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Graves’ Ophthalmopathy: the Role of Cytokines in Pathogenesis
Published in George H. Gass, Harold M. Kaplan, Handbook of Endocrinology, 2020
In general, the initiating event in an autoimmune disease is an abnormal response to infection, toxins, environmental factors, foreign antigens, or trauma. The host response to the abnormal immune process initially includes the synthesis of cytokines, which then contribute to the T-cell response, propagation of the disease process, and further production of cytokines. Cytokines have been shown to have “effector” functions in the pathogenesis of some autoimmune diseases.25 In insulin-dependent type I diabetes mellitus, IL-1 has a role in the selective destruction of beta cells during insulitis.29 In the BB rat model for type I diabetes mellitus, blocking the binding of IL-1 with the IL-1 receptor antagonist delays the onset of diabetes.25 In GO, instead of causing destruction of ocular connective tissue, IL-1 and IFN-γ stimulate orbital fibroblasts to produce excessive quantities of GAG.14,30 The accumulation of GAG and edema in the orbital tissues is primarily responsible for the development of the clinical signs and symptoms of the disease. In addition, particular cytokines stimulate the expression of immunomodulatory proteins on orbital fibroblasts11 and thus aid in the propagation of the disease (see below).
Immunopathogenesis of Type I Diabetes Mellitus
Published in George S. Eisenbarth, Immunotherapy of Diabetes and Selected Autoimmune Diseases, 2019
Richard J. Keller, George S. Eisenbarth
Insulitis, characterized by a mononuclear islet infiltrate especially rich in T cells, is associated with Type I diabetes.11 Insulitis is reportedly present only in islets which still contain beta cells. At the time of diagnosis, only 10% of beta cell mass remains.11 Within the diabetic pancreas, there are “pseudoatrophic” islets devoid of beta cells or inflammatory cells, but containing normal alpha, delta, and PP cells. Other islets have active insulitis, and yet others are completely intact. There are also some areas of beta cell regeneration. The histology is analogous to a plaque assay in microbiology, with only some islets affected, and those which are affected displaying various stages of beta cell destruction. One hypothesis to account for such plaquing is that a rare activated T cell in circulation occasionally seeds an individual islet to initiate the inflammatory process. From the histology one can hypothesize that the development of diabetes is a chronic process with gradual and progressive beta cell loss. It is not until several years after diagnosis that all the beta cells are destroyed, with the islets free of inflammation.11
Cellular and Molecular Imaging of the Diabetic Pancreas
Published in Michel M. J. Modo, Jeff W. M. Bulte, Molecular and Cellular MR Imaging, 2007
Autoimmune destruction of beta-cells is primarily a T-cell-mediated process. The most likely sequence of events leading to beta-cell death involves initial acquisition of beta-cell antigens by antigen presenting cells (APCs) in the islets of Langerhans, followed by activation and migration of APCs to pancreatic lymph nodes. Interaction between activated APCs and naïve T-lymphocytes present in the immediately draining pancreatic lymph nodes leads to activation of beta-cell-reactive T-lymphocytes, which subsequently migrate to the islets, where they reencounter beta-cell-derived antigen and are retained.3 Therefore, overt diabetes, characterized by hyperglycemia, is preceded by an occult phase, termed insulitis, during which leukocyte invasion of pancreatic islets occurs. This process effects the eventual specific destruction of the insulin-producing beta-cells. It is postulated that a loss of more than 90% of the beta-cells takes place before insulin production is no longer sufficient to regulate blood glucose levels, resulting in hyperglycemia.27 Importantly, this initial stage of insulitis begins a long time before the manifestation of overt symptoms, persists for many years, and progressively decreases after diabetes onset, as beta-cell mass declines.50,51 Therefore, the early detection and continuous monitoring of immune cell infiltration of the pancreas in real time would represent a significant step toward identifying the initial insult leading to beta-cell destruction and permit effective curative and not just palliative intervention. Furthermore, progress in this specific area would provide a better understanding of the time course of the pathology and possibly help unravel the mechanisms behind its progress.
Oral delivery of the intracellular domain of the insulinoma-associated protein 2 (IA-2ic) by bacterium-like particles (BLPs) prevents type 1 diabetes mellitus in NOD mice
Published in Drug Delivery, 2022
Ruifeng Mao, Menglan Yang, Rui Yang, Yingying Chen, Enjie Diao, Tong Zhang, Dengchao Li, Xin Chang, Zhenjing Chi, Yefu Wang
To clarify the potential mechanism responsible for preventing T1DM, the effect of oral vaccination with BLPs-IA-2ic on suppression of insulitis was analyzed and scored by HE staining at the end of the observation period (40-week-old). Compared with the BLPs group (Figure 6(A)) and IA-2ic-3LysM group (Figure 6(B)), there was less islet inflammation in BLPs-IA-2ic group (Figure 6(C)). Approximately, 78% and 75% of pancreatic islets in the BLPs group and IA-2ic-3LysM group exhibited severe insulitis, respectively. In contrast, this corresponding value of BLPs-IA-2ic group was only 21% (Figure 6(D)). Based on the obtained insulitis score (Figure 6(E)), the mice in BLPs-IA-2ic group exhibited a significant reduction in insulitis compared with the mice in IA-2ic-3LysM group (1.78 ± 0.21 vs. 3.59 ± 0.15, p < .05). These observations suggest that oral vaccination with BLPs-IA-2ic was useful to maintain islet integrity in NOD mice.
Differential expression of CRAC channel in alloxan induced Diabetic BALB/c mice
Published in Immunopharmacology and Immunotoxicology, 2020
Anantha Maharasi Ramakrishnan, Pavitra Kumar, Suvro Chatterjee, Kavitha Sankaranarayanan
The major pathogenic hallmark of Type 1 Diabetes (T1D) is the inflammatory lesions, called pancreatic insulitis, which is predominated by macrophages, cytotoxic CD8+ T cells and also by B cell mediated production of autoantibodies [1–3]. APCs (Antigen Presenting Cells) like macrophages present β cell antigen on MHC-II molecules to CD4+ T cells in PLN (Pancreatic Lymph Node), which mediate the differentiation and activation of the same. This differentiated CD4+ T cells, in turn, secrete enhanced level of cytokines. Besides this, cytokines produced from macrophages also activate and migrates cytotoxic CD8+ T cells to the site of pancreatic islets and mediate β cell destruction by secreting amplified amount of inflammatory cytokines [1,2,4]. Considering all these events, there are three major cell types involved in the adverse immune reaction in T1D: monocytes, macrophages and T cells. The monocytes sense inflammatory signal and then it differentiated into the classically activated macrophages (CAM) [5].The macrophages act as APCs and also provide co-stimulatory signals to cytotoxic effector T cells as well as directly mediate target cell killing by increased secretion of chemokines, inflammatory cytokines like IL-1β, TNF-α, proteases and free radicals [4,6–8]. Activated T cells are the predominant cell population in the β cell destruction and play an inevitable role in the pathogenesis of T1D, thus T1D known as T cell mediated autoimmune disease. T cells majorly attribute for the β cell destruction by the increased production of inflammatory cytokines like IL-1β, TNF-α and IFN-γ, also by the upregulated expression of FAS ligand, Perforin and Granzymes [2,4].
Transient B-cell depletion and regulatory T-cells mediation in combination with adenovirus mediated IGF-1 prevents and reverses autoimmune diabetes in NOD mice
Published in Autoimmunity, 2022
Shujun Ye, Saimei Hua, Meiyang Zhou
Previous publications have shown that B cell-mediated severe humoral immune abnormalities are one of the important mechanisms of T1D, in short, B cells promote memory T cell proliferation by secreting antibodies against pancreatic β cells, and activate reactive T cells as well as lead to the massive secretion of inflammatory factors, ultimately causing continuous killing of pancreatic β-cells [3]. The recognition and binding of CD20 on the surface of B cell via anti-CD20 mAb may induce efficient immunodepletion of B cells [13]. On the other hand, anti-CD3 monoclonal antibodies can bind to CD3 on the surface of T cells, stimulate or block the signals of cell activation, remove effector T cells or induce regulatory T cell (Treg) production and induce immune tolerance [29]. Bispecific antibodies targeting CD20 and CD30 have strong advantages over the combination of two monoclonal antibodies in terms of clinical dose, efficacy and toxicity [30]. Moreover, many studies suggested that pancreatic β-cells have the ability to regenerate themselves, it is partially dependent on IGF-1 secretion [22]. Previous studies also have shown that IGF-1 supplementation at higher doses plays a protective role in preventing the pathogenesis of T1D in mice. But it is difficult to effectively reduce glucose levels and improve the development of insulitis, and is more likely to cause impaired glucose tolerance and fasting hypoglycemia [31]. Based on this, we hope to achieve the inhibition of autoimmune effects and the improvement of the proliferation and functions of pancreatic β cells with the supplementation of bsAb against CD3 and CD20 combined with IGF-1, so as to achieve the prevention of T1D mice and reverse the synergistic effect of T1D.