Impaired hypothalamic-pituitary-adrenal axis activity in patients with multiple sclerosis.

OBJECTIVE: To investigate hypothalamic-pituitary-adrenal axis activity in well-defined multiple sclerosis (MS) patient subgroups. METHODS: A total of 173 patients with clinically definite MS were studied: 40 with primary progressive, 41 with secondary progressive, 58 with relapsing-remitting in remission, and 34 with relapsing-remitting during acute relapse. Sixty healthy subjects served as controls. No patients were receiving steroid or other immunomodulatory therapy. Plasma cortisol, adrenocorticotropic hormone (ACTH), and dehydroepiandrosterone sulfate (DHEAS), as well as urine cortisol levels, were measured using commercial radioimmunoassays. Glucocorticoid receptor (GR)-binding assay in peripheral blood mononuclear cells (PBMCs) was performed using [(3)H]dexamethasone (Dex). PBMC production of the proinflammatory peptide corticotrophin-releasing hormone (CRH), interleukin (IL)-1beta, IL-6, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha was evaluated using enzyme-linked immunosorbent spot assay. RESULTS: All four groups of patients displayed significantly higher cortisol, ACTH, and DHEAS plasma concentrations and urine cortisol values than controls. Although 62% of MS patients did not suppress Dex, suppression test results did not correlate with IL-1beta, IL-6, IFN-gamma, or TNF-alpha production. GR-binding assays showed no differences in binding sites between patients and controls; however, all MS groups showed decreased GR affinity and sensitivity compared with controls. The numbers of IL-1beta-, IL-6-, and TNF-alpha-secreting cells increased significantly in relapsing-remitting MS patients only during exacerbations; in contrast, IFN-gamma-secreting cells increased during both exacerbations and remission. Finally, PBMC CRH-secreting cell numbers were considerably greater in all forms of MS. CONCLUSIONS: Patients with multiple sclerosis show hypothalamic-pituitary-adrenal axis hyperactivity, with lymphocytes expressing similar glucocorticoid receptor numbers to controls; however, binding affinity and glucocorticoid sensitivity of these lymphocytes seem to be reduced.

Brain alterations in autoimmune and pharmacological models of diabetes mellitus: focus on hypothalamic-pituitary-adrenocortical axis disturbances.

Type 1 diabetes (T1D) is linked to an 'encephalopathy' explained by some features common to the aging process, degenerative and functional disorders of the central nervous system. In the present study we describe a manifest hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in two different experimental mouse models of T1D including the pharmacological one induced by streptozotocin and the spontaneous NOD (nonobese diabetic mice). The high expression of hypothalamic hormones like oxytocin and vasopressin were part to this alteration, together with elevated adrenal glucocorticoids and prominent susceptibility to stress. In the hippocampus of diabetic animals a marked astrogliosis, often associated with neural damage, was present. Dentate gyrus neurogenesis was also affected by the disease: proliferation and differentiation measured by bromodeoxyuridine immunodetection were significantly reduced in both experimental models used. Several facts, including changes associated with chronic hyperglycemia, hyperstimulation of the HPA axis, increased levels of circulating glucocorticoids in combination with brain inflammation and low production of new neurons, contribute to emphasize the impact of diabetes on the central nervous system.

Immune-endocrine interactions in autoimmune thyroid diseases.

Autoimmune thyroid diseases (AITD) are the most common organ-specific autoimmune disorders affecting approximately 5% of the overall population. An aberrant interaction between abnormal thyrocytes, abnormal antigen-presenting cells and abnormal T cells forms the basis for the atypical autoimmune reaction targeting thyroid antigens. It was proposed that nongenetic (environmental and hormonal) factors play a crucial etiological role in AITD development, through altering immune-endocrine interactions. The most outstanding fact is that in genetically predisposed individuals, the disruption of these neuroendocrine-immune interactions by environmental factors results in thyroid autoimmune dysfunction. These interactions are able to incline the balance between Th1-Th2 immune response toward one side, resulting in a Th1-cell-mediated autoimmune reaction with thyrocyte destruction and hypothyroidism in Hashimoto's thyroiditis but to a hyperreactive Th2-mediated humoral response against TSH receptor with stimulatory antibodies leading to Graves' disease hyperthyroidism. In this review the main mechanisms involved are summarized. In this sense, the participation of stress-mediated activation of the sympathoadrenal system and hypothalamic-pituitary-adrenal axis, the hormonal changes occurring during pregnancy and postpartum acting on antigen-presenting cells and influencing, in this way, the balance of the immune status are shown to participate in AITD etiology. The possibility that altered levels of thyroid hormones during the course of the AITD may alter immune function is also discussed.

Impaired immune responses in tuberculosis patients are related to weight loss that coexists with an immunoendocrine imbalance.

The study's objective was to examine whether factors related to the host status may bear some relation with the profile of the immune response displayed by tuberculosis (TB) patients. The in vitro immune response (antigen-driven lymphoproliferation and cytokine production) and the presence of alcoholism or disease-related factors, like heart and respiratory rates, and weight loss (body mass index, BMI) were investigated in 31 males with active, untreated TB. Compared to 16 age-matched healthy males, TB patients presented depressed lymphoproliferation and increased IL-10 and TGF-beta production. Multivariate analysis indicated that most differences were no longer significant when controlling for the BMI. Immune and endocrine changes coexisting with weight loss, such as circulating levels of TNF-alpha, IFN-gamma, IL-6, cortisol, dehydroepiandrosterone and thyroid hormones, were also analyzed. While pairwise correlations between serum levels of IFN-gamma, T3 or T4 and BMI were not significant, BMI was negatively correlated with IL-6 levels (p < 0.025). In turn, levels of IL-6 correlated positively with cortisol concentrations (p <0.001). Stepwise regression analysis demonstrated that BMI was only associated with IL-6 (r = -0.423, R(2) = 0.18), with the difference remaining significant following adjustment for the other variables. As regards IL-6, BMI, cortisol and IFN-gamma could explain 74% of variability in IL-6 concentrations (R(2) = 0.74). No evidence for effect modification was shown when performing adjusted calculations. To conclude, the relation between weight loss and abnormal immune response of TB patients is partly associated with the immunoendocrine imbalance observed in parallel.

Involvement of C4 allotypes in the pathogenesis of human diseases.

The complement system is an important humoral defense mechanism that plays a relevant role against microbial agents, inflammatory response control, and immunocomplex clearance. Classical complement pathway activation is antibody-dependent. The C4 component participates in the initial step of activation, and C4 expression is determined by 2 pairs of allotypes: C4A and C4B. Deficiencies in C4 allotypes have been associated with several diseases. The aim of the present review is evaluate the reported data in the literature regarding specific C4A and C4B deficiencies and characterize their clinical relevance. We searched the MEDLINE and LILACS databases. Papers referring to total C4 deficiency without allotype evaluation and case reports of primary C4 deficiency were not included. Deficiencies in C4 allotypes have been associated with Mycobacterium leprae infection, erythema nodosum, systemic sclerosis with anti-topoisomerase I antibodies, intermediate congenital adrenal hyperplasia with DR5 genotype, diabetes mellitus type 1 with DR3,4 genotype, and diabetes mellitus with antibodies against islet cells. C4 allotype deficiency is also related to C4B deficiency and autoimmune-associated diseases, such as systemic lupus erythematosus, or diseases with an autoimmune component, such as autism. Some reports associate C4A with thyroiditis after delivery as well as limited and systemic sclerosis without anti-topoisomerase I antibodies. However, the studies with C4A and C4B have been concentrated in isolated populations, and some of the studies could not be reproduced by other authors.

Involvement of C4 allotypes in the pathogenesis of human diseases

O sistema complemento constitui um importante sistema de defesa humoral, exercendo papel relevante na resposta contra agentes microbianos, no controle da resposta inflamatória e na depuração de imunocomplexos. A ativação da via clássica é dependente da formação do complexo antígeno-anticorpo. O componente C4 do complemento participa da etapa inicial de ativação desta via e a sua expressão é determinada por dois alótipos : C4A e C4B. A deficiência dos alótipos de C4 tem sido relacionada a várias doenças. O objetivo do presente estudo foi avaliar os dados de literatura que descrevem as deficiências específicas de C4A e C4B com a finalidade de caracterizar seu significado clínico. Foi realizada uma ampla revisão bibliográfica através do MEDLINE e LILACS, avaliando-se os dados de literatura. Excluiu-se estudos com a avaliação de C4 total sem a análise dos alótipos e relatos de caso isolados de deficiência total de C4. Verificou-se que a deficiência dos alótipos de C4 está relacionada com algumas doenças: hanseníase, esclerose sistêmica com anticorpos anti-topoisomerase I, hiperplasia adrenal congênita intermediária com genótipo DR5, diabetes mellitus tipo 1 com genótipo DR3,4 e diabetes mellitus tipo 1 com anticorpos anti-células das ilhotas. Também foram observadas algumas associações entre C4B e doenças auto-imunes como lupus eritematoso sistêmico, ou que se supõe terem um componente autoûimune como o autismo. Estudos demonstraram associações do C4A com tireoidite pós-parto, esclerose limitada e esclerose sistêmica sem anticorpos anti-topoisomerase I. Porém, os estudos dos alótipos de C4 se concentraram em populações isoladas e alguns destes não conseguiram ser reproduzidos por outros autores.

Autoantibodies against recombinant human steroidogenic enzymes 21-hydroxylase, side-chain cleavage and 17alpha-hydroxylase in Addison's disease and autoimmune polyendocrine syndrome type III.

OBJECTIVE: To evaluate the frequency of autoantibodies (Ab) against 21 hydroxylase (21OH), side-chain cleavage (SCC) and 17alpha-hydroxylase (17OH), in Addison's disease (AD) and autoimmune polyendocrine syndrome type III (APSIII). DESIGN AND METHODS: We used radiobinding assays and in vitro translated recombinant human (35)S-21OH, (35)S-SCC or (35)S-17OH and studied serum samples from 29 AD (18 idiopathic, 11 granulomatous) and 18 APSIII (autoimmune thyroid disease plus type 1 diabetes mellitus, without AD) patients. Results were compared with those of adrenocortical autoantibodies obtained with indirect immunofluorescence (ACA-IIF). RESULTS: ACA-IIF were detected in 15/18 (83%) idiopathic and in 1/11 (9%) granulomatous AD subjects. 21OHAb were found in 14/18 (78%) idiopathic and in the same (9%) granulomatous AD subject. A significant positive correlation was shown between ACA-IIF and 21OHAb levels (r(2)=0.56, P<0.02). The concordance rate between the two assays was 83% (24/29) in AD patients. SCCAb were found in 5/18 (28%) idiopathic (4 of whom were also positive for 21OHAb) and in the same (9%) granulomatous AD subject. 17OHAb were found in only 2/18 (11%) idiopathic and none of the granulomatous AD patients. Two APSIII patients were positive for ACA-IIF, but only one was positive for 21OHAb and SCCAb. 17OHAb were found in another two APSIII patients. CONCLUSIONS: Measurement of 21OHAb should be the first step in immune assessment of patients with AD and individuals at risk for adrenal autoimmunity, in addition to ACA-IIF. Due to their low prevalence in AD, measurement of SCCAb and 17OHAb should be indicated only for 21OHAb negative patients and/or for those with premature ovarian failure, regardless of ACA-IIF results.

[Autoimmune polyglandular syndrome. Clinical experience in 21 cases]. / Síndrome poliglandular autoinmune. Experiencia clínica en 21 casos.

The autoimmune polyglandular syndrome is characterized by the association of 2 or more endocrine disorders of autoimmune origin which may coexist with autoimmune disorders in other organs. Roughly 25% of patients with an autoimmune endocrinopathy show evidence of autoimmune disease elsewhere. We report 21 patients with autoimmune polyglandular syndrome classified according to Neufeld.

Imunologia e doenças endócrinas: conceitos atuais / Immunology and endocrine diseases: actual concepts

Os autores fazem uma síntese dos mecanismos imunitários e sua relaçäo com as endocrinopatias

Organ-specific autoantibodies in children with common endocrine diseases.

Sera from 438 children were examined for autoantibodies to thyroid microsomes, thyroglobulin, pancreatic islet cells, gastric parietal cells, and adrenocortical cells by indirect hemagglutination and immunofluorescence techniques. A modification of the indirect hemagglutination technique allowed specific detection of low titers of antithyroidal antibodies. The subjects included a control group (117) with no known autoimmune disease, and children with disorders of the thyroid (88), insulin-dependent diabetes mellitus (201), Turner's Syndrome (24), and Addison disease (8). A subject's age at the time of disease onset and the race and sex were correlated with the prevalence of autoantibodies. The coincidence of autoantibodies to components of the thyroid with autoantibodies to gastric parietal cells was increased in children with disorders of the thyroid (94%, 18/19) over that observed in diabetes (29%, 4/14), Turner syndrome (0%), or Addison disease (0%), perhaps indicating different genetic propensities for the development of parietal cell antibodies in these groups. Islet cell antibodies were not found in subjects with Turner syndrome, nor were they more prevalent in white or black subjects with diabetes. The incidence of organ-specific autoantibodies in individuals without overt clinical disease may reflect an altered immunologic state that will lead eventually to autoimmune disease. Islet cell antibodies decline in prevalence in diabetes, whereas thyroid antibodies in disorders of the thyroid do not; this may reflect differences in the pathogenesis of these common autoimmune endocrine disorders in children.

Inmunología y trastornos endocrinos / Immunology and endocrine disorders

Se revisan los distintos tipos de reacciones inmunológicas, así como su participación en la génesis de algunas enfermedades endocrinas tales como: bocio tóxico difuso, enfermedad de Hashimoto, insuficiencia adrenal crónica, hipofisitis, diabetes mellitus, etc. La repercusión o acción del sistema endocrino sobre la respuesta inmunológica puede producirse por: a) sus acciones sobre el sistema inmunitario como tal; b) su influencia sobre las reacciones alérgicas o inmunológicas secundarias a la administración de hormonas (AU)

LATS activity, pretibial myxoedema and thyroid actopachy - abstract

Thyroid acropachy is one of the more odd manifestaions of an endocrine disorder and is the last and rarest part of a syndrome comprising hyperthyroidism, exophthalmos and pretibial myxeodema, usually arising in that order. It is estimated that it occurs in 1 percent of patients with graves' disease and Melkinson (1963) could find only 26 authentic cases in the literature. Two cases of hyperthroidism and localized myxoedema are presented. In case I the mild degree of localized myxoedema disappeared with medical treatment of the hyperthyroidism. In case II thyroid acropachy. The McKenzie mouse bioassay for the long-acting thyroid stimulator (LATS) performed 3 years post thyroidectomy showed a moderately high LATS. This is in keeping with the observation that patients who develop pretibial myxoedema frequently have very high LATS levels. In contrast there is disagreement about the possible association between LATS and the eye signs of thyrotoxicosis (AU)