SHP-1 deficiency and increased inflammatory gene expression in PBMCs of multiple sclerosis patients

Christophi, George P.; Hudson, Chad A.; Gruber, Ross C.; Christophi, Christoforos P; Mihai, Cornelia; Mejico, Luis J.; Jubelt, Burk; Massa, Paul T.

doi:10.1038/labinvest.3700720

Cited by 56 publications

(81 citation statements)

References 88 publications

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“…The amount of SHP-1 levels may also be important for mediating autoimmune disease as Deng et al (43) reported enhanced EAE disease severity, more frequent relapses, and decreased survival following immunization of B10.PL me-v mice with myelin basic protein Ac 1-11. A further role for SHP-1 in the autoimmune T cell response is supported by the recent report detailing decreased SHP-1 gene activity in PBMC's of MS patients (44). Together, our results and the published findings highlight SHP-1 as an important point of control for autoimmune T cell responses.…”

Section: Discussionsupporting

confidence: 79%

MHC Variant Peptide-Mediated Anergy of Encephalitogenic T Cells Requires SHP-1

Wasserman

Beal

Zhang

et al. 2008

The Journal of Immunology

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Our lab has demonstrated that encephalitogenic T cells can be effectively anergized by treatment with MHC variant peptides, which are analogues of immunogenic peptides containing an amino acid substitution at an MHC anchor residue. The MHC variant peptide of myelin oligodendrocyte glycoprotein (MOG)35–55 proves an effective treatment as it does not induce symptoms of experimental autoimmune encephalomyelitis and fails to recruit macrophages or MOG35–55-specific T cells to the CNS. In this study, we sought to characterize the signaling pathways required for the induction of anergy by building upon the observations identifying the tyrosine phosphatase SHP-1 as a critical regulator of T cell responsiveness. Motheaten viable heterozygous mice, which contain a mutation in the SHP-1 gene resulting in a reduction in functional SHP-1, were challenged with MOG35–55 or the MOG35–55 MHC variant 45D. These mice display symptoms of experimental autoimmune encephalomyelitis upon immunization with MHC variant peptide and have significant CNS infiltration of tetramer-positive CD4+ cells and macrophages, unlike B6 mice challenged with the variant peptide. The effects of SHP-1 are directly on the T cell as Motheaten viable heterozygous mice autoreactive T cells are not anergized in vitro. Lastly, we demonstrate no distinguishable difference in the initial interaction between the TCR and agonist or MHC variant. Rather, an unstable interaction between peptide and MHC attenuates the T cell response, seen in a decreased half-life relative to MOG35–55. These results identify SHP-1 as a mediator of T cell anergy induced by destabilized peptide:MHC complexes.

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Section: Discussionsupporting

confidence: 79%

MHC Variant Peptide-Mediated Anergy of Encephalitogenic T Cells Requires SHP-1

Wasserman

Beal

Zhang

et al. 2008

The Journal of Immunology

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“…Taken together, the findings of these studies indicate that SHP-1 is a key regulator of inflammation in the CNS that may be relevant to the pathogenesis of MS. Indeed, we have recently reported that SHP-1 expression and function are deficient in the leukocytes of MS patients compared to those in the leukocytes of normal human subjects (21).…”

mentioning

confidence: 99%

“…For instance, macrophages have been identified as the major responders to CNS chemokines and producers of a number of proinflammatory cytokines, chemokines, and toxic molecules known to promote demyelination (32,44,63,85,90,91,93,103). Interestingly, both the brains of MS patients and the brains of experimental animals with MS-like diseases contain activated transcription factors like NF-B (34, 40), STAT1 (35,37,40), and STAT6 (18,21,109), which can lead to enhanced expression of these inflammatory molecules. Based on the findings of our previous work, we propose that the modulation of inflammatory signaling via these transcriptional pathways may be deficient in the leukocytes, including the macrophages, of MS patients and that this deficiency is responsible for susceptibility to inflammatory demyelinating processes within the CNS.…”

mentioning

confidence: 99%

Modulation of Macrophage Infiltration and Inflammatory Activity by the Phosphatase SHP-1 in Virus-Induced Demyelinating Disease

Christophi

Hudson

Panos³

et al. 2009

J Virol

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The protein tyrosine phosphatase SHP-1 is a crucial negative regulator of cytokine signaling and inflammatory gene expression, both in the immune system and in the central nervous system (CNS). Mice genetically lacking SHP-1 (me/me) display severe inflammatory demyelinating disease following inoculation with the Theiler's murine encephalomyelitis virus (TMEV) compared to infected wild-type mice. Therefore, it became essential to investigate the mechanisms of TMEV-induced inflammation in the CNS of SHP-1-deficient mice. Herein, we show that the expression of several genes relevant to inflammatory demyelination in the CNS of infected me/me mice is elevated compared to that in wild-type mice. Furthermore, SHP-1 deficiency led to an abundant and exclusive increase in the infiltration of high-level-CD45-expressing (CD45 hi ) CD11b Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) that remains a major cause of disability (76). Several studies demonstrated that MS lesions contain multiple leukocyte cell types, including lymphocytes, macrophages, and dendritic cells, all of which are believed to contribute to lesion formation by various distinct and interacting mechanisms (54, 61). Among these leukocyte subsets, infiltrating macrophages have been identified as major effectors of demyelination in both MS and animal models for MS (17,44,59,102). In accord with these studies, it was recently reported that the dominant mechanism of demyelination in MS is macrophage mediated (15). Indeed, in some models for MS, the requirement for lymphocytes is negligible and macrophages are the sole mediators of demyelination (6, 72).These findings have stimulated intense interest in the function of macrophages in lesion formation, including signaling events that draw these cells into the CNS white matter and trigger the effector mechanisms by which these cells damage myelin. For instance, macrophages have been identified as the major responders to CNS chemokines and producers of a number of proinflammatory cytokines, chemokines, and toxic molecules known to promote demyelination (32,44,63,85,90,91,93,103). Interestingly, both the brains of MS patients and the brains of experimental animals with MS-like diseases contain activated transcription factors like NF-B (34, 40), STAT1 (35,37,40), and STAT6 (18,21,109), which can lead to enhanced expression of these inflammatory molecules. Based on the findings of our previous work, we propose that the modulation of inflammatory signaling via these transcriptional pathways may be deficient in the leukocytes, including the macrophages, of MS patients and that this deficiency is responsible for susceptibility to inflammatory demyelinating processes within the CNS.SHP-1 is a protein tyrosine phosphatase with two Src homology 2 domains which acts as a negative regulator of both innate and acquired immune cytokine signaling via NF-B (52, 67), STAT1 (29,68), and STAT6 (13,43,45,50). Mice genetically lacking SHP-1 (motheaten mice) display myelin de...

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“…SHP-1 mRNA and protein expression and that MS patients have elevated levels of inflammatory gene expression controlled by SHP-1 (Christophi et al 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Loss of SHP-1 in the CNS as seen in motheaten (me/ me) mice leads to myelin pathology (Massa et al 2000(Massa et al , 2004 that may be caused by effects of an increased inflammatory milieu and/or specific alterations in cytokine signaling on the myelin-forming oligodendrocytes. Importantly, it was recently shown that leukocytes of MS patients have decreased levels of the phosphatase SHP-1, which results in increased inflammatory gene expression (Christophi et al 2008). Furthermore, SHP-1 plays a critical role in fighting CNS viral infections such as Theiler's murine encephalomyelitis virus (TMEV) (Massa et al 2002).…”

mentioning

confidence: 99%

Promoter‐specific induction of the phosphatase SHP‐1 by viral infection and cytokines in CNS glia

Christophi¹,

Hudson²,

Gruber³

et al. 2008

Journal of Neurochemistry

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We have previously shown that the protein tyrosine phosphatase SHP-1 is highly expressed in CNS glia and is an important modulator of cytokine signaling. As such, mice genetically lacking SHP-1 display constitutive myelin abnormalities, severe virus-induced demyelinating disease, and defects in innate anti-viral responses in the CNS. In this study, we show the differential distribution of the SHP-1 promoterspecific transcripts and demonstrate that several cytokines significantly induce SHP-1 expression in CNS glia. Consistent with these cytokine effects, infection with a neurotropic virus both in vitro and in vivo up-regulates SHP-1 transcripts and protein in CNS cells. Using CNS glial cultures of gene knockout mice, we show that interferons-b and interferons-c act through STAT-1 and interferon regulatory factor-1 to induce the SHP-1 promoter I transcripts. Conversely, interferons-b and IL-6 act through STAT-3 to induce SHP-1 promoter II transcripts. This study demonstrates that interferons and other cytokines associated with virus infections in the CNS can significantly induce the expression of SHP-1 through STAT-1/3 activity and provides a better understanding of the molecular mechanisms regulating cytokine-induced expression important for multiple homeostatic functions of SHP-1 in the CNS.

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SHP-1 deficiency and increased inflammatory gene expression in PBMCs of multiple sclerosis patients

Cited by 56 publications

References 88 publications

MHC Variant Peptide-Mediated Anergy of Encephalitogenic T Cells Requires SHP-1

MHC Variant Peptide-Mediated Anergy of Encephalitogenic T Cells Requires SHP-1

Modulation of Macrophage Infiltration and Inflammatory Activity by the Phosphatase SHP-1 in Virus-Induced Demyelinating Disease

Promoter‐specific induction of the phosphatase SHP‐1 by viral infection and cytokines in CNS glia

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