• Diabetes and Metabolism Journal
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• v.42 no.6
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• pp.451-464
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• 2018

Latent autoimmune diabetes in adults (LADA) is a heterogeneous disease characterized by a less intensive autoimmune process and a broad clinical phenotype compared to classical type 1 diabetes mellitus (T1DM), sharing features with both type 2 diabetes mellitus (T2DM) and T1DM. Since patients affected by LADA are initially insulin independent and recognizable only by testing for islet-cell autoantibodies, it could be difficult to identify LADA in clinical setting and a high misdiagnosis rate still remains among patients with T2DM. Ideally, islet-cell autoantibodies screening should be performed in subjects with newly diagnosed T2DM, ensuring a closer monitoring of those resulted positive and avoiding treatment of hyperglycaemia which might increase the rate of ${\beta}-cells$ loss. Thus, since the autoimmune process in LADA seems to be slower than in classical T1DM, there is a wider window for new therapeutic interventions that may slow down ${\beta}-cell$ failure. This review summarizes the current understanding of LADA, by evaluating data from most recent studies, the actual gaps in diagnosis and management. Finally, we critically highlight and discuss novel findings and future perspectives on the therapeutic approach in LADA.

• Archives of Pharmacal Research
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• v.22 no.5
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• pp.437-447
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• 1999

Type I diabetes, also known as insulin-dependent diabetes mellitus (IDDM) results from the destruction of insulin-producing pancreatic $\beta$ cells by a progressive $\beta$ cell-specific autoimmune process. The pathogenesis of autoimmune IDDM has been extensively studied for the past two decades using animal models such as the non-obese diabetic (NOD) mouse and the Bio-Breeding (BB) rat. However, the initial events that trigger the immune responses leading to the selective destruction of the $\beta$ cells are poorly understood. It is thought that $\beta$ cell auto-antigens are involved in the triggering of $\beta$ cell-specific autoimmunity. Among a dozen putative $\beta$ cell autoantigens, glutamic acid decarboxylase (GAD) has bee proposed as perhaps the strongest candidate in both humans and the NOD mouse. In the NOD mouse, GAD, as compared with other $\beta$ cell autoantigens, provokes the earliest T cell proliferative response. The suppression of GAD expression in the $\beta$ cells results in the prevention of autoimmune diabetes in NOD mice. In addition, the major populations of cells infiltrating the iselts during the early stage of insulitis in BB rats and NOD mice are macrophages and dendritic cells. The inactivation of macrophages in NOD mice results in the prevention of T cell mediated autoimmune diabetes. Macrophages are primary contributors to the creation of the immune environment conducive to the development and activation of $\beta$cell-specific Th1-type CD4+ T cells and CD8+ cytotoxic T cells that cause autoimmune diabetes in NOD mice. CD4+ and CD8+ T cells are both believed to be important for the destruction of $\beta$ cells. These cells, as final effectors, can kill the insulin-producing $\beta$ cells by the induction of apoptosis. In addition, CD8+ cytotoxic T cells release granzyme and cytolysin (perforin), which are also toxic to $\beta$ cells. In this way, macrophages, CD4+ T cells and CD8+ T cells act synergistically to kill the $\beta$ cells in conjunction with $\beta$ cell autoantigens and MHC class I and II antigens, resulting in the onset of autoimmune type I diabetes.

• Archives of Pharmacal Research
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• v.26 no.7
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• pp.559-563
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• 2003

Cytokines produced by immune cells infiltrating pancreatic islets have been incriminated as important mediators of $\beta$-cell destruction in insulin-dependent diabetes mellitus. In non insulin-dependent diabetes, cytokines are also associated with impaired $\beta$-cell function in high glucose condition. By the screening of various natural products blocking $\beta$-cell destruction, we have recently found that epigallocatechin gallate (EGCG) can prevent the in vitro destruction of RINm5F cell, an insulinoma cell line, that is induced by cytokines. In that study we suggested that EGCG could prevent cytokine-induced $\beta$-cell destruction by down-regulation of nitric oxide synthase (NOS) through inhibition of NF-kB activation. Here, to verify the in vivo antidiabetogenic effect of EGCG, we examined the possibility that EGCG could also prevent the experimental autoimmune diabetes induced by the treatment of multiple low doses of streptozotocin (MLD-STZ), which is recognized as an inducer of type I autoimmune diabetes. Administration of EGCG (100 mg/day/kg for 10 days) during the MLD-STZ induction of diabetes reduced the increase of blood glucose levels caused by MLD-STZ. Ex vivo analysis of $\beta$-islets showed that EGCG downregulates the MLD-STZ-induced expression of inducible NOS (iNOS). In addition, morphological examination showed that EGCG treatment ameliorated the decrease of islet mass induced by MLD-STZ. In combination these results suggest that EGCG could prevent the onset of MLD-STZ-induced diabetes by protecting pancreatic islets. Our results therefore revealed the possible therapeutic value of EGCG for the prevention of diabetes mellitus progression.

• Proceedings of the Korean Biophysical Society Conference
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• 2002.06b
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• pp.16-17
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• 2002

The major histocompatibility complex (MHC) is an important susceptibility locus for many human autoimmune diseases. The structural and functional properties of HLA-DR molecules that are associated with susceptibility to several autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, have been defined.(omitted)

• Journal of Genetic Medicine
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• v.11 no.1
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• pp.1-10
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• 2014

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by selective destruction of pancreatic ${\beta}$-cells resulting in insulin deficiency. The genetic determinants of T1D susceptibility have been linked to several loci, in particular to the human leukocyte antigen (HLA) region, which accounts for 50% of the genetic risk of developing T1D. Multiple genes in the HLA region, which are in strong linkage disequilibrium, are thought to be involved. Another important locus, with a smaller effect on genetic predisposition to T1D, is the insulin gene. The advent of numerous single nucleotide polymorphism markers and genome screening has enabled the identification of dozens of new T1D susceptibility loci. Some of them appear to predispose to T1D independently of the HLA and may be important in families with T1D who lack strong HLA susceptibility. Other loci may interact with each other to cause susceptibility. The autoimmune response against ${\beta}$-cells can also be triggered by environmental factors in the presence of a predisposing genetic background. Deciphering the environmental and genetic factors involved should help to understand the origin of T1D and aid in the design of individualized prevention programs.

• Journal of Acupuncture Research
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• v.18 no.6
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• pp.232-239
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• 2001

Objective & Method : To identify current state of bee venom therapy(BVT) research as a treatment of autoimmune diseases, we reviewed the PubMed electronic database. 9 articles with clinical implications were discussed. Results : BVT is reported as effective in the treatment of such autoimmune related diseases as rheumatoid arthritis and insulin dependent diabetes mellitus in animal experiment, The lack of evidence on BVT as a treatment of multiple sclerosis deters us from reaching any determination. There also lacks firm evidences of immune response regulative or anti inflammatory mechanism of BVT. No clinicla trial was found. Conculsion : This review raises the urgent need of study to provide scientific and clinical evidences.

• Korean journal of dermatology
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• v.56 no.10
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• pp.620-623
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• 2018

Vitiligo is a multifactorial disorder. Neural, biochemical, and autoimmune mechanisms have been hypothetically suggested as etiopathological contributors to this condition. Autoimmunity focuses primarily on genetic factors and the association between vitiligo and other autoimmune disorders including autoimmune thyroid disease, rheumatoid arthritis, psoriasis, type 1 diabetes, pernicious anemia, and Addison's disease. We describe a 35-year-old man with systemic lupus erythematosus who developed concurrent vitiligo and discoid lupus erythematosus suggesting the possible autoimmune association between these 2 different diseases.

• Journal of Life Science
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• v.13 no.2
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• pp.236-240
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• 2003

Human immune system acts to protect the host from infectious agents (bacteria, viruses, fungi, parasites) and from other noxious insults. However, immune diseases are sometimes caused by the impairment of immune system leading to abnormal immune response. Especially, autoimmune diseases are very diverse and often bring serious damage Although many active investigations to reveal the etiological mechanisms concerning the autoimmune diseases, it still remains unclear. After proposing a HERV (human endogenous retrovirus) as a candidate autoimmune gene in type I diabetes, it is newly attracting our attention for demonstrating that an endogenous human retroviral superantigen can be transactivated by interferon-$\alpha$ (IFN- $\alpha$) or Epstein-Barr virus (EBV) infection. These might provide us with powerful clues to carry out further studies to overcome autoimmune diseases as the presentation of a relatively clear connection between endogenous superantigens and human diseases.

• BMB Reports
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• v.38 no.6
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• pp.717-724
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• 2005

The nontoxic B subunit of cholera toxin (CTB) can significantly increase the ability of proteins to induce immunological tolerance after oral administration, when it was conjugated to various proteins. Recombinant CTB offers great potential for treatment of autoimmune disease. Here we firstly investigated the feasibility of silkworm baculovirus expression vector system for the cost-effective production of CTB under the control of a strong polyhedrin promoter. Higher expression was achieved via introducing the partial non-coding and coding sequences (ATAAAT and ATGCCGAAT) of polyhedrin to the 5' end of the native CTB gene, with the maximal accumulation being approximately 54.4 mg/L of hemolymph. The silkworm bioreactor produced this protein vaccine as the glycoslated pentameric form, which retained the GM1-ganglioside binding affinity and the native antigenicity of CTB. Further studies revealed that mixing with silkworm-derived CTB increases the tolerogenic potential of insulin. In the nonconjugated form, an insulin : CTB ratio of 100 : 1 was optimal for the prominent reduction in pancreatic islet inflammation. The data presented here demonstrate that the silkworm bioreactor is an ideal production and delivery system for an oral protein vaccine designed to develop immunological tolerance against autoimmune diabetes and CTB functions as an effective mucosal adjuvant for oral tolerance induction.

• Proceedings of the PSK Conference
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• 2003.04a
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• pp.82-83
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• 2003

In the past it was thought that autoimmunity is mediated by antibodies and immune complexes. It has now become clear that many diseases, especially tissue specific, are T cell mediated or at least T cell dependent. The pathogenesis of cell-mediated autoimmune diseases, such as multiple sclerosis, uveitis, diabetes, arthritis, and others, is thought to be in a large measure driven by interferon-gamma-producing antigen-specific T cells polarized toward the Th1 phenotype. (omitted)