- Spring Song.
- The Embodied Mind: Cognitive Science and Human Experience.
- Poetry into song : performance and analysis of lieder;
Those patients with multiple autoantibodies are at increased risk for developing a second disease 3. These proteins are autoimmune targets, the expression of which had been believed to be limited to pancreatic islet cells.
Subsequently, many tissue-specific proteins have been detected in multiple peripheral organs. Initially, epithelial cells in the thymus were shown to express self-antigens, providing an attractive mechanism for establishing central immune tolerance to these proteins through a process known as thymic education More recent studies have disclosed autoantigen expression in extrathymic cells residing in the spleen and lymph nodes These ground-breaking discoveries have now prompted a wider scope of inquiry into the broader expression of proteins previously thought to be tightly restricted.
They support immune function by presenting antigens, providing second signals to lymphocytes, and producing a wide array of cytokines in response to inflammatory cues 16 — In experimental animals, fibrocytes are recruited to areas of injury, such as in models of lung fibrosis in which they serve as precursor cells They exhibit substantial plasticity and as cultured cells can terminally differentiate into adipocytes and myofibroblasts, depending on the molecular cues they receive from their environment Very recently we reported that circulating fibrocytes cultivated from the peripheral circulation become overabundant in Graves' disease GD , and infiltrate the orbit and thyroid 23 , Unexpectedly, fibrocytes from healthy donors and those with GD were found to express two functional thyroid-specific proteins, namely the thyrotropin receptor TSHR 23 and thyroglobulin Tg This expression derives from moderately abundant steady-state levels of their respective transcripts.
These two proteins continue to represent leading candidate autoantigens involved in thyroid autoimmunity, including GD and Hashimoto's thyroiditis. Thus, fibrocytes might participate directly in the immunological reactions associated with these diseases. Their respective transcripts are detectable in fibrocytes cultivated from peripheral blood of healthy donors and those with T1DM, multiple sclerosis MS , and GD.
Expression of these antigens is the consequence of activity in fibrocytes of the respective gene promoters.
Autoimmune Addison disease: pathophysiology and genetic complexity
Our identification of promiscuous islet-specific protein expression in fibrocytes suggests that these cells may play a role in multiple autoimmune endocrine diseases. DMEM containing 4. The gene promoter construct for IA-2 was generously provided by Dr A. Wild-type and mutant ICA69 gene promoter constructs were cloned as reported previously Five individuals with GD donated orbital fibroblasts, whereas two healthy individuals provided dermal fibroblasts and two donated orbital fibroblasts. Surgical waste from which orbital fibroblasts were cultivated was obtained during orbital decompressions for severe thyroid-associated ophthalmopathy TAO or from healthy tissues removed during cosmetic surgery.
Culture strains were used between the fifth and 12th passages, an interval during which cell phenotypes remain constant 28 , The medium was changed every 4 days. Human fibrocytes were isolated from peripheral blood by Ficoll density centrifugation as described Established NMB7, a brain-derived cell line 27 , was cultured to near confluence in the same medium. Each sample was analyzed in triplicate with glyceraldehydephosphate dehydrogenase GAPDH used as the reference control. After washes these filters were then incubated with antirabbit IgG-horseradish peroxidase Amersham or antigoat IgG-horseradish peroxidase Santa Cruz Biotechnology both dilution , respectively.
Constructs containing and bp fragments of the ICA69 and IA-2 gene promoters, respectively, were transiently transfected into fibrocytes using Lipofectamine according to a protocol provided by the supplier Invitrogen; catalog number — and as published previously Twenty hours after transfection, cells were harvested and subjected to the dual-luciferase reporter assay Promega. All transfection assays were performed in triplicate and repeated at least three times. Lumicount data were normalized to their Renilla transfection controls. Fibrocyte transfections used Amaxa nucleofection Technology Amaxa, Koeln using program U23 as described Cells were then recultured for 48 hours before triplicate samples were subjected to the luciferase assay.
Results were normalized to cellular protein content. Cell sorting was performed as previously described Sorted cells were recultured for 48 hours before harvest and RNA extraction. Significance was determined with a two-tailed Student's t test. Migration of both proteins resembles that of their respective recombinant controls. Thus, fibrocytes express not only antigens associated with thyroid autoimmunity 24 but also two proteins usually associated with pancreatic islet cells and neuroepithelium that have been implicated in T1DM 4 , 6 , 32 — In contrast, glutamate decarboxylase 65 and insulin were undetectable data not shown.
We next examined fibrocytes for their expression of the transcripts encoding these two pancreatic proteins by real-time PCR. As the data in Figure 2 A indicate, ICA69 mRNA was detectable in all 26 fibrocyte strains tested but was undetectable in any of the fibroblasts, regardless of the health status of the donor or anatomic location from which they derived. Moreover, levels were considerably lower than those of ICA Surprisingly, it could be detected in two orbital fibroblast strains from donors with GD as well as dermal fibroblasts from two healthy donors.
It should be noted that human pancreatic tissue expressed approximately fold higher levels of these transcripts than did any of the isolated, cultured cells examined.
Growth Hormone Deficiency in Autoimmune Pituitary Disorders – touchENDOCRINOLOGY
As Figure 3 demonstrates, all fibrocyte strains, regardless of the health status of the donor, exhibited at least a low-level expression of both transcripts. Thus, it would appear that fibrocytes express autoantigens associated with multiple endocrine diseases, regardless of the state of health of the donor. We next transfected fragments of the respective gene promoters that had been fused to luciferase reporters into fibrocytes and NMB7 cells.
The activity is approximately 4-fold greater than that of the empty vector control.
kb.crosspoint.es/roman-empresses.php Fibrocyte cultures were transfected with plasmid containing empty reporter or one fused with the respective constructs, as described in Materials and Methods. From the results thus far obtained, it appears that ICA69 expression is more frequently detected in fibrocytes, whereas IA-2 is detected more consistently in fibroblasts Figures 2. Therefore, we interrogated these cells by subjecting them to sorting into pure subsets based on the display of CD Data from all experiments performed with sorted fibroblasts appear in Supplemental Table 2. Right panel, Cytometric sorting results in two pure populations.
Results shown are representative of four separate experiments. The basis for implicating these antibodies in that disease derives from their frequent detection in newly diagnosed patients and their first-degree relatives 7 , 35 — T suppressor cells regulate the immune responses; when immune tolerance is lost, autoaggression occurs. These T cells regulate autoaggressive T and B cells and may have profound influence on the control of human autoimmune diseases Modified according to Ref. Animal models of the immunopathogenesis of PAS are consistent with a viral infection theory as well as a suppressor effect theory.
The viral infection-theory couples autoimmune disease with viral infection. The so-called molecular mimicry is characterized by an immune response to an environmental agent that cross-reacts with a host antigen, resulting in disease. In an animal model, mice infected with reovirus type 1 developed an autoimmune polyendocrinopathy Some of the resultant autoantibodies showed cross-species reactivity, recognizing similar antigenic determinants in mouse and human organs Thymectomy conserved the T cell defect and produced autoimmune diseases in a wide spectrum of organs i. These pathological processes lead to the preclinical phase of PAS, with production of organ-specific antibodies and progressive immune-mediated destruction of endocrine tissues.
In the clinical phase, major organ destruction occurs due to the autoimmune activity that is primarily characterized by chronic inflammatory infiltration of lymphocytes Destruction of endocrine glands causes their secretory insufficiency. The role of apoptosis in immunodestruction has been associated with dysregulation of apoptotic signaling pathways. Dysfunction of the Fas apoptotic pathway or production of soluble factors including soluble Fas and soluble Fas ligand may be involved in the pathogenesis of endocrine diseases.
The clinical presentation of PAS component diseases is often preceded by an asymptomatic latent period of months or years characterized by the presence of circulating disease-associated antibodies. Autoantibodies are useful markers for the prediction of the development of PAS. The absence of these antibodies does not exclude the disease, because not all patients show positive antibodies. The present long-term follow-up data emphasize that the detection of these antibodies facilitates early diagnosis of autoimmune endocrine disorders.
In view of the possibly long time interval between the manifestation of the first and further autoimmune endocrinopathies, regular and long-term observation of patients with endocrine autoimmune disorders seems necessary. For patients with monoglandular autoimmune endocrinopathy, functional screening for PAS is recommended every 3 yr until the age of 75 yr. If pathological findings, e. Furthermore, functional screening for autoimmune endocrine diseases of the first-degree relatives of these patients with newly diagnosed PAS may also be done.
Especially in the offspring of patients with type 1 diabetes, serological testing for the presence of diabetes-associated antibodies should be considered. According to the literature, genetic screening may be useful in PAS I, only In summary, functional screening rather than a combination of functional, serological, and genetic screening makes actual diagnosis. We thank David S. Cooper, M. Baltimore, MD , for his most constructive criticism. This study contains parts of the doctoral theses of S. Drewitz, C. Kautzmann, U. Klein, A. Leischker, and J. Svitek Endocrine Research Laboratory.
Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents.
Subjects and Methods. Oxford Academic. Google Scholar. George J. Cite Citation. Permissions Icon Permissions. TABLE 1. Open in new tab. Open in new tab Download slide. TABLE 2. TABLE 3. TABLE 4. TABLE 5. Search ADS.
Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy APECED in a series of 68 patients. Autoimmune diseases of the adrenal glands, parathyroid glands, gonads, and hypothalamic-pituitary axis. Leischker A Pluriglandular insufficiency in insulin-dependent diabetes mellitus. Exp Clin Endocrinol Diab S50 abstract. Symposium on autoimmune aspects of endocrine disorders. New York: Academic Press, p — Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction.
Malabsorption due to cholecystokinin deficiency in a patient with autoimmune polyglandular syndrome type I. Type I diabetes mellitus as component of the polyglandular autoimmune syndromes. The number of markers of pancreatic autoimmunity is proportional to the risk for type I diabetes mellitus in Italian and English patients with organ-specific autoimmune disease. First years of life are crucial for the development of type 1 diabetes. The polyglandular failure syndrome: disease inheritance, HLA type, and immune function.
Linkage analysis of candidate genes in autoimmune thyroid disease: 1. Selected immunoregulatory genes.
AIRE mutations and human leukocyte antigen genotypes as determinants of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype. An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome High-resolution physical and transcriptional mapping of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy locus on chromosome 21q The gene responsible for autoimmune polyglandular syndrome type 1 maps to chromosome 21q Women have a greater risk than men; however, in both sexes, the prevalence of other autoimmune disease increases with age.
McGill told EndocrineWeb. Can Patients Find You? List your practice in our directory. Email Print Discuss. McGill, MD The prevalence of multiple autoimmune syndrome MAS —the cascade of 3 or more autoimmune diseases presenting in a signal individual— is on the rise. Type 1 Diabetes Elevates Risk for Multiple Autoimmune Syndrome Although Type 1 diabetes T1D has been recognized as a common autoimmune disorder, minimal attention has focused on nondiabetes-related complications and comorbidities, particularly in adults.
The multiple autoimmune syndromes. A clue for the autoimmune tautology. Clin Rev Allergy Immunol. Introducing polyautoimmunity: secondary autoimmune diseases no longer exist. Autoimmune Dis. The association of other autoimmune diseases in patients with autoimmune thyroiditis: Review of the literature and report of a large series of patients. Autoimmun Rev. High prevalence of systemic rheumatic diseases in women with type 1 diabetes.