Advances in the cellular immunological pathogenesis of type 1 diabetes

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Abstract

Type 1 diabetes is an autoimmune disease caused by the immune-mediated destruction of insulin-producing pancreatic β cells. In recent years, the incidence of type 1 diabetes continues to increase. It is supposed that genetic, environmental and immune factors participate in the damage of pancreatic β cells. Both the immune regulation and the immune response are involved in the pathogenesis of type 1 diabetes, in which cellular immunity plays a significant role. For the infiltration of CD4 ⁺ and CD8 ⁺ T lymphocyte, B lymphocytes, natural killer cells, dendritic cells and other immune cells take part in the damage of pancreatic β cells, which ultimately lead to type 1 diabetes. This review outlines the cellular immunological mechanism of type 1 diabetes, with a particular emphasis to T lymphocyte and natural killer cells, and provides the effective immune therapy in T1D, which is approached at three stages. However, future studies will be directed at searching for an effective, safe and long-lasting strategy to enhance the regulation of a diabetogenic immune system with limited toxicity and without global immunosuppression.

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Most cited references 125

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The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes.

Janet Wenzlau, Kirstine Juhl, Liping Yu … (2007)

Type 1 diabetes (T1D) results from progressive loss of pancreatic islet mass through autoimmunity targeted at a diverse, yet limited, series of molecules that are expressed in the pancreatic beta cell. Identification of these molecular targets provides insight into the pathogenic process, diagnostic assays, and potential therapeutic agents. Autoantigen candidates were identified from microarray expression profiling of human and rodent pancreas and islet cells and screened with radioimmunoprecipitation assays using new-onset T1D and prediabetic sera. A high-ranking candidate, the zinc transporter ZnT8 (Slc30A8), was targeted by autoantibodies in 60-80% of new-onset T1D compared with <2% of controls and <3% type 2 diabetic and in up to 30% of patients with other autoimmune disorders with a T1D association. ZnT8 antibodies (ZnTA) were found in 26% of T1D subjects classified as autoantibody-negative on the basis of existing markers [glutamate decarboxylase (GADA), protein tyrosine phosphatase IA2 (IA2A), antibodies to insulin (IAA), and islet cytoplasmic autoantibodies (ICA)]. Individuals followed from birth to T1D showed ZnT8A as early as 2 years of age and increasing levels and prevalence persisting to disease onset. ZnT8A generally emerged later than GADA and IAA in prediabetes, although not in a strict order. The combined measurement of ZnT8A, GADA, IA2A, and IAA raised autoimmunity detection rates to 98% at disease onset, a level that approaches that needed to detect prediabetes in a general pediatric population. The combination of bioinformatics and molecular engineering used here will potentially generate other diabetes autoimmunity markers and is also broadly applicable to other autoimmune disorders.

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Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus.

Kevan C. Herold, William Hagopian, Julie A Auger … (2002)

Type 1 diabetes mellitus is a chronic autoimmune disease caused by the pathogenic action of T lymphocytes on insulin-producing beta cells. Previous clinical studies have shown that continuous immune suppression temporarily slows the loss of insulin production. Preclinical studies suggested that a monoclonal antibody against CD3 could reverse hyperglycemia at presentation and induce tolerance to recurrent disease. We studied the effects of a nonactivating humanized monoclonal antibody against CD3--hOKT3gamma1(Ala-Ala)--on the loss of insulin production in patients with type 1 diabetes mellitus. Within 6 weeks after diagnosis, 24 patients were randomly assigned to receive either a single 14-day course of treatment with the monoclonal antibody or no antibody and were studied during the first year of disease. Treatment with the monoclonal antibody maintained or improved insulin production after one year in 9 of the 12 patients in the treatment group, whereas only 2 of the 12 controls had a sustained response (P=0.01). The treatment effect on insulin responses lasted for at least 12 months after diagnosis. Glycosylated hemoglobin levels and insulin doses were also reduced in the monoclonal-antibody group. No severe side effects occurred, and the most common side effects were fever, rash, and anemia. Clinical responses were associated with a change in the ratio of CD4+ T cells to CD8+ T cells 30 and 90 days after treatment. Treatment with hOKT3gamma1(Ala-Ala) mitigates the deterioration in insulin production and improves metabolic control during the first year of type 1 diabetes mellitus in the majority of patients. The mechanism of action of the anti-CD3 monoclonal antibody may involve direct effects on pathogenic T cells, the induction of populations of regulatory cells, or both.

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Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice.

Dongmei Miao, Norio Abiru, George S. Eisenbarth … (2005)

A fundamental question about the pathogenesis of spontaneous autoimmune diabetes is whether there are primary autoantigens. For type 1 diabetes it is clear that multiple islet molecules are the target of autoimmunity in man and animal models. It is not clear whether any of the target molecules are essential for the destruction of islet beta cells. Here we show that the proinsulin/insulin molecules have a sequence that is a primary target of the autoimmunity that causes diabetes of the non-obese diabetic (NOD) mouse. We created insulin 1 and insulin 2 gene knockouts combined with a mutated proinsulin transgene (in which residue 16 on the B chain was changed to alanine) in NOD mice. This mutation abrogated the T-cell stimulation of a series of the major insulin autoreactive NOD T-cell clones. Female mice with only the altered insulin did not develop insulin autoantibodies, insulitis or autoimmune diabetes, in contrast with mice containing at least one copy of the native insulin gene. We suggest that proinsulin is a primary autoantigen of the NOD mouse, and speculate that organ-restricted autoimmune disorders with marked major histocompatibility complex (MHC) restriction of disease are likely to have specific primary autoantigens.

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Author and article information

Journal

Journal ID (nlm-ta): J Cell Mol Med

Journal ID (iso-abbrev): J. Cell. Mol. Med

Journal ID (publisher-id): jcmm

Title: Journal of Cellular and Molecular Medicine

Publisher: BlackWell Publishing Ltd (Oxford, UK )

ISSN (Print): 1582-1838

ISSN (Electronic): 1582-4934

Publication date (Print): May 2014

Publication date (Electronic): 14 March 2014

Volume: 18

Issue: 5

Pages: 749-758

Affiliations

[a ]Department of General Surgery, Zhongshan Hospital, Fudan University Shanghai, China

Author notes

*Correspondence to: Xinyu QIN, Department of General Surgery, Zhongshan Hospital, Shanghai Medical School, Fudan University, 180, Fenglin Road, Shanghai 200032, China. Tel.: +86 21 64037224 Fax: +86 21 64037224 E-mail: qin.xinyu@ 123456zs-hospital.sh.cn

[#]

These authors contributed equally to this work.

Article

DOI: 10.1111/jcmm.12270

PMC ID: 4119381

PubMed ID: 24629100

SO-VID: 7d1a50b4-1105-4ca8-87b9-b36f4a4c06b0

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This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Advances in the cellular immunological pathogenesis of type 1 diabetes

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Most cited references 125

The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes.

Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus.

Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice.

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