PTPN22 Deficiency Cooperates with the CD45 E613R Allele to Break Tolerance on a Non-Autoimmune Background

University of California, San Francisco, 94143, USA.
The Journal of Immunology (Impact Factor: 5.36). 05/2009; 182(7):4093-106. DOI: 10.4049/jimmunol.0803317
Source: PubMed

ABSTRACT Pep and CD45 are tyrosine phosphatases whose targets include the Src-family kinases, critical mediators of Ag receptor signaling. A polymorphism in PTPN22, the gene that encodes the human Pep orthologue Lyp, confers susceptibility to multiple human autoimmune diseases in the context of complex genetic backgrounds. However, the functional significance of the R620W risk allele is not clear. We report that misexpression of wild-type or R620W Pep/Lyp in Jurkat cells, in the context of its binding partner Csk, unmasks the risk allele as a hypomorph. It has been shown previously that although Pep-deficient mice on the B6 background have hyperresponsive memory T cells, autoimmunity does not develop. Mice containing a point mutation in the CD45 juxtamembrane wedge domain (E613R) develop a B cell-driven, lupus-like disease on the mixed 129/B6 background, but not on the B6 background. We studied the ability of Pep deficiency to act as a genetic modifier of the CD45 E613R mutation on the nonautoimmune B6 background to understand how complex susceptibility loci might interact in autoimmunity. In this study we report that double mutant mice develop a lupus-like disease as well as lymphadenopathy, polyclonal lymphocyte activation, and accelerated memory T cell formation. Following Ag receptor stimulation, peripheral B cells in the double mutant mice phenocopy hyperresponsive CD45 E613R B cells, whereas peripheral T cells respond like Pep(-/-) T cells. These studies suggest that Pep(-/-) T cells in the context of a susceptible microenvironment can drive hyperresponsive CD45 E613R B cells to break tolerance.

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Available from: Arthur Weiss, Jun 30, 2014
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    • "In murine systems, mutations conferring BCR hyperresponsiveness , such as those involving negative signaling molecules such as SHP-1 (Zouali & Sarmay, 2004), CD22 (O'Keefe et al., 1999), or FCγRIIb (Fukuyama et al., 2005), are associated with a SLE-like disease. On the other hand, mutations involving positive regulators such as CD45 can disrupt immune tolerance via constitutive activation of Src kinases, leading to autoantibody production (Zikherman et al., 2009). Given the central role of SYK and BTK in transmission of antigen receptor signals that are critical for autoantibody production and the various innate immune effector functions discussed above (Table 2), pharmacological inhibition of the catalytic function of these enzymes is expected to have pleiotropic anti-inflammatory effects and impact multiple steps in the pathogenesis of autoimmune disorders. "
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    ABSTRACT: Spleen Tyrosine Kinase (SYK) and Bruton's Tyrosine Kinase (BTK) are non-receptor cytoplasmic tyrosine kinases that are primarily expressed in cells of hematopoietic lineage. Both are key mediators in coupling activated immunoreceptors to downstream signaling events that affect diverse biological functions, from cellular proliferation, differentiation and adhesion to innate and adaptive immune responses. As such, pharmacological inhibitors of SYK or BTK are being actively pursued as potential immunomodulatory agents for the treatment of autoimmune and inflammatory disorders. Deregulation of SYK or BTK activity has also been implicated in certain hematological malignancies. To date, from a clinical perspective, pharmacological inhibition of SYK activity has demonstrated encouraging efficacy in patients with rheumatoid arthritis (RA), while patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) have benefited from covalent inhibitors of BTK in early clinical studies. Here, we review and discuss recent insights into the emerging role of the SYK-BTK axis in innate immune cell function as well as in the maintenance of survival and homing signals for tumor cell progression. The current progress on the clinical development of SYK and BTK inhibitors is also highlighted.
    Pharmacology [?] Therapeutics 02/2013; 138. DOI:10.1016/j.pharmthera.2013.02.001 · 7.75 Impact Factor
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    • "To date, there have been no reports that PEP deficient mice are more susceptible to autoimmune or lymphoproliferative disease. One group have shown, however, that mice deficient of PEP which also harbour a CD45 SNP encoding a constitutively active phosphatase that positively regulates antigen receptor signalling cooperate to break tolerance [83] "
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    ABSTRACT: The PTPN22 locus is one of the strongest risk factors outside of the major histocompatability complex that associates with autoimmune diseases. PTPN22 encodes lymphoid protein tyrosine phosphatase (Lyp) which is expressed exclusively in immune cells. A single base change in the coding region of this gene resulting in an arginine to tryptophan amino acid substitution within a polyproline binding motif associates with type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosis, Hashimotos thyroiditis, Graves disease, Addison's disease, Myasthenia Gravis, vitiligo, systemic sclerosis juvenile idiopathic arthritis and psoriatic arthritis. Here, we review the current understanding of the PTPN22 locus from a genetic, geographical, biochemical and functional perspective.
    FEBS letters 04/2011; 585(23):3689-98. DOI:10.1016/j.febslet.2011.04.032 · 3.34 Impact Factor
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    • "This activity was linked to the ability of PTP-PEST to dephosphorylate Src kinases, FAK, Pyk2, Shc, or WASP. Thus, like LYP (Zikherman et al., 2009; Hasegawa et al., 2004), PTP-PEST may be a negative regulator of T cell activation. However, the physiological relevance of this effect has not been confirmed because conventional PTP-PEST-deficient mice exhibit an early embryonic lethality (Sirois et al., 2006). "
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    ABSTRACT: PTP-PEST (encoded by Ptpn12) is an intracellular protein tyrosine phosphatase belonging to the same family as LYP. LYP inhibits secondary T cell responses by suppressing Src family protein tyrosine kinases and is implicated in human autoimmunity. To determine the function of PTP-PEST in T cells, we generated mice with a conditionally deleted allele of Ptpn12. By removing PTP-PEST in T cells, we determined that PTP-PEST was not necessary for T cell development or primary responses. However, PTP-PEST was required for secondary T cell responses, anergy prevention, and autoimmunity induction. PTP-PEST specifically regulated the phosphorylation of Pyk2, a substrate of the Src family kinase Fyn. It also promoted the formation of T cell homoaggregates, which are known to enhance T cell activation. Thus, PTP-PEST controls Pyk2 activity and is a positive regulator of secondary T cell activation. These data illustrate the critical role of protein tyrosine phosphatases in T cell regulation.
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