Type I (Insulin-Dependent) Diabetes Is a Th1- and Th2-Mediated Autoimmune Disease

Azar, Sami T.; Tamim, Hani; Beyhum, Hayfa N.; Habbal, Zuheir; Almawi, Wassim Y.

doi:10.1128/cdli.6.3.306-310.1999

Cited by 54 publications

(46 citation statements)

References 92 publications

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“…It further provides new insights into the regulation of TGF-β-induced FoxP3 expression as well as lymphopenia-induced expansion of T cells by Tpl2. These findings support the use of Tpl2 inhibitors for the targeted treatment of Th1-driven autoimmune diseases, such as diabetes and colitis [ 38 , 54 , 55 ] but suggest that Tpl2 inhibitors may have more limited utility in treating Th17-mediated diseases. Further studies are needed to fully elucidate the effects of Tpl2 in specific autoimmune disease settings on a case-by-case basis, as the specific cytokine milieu will differentially engage the Tpl2 kinase.…”

Section: Discussionsupporting

confidence: 67%

Tumor Progression Locus 2 Differentially Regulates IFNγ and IL-17 Production by Effector CD4+ T Cells in a T Cell Transfer Model of Colitis

Acuff

Kirkland

et al. 2015

PLoS ONE

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Autoimmune diseases are approaching epidemic levels, estimated to affect 5–8% of the population. A number of autoimmune diseases are believed to be driven by autoreactive T cells, specifically by T helper 1 (Th1) cells and T helper 17 (Th17) cells. One molecule gaining interest as a therapeutic target is the serine-threonine kinase, Tpl2, which promotes expression of proinflammatory mediators. We previously demonstrated that Tpl2 regulates Th1 differentiation, secretion of the inflammatory cytokine IFNγ, and host defense against the intracellular parasite Toxoplasma gondii. The goal of this study was to determine whether Tpl2 also regulates Th1 or Th17 differentiation in vivo in a model of colitis associated with mixed Th1/Th17 pathology. In vitro, Tpl2−/− naïve CD4 T cells were significantly impaired in IL-17A secretion under traditional Th17 inducing conditions. Reduced IL-17A secretion correlated with increased expression of FoxP3, a transcription factor known to antagonize RORγt function. In a murine T cell transfer model of colitis, transfer of Tpl2−/− T cells resulted in reduced proportions of CD4 T cells expressing IFNγ, but not IL-17A, compared to that induced by wild type T cells. Further studies revealed that IL-17A differentiation induced by IL-6 and IL-23, cytokines implicated in driving Th17 differentiation in vivo, was unaffected by Tpl2 deficiency. Collectively, these results implicate Tpl2 in TGF-β-induced FoxP3 expression. Additionally, they underscore the contribution of Tpl2 to Th1 immunopathology specifically, which suggests that Tpl2 inhibitors may selectively target Th1-based inflammation.

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Section: Discussionsupporting

confidence: 67%

Tumor Progression Locus 2 Differentially Regulates IFNγ and IL-17 Production by Effector CD4+ T Cells in a T Cell Transfer Model of Colitis

Acuff

Kirkland

et al. 2015

PLoS ONE

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“…Although numerous studies support a Th1 bias in T1D, not all evidence is consistent with this conclusion. Some studies using the NOD mouse concluded that beta cell destruction was a Th2-rather than a Th1-mediated event [23], while others concluded that both types of response were involved [24]. At odds with data from short-term Th2 clones [5], long-term cultured Th2 clones derived from the same TCR transgenic animals have the capacity to induce diabetes, and could even enhance the ability of Th1 cells to cause disease [25].…”

Section: Evidence Against the Th1 Paradigmmentioning

confidence: 99%

CD4 T cell differentiation in type 1 diabetes

Walker

Herrath

2015

Clinical and Experimental Immunology

155

113

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SummarySusceptibility to type 1 diabetes is associated strongly with human leucocyte antigen (HLA) genes, implicating T cells in disease pathogenesis. In humans, CD8 T cells predominantly infiltrate the islets, yet their activation and propagation probably requires CD4 T cell help. CD4 T cells can select from several differentiation fates following activation, and this choice has profound consequences for their subsequent cytokine production and migratory potential. In turn, these features dictate which other immune cell types T cells interact with and influence, thereby determining downstream effector functions. Obtaining an accurate picture of the type of CD4 T cell differentiation associated with a particular immune-mediated disease therefore constitutes an important clue when planning intervention strategies. Early models of T cell differentiation focused on the dichotomy between T helper type 1 (Th1) and Th2 responses, with type 1 diabetes (T1D) being viewed mainly as a Th1-mediated pathology. However, several additional fate choices have emerged in recent years, including Th17 cells and follicular helper T cells. Here we revisit the issue of T cell differentiation in autoimmune diabetes, highlighting new evidence from both mouse models and patient samples. We assess the strengths and the weaknesses of the Th1 paradigm, review the data on interleukin (IL)-17 production in type 1 diabetes and discuss emerging evidence for the roles of IL-21 and follicular helper T cells in this disease setting. A better understanding of the phenotype of CD4 T cells in T1D will undoubtedly inform biomarker development, improve patient stratification and potentially reveal new targets for therapeutic intervention.

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“…However, this T H 1/T H 2 dichotomy represents a simplified view of the immunological mechanisms underlying these diseases. For example, in chronic asthma - unlike in acute asthma - T H 1 cytokines have also been shown to play a prominent role [Barnes, 2008 ], whereas in type 1 diabetes, T H 2 mechanisms are important [Azar et al, 1999 ]. Furthermore, other immune cells, such as regulatory T cells and T H 17 cells and their respective cytokines, as well as aspects of the innate immune system, have similarly been shown to play important roles in the pathogenesis both of asthma [Barnes, 2008 ] and autoimmune diseases, such as type 1 diabetes [Kim & Lee, 2009 ].…”

Section: The Hygiene Hypothesismentioning

confidence: 99%

Exploring the origins of asthma: Lessons from twin studies

Thomsen

2014

European Clinical Respiratory Journal

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This thesis explores the contribution of twin studies, particularly those studies originating from the Danish Twin Registry, to the understanding of the aetiology of asthma. First, it is explored how twin studies have established the contribution of genetic and environmental factors to the variation in the susceptibility to asthma, and to the variation in several aspects of the clinical expression of the disease such as its age at onset, its symptomatology, its intermediate phenotypes, and its relationship with other atopic diseases. Next, it is explored how twin studies have corroborated theories explaining asthma's recent increase in prevalence, and last, how these fit with the explanations of the epidemiological trends in other common chronic diseases of modernity.

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Type I (Insulin-Dependent) Diabetes Is a Th1- and Th2-Mediated Autoimmune Disease

Cited by 54 publications

References 92 publications

Tumor Progression Locus 2 Differentially Regulates IFNγ and IL-17 Production by Effector CD4+ T Cells in a T Cell Transfer Model of Colitis

Tumor Progression Locus 2 Differentially Regulates IFNγ and IL-17 Production by Effector CD4+ T Cells in a T Cell Transfer Model of Colitis

CD4 T cell differentiation in type 1 diabetes

Exploring the origins of asthma: Lessons from twin studies

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