Lymphotoxin-LIGHT Pathway Regulates the Interferon Signature in Rheumatoid Arthritis

Bienkowska, Jadwiga; Allaire, Norm; Thai, Alice; Goyal, Jaya; Plavina, Tatiana; Nirula, Ajay; Weaver, Megan; Newman, Charlotte; Petri, Michelle; Beckman, Evan M.; Browning, Jeffrey L.

doi:10.1371/journal.pone.0112545

Cited by 48 publications

(39 citation statements)

References 75 publications

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“…Importantly, a recently published clinical trial in psoriatic arthritis has shown that LTbR-Ig therapy has the capacity to reduce the IFN-I signature in those arthritic patients that exhibit such a signature pretreatment, linking the LT pathway with IFN-I production in humans in vivo (53). In conclusion, inhibitors of the LT pathway, through their effect on IFN-I production, may have therapeutic potential in CD8 + T cell-driven disease states.…”

Section: Discussionmentioning

confidence: 92%

A Lymphotoxin/Type I IFN Axis Programs CD8+ T Cells To Infiltrate a Self-Tissue and Propagate Immunopathology

Maître

Cummings

et al. 2015

The Journal of Immunology

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Type I IFNs (IFN-I) are cytokines that can mediate both immune suppression and activation. Dendritic cells (DC) are significant producers of IFN-I, and depending on the context (nature of Ag, duration of exposure to Ag), DC-derived IFN-I can have varying effects on CD8+ T cell responses. In this study, we report that in the context of a CD8+ T cell response to a self-Ag, DC-intrinsic expression of IFN regulatory factor 3 is required to induce optimal proliferation and migration of autoreactive CD8+ T cells, ultimately determining their ability to infiltrate a target tissue (pancreas), and the development of glucose intolerance in rat insulin promoter–glycoprotein (RIP-GP) mice. Moreover, we show that signals through the lymphotoxin-β receptor (LTβR) in DC are also required for the proliferation of autoreactive CD8+ T cells, the upregulation of VLA4/LFA1 on activated CD8+ T cells, and their subsequent infiltration into the pancreas both in vitro and in vivo. Importantly, the defects in autoreactive CD8+ T cell proliferation, accumulation of CD8+ T cells in the pancreas, and consequent glucose intolerance observed in the context of priming by LTβR−/− DC could be rescued by exogenous addition of IFN-I. Collectively, our data demonstrate that the LTβR/IFN-I axis is essential for programming of CD8+ T cells to mediate immunopathology in a self-tissue. A further understanding of the IFN-I/LTβR axis will provide valuable therapeutic insights for treatment of CD8+ T cell–mediated autoimmune diseases.

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Section: Discussionmentioning

confidence: 92%

A Lymphotoxin/Type I IFN Axis Programs CD8+ T Cells To Infiltrate a Self-Tissue and Propagate Immunopathology

Maître

Cummings

et al. 2015

The Journal of Immunology

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“…This finding, together with other RA and animal studies (10,36,44,45), indicates that these genes could be important for the development of arthritis. One recent study demonstrated the linkage between the Lymphotoxin/LIGHT axis and IFN responses in RA patients and suggested that Lymphotoxin/LIGHT could act as an upstream modulator of IFN-signaling genes in RA (46). Furthermore, similar to our observations in DA.1HR56D rats, we found that the group of patients with mild RA showed lower expression of LST1 and higher expression of NCR3 than the group of patients with severe RA, indicating that LST1 and NCR3 could be associated with the severity of arthritis.…”

Section: Discussionmentioning

confidence: 99%

Conserved 33-kb haplotype in the MHC class III region regulates chronic arthritis

Yau

Tuncel

Haag

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Genome-wide association studies have revealed many genetic loci associated with complex autoimmune diseases. In rheumatoid arthritis (RA), the MHC gene HLA-DRB1 is the strongest candidate predicting disease development. It has been suggested that other immune-regulating genes in the MHC contribute to the disease risk, but this contribution has been difficult to show because of the strong linkage disequilibrium within the MHC. We isolated genomic regions in the form of congenic fragments in rats to test whether there are additional susceptibility loci in the MHC. By both congenic mapping in inbred strains and SNP typing in wild rats, we identified a conserved, 33-kb large haplotype Ltab-Ncr3 in the MHC-III region, which regulates the onset, severity, and chronicity of arthritis. The Ltab-Ncr3 haplotype consists of five polymorphic immunoregulatory genes: Lta (lymphotoxin-α), Tnf, Ltb (lymphotoxin-β), Lst1 (leukocyte-specific transcript 1), and Ncr3 (natural cytotoxicity-triggering receptor 3). Significant correlation in the expression of the Ltab-Ncr3 genes suggests that interaction of these genes may be important in keeping these genes clustered together as a conserved haplotype. We studied the arthritis association and the spliceo-transcriptome of four different Ltab-Ncr3 haplotypes and showed that higher Ltb and Ncr3 expression, lower Lst1 expression, and the expression of a shorter splice variant of Lst1 correlate with reduced arthritis severity in rats. Interestingly, patients with mild RA also showed higher NCR3 expression and lower LST1 expression than patients with severe RA. These data demonstrate the importance of a conserved haplotype in the regulation of complex diseases such as arthritis.arthritis | major histocompatibility complex | congenic mapping | haplotype | inflammation

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“…Additionally, genetic deletion of LIGHT protects mice from lung and skin inflammation and tissue remodelling in models of SSc 144,149 . Despite these results, targeting the LTαβ–LIGHT axis with baminercept, a soluble LTβR-Fc fusion protein, did not demonstrate clinical efficacy in RA and Sjögren’s syndrome (TABLE 1), although some modulation of immune reactivity was noted 150 . A caveat of these trials was the recruitment of difficult-to-treat patient populations that had previously shown inadequate responses to TNF inhibitors or other DMARDs.…”

Section: Increasing Tissue Inflammationmentioning

confidence: 99%

Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases

2017

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TNF blockers are highly efficacious at dampening inflammation and reducing symptoms in rheumatic diseases such as rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, and also in nonrheumatic syndromes such as inflammatory bowel disease. As TNF belongs to a superfamily of 19 structurally related proteins that have both proinflammatory and anti-inflammatory activity, reagents that disrupt the interaction between proinflammatory TNF family cytokines and their receptors, or agonize the anti-inflammatory receptors, are being considered for the treatment of rheumatic diseases. Biologic agents that block B cell activating factor (BAFF) and receptor activator of nuclear factor-κB ligand (RANKL) have been approved for the treatment of systemic lupus erythematosus and osteoporosis, respectively. In this Review, we focus on additional members of the TNF superfamily that could be relevant for the pathogenesis of rheumatic disease, including those that can strongly promote activity of immune cells or increase activity of tissue cells, as well as those that promote death pathways and might limit inflammation. We examine preclinical mouse and human data linking these molecules to the control of damage in the joints, muscle, bone or other tissues, and discuss their potential as targets for future therapy of rheumatic diseases.

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Lymphotoxin-LIGHT Pathway Regulates the Interferon Signature in Rheumatoid Arthritis

Cited by 48 publications

References 75 publications

A Lymphotoxin/Type I IFN Axis Programs CD8+ T Cells To Infiltrate a Self-Tissue and Propagate Immunopathology

A Lymphotoxin/Type I IFN Axis Programs CD8+ T Cells To Infiltrate a Self-Tissue and Propagate Immunopathology

Conserved 33-kb haplotype in the MHC class III region regulates chronic arthritis

Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases

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