RESUMEN
Chicken interleukin 2 (chIL-2) has low, but significant, homology to both mammalian IL-2 and mammalian IL-15. In view of its unique phylogenetic position and potential use as a vaccine adjuvant, a detailed mutational analysis for critical functional sites was undertaken. It was found that Asp17 is a critical N terminal contact site for binding to the putative chIL-2 receptor, which is similar to results obtained for mammalian IL-2 and IL-15. Analysis of the C terminus did not reveal a single critical amino acid. However, deletion mutant studies demonstrated that removal of C terminal amino acids yielded proteins with decreased bioactivity and that this decrease was a function of the number and kind of amino acids removed. This study is the first non-mammalian IL-2 mutational analysis and proposes a model for the interaction between chIL-2 and its receptor.
Asunto(s)
Interleucina-2/química , Interleucina-2/genética , Alanina/química , Secuencia de Aminoácidos , Animales , Ácido Aspártico/química , Sitios de Unión , División Celular , Pollos , Concanavalina A/farmacología , Análisis Mutacional de ADN , ADN Complementario/metabolismo , Eliminación de Gen , Humanos , Interleucina-15/química , Interleucina-2/metabolismo , Ratones , Datos de Secuencia Molecular , Filogenia , Unión Proteica , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Homología de Secuencia de Aminoácido , Bazo/citologíaRESUMEN
Mammalian interleukin-2 (IL-2) is a well-characterized cytokine that plays key roles in T cell differentiation and activation, B cell development, and natural killer (NK) cell stimulation. Chicken IL-2, which is the first nonmammalian IL-2 cloned, differs substantially from mammalian IL-2 molecules. We undertook to study the functions of chicken IL-2 by producing recombinant molecules in prokaryotic and eukaryotic expression systems, determining the in vitro properties of these molecules, and examining the kinetics of endogenous IL-2 production in vitro. Recombinant chicken IL-2 (rChIL-2) produced in prokaryotic and eukaryotic expression systems induced proliferation of chicken splenocytes in vitro, demonstrating that glycosylation is not required for this activity. Polyclonal antibodies generated against prokaryotically produced rChIL-2 inhibited proliferation of splenocytes induced by eukaryotically and prokaryotically produced rChIL-2, as well as endogenously produced cIL-2 obtained from ConA-stimulated splenocytes. Human IL-2 or IL-15-induced CTLL proliferation was not blocked by rChIL-2 or polyclonal anti-rChIL-2 antibodies, indicating that chicken IL-2 cannot act as an antagonist of the mammalian IL-2 response. Endogenous chicken IL-2 appears to occur in vitro as a monomer of about 14.2 kDa and is secreted within 4 h after ConA stimulation. The production of rChIL-2 provides us with a useful tool for studying avian immunology as well as a potential vaccine-enhancing agent.
Asunto(s)
Interleucina-2/biosíntesis , Animales , Bioensayo , Células Cultivadas , Pollos , Humanos , Interleucina-2/análisis , Cinética , Proteínas Recombinantes/análisis , Proteínas Recombinantes/biosíntesis , Bazo/citología , Bazo/metabolismoRESUMEN
Iodine depletion prevents disease and iodine repletion, which may cause thyroid cell injury by reactive oxygen intermediates, initiates disease in the Obese Strain chicken model of spontaneous autoimmune thyroiditis (AT). To examine the role of cell injury and autoantigen availability in AT induction we compared the immune responses that followed blunt trauma to the OS thyroid in the absence of iodine and the administration of normal dietary iodine in the absence of thyroid injury. Serum thyroglobulin concentrations were elevated following thyroid injury and the extensive thyroid infiltrates had high macrophage/CD4+, CD8+, B cell ratios consistent with an acute inflammatory response. The response was self limiting and undetectable in all animals 2 weeks later. Birds raised on a similar low iodine regimen were withdrawn from the regimen and given normal dietary iodine. Their thyroids showed no evidence of acute ultrastructural damage. The resulting early thyroid infiltrates had low macrophage/CD4+, CD8+, B cell ratios. Two weeks later these animals showed severe thyroid infiltration (43%) and after 4 weeks all animals had >90% infiltration. Thus, the presence or absence of thyroidal iodine, whether accompanied by injury or not, determined the nature and consequence of the immune response which argues against hypotheses that include obligatory injury at disease onset. Taken with previous work, this study suggests that iodination of an autoreactive thyroglobulin epitope is a requisite pathogenic action of iodine and supports the notion that in some organ-specific autoimmunity, a component of the dysregulation is associated with aberrant activity of the target tissue.
Asunto(s)
Autoantígenos/sangre , Glándula Tiroides/inmunología , Glándula Tiroides/lesiones , Tiroiditis Autoinmune/etiología , Factores de Edad , Animales , Linfocitos B/citología , Linfocitos B/inmunología , Disponibilidad Biológica , Pollos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Inflamación , Yodo/inmunología , Macrófagos/citología , Macrófagos/inmunología , Linfocitos T/citología , Linfocitos T/inmunología , Tiroglobulina/sangre , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/ultraestructura , Tiroiditis Autoinmune/inmunologíaRESUMEN
IL-2, cloned in several mammalian species, plays a critical role in immune system function. Indirect evidence suggests that IL-2-like molecules also exist in lower vertebrates, although none has been cloned. In view of the commercial importance of poultry and the lack of any IL-2 sequence data in lower vertebrates, we undertook to clone a chicken IL-2-like molecule. To this end, a cDNA library was constructed from activated chicken spleen cells and screened for T cell proliferative activity. Three clones of a single gene were isolated that produced a protein stimulatory for activated T cell blasts. This protein had 24 to 25% amino acid identity and 44 to 46% similarity to both bovine IL-2 and IL-15. The homology with IL-15 was unexpected, since primate IL-15 was reported to have no homology with IL-2. However, genetic distance analysis indicated that the chicken interleukin homology is closer to the mammalian IL-2 than to the mammalian IL-15 homology. Furthermore, the chicken gene has several characteristics of mammalian IL-2s: e.g., expression only by activated T cells, mRNA with a short 5' region preceding the open reading frame, and a short leader sequence. It has one characteristic that is unique to IL-15: four conserved cysteines allowing for two intrachain disulfide bonds.
Asunto(s)
Interleucina-15/genética , Interleucina-2/genética , Homología de Secuencia , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Bovinos , Pollos , Clonación Molecular , Interleucina-15/inmunología , Interleucina-2/inmunología , Mamíferos , Datos de Secuencia Molecular , Alineación de SecuenciaRESUMEN
The effect of thyroglobulin (Tg)iodination on the proliferation and suppression of thyroid-specific lymphocytes was examined in vivo in the obese strain (OS) and Cornell strain chicken models of autoimmune thyroiditis. Spleen cells from OS chickens were able to transfer disease to Cornell strain recipients. The ability to transfer disease was markedly reduced if the donors were raised on an iodine-depleting regimen. This deficiency was corrected by immunization of donor chickens with iodinated Tg. Immunization with low iodine Tg was ineffective. Neonatal tolerance induction with either iodinated or low iodine Tg reduced thyroiditis in 2-week-old OS chickens. Spleen cells from these tolerized chickens transferred to 4-day-old OS chickens were less thyroiditogenic. These results indicate that thyroid autoreactive cells are responsive to iodinated Tg, but not to low iodine Tg. Both of the Tg preparations, however, can induce tolerance to the disease. We conclude that distinct regions of the Tg molecule regulate the proliferation and suppression of thyroid-reactive lymphocytes, respectively. Only the former is dependent on the iodination of Tg. These results emphasize the importance of Tg as a self-antigen and provide one mechanism by which iodine may induce autoimmune thyroiditis.
Asunto(s)
Activación de Linfocitos/fisiología , Linfocitos/patología , Linfocitos/fisiología , Obesidad/fisiopatología , Tiroglobulina/fisiología , Glándula Tiroides/patología , Animales , Autoanticuerpos/análisis , División Celular/fisiología , Pollos/genética , Tolerancia Inmunológica , Yodo/deficiencia , Yodo/metabolismo , Obesidad/genética , Obesidad/patología , Tiroglobulina/inmunología , Tiroiditis Autoinmune/inmunología , Tiroiditis Autoinmune/metabolismo , Tiroiditis Autoinmune/patologíaRESUMEN
The OS and the related Cornell C strain are interesting animal models for the study of the etiology of autoimmune thyroiditis. They are especially valuable for studying the etiologic role of thyroid abnormalities and abnormalities in the processing of iodine. Limitations of the model are the scarcity of immunological reagents for chickens, the absence of avian cloned thyroid-specific genes, minimal amounts of microsomal antibody and some differences between OS chickens and Hashimoto's patients in the types of thyroid abnormalities observed.
Asunto(s)
Pollos , Modelos Animales de Enfermedad , Obesidad , Tiroiditis Autoinmune , Animales , Humanos , Yodo/metabolismo , Glándula Tiroides/patología , Glándula Tiroides/fisiopatología , Tiroiditis Autoinmune/patología , Tiroiditis Autoinmune/fisiopatologíaRESUMEN
The present study examines the role of thyroid cell injury in the initiation of autoimmune thyroiditis by iodine in Obese strain (OS) chickens, a strain genetically susceptible to spontaneous autoimmune thyroiditis. OS and normal strain chickens were placed on an iodine depletion regimen started in ovo. This regimen is known to prevent thyroiditis in OS chickens. The chickens were injected with NaI every 24 h for up to 7 days starting at 3 weeks of age. Both strains showed evidence of mild thyrocyte injury 12 h after NaI. However, significant and sustained infiltration, beginning 24 h after NaI, was seen only in the OS. The infiltrating cells were primarily mononuclear. Polymorphonuclear cells were not observed. Immunohistological analysis showed the infiltrate to be composed of CD8 T cells, CD4 T cells, B cells, and macrophages in the ratio 40:20:22:17. The infiltration was sustained and progressive for at least 7 days. Thyroid infiltration after NaI repletion was significantly reduced in OS chickens tolerized to thyroglobulin at hatching. Prior treatment with the antioxidant drug ethoxyquin completely prevented both the thyrocyte injury and the infiltration induced by iodine. Treatment with antioxidant drugs had no effect on the uptake and incorporation of iodine by the thyroid. In summary, 1) iodine caused thyrocyte injury in both OS and normal chickens. 2) The injury was followed by cellular infiltration in the OS but not in normal chickens. 3) The infiltration appeared to be immune mediated in being primarily lymphocytic and at least partially thyroglobulin sensitive. 4) Prevention of thyroid injury by antioxidant drug treatment also prevented infiltration. We conclude that thyroid cell injury may be an initial event in the induction of autoimmune thyroiditis by iodine.
Asunto(s)
Yodo , Obesidad/complicaciones , Glándula Tiroides/patología , Tiroiditis Autoinmune/inducido químicamente , Animales , Pollos , Tolerancia a Medicamentos , Etoxiquina/farmacología , Yodo/metabolismo , Linfocitos/patología , Macrófagos/patología , Microscopía Electrónica , Yoduro de Sodio/farmacología , Tiroglobulina/farmacología , Glándula Tiroides/efectos de los fármacos , Tiroiditis Autoinmune/complicacionesRESUMEN
We have characterized a monoclonal antibody (AT389), produced by immunization of mice with 4-day-old avian Concanavalin A blasts, which recognizes a 38-40 kDa homodimer present on the surface of all chicken T cells. AT389 increased the spontaneous and IL-2-driven proliferation of 3-day-old T-cell blasts. This antibody, in synergy with IL-2, increased cellular proliferation and cell survival of T-cell blasts over time. Together, these data suggest that AT389 recognizes a surface protein on avian T cells which may be related to known stimulatory surface markers on mammalian T cells.
Asunto(s)
Antígenos de Superficie/análisis , Activación de Linfocitos , Linfocitos T/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Antígenos CD/análisis , Antígenos de Diferenciación de Linfocitos T/análisis , Antígenos CD28 , Complejo CD3/análisis , Línea Celular , Pollos , Femenino , Ratones , Ratones Endogámicos BALB CRESUMEN
Many genes are induced after T cell activation to make a cell competent for proliferation and ultimately, function. Many of these genes encode surface receptors for growth factors that signal a cell to proliferate. We have cloned a novel gene (clone 6H1) that codes for a member of the G protein-coupled receptor superfamily. This gene was isolated from a chicken activated T cell cDNA library by low level hybridization to mammalian IL-2 cDNA probes. The 308 amino acid open reading frame has seven hydrophobic, presumably transmembrane domains and a consensus site for interaction with G proteins. Tissue distribution studies suggest that gene expression is restricted to activated T cells. The message appears by 1 h after activation and is maintained for at least 45 h. Transcription of 6H1 is induced by a number of T cell stimuli and is inhibited by cyclosporin A, but not by cycloheximide. This is the first description of a member of this superfamily expressed specifically in activated T cells. The gene product may provide a link between T cell growth factors and G protein activation.
Asunto(s)
Proteínas de Unión al GTP/análisis , Activación de Linfocitos , Receptores de Superficie Celular/análisis , Receptores Acoplados a Proteínas G , Receptores Purinérgicos P2 , Linfocitos T/química , Secuencia de Aminoácidos , Animales , Pollos , Proteínas de Unión al GTP/fisiología , Datos de Secuencia Molecular , Receptores de Superficie Celular/química , Receptores de Superficie Celular/genética , Linfocitos T/inmunología , Transcripción GenéticaRESUMEN
Current assays for chicken interleukin-2 (IL-2) utilize mitogen-activated lymphocytes. However, very high inter-assay variability and sporadic high background proliferation limit their usefulness. In view of the above, several Marek's disease virus (MDV)-transformed T-cell lines (which grow well in a serum-supplemented medium) were tested for a response to chicken IL-2 when grown in serum-free media. Five of six lines examined showed a dose-dependent proliferative response to chicken T-cell conditioned media. One line, MDCC-CU14, was chosen for further studies. In addition to the tumor cells' dose-dependent responses to semi-purified chicken IL-2, they expressed T-cell activation antigens on the cell surface. Furthermore, the level of surface expression was enhanced on cells provided IL-2. Co-incubation of the tumor cells with monoclonal antibody INN-CH-16 (specific for an antigen on the surface of activated T-cells) and IL-2 resulted in a modulation of lymphokine-induced proliferation. Together, these data suggest that signalling mechanisms in MDV T-cell tumors are intact and that these lines can be used as an assay for chicken T-cell lymphokines. Furthermore, they provide an interesting model for the study of avian and mammalian T-cell transformation. Implications for the study of Marek's disease are also discussed.
Asunto(s)
Transformación Celular Viral/inmunología , Pollos/inmunología , Herpesvirus Gallináceo 2/fisiología , Linfocitos T/inmunología , Animales , Anticuerpos Monoclonales , Antígenos de Diferenciación de Linfocitos T/inmunología , Línea Celular Transformada , Medios de Cultivo Condicionados/farmacología , Citometría de Flujo , Interleucina-2/fisiología , Activación de Linfocitos/inmunología , Enfermedad de Marek/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis TumoralRESUMEN
Evidence has been presented to support the idea that iodine plays an important role in autoimmune thyroiditis. Excessive amounts induce thyroiditis in genetically susceptible animal strains, while intrathyroidal depletion of iodine prevents disease in strains susceptible to severe thyroiditis. While the mechanisms by which iodine promotes thyroiditis is unknown, several hypotheses have been proposed. (1) T and/or B cells may react specifically to iodinated portions of thyroglobulin (Tg) so that severe iodine depletion renders Tg non-immunogenic. (2) A defect in the iodine processing machinery in thyroid epithelial cells of a susceptible person or animal may, in the presence of iodine, result in elevated levels of oxygen or iodine radicals, which could damage membrane lipids or proteins. (3) Defective iodine processing may result in the iodination of lipid or proteins (other than Tg) which could act either as immunogens or polyclonal activators.
Asunto(s)
Yodo/fisiología , Tiroiditis Autoinmune/etiología , Animales , Pollos , Humanos , Obesidad/complicaciones , Obesidad/veterinaria , Enfermedades de las Aves de Corral/inmunología , Linfocitos T/inmunología , Tiroglobulina/inmunología , Tiroglobulina/metabolismo , Tiroiditis Autoinmune/metabolismo , Tiroiditis Autoinmune/veterinariaRESUMEN
To assess the importance of the role of thyroidal iodine in the pathogenesis of thyroiditis in the obese strain (OS) chicken, a model of spontaneous and severe disease, we studied the effect of antithyroid drugs that reduce thyroidal iodine or prevent its metabolism. Reduction of thyroidal iodine was achieved with KClO4, an inhibitor of iodine transport and mononitrotyrosine (MNT), a drug that promotes loss of thyroidal iodine as iodotyrosines. A regimen consisting of KClO4 and MNT administration beginning in ovo and continuing after hatching reduced thyroidal infiltration to 2% of control values and decreased thyroglobulin antibody (TgAb) production for as long as 9 wk. Untreated birds had severe disease by 5 wk of age. The suppression of disease was independent of TSH, not mediated by generalized immunosuppression and reversed by excess dietary iodine. Two drugs that inhibit the metabolism of iodine, propylthiouracil (PTU) and aminotriazole, reduced thyroidal infiltration and TgAb levels, although to a lesser extent. When splenocytes from OS chickens with thyroiditis were transferred to Cornell strain (CS) chickens, a related strain that develops late onset mild disease, only the recipients that were iodine supplemented developed thyroiditis. In conclusion, autoimmune thyroiditis in an animal model can be prevented by reducing thyroidal iodine or its metabolism and optimal effects require intervention at the embryonic stage.
Asunto(s)
Yodo/metabolismo , Obesidad/metabolismo , Compuestos de Potasio , Tiroiditis Autoinmune/etiología , Amitrol (Herbicida)/farmacología , Animales , Pollos , Inmunoterapia Adoptiva , Yodo/farmacología , Obesidad/inmunología , Percloratos/farmacología , Potasio/farmacología , Propiltiouracilo/farmacología , Glándula Tiroides/efectos de los fármacos , Tiroiditis Autoinmune/metabolismo , Tirotropina/fisiología , Tirosina/análogos & derivados , Tirosina/farmacologíaRESUMEN
Several studies have shown that iodine plays a role in spontaneous autoimmune thyroiditis in man and other animals. In addition, abnormalities of iodine metabolism have been found in patients with Hashimoto's thyroiditis and in chickens of the obese strain (OS), an animal model of spontaneous autoimmune thyroiditis. We have examined several parameters of iodine metabolism before immune damage in this model and in the related Cornell strain (CS), a strain which develops a late-onset mild thyroiditis, to discover a possible causal relationship between altered iodine metabolism and the initiation of autoimmunity. Thyroglobulin was purified from individual chicken thyroid glands and analysed for iodine by the ceric sulphate method. Analogous to the thyroglobulin of Hashimoto's patients, the iodine content of OS thyroglobulin (27 atoms/molecule) was lower than that of normal-strain thyroglobulin (46 atoms/molecule) when the chickens were provided with a normal diet. Also, under conditions of TSH suppression, the iodine content of OS thyroglobulin (18 atoms/molecule) was lower than that of CS thyroglobulin (36 atoms/molecule) and of normal-strain thyroglobulin (32 atoms/molecule). In contrast with Hashimoto's patients, however, the OS and CS chickens had practically no inorganic iodide in their thyroid glands; electrophoretic analysis of thyroid homogenates revealed that essentially all (greater than 99.62%) 125I was organified by 16 h in all strains of birds tested. Despite the relatively poor iodination of thyroglobulin exhibited by OS chickens, they did not iodinate additional 'unique' proteins, when examined by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) of thyroid proteins labelled with 125I in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Autoinmunidad/fisiología , Pollos/metabolismo , Yodo/metabolismo , Obesidad/metabolismo , Glándula Tiroides/metabolismo , Animales , Autorradiografía , Modelos Animales de Enfermedad , Yodo/análisis , Obesidad/fisiopatología , Tiroglobulina/análisis , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/fisiopatología , Tiroiditis Autoinmune/metabolismo , Tiroxina/farmacologíaRESUMEN
Dietary iodine has been shown to be important in the induction of thyroiditis in susceptible chicken strains although the underlying mechanism remains unknown. Iodine may exert its effects through the formation of reactive oxidative radicals which would cause thyroidal injury and initiate infiltration. We have tested this hypothesis by examining the ability of butylated hydroxyanisole (BHA), ethoxyquin, and other antioxidants to prevent thyroiditis in Obese strain (OS) chickens, a strain that develops severe disease by 4 weeks of age. BHA, when administered from hatching until death at 5 weeks of age, reduced thyroidal infiltration and serum levels of antibodies binding thyroglobulin, T3, T4. Similar effects were observed with the antioxidant ethoxyquin. Weaker antioxidants such as vitamins C and E and beta-carotene had only slight or negligible effects on these parameters. BHA reduced thyroiditis in OS chicks killed at 3 and 5 weeks of age, but not at 8 weeks. When BHA treatment was initiated after the development of severe disease, it did not reduce thyroglobulin antibody levels. To determine the mechanism by which BHA reduces thyroiditis, studies were performed to assess the effect of BHA on thyroid function and on the immune responses to exogenous antigens. BHA had no effect on thyroid function in normal strain chickens since thyroidal radioiodine uptake and organification and serum T3 and T4 levels were unaffected. BHA did not alter immune responses to exogenous antigens such as sheep red blood cells or Brucella abortus in OS chickens. In summary, potent antioxidant drugs delayed the onset of thyroiditis when treatment was initiated before the onset of disease, suggesting that reactive oxygen intermediates are involved in the early stages of pathogenesis. However, the site of action remains unknown since they had no detectable effects on thyroid function or general immune responses.
Asunto(s)
Antioxidantes/uso terapéutico , Obesidad/complicaciones , Tiroiditis Autoinmune/prevención & control , Animales , Antioxidantes/administración & dosificación , Autoanticuerpos/sangre , Hidroxianisol Butilado/administración & dosificación , Hidroxianisol Butilado/farmacología , Hidroxianisol Butilado/uso terapéutico , Pollos , Etoxiquina/administración & dosificación , Etoxiquina/uso terapéutico , Tiroglobulina/inmunología , Glándula Tiroides/efectos de los fármacos , Tiroiditis Autoinmune/etiología , Tiroiditis Autoinmune/inmunología , Tiroxina/inmunología , Factores de Tiempo , Triyodotironina/inmunologíaRESUMEN
The aim of this chapter was to present a theory or concept of autoimmune disease that, in a sense, deemphasized the importance of immunoregulatory defects but rather concentrated on defects and/or changes in a target organ that might stimulate immune responses. Defects in immune regulation were not discussed because there is little evidence that generalized defects in immunoregulation occur in patients with autoimmune thyroid disease (38). There is some evidence of decreased numbers of thyroid-antigen-specific T-suppressor cells in patients with autoimmune thyroid disease; however, this has been detected only after the appearance of frank disease (38). Thus a reduction of T-suppressor cells specific for the thyroid microsomal antigen at a time when the immune system is responding vigorously to that antigen is to be expected and cannot a priori be assumed to be the reason for the immune response. One other reason for questioning the role of defective antigen-specific T-suppressor cells as an initiating event is that individual patients with autoimmune thyroid disease produce antibodies to a variety of unrelated thyroid antigens (Tg, microsomal antigen, which is now known to be thyroid peroxidase, TSH receptor, and others) (39). One would have to assume that the majority of thyroid patients spontaneously lose several unrelated clones of specific suppressor T cells. An alternative scenario of events in the pathogenesis of autoimmune disease is as follows: An environmental agent, whether it be iodide, alone, or in combination with high TSH, or a virus causes damage to the thyroid gland. The iodide-induced damage, perhaps mediated by hydroxyl radicals (40), is more severe and/or prolonged if the gland has a defect in iodide organification or perhaps, as seen in some susceptible chicken strains, partially autonomous thyroid function. As a result of the damage, leukocytes migrate into the gland. Once leukocytes arrive, a number of interesting phenomena occur. First, monocytes may secrete IL-1, which is directly cytotoxic for endocrine cells (41) and provides an accessory signal to T-helper cells. Second, T and B cells migrate into the damaged gland and into the follicles, where at least two of the important thyroid antigens are located, thyroglobulin and thyroid peroxidase. These two proteins are highly immunogenic: the thyroglobulin due to its increased iodine content and the thyroid peroxidase because it is a membrane-bound antigen sequestered in thyroid follicles. Third, the T cells, once activated, provide help to B cells and secrete gamma interferon, which induces the expression of class II MHC antigens on the thyroid epithelial cells (42).(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Yodo/efectos adversos , Tiroiditis Autoinmune/etiología , Animales , Modelos Animales de Enfermedad , Humanos , Yodo/administración & dosificación , Linfocitos T Reguladores/inmunologíaRESUMEN
Experiments were performed to analyze one mechanism by which elevated levels of dietary iodine may induce thyroglobulin (Tg) autoantibodies. We tested the hypothesis that highly iodinated Tg synthesized by animals fed a high iodine diet is significantly more immunogenic than Tg containing fewer iodine atoms. Cornell strain (CS) chickens, genetically susceptible to iodide-induced thyroiditis, were fed either a high or a low iodine diet. They were killed, and their thyroidal Tg was analyzed for iodine; the high iodine Tg (HI-Tg) had at least 60 and the low iodine Tg (LI-Tg) had less than 13 atoms/molecule of Tg. To determine if the degree of Tg iodination affected its immunogenicity, these Tg preparations were administered iv to normal chickens without adjuvants. Their sera were tested for antibodies by direct binding radioassays and RIAs. HI-Tg stimulated the synthesis of antibodies that reacted well with HI-Tg and the thyroid hormones T3 and T4, but only weakly with LI-Tg. The birds immunized with LI-Tg produced very little antibody to LI-Tg, T3, or T4, but a modest amount to HI-Tg. In other experiments, Tg autoantibodies found in chickens maintained on a high iodine diet similarly demonstrated enhanced binding to HI-Tg. The present studies show that HI-Tg is more immunogenic than LI-Tg and supports the hypothesis that a high iodine diet induces Tg autoantibodies by increasing the immunogenicity of the Tg molecule. In marked contrast with iodide-induced Tg antibodies, the Tg antibodies accompanying the severe and early-onset thyroiditis of obese strain chickens are to a large degree independent of dietary iodine intake.
Asunto(s)
Anticuerpos/inmunología , Yodo/metabolismo , Tiroglobulina/inmunología , Animales , Especificidad de Anticuerpos , Antígenos/inmunología , Autoanticuerpos/biosíntesis , Pollos , Dieta , Inmunización , Yodo/administración & dosificación , Obesidad/inmunología , Radioinmunoensayo , Tiroglobulina/metabolismo , Tiroiditis Autoinmune/inmunología , Tiroxina/inmunología , Triyodotironina/inmunologíaRESUMEN
Immunologists working in the field of autoimmunity tend to concentrate all their efforts on the elucidation of possible malfunctions of the immune system, particularly pathologic changes of immune regulation. Also in the OS model various groups of investigators emphasized this approach, although it was already clear early in the history of this model that SAT has a multigenic background. The fact that this disease cannot be transferred into normal, histocompatible animals without an appropriate non-MHC linked genetic background was a strong indication that detailed studies of thyroid-associated factors may be warranted for the elucidation of the pathogenesis of this disease and perhaps also its human counterpart, Hashimoto thyroiditis. Since several reviews on the immunologic aspects in the OS model have been published in recent years we have in this communication attempted to discuss the - mostly still rudimentary - findings concerning the target organ itself, including morphological changes before the beginning of infiltration, the analysis of Tg, the altered thyroid function before onset of SAT, the results of cross-breeding studies of OS and inbred normal chickens in respect to the susceptibility of the offspring for the transfer of SAT, the possible role of a virus infection and the aberrant expression of MHC class II antigens on TEC. Cross-breeding studies revealed that most probably a single gene is responsible for the primary altered thyroid function and at least 3 genes code for the susceptibility of the OS thyroid gland to the autoimmune attack. It is not yet clear for which of the above-mentioned observations each of these genes is responsible and what is/are the initial triggering mechanism(s). Ongoing studies in our laboratory concentrate on this question, specifically the potential role of endogenous viruses in this process.
Asunto(s)
Pollos/inmunología , Glándula Tiroides/inmunología , Tiroiditis Autoinmune/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Autoanticuerpos/inmunología , Pollos/genética , Epitelio/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Obesidad/complicaciones , Obesidad/genética , Tiroglobulina/inmunología , Tiroiditis Autoinmune/genéticaRESUMEN
Clinical studies have suggested that excess dietary iodine promotes autoimmune thyroiditis; however, the lack of a suitable animal model has hampered investigation of the phenomenon. In this study, different amounts of potassium iodide were added to the diets of chicken strains known to be genetically susceptible to autoimmune thyroiditis. Administration of iodine during the first 10 weeks of life increased the incidence of the disease, as determined by histology and the measurement of autoantibodies to triiodothyronine, thyroxine, and thyroglobulin. Further support for the relation between iodine and autoimmune thyroiditis was provided by an experiment in which iodine-deficient regimens decreased the incidence of thyroid autoantibodies in a highly susceptible strain. These results suggest that excessive consumption of iodine in the United States may be responsible for the increased incidence of autoimmune thyroiditis.
Asunto(s)
Autoanticuerpos/análisis , Enfermedades Autoinmunes/inducido químicamente , Yodo/efectos adversos , Tiroiditis/inmunología , Animales , Pollos , Dieta , Linfocitos/inmunología , Glándula Tiroides/inmunologíaRESUMEN
Lymphocytes were isolated from the infiltrated thyroid glands of 2- to 5-wk-old Obese strain (OS) chickens with spontaneous autoimmune thyroiditis (SAT). Immunofluorescence analysis performed by using a panel of monoclonal and polyclonal antibodies revealed that 60% of thyroid infiltrating leukocytes (TIL) were mature T cells, a large portion of which seemed to be in an activated state bearing Ia-like antigens (10%) as well as a surface determinant associated with T cell activation (16%), i.e., possibly the receptor for interleukin 2 (IL 2). Furthermore, a relatively high plasma cell content (5%) was observed. TIL exhibited high proliferative responses to T cell mitogens (concanavalin A, phytohemagglutinin) and IL 2, but only weak responses to the B cell mitogen LPS from Salmonella typhimurium. When injected into newly hatched, MHC-identical, irradiated normal chickens, TIL induced both the production of autoantibodies and thyroid infiltration. Peripheral lymphocytes from spleen and blood and thymocytes from the same OS donors had no effect. Analysis of chemically (cyclophosphamide) bursectomized OS chickens suggested that an intact B cell system was not obligatory for the induction of SAT. TIL from these chickens consisted of 77% T cells and less than 1% B lymphocytes, yet were capable of inducing severe thyroid infiltration upon transfer into normal recipients. These findings emphasize the importance of the T cell system in the initiation of SAT.