Complement C3 deficiency prevent against the onset of streptozotocin-induced autoimmune diabetes involving expansion of regulatory T cells

Gao, Xiaogang; Liu, Huanhai; Ding, Guoyu; Wang, Zhengxin; Fang, Hong; Ni, Zhijia; Ma, Jun; Liu, Fang; Fu, Zhi-ren

doi:10.1016/j.clim.2011.02.004

Cited by 19 publications

(24 citation statements)

References 27 publications

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“…Therefore, the change quantification of C3 level in AIH patient’s serum is key to understand the alterations that biological systems undergo. Recent studies have demonstrated that complement contributes to the development of autoimmune diabetes [33,34]. Also reports showed that complement could play a pivotal role in liver specific autoantibody, which mediated hepatocyte injury in AIH, and that complement inhibitors could be, in principle, developed as novel therapeutics against AIH [35].…”

Section: Discussionmentioning

confidence: 99%

Complementary serum proteomic analysis of autoimmune hepatitis in mice and patients

Zhao

et al. 2013

J Transl Med

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BackgroundAutoimmune hepatitis (AIH) is a chronic liver disease caused by inflammation of the liver. The etiology of AIH remains elusive, and there are no reliable serum biomarkers.MethodsIn order to identify candidate biomarkers, 2-DE analysis of serum proteins was performed using a mouse model of AIH induced by treatment with concanavalin A (ConA). To enrich samples for low abundance molecules a commercial albumin removal reagent was used. In an independent analysis, candidate biomarkers were identified in AIH patient’s serum by a targeted iTRAQ (isobaric tags for relative and absolute quantification) identification. Candidates were validated in independent cohorts of ConA treated mice and AIH patients by ELISA (enzyme-linked immuno sorbent assay).ResultsNine proteins were differentially expressed in AIH mice treated with con-A. Two of these, the third component of complement (C3) and alpha-2-macroglobulin (A2M) were also up-regulated in AIH patient’s sera by a targeted iTRAQ identification. In separate validation studies, serum C3 and A2M levels were increased in mice with ConA treatment after 20-40 h and in 34 AIH patients in a subgroup analysis, females with AIH aged 20–50 years old displayed the largest increases in serum A2M level. Biological network analysis implements the complement cascade and protease inhibitors in the pathogenesis of AIH.ConclusionThe serum proteins C3 and A2M are increased both in a mouse model and in patients with AIH by both 2-DE and iTRAQ methods. This integrated serum proteomics investigation should be applicable for translational researchers to study other medical conditions.

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Section: Discussionmentioning

confidence: 99%

Complementary serum proteomic analysis of autoimmune hepatitis in mice and patients

Zhao

et al. 2013

J Transl Med

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“…The blocking of complement receptors C3a and C5a has been shown to induce expression of TGF-β and IL-10 leading to generation of iTregs which when adoptively transferred potently suppressed the disease [210]. Other studies have also suggested a link between reduced complement expression with increased Treg numbers [211, 212]. Additionally, TGF-β has been shown to reduce iNOS production, again leading to concomitant Treg proliferation [213].…”

Section: Main Textmentioning

confidence: 99%

Regulatory T cells in multiple sclerosis and myasthenia gravis

Danikowski

Jayaraman

Prabhakar

2017

J Neuroinflammation

262

171

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Multiple sclerosis (MS) is a chronic debilitating disease of the central nervous system primarily mediated by T lymphocytes with specificity to neuronal antigens in genetically susceptible individuals. On the other hand, myasthenia gravis (MG) primarily involves destruction of the neuromuscular junction by antibodies specific to the acetylcholine receptor. Both autoimmune diseases are thought to result from loss of self-tolerance, which allows for the development and function of autoreactive lymphocytes. Although the mechanisms underlying compromised self-tolerance in these and other autoimmune diseases have not been fully elucidated, one possibility is numerical, functional, and/or migratory deficits in T regulatory cells (Tregs). Tregs are thought to play a critical role in the maintenance of peripheral immune tolerance. It is believed that Tregs function by suppressing the effector CD4+ T cell subsets that mediate autoimmune responses. Dysregulation of suppressive and migratory markers on Tregs have been linked to the pathogenesis of both MS and MG. For example, genetic abnormalities have been found in Treg suppressive markers CTLA-4 and CD25, while others have shown a decreased expression of FoxP3 and IL-10. Furthermore, elevated levels of pro-inflammatory cytokines such as IL-6, IL-17, and IFN-γ secreted by T effectors have been noted in MS and MG patients. This review provides several strategies of treatment which have been shown to be effective or are proposed as potential therapies to restore the function of various Treg subsets including Tr1, iTr35, nTregs, and iTregs. Strategies focusing on enhancing the Treg function find importance in cytokines TGF-β, IDO, interleukins 10, 27, and 35, and ligands Jagged-1 and OX40L. Likewise, strategies which affect Treg migration involve chemokines CCL17 and CXCL11. In pre-clinical animal models of experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune myasthenia gravis (EAMG), several strategies have been shown to ameliorate the disease and thus appear promising for treating patients with MS or MG.

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“…Depending on dose and other factors (e.g., diet), streptozotocin (STZ)-induced diabetes can be considered either T1D or T2D (Reed et al, 2000; Zhang et al, 2008; Gao et al, 2011; Muller et al , 2011; Shpilberg et al, 2012; Ramos-Rodriguez et al, 2013). The multiple low dose (MLD)-STZ-induced diabetes in mice that do not develop diabetes spontaneously is also a disease of immune origin since it is associated with a secondary autoimmune insulitis following apoptotic injury of the pancreatic β-cells (Thomas-Vaslin et al, 1997; Ablamunits et al, 1999; Gao et al, 2013; Barbu-Tudoran et al, 2013; Yaochite et al, 2013), which confers this model the ability to detect nutrient or toxicant modulation of diabetes.…”

Section: Introductionmentioning

confidence: 99%

Genistein modulation of streptozotocin diabetes in male B6C3F1 mice can be induced by diet

Guo

Wang

Xiong

et al. 2014

Toxicology and Applied Pharmacology

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Diet and phytoestrogens affect the development and progression of diabetes. The objective of the present study was to determine if oral exposure to phytoestrogen genistein (GE) by gavage changed blood glucose levels (BGL) through immunomodulation in streptozotocin (STZ)-induced diabetic male B6C3F1 mice fed three different diets. These three diets were: NTP-2000 diet (NTP), soy- and alfalfa-free 5K96 diet (SOF) and high fat diet (HFD) with 60% of kcal from fat, primarily rendered fat of swine. The dosing regimen for STZ consisted of three 100 mg/kg doses (i.p.): the first dose was administered at approximately 2 weeks following the initiation of daily GE (20 mg/kg) gavage, and the second dose was on day 19 following the first dose, and the third dose was on day 57 following the first dose. In mice on the NTP diet, GE treatment decreased BGL with statistical significances observed on days 33 and 82 following the first STZ injection. In mice fed the HFD diet, GE treatment produced a significant decrease and a significant increase in BGL on days 15 and 89 following the first STZ injection, respectively. In mice fed the SOF diet, GE treatment had no significant effects on BGL. Although GE treatment affected phenotypic distributions of both splenocytes (T cells, B cells, natural killer cells and neutrophils) and thymocytes (CD4/CD8 and CD44/CD25), and their mitochondrial transmembrane potential and generation of reactive oxygen species, indicators of cell death (possibly apoptosis), GE modulation of neutrophils was more consistent with its diabetogenic or anti-diabetic potentials. The differential effects of GE on BGL in male B6C3F1 mice fed three different diets with varied phytoestrogen contents suggest that the estrogenic properties of this compound may contribute to its modulation of diabetes.

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Complement C3 deficiency prevent against the onset of streptozotocin-induced autoimmune diabetes involving expansion of regulatory T cells

Cited by 19 publications

References 27 publications

Complementary serum proteomic analysis of autoimmune hepatitis in mice and patients

Complementary serum proteomic analysis of autoimmune hepatitis in mice and patients

Regulatory T cells in multiple sclerosis and myasthenia gravis

Genistein modulation of streptozotocin diabetes in male B6C3F1 mice can be induced by diet

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