CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation

Manjarrez‐Orduño, Nataly; Marasco, Emiliano; Chung, Sharon A.; Katz, Matthew S.; Kiridly, Jenna F; Simpfendorfer, Kim R.; Freudenberg, Jan; Ballard, Dean W.; Nashi, Emil; Hopkins, Thomas; Graham, Deborah S. Cunninghame; Lee, Annette T.; Coenen, Marieke J. H.; Franke, Barbara; Swinkels, Dorine W.; Graham, Robert; Kimberly, Robert P.; Gaffney, Patrick M.; Vyse, Timothy J.; Behrens, Timothy W.; Criswell, Lindsey A.; Diamond, Betty; Gregersen, Peter K.

doi:10.1038/ng.2439

Cited by 105 publications

(90 citation statements)

References 29 publications

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“…Thy1 and Cbl, among many others, also present as likely candidate genes for influencing the proportion of DN T cells. However, these genes have also been associated with autoimmune phenotype (52)(53)(54)(55)(56), and 3A9 TCR NOD.H2 k -Chr9S congenic mice exhibit little, if any, resistance to autoimmune diabetes, suggesting that the gene contributing to the DN T cell phenotype in the Chr9S interval is likely to be distinct from these. Still, it is possible that the Chr9S interval would contribute to diabetes resistance in a setting other than in the 3A9 TCR transgenic model, such that these candidate genes cannot be readily discarded.…”

Section: Discussionmentioning

confidence: 99%

The Mouse Idd2 Locus Is Linked to the Proportion of Immunoregulatory Double-Negative T Cells, a Trait Associated with Autoimmune Diabetes Resistance

Collin

Dugas

Pelletier

et al. 2014

The Journal of Immunology

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Autoimmune diseases result from a break in immune tolerance. Various mechanisms of peripheral tolerance can protect against autoimmunity, including immunoregulatory CD4−CD8− double-negative (DN) T cells. Indeed, we have previously shown that diabetes-prone mouse strains exhibit a low proportion of DN T cells relative to that of diabetes-resistant mice, and that a single autologous transfer of DN T cells can impede autoimmune diabetes development, at least in the 3A9 TCR transgenic setting. In this study, we aim to understand the genetic basis for the difference in DN T cell proportion between diabetes-resistant and diabetes-prone mice. We thus perform an unbiased linkage analysis in 3A9 TCR F2 (NOD.H2k × B10.BR) mice and reveal that a locus on chromosome 9, which coincides with Idd2, is linked to the proportion of DN T cells in the lymph nodes. We generate two NOD.H2k.B10-Chr9 congenic mouse strains and validate the role of this genetic interval in defining the proportion of DN T cells. Moreover, we find that the increased proportion of DN T cells in lymphoid organs is associated with a decrease in both diabetes incidence and serum IgG Ab levels. Together, the data suggest that Idd2 is linked to DN T cell proportion and that a physiological increase in DN T cell number may be sufficient to confer resistance to autoimmune diabetes. Altogether, these findings could help identify new candidate genes for the development of therapeutic avenues aimed at modulating DN T cell number for the prevention of autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

The Mouse Idd2 Locus Is Linked to the Proportion of Immunoregulatory Double-Negative T Cells, a Trait Associated with Autoimmune Diabetes Resistance

Collin

Dugas

Pelletier

et al. 2014

The Journal of Immunology

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“…LYP inhibits the responses of these cells to antigens. The mechanism of this action includes the binding and inhibition of the Csk kinase and an association of LYP with the adaptor protein CBL [1,2]. The single nucleotide polymorphisms (SNPs) of PTPN22 , predominantly p.Arg620Trp (c.1858C>T), are among the major causative agents of human autoimmune disorders.…”

Section: Introductionmentioning

confidence: 99%

Low Frequencies of Autoimmunity-Associated <b><i>PTPN22</i></b> Polymorphisms in MODY Patients, Including Those Transiently Expressing Islet Cell Autoantibodies

Heneberg¹,

Malá²,

Yorifuji³

et al. 2015

Int Arch Allergy Immunol

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Background: The protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene encodes lymphoid tyrosine phosphatase (LYP), which is expressed primarily in lymphoid tissues. The functional but geographically highly variable PTPN22 single-nucleotide polymorphisms (SNPs), particularly c.1858C>T, contribute to the onset and progression of autoimmunity-associated diseases and facilitate the expression of disease-associated autoantibodies. In Central Europe, 17-25% of patients with monogenic diabetes (maturity-onset diabetes of the young, MODY) transiently express islet cell autoantibodies. Methods: We addressed the links between the functional and geographically variable PTPN22 SNPs with MODY manifestation and the expression of islet cell autoantibodies in 276 MODY patients who originated from four regions (the Czech Republic, Israel, Japan and Brazil). Results: The frequency of PTPN22 polymorphisms in the MODY patients was similar to those in geographically matched healthy populations, with the exception of c.788G>A, the minor allele frequency of which was significantly elevated in the Czech hepatocyte nuclear factor 1-α (HNF1A) MODY patients [odds ratio (OR) 4.8, 95% confidence interval (CI) 2.2-10.7] and the Brazilian MODY patients (OR 8.4, 95% CI 1.8-39.1). A barely significant increase in the c.788G>A minor allele was also detected in the islet cell autoantibody-positive Czech MODY patients. However, c.788A behaves as a loss-of-function mutant in T cells, and thus protects against autoimmunity. Conclusions: MODY patients (including islet cell autoantibody-positive cases) do not display any increase in autoimmunity-associated PTPN22 alleles. The absence of autoimmunity-associated PTPN22 alleles was also demonstrated in latent autoimmune diabetes in adults, which suggests that the slow kinetics of the onset of autoantibodies is subject to a regulation that is different from that experienced in type 1 diabetes and other autoimmune disorders.

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“…Csk phosphorylates an inhibitory C-terminal regulatory tyrosine on Lyn. The disease-associated Csk allele leads to enhanced Lyn inactivation [132]. Lyn deficiency represents another compromised negative regulatory feedback pathway that contributes to B cell-mediated autoimmunity.…”

Section: Genes That Affect B Cell Activationmentioning

confidence: 99%

B Cells Producing Pathogenic Autoantibodies

Zou

Diamond

2015

Molecular Biology of B Cells

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CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation

Cited by 105 publications

References 29 publications

The Mouse Idd2 Locus Is Linked to the Proportion of Immunoregulatory Double-Negative T Cells, a Trait Associated with Autoimmune Diabetes Resistance

The Mouse Idd2 Locus Is Linked to the Proportion of Immunoregulatory Double-Negative T Cells, a Trait Associated with Autoimmune Diabetes Resistance

Low Frequencies of Autoimmunity-Associated <b><i>PTPN22</i></b> Polymorphisms in MODY Patients, Including Those Transiently Expressing Islet Cell Autoantibodies

B Cells Producing Pathogenic Autoantibodies

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