Polyendocrine Disease Research Articles

Cystic fibrosis being a polyendocrine disease (Review)

Ген CFTR (cystic fibrosis transmembrane regulator) кодирует синтез одноименного белка, который функционирует как прямой активатор анионного транспорта. Cl– является наиболее распространенным анионом, в качестве антагониста катионов натрия и калия обеспечивает электронейтральность клеточных мембран в покое, вместе с катионами служит важным осмолитом и формирует поток воды через клеточные мембраны для трансэпителиальной секреции. Железистые клетки при муковисцидозе (МВ) задерживают Cl– и Na+, а выделяемый ими секрет отличается чрезмерной вязкостью. Субнормальная активность CFTR приводит к застою мукоцилиарного клиренса, торможению кишечного транспорта.Помимо экзокринных нарушений, мутации CFTR ассоциируются с уменьшением объема, массы, усилением апоптоза β-клеток поджелудочной железы, значительным подавлением экзоцитоза инсулина в ответ на стимуляцию глюкозой и глюкагоноподобным пептидом-1, гиперглюкагонемией на фоне дефекта подавления инсулином функции α-клеток, но снижением максимальной емкости α-клеток.Дефицит и прогрессирующее снижение минеральной плотности костной ткани являются ожидаемыми вторичными проявлениями МВ ввиду панкреатической экзокринной недостаточности с мальабсорбцией питательных веществ и жирорастворимых витаминов. Но у пациентов с мутацией F508del установлены значимое уменьшение синтеза в остеобластической формации OPG, COX-2, PGE2, повышение активности антианаболического NF-kB. Речь идет о дефекте канонического сигнального пути (Wnt/β-катенин), который регулирует экспрессию генов-активаторов остеобластогенеза, разобщении этапности физиологического костного ремоделирования.Помимо врожденной двусторонней или односторонней аплазии семявыносящих протоков, увеличение частоты мутаций CFTR также обнаруживается при необструктивной азооспермии, олиго-, астено- и тератоспермии. CFTR участвует во входе HCO3– в клетки Сертоли для запуска cAMP-зависимой транскрипции, и его дефекты приводят к подавлению ФСГ-зависимой экспрессии генов сперматогенеза, потере последовательности в каскаде Wnt, разрушению зависимого от PGE2 трансэпителиального взаимодействия и, как следствие, гематотестикулярного барьера.МВ характеризуется, наряду с классическими признаками, эндокринной дисфункцией поджелудочной железы, остеопорозом с подавлением остеобластогенеза, дефектом сперматогенеза.

Lymphocytic Adenohypophysitis and Adrenalitis in a Dog With Adrenal and Thyroid Atrophy

A 4.5-year-old spayed female Great Pyrenees with hypothyroidism and hypoadrenocorticism had a slightly enlarged pituitary gland and bilaterally atrophic adrenal and thyroid glands. Lymphocytic adenohypophysitis and adrenalitis were found in which B lymphocytes and plasma cells dominated the adenohypophysitis but T cells dominated the adrenalitis. The thyroid gland had extensive follicular atrophy and collapse. The combination of primary hypothyroidism and hypoadrenocorticism resembles type II autoimmune polyendocrine syndrome or Schmidt syndrome in humans. Adenohypophysitis is rare in dogs and not reported in polyendocrine disease in animals.

Human B Cells Secreting Immunoglobulin G to Glutamic Acid Decarboxylase-65 from a Nondiabetic Patient with Multiple Autoantibodies and Graves’ Disease: A Comparison with Those Present in Type 1 Diabetes1

Antibodies to glutamic acid decarboxylase-65 (GAD65) are present in a number of autoimmune disorders, such as insulin-dependent (type 1) diabetes mellitus (IDDM), stiff man syndrome, and polyendocrine autoimmune disease. Antibodies to GAD in IDDM patients usually recognize conformation-dependent regions on GAD65 and rarely bind to the second isoform, glutamic acid decarboxylase-67 (GAD67). In contrast, those present in stiff man syndrome and polyendocrine disease commonly target the second isoform (GAD67) and include antibodies that are less dependent on the conformation of the molecule. By immortalizing peripheral blood B cells with Epstein-Barr virus, we have generated three human IgG autoantibodies, termed b35, b78, and b96, to GAD65 from one patient with multiple autoantibodies to endocrine organs and Graves' disease. All three autoantibodies are of the IgG1 isotype, with islet cell activity, and do not react with GAD67. The regions on GAD65 recognized by the three autoantibodies have been investigated by immunoprecipitation with a series of chimeras, by binding to denatured and reduced antigens, and using protein footprinting techniques. Using chimeric GAD proteins, we have shown that b35 targets the IDDM-E1 region of GAD65 (amino acids 240-435) whereas both b78 and b96 target the IDDM-E2 region of GAD65 (amino acids 451-570). Furthermore, examination of binding to recombinant GAD65 and GAD67 by Western blotting revealed some differences in epitope recognition, where only b78 bound denatured and reduced GAD65. However, b35, b78, and b96 autoantibodies had different footprinting patterns after trypsin treatment of immune complexes with GAD65, again indicating different epitope recognition. Our results indicate that antibodies to GAD65 present in nondiabetic patients with multiple autoantibodies to endocrine organs show similarities to those in IDDM (by targeting IDDM-E1 and IDDM-E2 regions of GAD65) as well as subtle differences in epitope recognition (such as binding to denatured and reduced GAD65 and by protein footprinting). Thus, the GAD65 epitopes recognized by autoantibodies in different autoimmune diseases may overlap and be more heterogeneous than previously recognized.

Glutamate Decarboxylase–Reactive Peripheral Blood Lymphocytes From Patients With IDDM Express Gut-Specific Homing Receptor α4β7-Integrin

Migration of lymphocytes to the pancreas is a prerequisite for insulitis in IDDM. Mucosal vascular addressin (MAdCAM-1), involved in the recirculation of lymphocytes to the gut, has been found in the inflamed islets in NOD mice. In humans, triggers of the gut immune system (e.g., early exposure to cow's milk proteins in infancy, exposure to enteroviral infections) have been associated with IDDM. To study the possible link between the gut immune system and IDDM, we tested the expression of the alpha4beta7-integrin, a homing receptor for MAdCAM-1, on GAD65-reactive lymphocytes. Using immunomagnetic cell sorting, we depleted the lymphocytes with high expression of alpha4beta7-integrin in the peripheral blood mononuclear cell population from IDDM patients and patients with autoimmune polyendocrine disease type 1 (APD-I). The depletion led to a marked decrease (mean 70%) in the cellular response against GAD65 in three of six IDDM patients and in one subject at high risk for IDDM. A decrease of 37% in the GAD response was observed after depletion in the case of one APD-I patient who also had IDDM. Cellular response to tetanus toxoid increased in the majority of patients as well as in three control subjects studied. We demonstrated that a remarkable population of islet cell antigen-reactive lymphocytes express the gut-specific homing receptor, which emphasizes the role of gut immunity in IDDM. The manipulation of the gut immune system is therefore proposed as a tool for modulation of the autoimmunity against pancreatic beta-cells in IDDM.

Slow metabolic deterioration towards diabetes in islet cell antibody positive patients with autoimmune polyendocrine disease

Slow metabolic deterioration towards diabetes in islet cell antibody positive patients with autoimmune polyendocrine disease

Slow metabolic deterioration towards diabetes in islet cell antibody positive patients with autoimmune polyendocrine disease.

We studied metabolic progression to IDDM in a cohort of adults who are ICA-positive and have associated autoimmune endocrine disease or circulating organ-specific autoantibodies (the Polyendocrine Study). Of the 186 individuals recruited 27 developed overt diabetes after a median follow-up of 4.5 years (range 0.4-12). Of these, eight patients did not require insulin treatment until at least 6 months after clinical diagnosis, with an interval of 1.8 years (1.2-5.7). An IVGTT was performed in 38 subjects and 23 had sequential studies. Of the initial 38 subjects six developed diabetes and only three showed a loss of FPIR to glucose (below the first percentile of a normal control group) before clinical onset of the disease. An additional three subjects showed a loss of the FPIR, and all still have normal glucose tolerance after median follow-up of 28 months (22-95). A "whole" or "mixed" pattern of islet cell staining was found in five of the six patients who developed diabetes and antibodies against an islet 37 k-antigen were detectable in four patients, all of whom required insulin soon after diagnosis. A beta-cell "selective" ICA staining pattern was seen in 14 of 17 subjects who did not develop diabetes and the "mixed" pattern in only three. None of this group had detectable 37 k-antibodies. We conclude that metabolic deterioration is slow in polyendocrine patients, and that the IVGTT has less prognostic significance in this group than in first degree relatives of patients with IDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Virus-induced thyroiditis.

Mice infected with reovirus type 1 developed a mild thyroiditis characterized by focal destruction of acinar tissue, infiltration of inflammatory cells, and autoantibodies to thyroglobulin and microsomal antigens. Thyroid involvement appears to be part of a more generalized virus-induced polyendocrine disease.

Multiple organ-reactive monoclonal autoantibodies.

Autoantibodies directed against a wide range of normal tissue antigens have been found in the sera of patients with autoimmune diseases. It is generally thought that different and specific autoantibodies react with different tissues but the possibility exists that some autoantibodies may react with common antigens found in different tissues and organs. Recently, we showed that mice infected with reovirus developed a polyendocrine disease with autoantibodies to the pancreas, anterior pituitary, thymus and gastric mucosa. Using hybridoma technology, we obtained a number of monoclonal autoantibodies which reacted with antigens in single organs. We now report the production and pattern of reactivity of seven multiple organ-reactive monoclonal autoantibodies. By using antibody-affinity columns, autoantigens also have been isolated and their molecular weights determined. The results suggest that monoclonal multiple organ-reactive autoantibodies react either with the same molecule present in several organs or with common antigenic determinants on different molecules in multiple organs. In either case, the existence of multiple organ-reactive antibodies may be a partial explanation for multiple organ autoimmunity.

Virus-induced autoimmunity: monoclonal antibodies that react with endocrine tissues.

Mice infected with reovirus type 1 develop an autoimmune polyendocrine disease. Spleen cells from these mice were fused with myeloma cells and the culture fluids were screened by indirect immunofluorescence for autoantibodies reactive with normal mouse tissues. A large panel of cloned, stable antibody-producing hybridomas has been obtained. Fourteen of the hybridomas make autoantibodies that react with cells in the islets of Langerhans, 24 with cells in the anterior pituitary, 11 with cells in gastric mucosa, and 5 with nuclei. Except for the antibodies to nuclei, the monoclonal autoantibodies are organ-specific. Some, however, show broad cross-species reactivity, recognizing similar antigenic determinants in mouse, rat, pig, and human organs, whereas other recognize determinants only in rodent tissues. Several of the antigens recognized by these monoclonal autoantibodies have been identified as hormones (for example, glucagon, growth hormone, and insulin).

Virus-induced diabetes mellitus: autoimmunity and polyendocrine disease prevented by immunosuppression.

Autoantibodies to cytoplasmic and surface antigens on pancreatic islet cells have been found in many newly diagnosed cases of insulin-dependent diabetes mellitus (IDDM)1–9. Various autoantibodies (for example, against islet cells, adrenals, thyroid, gastric mucosa and intrinsic factor) have also been found in patients with polyendocrine disease1,2,8,9. What triggers the production of these antibodies and their importance in the pathogenesis of these diseases are still unclear. Recently, we found in an animal model for studing polyendocrine disease10 that reovirus type 1 (reo-1) infected cells in both the pancreas and pituitary, and produced a disease characterized by hyperglycaemia and retarded growth10. Moreover, autoantibodies that reacted with antigens in pancreatic islets, the anterior pituitary and gastric mucosa were found, one of which reacted with insulin and another with growth hormone (GH). Using recombinant viruses11 we showed that the S1 gene segment from reo-1 was required for the induction of auto-antibodies to GH. We report here our search for additional autoantibodies, especially against surface antigens, and our efforts to evaluate the pathological contributions of the lytic effect of the virus on cells compared with the immunopathological response of the host. Our experiments showed that reo-1 induced autoantibodies that reacted with antigens on the surface of islet cells, thymocytes and a GH-producing cell line. In addition, we found that treatment with immunosuppressive agents depressed autoantibody production and prevented development of the polyendocrine disease.

THE EFFECT OF CORTICOTROPIN ON THE ANTRAL PHASE OF GASTRIC SECRETION.

IN RECENT YEARS there has been increasing interest in the hormonal aspects of peptic ulcer. Numerous reports of peptic ulcer associated with polyendocrine disease have appeared in the literature. 1,2 In addition, the availability of various purified hormones for administration to patients has been accompanied by case reports of peptic ulcer reactivation or formation during their administration. The hormones most frequently associated with peptic ulceration are cortisone and corticotropin. Since these hormones are available in a pure state, it is possible to determine their effect on various body functions in both the experimental animal and the patient. Case reports of peptic ulcer formation in patients receiving corticotropin or cortisone would seem to support the concept that stress and anxiety play an important role in the development of acute and chronic peptic ulcers. 3-5 The exact mechanisms that are responsible for this relationship are poorly understood. Whether the peptic ulcers