Natural Genetic Variants Influencing Type 1 Diabetes in Humans and in the NOD Mouse

Wicker, Linda S.; Moule, Carolyn; Fraser, Heather I.; Penha‐Gonçalves, Carlos; Rainbow, Dan; Garner, Valerie E S; Chamberlain, Giselle; Hunter, Kara; Howlett, Sarah; Clark, J. Stephen; González-Muñoz, Andrea; Cumiskey, Anne Marie; Tiffen, Paul G.; Howson, Joanna M. M.; Healy, Barry; Smink, Luc J.; Kingsnorth, Amanda; Lyons, Paul; Gregory, Simon; Rogers, Jane; Todd, John A.; Peterson, Laurence B.

doi:10.1002/047002139x.ch6

Cited by 9 publications

(10 citation statements)

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“…NOD mouse studies have also shown that different combinations of alleles of multiple susceptibility genes can lead to a variety of autoimmune phenotypes, including liver disease and AITD, as well as type 1 diabetes with different rates of progression [32] (K. Hunter, J. A. Todd, L. S. Wicker, unpublished data).…”

Section: Discussionmentioning

confidence: 98%

A type 1 diabetes subgroup with a female bias is characterised by failure in tolerance to thyroid peroxidase at an early age and a strong association with the cytotoxic T-lymphocyte-associated antigen-4 gene

et al. 2007

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Aims/hypothesis HLA haplotypes DRB1*03_DQB1*02 and DRB1*04_DQB1*0302, and allelic variation of the T cell regulatory gene cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) and of the T cell activation gene protein tyrosine phosphatase, non-receptor type 22 (lymphoid) (PTPN22) have been associated with type 1 diabetes and autoimmune thyroid disease. Using thyroid peroxidase autoantibodies (TPOAbs) as an indicator of thyroid autoimmunity, we assessed whether the association of these loci is different in type 1 diabetes patients with TPOAbs than in those without. Materials and methods TPOAbs were measured in 4,364 type 1 diabetic patients from across Great Britain, 67% of whom were aged under 18 years. These patients and 6,866 geographically matched control subjects were genotyped at CTLA4, PTPN22, HLA-DRB1 and HLA-DQB1. Results TPOAbs were detected in 462 (10.6%) of the type 1 diabetic patients. These patients had a stronger association with CTLA4 (odds ratio [OR]=1.49 for the G allele of the single nucleotide polymorphism rs3087243; 95% CI=1.29-1.72) than did the TPOAbs-negative patients (p=0.0004; OR=1.16; 95% CI=1.10-1.24) or type 1 diabetes patients overall (OR=1.20; 95% CI=1.13-1.27). The ratio of women:men was higher (1.94:1) in this subgroup than in type 1 diabetes patients without TPOAbs (0.94:1; p=1.86× 10 −15

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Section: Discussionmentioning

confidence: 98%

A type 1 diabetes subgroup with a female bias is characterised by failure in tolerance to thyroid peroxidase at an early age and a strong association with the cytotoxic T-lymphocyte-associated antigen-4 gene

et al. 2007

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“…[13][14][15][16] NOD mice have genetic risk variants in common with the human disease, in particular remarkable similarity in the MHC class II antigen-binding site with high risk human HLA class 2 haplotypes. 16,17 We have used the NOD mouse to address two key issues in the causes of autoimmunity. First, the model enables us to test how environmental exposures, particularly commensal microbes, contribute to T1D risk by direct microbiome alterations and assessment of their immunological consequences.…”

Section: Benefits Of the Nod Mouse Modelmentioning

confidence: 99%

Microbiome manipulation modifies sex-specific risk for autoimmunity

et al. 2014

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Despite growing evidence for a causal role of environmental factors in autoimmune diseases including the rise in disease frequencies over the past several decades we lack an understanding of how particular environmental exposures modify disease risk. In addition, many autoimmune diseases display sex-biased incidence, with females being disproportionately affected but the mechanisms underlying this sex bias remain elusive. Emerging evidence suggests that both host metabolism and immune function is crucially regulated by the intestinal microbiome. Recently, we showed that in the non-obese diabetic (NOD) mouse model of Type 1 Diabetes (T1D), the gut commensal microbial community strongly impacts the pronounced sex bias in T1D risk by controlling serum testosterone and metabolic phenotypes (1). Here we present new data in the NOD model that explores the correlations between microbial phylogeny, testosterone levels, and metabolic phenotypes, and discuss the future of microbiome-centered analysis and microbe-based therapeutic approaches in autoimmune diseases.

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“…Environmental or genetic insults may negatively impact their development or function, and in turn may represent a major factor underlying susceptibility to T1D [1,110]. The ultimate goal in the treatment of T1D is to re-establish tolerance to β-islet specific antigens by potentiating T reg cell numbers and/or function in vivo or by in vitro conditioning prior to infusion into affected individuals at risk or with overt disease [111].…”

Section: T Reg Cellsmentioning

confidence: 99%

Control of type 1 diabetes by CD4⁺Foxp3⁺ regulatory T cells: lessons from mouse models and implications for human disease

Sgouroudis

Piccirillo

2009

Diabetes Metabolism Res

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In recent years, there has been a revival of the concept of CD4(+) regulatory T (T(reg)) cells as being a central control point in various immune responses, including autoimmune responses and immunity to transplants, allergens, tumours and infectious microbes. The current literature suggests that T(reg) cells are diverse in their phenotype and mechanism(s) of action, and as such, may constitute a myriad of naturally occurring and induced T cell precursors with variable degrees of regulatory potential. In this review, we summarize research from various laboratories, including our own, showing that CD4(+)Foxp3(+) T(reg) cells are critical in the control of type 1 diabetes (T1D) in mouse models and humans. In this review, we also discuss cellular and molecular determinants that impact CD4(+)Foxp3(+) T(reg) cell development and function and consequential resistance to organ-specific autoimmune disease. Recent advances in the use of CD4(+)Foxp3(+) T(reg) cellular therapy to promote immunological tolerance in the absence of long-term generalized immunosuppression are also presented.

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Natural Genetic Variants Influencing Type 1 Diabetes in Humans and in the NOD Mouse

Cited by 9 publications

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A type 1 diabetes subgroup with a female bias is characterised by failure in tolerance to thyroid peroxidase at an early age and a strong association with the cytotoxic T-lymphocyte-associated antigen-4 gene

A type 1 diabetes subgroup with a female bias is characterised by failure in tolerance to thyroid peroxidase at an early age and a strong association with the cytotoxic T-lymphocyte-associated antigen-4 gene

Microbiome manipulation modifies sex-specific risk for autoimmunity

Control of type 1 diabetes by CD4⁺Foxp3⁺ regulatory T cells: lessons from mouse models and implications for human disease

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Natural Genetic Variants Influencing Type 1 Diabetes in Humans and in the NOD Mouse

Cited by 9 publications

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A type 1 diabetes subgroup with a female bias is characterised by failure in tolerance to thyroid peroxidase at an early age and a strong association with the cytotoxic T-lymphocyte-associated antigen-4 gene

A type 1 diabetes subgroup with a female bias is characterised by failure in tolerance to thyroid peroxidase at an early age and a strong association with the cytotoxic T-lymphocyte-associated antigen-4 gene

Microbiome manipulation modifies sex-specific risk for autoimmunity

Control of type 1 diabetes by CD4+Foxp3+ regulatory T cells: lessons from mouse models and implications for human disease

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Control of type 1 diabetes by CD4⁺Foxp3⁺ regulatory T cells: lessons from mouse models and implications for human disease