Adolescente , Adulto , Unión Competitiva , Línea Celular , Niño , Preescolar , Estudios de Cohortes , Estudios Transversales , Femenino , Citometría de Flujo , Humanos , Inmunoglobulina G/análisis , Inmunoglobulinas/análisis , Lactante , Cinética , Estudios Longitudinales , Masculino , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Proteínas de la Mielina , Glicoproteína Mielina-Oligodendrócito , Estudios Prospectivos , TransfecciónRESUMEN
BACKGROUND: Voltage-gated potassium channel antibodies (VGKC Ab) are associated with limbic encephalitis and neuromyotonia in adults. There have been no systematic investigations in children to date. METHODS: We looked for antibodies that are associated with CNS syndromes in adults including antibodies to VGKCs, NMDARs, glutamic acid decarboxylase (GAD), and glycine receptor (GlyR) in the stored acute serum from 10 children with unexplained encephalitis presenting with encephalopathy and status epilepticus. We also looked for antibodies to leucine-rich glioma-inactivated 1 (Lgi1) and contactin-associated protein-like 2 (Caspr2), which are now known to be tightly complexed with VGKCs in vivo. Sixty-nine pediatric controls were used for comparison. RESULTS: An elevated VGKC Ab (>100 pM) was detected in 4/10 patients with encephalitis compared to only 1/69 controls (p < 0.001). The outcome in the 4 VGKC Ab-positive patients with encephalitis was variable including good recovery (n = 1), cognitive impairment (n = 3), temporal lobe epilepsy (n = 2), and mesial temporal sclerosis (n = 1). No other antibodies were detected, including those to Lgi1 and Caspr2. CONCLUSION: Encephalitis associated with VGKC Ab occurs in children and presents with status epilepticus and focal epilepsy. These antibodies are not directed against Lgi1 or Caspr2.
Asunto(s)
Autoanticuerpos/biosíntesis , Encefalitis Límbica/diagnóstico , Encefalitis Límbica/inmunología , Canales de Potasio con Entrada de Voltaje/inmunología , Estado Epiléptico/diagnóstico , Estado Epiléptico/inmunología , Adolescente , Autoanticuerpos/sangre , Biomarcadores/sangre , Niño , Preescolar , Femenino , Humanos , Lactante , Encefalitis Límbica/sangre , Masculino , Estado Epiléptico/sangreRESUMEN
OBJECTIVE: To test the hypothesis that Sydenham chorea (SC) immunoglobulin G (IgG) autoantibodies bind to specific neuronal surface proteins, whereas IgG from patients with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) or Tourette syndrome (TS) do not bind to neuronal surface proteins. METHODS: We used live differentiated SH-SY5Y cells, which have neuronal and dopaminergic characteristics. Using flow cytometry, we measured serum IgG cell surface binding in patients with SC (n = 11), PANDAS (n = 12), and TS (n = 11), and compared the findings to healthy controls (n = 11) and other neurologic controls (n = 11). In order to determine the specificity of binding to neuronal antigens, we also used a non-neuronal cell line, HEK 293. RESULTS: The mean IgG cell surface binding was significantly higher in the SC group compared to all other groups (p < 0.001). By contrast, there was no difference between the PANDAS or TS groups and the controls. Using the non-neuronal HEK-293 cells, there was no significant difference in IgG cell surface binding between any groups. CONCLUSIONS: Serum autoantibodies that bind to neuronal cell surface antigens are present in SC, but not in PANDAS or TS. These findings strengthen the hypothesis that SC is due to a pathogenic autoantibody, but weaken the autoantibody hypothesis in PANDAS and TS.
Asunto(s)
Corea/inmunología , Inmunoglobulina G/metabolismo , Neuronas/metabolismo , Síndrome de Tourette/inmunología , Adolescente , Antineoplásicos/farmacología , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/inmunología , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Niño , Preescolar , Corea/sangre , Femenino , Citometría de Flujo/métodos , Humanos , Masculino , Neuroblastoma/patología , Neuronas/efectos de los fármacos , Trastorno Obsesivo Compulsivo , Estadísticas no Paramétricas , Infecciones Estreptocócicas/sangre , Infecciones Estreptocócicas/inmunología , Síndrome de Tourette/sangre , Tretinoina/farmacologíaRESUMEN
BACKGROUND: Epstein-Barr virus (EBV) has been discussed as a possible causative agent in inflammatory demyelinating diseases of the CNS. Cross-reactivity between EBV and myelin proteins has been proposed as a potential mechanism by which EBV could elicit an autoimmune response targeting the CNS. Recently, high antibody titers to native myelin oligodendrocyte glycoprotein (nMOG) were found in children affected by the first inflammatory demyelinating event. The relation between antibody responses to EBV and nMOG has not been addressed in children so far. METHODS: We investigated the occurrence of antibodies to nMOG, EBV nuclear antigen 1 (EBNA-1), and early antigen (EA) in a case-control study including children with acute disseminated encephalomyelitis (ADEM, n = 19), children with clinically isolated syndrome (CIS, n = 25), children with other neurologic diseases (n = 28), and healthy children (n = 30). Immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies against the extracellular part of nMOG were assessed by a cell-based assay, and EBV-specific IgG antibodies to EBNA-1 and IgM antibodies to EA were assessed by ELISA. RESULTS: Serum IgG antibodies to EBNA-1 were present in 43% of controls (25/58), 42% of children with ADEM (8/19), and 64% of children with CIS (16/25), whereas IgM antibodies to EA were detected in only 16% of children with ADEM (3/19). High antibody titers to nMOG were only found in children with ADEM and CIS but were not related to the seropositivity to EBV. Moreover, in EBV-seropositive children, we did not observe any correlation between anti-EBNA-1 and anti-nMOG IgG antibody titers. CONCLUSION: High serum immunoglobulin G titers to native myelin oligodendrocyte glycoprotein are found in a significant number of children affected by clinically isolated syndrome or acute disseminated encephalomyelitis. These antibodies are not related to the antibody response to Epstein-Barr virus.
Asunto(s)
Anticuerpos Antivirales/inmunología , Formación de Anticuerpos/inmunología , Encefalitis/inmunología , Antígenos Nucleares del Virus de Epstein-Barr/inmunología , Glicoproteína Asociada a Mielina/inmunología , Adolescente , Niño , Preescolar , Enfermedades Autoinmunes Desmielinizantes SNC/complicaciones , Enfermedades Autoinmunes Desmielinizantes SNC/inmunología , Enfermedades Autoinmunes Desmielinizantes SNC/virología , Encefalitis/complicaciones , Encefalitis/virología , Femenino , Humanos , Lactante , Masculino , Proteínas de la Mielina , Glicoproteína Mielina-Oligodendrócito , Pediatría , Estudios Retrospectivos , Estadísticas no ParamétricasRESUMEN
The autoimmune nature of the diabetogenic process and the major contribution of T lymphocytes stand now beyond any doubt. However, despite the identification of the three major type 1-diabetes-related autoantigens (insulin, GAD65 and phosphatase IA-2), the origin of this immune dysregulation still remains unknown. More and more evidence supports a thymic dysfunction in the establishment of central self-tolerance to the insulin family as a crucial factor in the development of the autoimmune response selective of pancreatic insulin-secreting islet beta cells. All the genes of the insulin family (INS, IGF1 and IGF2) are expressed in the thymus network. However, IGF-2 is the dominant member of this family first encountered by T cells in the thymus, and only IGFs control early T-cell differentiation. IGF2 transcription is defective in the thymus in one animal model of type 1 diabetes, the Bio-Breeding (BB) rat. The sequence B9-23, one dominant autoantigen of insulin, and the homologous sequence B11-25 derived from IGF-2 exibit the same affinity and fully compete for binding to DQ8, one class-II major histocompatibility complex (MHC-II) conferring major genetic susceptibility to type 1 diabetes. Compared to insulin B9-23, the presentation of IGF-2 B11-25 to peripheral mononuclear cells (PBMCs) isolated from type 1 diabetic DQ8+ adolescents elicits a regulatory/tolerogenic cytokine profile (*IL-10, *IL-10/IFN-g, *IL-4). Thus, administration of IGF-2 derived self-antigen(s) might constitute a novel form of vaccine/immunotherapy combining both an antagonism for the site of presentation of a susceptible MHC allele, as well as a downstream tolerogenic/regulatory immune response.
Asunto(s)
Enfermedades Autoinmunes/fisiopatología , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/fisiopatología , Timo/inmunología , Timo/patología , Autoantígenos/inmunología , Diabetes Mellitus Tipo 1/genética , Predisposición Genética a la Enfermedad , Humanos , Tolerancia InmunológicaRESUMEN
The precise role of viral infections in the pathogenesis of type 1 diabetes is still the subject of an important discussion. Coxsackievirus B4 (CVB4) is the virus the most implicated by a series of epidemiological studies. Pathogenic mechanisms underlying such a relationship implicate a molecular mimicry between CVB4 sequences and beta-cell autoantigens, but mainly a persistent CVB4 infection of pancreatic beta cells followed by a release of sequestered beta antigens and a "bystander" activation of autoreactive T cells. The demonstration of intrathymic expression of antigens specific of peripheral tissues has opened a novel research perspective. We have shown that CVB4 is able to infect in a persistent and producive manner human thymic epithelial cell cultures and human fetal thymic lobes in organotypic cultures. This infection induces an important thymic dysfunction characterized by a severe depletion of thymocytes (thymic T cells) and an up-regulated expression by thymic epithelial and T cells of class I proteins encoded by the major histocompatibility complex (MHC-I). Such thymic dysfunction might be responsible for a decrease of beta-cell central self-tolerance and anti-CVB4 cytotoxic CD8 T-cell activity. CVB4-induced thymic dysfunction would contribute in close association with the peripheral "bystander" effect to the destruction of insulin-secreting islet beta cells and to the development of type 1 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 1/fisiopatología , Diabetes Mellitus Tipo 1/virología , Enterovirus Humano B/patogenicidad , Infecciones por Enterovirus/complicaciones , Timo/virología , Autoantígenos , Humanos , Imitación Molecular , Linfocitos T , Timo/patologíaRESUMEN
Ontogenesis of oxytocin (OT) and vasopressin (VP) gene expression and function were investigated in murine thymus. OT and VP transcripts were detected in the thymus on embryonic days 13 and 15, respectively. Corresponding messenger RNAs were evidenced in thymic epithelial cells by in situ hybridization with a neurophysin probe. From all OT and VP receptors, only OTR was expressed by all T-cell subsets, while V1bR was found in double positive and single positive CD8 cells. In fetal thymic organ cultures, OTR antagonist d[D-Tyr(Et)2, Thr4]OVT increased early apoptosis of CD8 cells, while V1bR antagonist (Sanofi SSR149415) inhibited T-cell differentiation, and favored CD8 T-cell commitment.
Asunto(s)
Expresión Génica , Oxitocina/metabolismo , Transducción de Señal/fisiología , Timo/metabolismo , Vasopresinas/metabolismo , Vasotocina/análogos & derivados , Análisis de Varianza , Animales , Animales Recién Nacidos , Antagonistas de los Receptores de Hormonas Antidiuréticas , Southern Blotting/métodos , Encéfalo/metabolismo , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Embrión de Mamíferos , Citometría de Flujo/métodos , Hibridación in Situ/métodos , Indoles/farmacología , Ratones , Neurofisinas/genética , Técnicas de Cultivo de Órganos , Oxitocina/genética , Pirrolidinas/farmacología , ARN Mensajero/biosíntesis , Receptores de Oxitocina/antagonistas & inhibidores , Receptores de Oxitocina/genética , Receptores de Vasopresinas/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Transducción de Señal/efectos de los fármacos , Subgrupos de Linfocitos T/clasificación , Subgrupos de Linfocitos T/metabolismo , Timo/citología , Vasopresinas/genética , Vasotocina/farmacologíaRESUMEN
Thymus exerts a prominent role in the establishment os central T-cell tolerance, as well as in the development of self major histocompatibility complex (MHC)-restricted T lymphocytes. Like others autoimmune diseases, type 1 diabetes emergence implies central or peripheric self tolerance breakdown. Environmental factors, especially enterovirus infections, are supposed to be involved in diabetes pathophysiology. Epidemiological studies have highlighted a frequent association between enterovirus Coxsackievirus B4 (CVB4) and type 1 diabetes. The aim of our work was to study whether a thymus infection by CVB4 could induce modifications of thymic function. In primary cultures of thymic epithelial cells (TEC), we detected viral proteins, positive- and negative- strand RNA, and infectious virus in the supernatants, meaning that TEC cultures were susceptible to CVB4 infection and that CVB4 induced a persistent infection in those cells. CVB4 also modulated TEC proliferation and cytokine, such as IL-6, GM-CSF and LIF secretions. Studies using fetal organ thymus culture (FTOC) showed that CVB4 induced a marked and progressive thymocytes depletion, in particular double positive (DP) and CD4+ cells. CVB4 replicated in those subpopulations, indeed positive- and negative-atrand RNA were detected. CVB4 also upregulated MHC class I expression on DP thymocytes. The upregulation of MHC expression required viral infection in DP cells. IL-6 and GM-CSF secretions were also involved in this phenomenom, but IFN-alpha was shown not to be involved. Taken together, our results showed the susceptibility of the human thymus to CVB4 infection, and an important thymic dysfuntion due to this infection. Our work is a novel approach in the understanding of the mechanisms of CVB4-induced type 1 diabetes.
Asunto(s)
Diabetes Mellitus/virología , Enfermedades del Sistema Endocrino/inmunología , Enterovirus Humano B , Infecciones por Enterovirus/inmunología , Timo/inmunología , Timo/virología , Diabetes Mellitus/inmunología , Enfermedades del Sistema Endocrino/virología , Enterovirus Humano B/patogenicidad , HumanosRESUMEN
Intimate interactions between the two major systems of cell-to-cell communication, the neuroendocrine and immune systems, play a pivotal role in homeostasis and developmental biology. During phylogeny as well as during ontogeny, the molecular foundations of the neuroendocrine system emerge before the generation of diversity within the system of immune defenses. Before reacting against non-self infectious agents, the immune system has to be educated in order to tolerate the host molecular structure (self). The induction of self-tolerance is a multistep process that begins in the thymus during fetal ontogeny (central tolerance) and also involves anergizing mechanisms outside the thymus (peripheral tolerance). The thymus is the primary lymphoid organ implicated in the development of competent and self-tolerant T-cells. During ontogeny, T-cell progenitors originating from hemopoietic tissues (yolk sac, fetal liver, then bone marrow) enter the thymus and undergo a program of proliferation, T-cell receptor (TCR) gene rearrangement, maturation and selection. Intrathymic T-cell maturation proceeds through discrete stages that can be traced by analysis of their cluster differentiation (CD) surface antigens. It is well established that close interactions between thymocytes (pre-T-cells) and the thymic cellular environment are crucial both for T-cell development and for induction of central self-tolerance. Particular interest has focused on the ability of thymic stromal cells to synthesize polypeptides belonging to various neuroendocrine families. The thymic repertoire of neuroendocrine-related precursors recapitulates at the molecular level the dual role of the thymus in T-cell negative and positive selection. Thymic precursors not only constitute a source of growth factors for cryptocrine signaling between thymic stromal cells and pre-T-cells, but are also processed in a way that leads to the presentation of self-antigens by (or in association with) thymic major histocompatibility complex (MHC) proteins. Thymic neuroendocrine self-antigens usually correspond to peptide sequences highly conserved during the evolution of their corresponding family. The thymic presentation of some neuroendocrine self-antigens does not seem to be restricted by MHC alleles. Through the presentation of neuroendocrine self-antigens by thymic MHC proteins, the T-cell system might be educated to tolerate main hormone families. More and more recent experiments support the concept that a defect in thymic tolerogenic function is implicated as an important factor in the pathophysiology of autoimmunity.
Asunto(s)
Autoantígenos/inmunología , Sistemas Neurosecretores/inmunología , Autotolerancia/inmunología , Linfocitos T/inmunología , Timo/inmunología , Animales , Autoinmunidad , Diferenciación Celular , Humanos , Tolerancia Inmunológica/inmunología , Péptidos/inmunología , Precursores de Proteínas/inmunología , Timo/citología , VacunaciónRESUMEN
The expression of insulin-like growth factor (IGF) and IGF receptor genes was investigated by RT-PCR during ontogeny of the murine thymus. IGF-1, IGF-1R, M6P/IGF-2R genes are expressed in the thymus both in fetal and postnatal life, whereas IGF-2 messenger RNAs (mRNAs) decline after birth but are still detectable on the seventh week. By in situ hybridization, IGF-2 transcripts were located in the outer cortex and medulla of the postnatal thymus, and on the whole surface ofthe epithelial-like network in the fetal thymus. The effects of anti-IGFs and IGF-receptors neutralizing Abs on the generation of pre-T cell subpopulations were then investigated using fetal thymic organ cultures (FTOC). FTOC treatment with an anti-IGF-2 mAb, an anti-IGF-1R mAb, or an anti-M6P/IGF-2R polyclonal Ab induced a blockade of T cell differentiation at the CD4-CD8- stage, as shown by a significant increase in the percentage of CD4-CD8- cells and a decrease in the percentage of CD4+CD8+ cells. Moreover, anti-IGF-2 Ab treatment induced an increase in CD8+ cells suggesting that thymic IGF-2 might have a role in determining differentiation into the CD4 or CD8 lineage. Anti-IGF-1 Ab treatment decreased the proportion in CD4-CD8- cells and increased the frequency in CD4+CD8+. FTOC treatment with anti-(pro)insulin did not exert any significant effect on T cell development. These data indicate that the intrathymic IGF-mediated signaling plays an active role in the early steps of T cell differentiation during fetal development.
Asunto(s)
Somatomedinas/fisiología , Timo/citología , Timo/embriología , Animales , Southern Blotting , Diferenciación Celular/fisiología , Femenino , Citometría de Flujo , Hibridación in Situ , Factor II del Crecimiento Similar a la Insulina/biosíntesis , Ratones , Ratones Endogámicos BALB C , Técnicas de Cultivo de Órganos , Embarazo , ARN Mensajero/biosíntesis , Receptores de Somatomedina/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/fisiología , Linfocitos T/fisiologíaRESUMEN
The induction of immunological self-tolerance begins in the thymus during fetal life. The random recombination of gene segments coding for TCR is followed by the negative selection of T cells bearing a TCR directed against self-antigens presented by thymic MHC. Insulin-like growth factor type 2 (IGF-2) is the dominant gene of the insulin family that is transcribed and translated in the thymus of different species. Contrary to the other members of the insulin gene family, IGF-2 gene (IGF2) is not transcribed in the thymus of diabetes-prone BB rats. The absence of thymic IGF2 expression is associated with the diabetogenic autoimmune process in BB rats. This defect could not only contribute to the lymphopenia of BB rats, but also to the absence of central self-tolerance of the insulin family in this animal.
Asunto(s)
Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/fisiopatología , Autotolerancia/inmunología , Timo/inmunología , Animales , Diabetes Mellitus Tipo 1/genética , Modelos Animales de Enfermedad , Humanos , Factor II del Crecimiento Similar a la Insulina/genética , Factor II del Crecimiento Similar a la Insulina/inmunología , Ratas , Recombinación Genética/genética , Recombinación Genética/inmunología , Autotolerancia/genética , Linfocitos T/inmunologíaRESUMEN
The repertoire of thymic neuroendocrine precursors plays a dual role in T-cell differentiation as the source of either cryptocrine accessory signals in T-cell development or neuroendocrine self-antigens presented by the thymic major histocompatibility complex (MHC) machinery. Thymic neuroendocrine self-antigens usually correspond to peptide sequences highly conserved during the evolution of one family. The thymic presentation of some neuroendocrine self-antigens is not restricted by MHC alleles. Oxytocin (OT) is the dominant peptide of the neurohypophysial family. It is expressed by thymic epithelial and nurse cells (TEC/TNCs) of different species. Ontogenetic studies have shown that the thymic expression of the OT gene precedes the hypothalamic one. Both OT and VP stimulate the phosphorylation of p125FAK and other focal adhesion-related proteins in murine immature T cells. These early cell activation events could play a role in the promotion of close interactions between thymic stromal cells and developing T cells. It is established that such interactions are fundamental for the progression of thymic T-cell differentiation. Insulin-like growth factor 2 (IGF-2) is the dominant thymic polypeptide of the insulin family. Using fetal thymic organ cultures (FTOCs), the inhibition of thymic IGF-2-mediated signaling was shown to block the early stages of T-cell differentiation. The treatment of FTOCs with an mAb anti-(pro)insulin had no effect on T-cell development. In an animal model of autoimmune type 1 diabetes (BB rat), thymic levels of (pro)insulin and IGF-1 mRNAs were normal both in diabetes-resistant and diabetes-prone BB rats. IGF-2 transcripts were clearly identified in all thymuses from diabetes-resistant adult (5-week) and young (2- and 5-days) BB rats. In marked contrast, the IGF-2 transcripts were absent and the IGF-2 protein was almost undetectable in +/- 80% of the thymuses from diabetes-prone adult and young BB rats. These data show that a defect of the thymic IGF-2-mediated tolerogenic function might play an important role in the pathophysiology of autoimmune Type 1 diabetes.
Asunto(s)
Tolerancia Inmunológica , Neuroinmunomodulación , Sistemas Neurosecretores/inmunología , Linfocitos T/inmunología , Adulto , Animales , Presentación de Antígeno/fisiología , Autoantígenos/inmunología , HumanosRESUMEN
Thymic epithelium, including nurse cells (TEC/TNC), as well as other thymic stromal cells (macrophages and dentritic cells), express a repertoire of polypeptide belonging to various neuroendocrine protein families (such as the neurophypophysial, tachykinin, neurotensin and insulin families). A hierarchy of dominance exists in the organization of the thymic repertoire of neuroendocrine precursors. Oxytocin (OT) is more expressed in the TEC/TNC than vasopressin (VP); insulin-like growth factor 2 (IGF-2) thymic expression predominates over IGF-1, and much more over (pro)insulin. Thus, OT was proposed to be the self antigen of the neurohypophysial family, and IGF-2 the self antigen precursor of the insulin family. The dual role of the thymus in T-cell life and death is recapitulated at the level of the thymic neuroendocrine protein repertoire. Indeed, thymic polypeptides behave as accessory signals involved in T-cell development and positive selection according to the cryptocrine model of signaling. Moreover, thymic neuroendocrine polypeptides are the source of self antigens presented by thymic MHC molecules to developing pre-T cells. This presentation might induce the negative selection of T cells bearing a randomly rearranged antigen receptor (TCR) oriented against neuroendocrine families. Using an animal model of autoimmune type 1 diabetes (BB rat), we have shown a defect in intrathymic expression of the self antigen of the insulin family (IGF-2) and in IGF-2-mediated T-cell education to recognize and tolerate the insulin family. Altogether these studies have enlightened the crucial role played by the thymus in the induction of the central self tolerance of neuroendocrine families. The tolerogenic properties of thymic self peptides could be used in a novel type of vaccination for the prevention of autoimmune diseases.
Asunto(s)
Sistemas Neurosecretores/fisiología , Autotolerancia/fisiología , Linfocitos T/inmunología , Timo/fisiología , Animales , Enfermedades Autoinmunes/prevención & control , Autoinmunidad/fisiología , Humanos , Sistemas Neurosecretores/inmunología , Hormonas Hipofisarias/biosíntesis , Hormonas Hipofisarias/fisiologíaRESUMEN
Aquaporins are transmembrane proteins mediating water transport across plasma membrane of animal, vegetal or bacterial cells. Among the ten aquaporins known in mammals, six are located in kidney and take part in urine concentration. AQP2 is vasopressin regulated, it is the only family member to be implicated in human pathology, such as nephrogenic diabetes insipidus, congestive heart failure, hepatic cirrhosis, nephrotic syndrome or SIADH. Aquaporins are expressed in a wide variety of tissues, such as brain or gastrointestinal tractus, and suggest a role in water tissue exchange, but their real function is still not define. To know the physiological impact of aquaporins, AQP1, AQP3, AQP4 and AQP5 knockout mice have been created and their phenotype analysed.