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      Comment on: Meagher et al. Neutralization of Interleukin-16 Protects Nonobese Diabetic Mice From Autoimmune Type 1 Diabetes by a CCL4-Dependent Mechanism. Diabetes 2010;59:2862–2871

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      1 , 2 , 2 , 3
      Diabetes
      American Diabetes Association

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          Abstract

          We read with great interest and appreciation the article by Meagher et al. (1). Here, treatment of NOD mice with anti–interleukin-16 (IL-16) antibodies results in type 1 diabetes prevention by interfering with CD4+ T-cell recruitment to the pancreas. IL-16 is a chemoattractant factor for CD4+ T cells that is released in its bioactive form by caspase-3 cleavage of pro–IL-16. In the current study, IL-16 is reported to be produced within the insulitic lesion by B220 B cells and CD4+/CD8+ T cells, rather than by the pancreatic islets. However, immunofluorescence studies with colocalization for IL-16 and active caspase-3 in islet-infiltrating cells show that although many lymphocytes constitutively express pro–IL-16, only a few stain for activated caspase-3 resulting in low levels of mature IL-16. We have previously shown that patients who have type 1 diabetes or are affected by endocrinopathies such as autoimmune polyendocrine syndrome type 2 and autoimmune thyroiditis present a reduced expression of active caspase-3 in peripheral T cells (2,3). Similar findings have also been recently extended to the peripheral T cells of patients with multiple sclerosis (4). Importantly, in NOD mice treated with cyclophosphamide to accelerate diabetes development, active caspase-3 expression within the islets is rarely observed in CD4+ and CD8+ T cells (5). Overall, we believe that these studies can explain the low levels of mature IL-16 detected in the inflamed islets. Although signal amplification with tyramide, similar to IL-16 stainings, could have improved the detection of active caspase-3, in our opinion a reduced expression of active caspase-3 in infiltrating T cells could account for the low levels of IL-16 detected in the insulitic lesion. The observation that the treatment of NOD mice with anti–IL-16 results in an increased apoptosis of CD4+ T cells is not detrimental to this hypothesis because the exact mechanism underlying this process is unknown. In the NOD mouse, T cells may then be partially defective in IL-16 secretion, but still capable of releasing enough IL-16 for the recruitment of CD4+ T cells and diabetes development.

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          IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H).

          Phase II clinical trials revealed that the lymphocyte-depleting humanized monoclonal antibody alemtuzumab (Campath-1H) is highly effective in the treatment of early relapsing-remitting multiple sclerosis. However, 30% of patients develop autoimmunity months to years after pulsed exposure to alemtuzumab, usually targeting the thyroid gland and, more rarely, blood components. In this study, we show that autoimmunity arose in those patients with greater T cell apoptosis and cell cycling in response to alemtuzumab-induced lymphocyte depletion, a phenomenon that is driven by higher levels of IL-21. Before treatment, patients who went on to develop secondary autoimmunity had more than 2-fold greater levels of serum IL-21 than the nonautoimmune group. We suggest that serum IL-21 may, therefore, serve as a biomarker for the risk of developing autoimmunity months to years after alemtuzumab treatment. This has implications for counseling those patients with multiple sclerosis who are considering lymphocyte-depleting therapy with alemtuzumab. Finally, we demonstrate through genotyping that IL-21 expression is genetically predetermined. We propose that, by driving cycles of T cell expansion and apoptosis to excess, IL-21 increases the stochastic opportunities for T cells to encounter self antigen and, hence, for autoimmunity.
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            Immunohistochemical study of caspase-3-expressing cells within the pancreas of non-obese diabetic mice during cyclophosphamide-accelerated diabetes.

            During insulin-dependent diabetes mellitus, immune cells infiltrate pancreatic islets progressively and mediate beta cell destruction over a prolonged asymptomatic prediabetic period. Apoptosis may be a major mechanism of beta cell loss during the disease. This process involves a proteolytic cascade in which upstream procaspases are activated which themselves activate downstream caspases, including caspase-3, a key enzyme involved in the terminal apoptotic cascade. Here dual-label immunohistochemistry was employed to examine the intra-islet expression, distribution and cellular sources of active caspase-3 in the non-obese diabetic (NOD) mouse given cyclophosphamide to accelerate diabetes. NOD mice were treated at day 95 and caspase-3 expression was studied at days 0, 4, 7, 11 and 14. Its expression was also correlated with advancing disease and compared with age-matched NOD mice treated with diluent alone. At day 0 (=day 95), caspase-3 immunolabelling was observed in several peri-islet and intra-islet macrophages, but not in CD4 and CD8 cells and only extremely rarely in beta cells. At day 4, only a few beta cells weakly expressed the enzyme, in the absence of significant insulitis. At day 7, caspase-3 expression was observed in a small proportion of intra-islet macrophages. At day 11, there was a marked increase in the number of intra-islet macrophages positive for caspase-3 while only a few CD4 cells expressed the enzyme. At day 14, caspase-3 labelling became prominent in a significant proportion of macrophages. Only a few CD4 and CD8 cells expressed the enzyme. Capase-3 labelling was also present in a proportion of macrophages in perivascular and exocrine regions. Surprisingly, beta cell labelling of caspase-3 at days 11 and 14 was rare. At this stage of heightened beta cell loss, a proportion of intra-islet interleukin-1beta-positive cells coexpressed the enzyme. Caspase-3 was also observed in numerous Fas-positive cells in heavily infiltrated islets. During this late stage, only a proportion of caspase-3-positive cells contained apoptotic nuclei, as judged by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL). We conclude that during cyclophosphamide-accelerated diabetes in the NOD mouse, the predominant immunolabelling of caspase-3 in intra-islet macrophages suggests that apoptosis of macrophages may be an important mechanism for its elimination. The virtual absence of caspase-3 immunolabelling in most beta cells even during heightened beta cell loss supports their rapid clearance following their death during insulin-dependent diabetes mellitus.
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              Impaired caspase-3 expression by peripheral T cells in chronic autoimmune thyroiditis and in autoimmune polyendocrine syndrome-2.

              Activation-induced cell death (AICD) is a major mechanism in the regulation of peripheral tolerance, and caspase-3 represents its major executioner. AICD impairment contributes to the persistence of autoreactive T cells, and defective AICD has been reported in autoimmune thyroiditis as well as in type 1 diabetes mellitus. The objective of this study was to evaluate the involvement of caspase-3 in the regulation of AICD resistance in thyroid and polyendocrine autoimmunity. DESIGN/SETTINGS/PATIENTS/INTERVENTION: Caspase-3 expression was analyzed in peripheral blood lymphocytes from 26 adults (A-AT) and 25 children (Y-AT) affected by autoimmune thyroiditis and 13 individuals affected by chronic autoimmune thyroiditis plus Addison's disease [autoimmune polyendocrine syndrome-2 (APS-2)] in comparison with 32 age-matched normal control subjects (NC). Caspase-3 mRNA expression in peripheral T cells was evaluated by quantitative real-time PCR; protein expression of both procaspase-3 and activated caspase-3 by Western blot analysis was followed by scanning densitometry. Caspase-3 mRNA expression was significantly reduced in resting lymphocytes from both A-AT (P = 0.001) and Y-AT (P = 0.016) compared with NC. After lymphocyte activation, protein levels of caspase-3 active form were significantly reduced in A-AT (P = 0.023) and Y-AT (P = 0.001) compared with NC. The APS-2 group displayed characteristics similar to the A-AT group because both caspase-3 mRNA and protein active form levels were significantly reduced compared with NC (P = 0.004 and 0.002, respectively). Our data show that peripheral lymphocytes of subjects affected by thyroid autoimmunity or APS-2 show defective expression of the major executioner of AICD, thus potentially contributing to AICD resistance and to the development of autoimmunity.
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                Author and article information

                Journal
                Diabetes
                diabetes
                diabetes
                Diabetes
                Diabetes
                American Diabetes Association
                0012-1797
                1939-327X
                February 2011
                21 January 2011
                : 60
                : 2
                : e12
                Affiliations
                From the [1 ]Diabetes Research Institute, University of Miami, Miami, Florida; the
                [2 ]Fondazione Umberto Di Mario Organizzazione Non Lucrativa di Utilita' Sociale, Toscana Life Science Park, Siena, Italy; and the
                [3 ]Diabetes Unit, Department of Internal Medicine, Endocrine and Metabolic Sciences and Biochemistry, University of Siena, Siena, Italy
                Author notes
                Corresponding author: Francesco Vendrame, fvendrame@ 123456med.miami.edu .
                Article
                1489
                10.2337/db10-1489
                3028376
                21270245
                8e389f04-77b7-4399-9716-753cb95a066c
                © 2011 by the American Diabetes Association.
                History
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                Endocrinology & Diabetes

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