Reversal of Spontaneous Autoimmune Insulitis in Nonobese Diabetic Mice by Soluble Lymphotoxin Receptor

Wu, Qiang; Salomon, Benoı̂t L.; Chen, Min; Wang, Yang; Hoffman, Lisa; Bluestone, Jeffrey A.; Fu, Yang–Xin

doi:10.1084/jem.193.11.1327

Cited by 117 publications

(100 citation statements)

References 21 publications

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“…They show that in NOD mice, which spontaneously develop insulin-dependent diabetes mellitus due to T cell-dependent destruction of insulin-producing β cells, the neutralization of LIGHT signaling via HVEM-Fc decoy receptor decreases the incidence of diabetes. This conclusion is supported in tumor and allograft models as well (11,12).…”

supporting

confidence: 64%

Turning on LIGHT

Granger

Ware

2001

J. Clin. Invest.

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The delicate balance between the proliferation and elimination of antigenactivated lymphocytes achieves homeostasis in peripheral lymphoid tissues. The TNF-related cytokines activate cellular differentiation, survival, and death pathways that orchestrate tissue development, organization, and homeostasis (1). Several members of the TNF superfamily of cytokines play opposing roles in lymphocyte homeostasis by enhancing effector cell activation and survival, or by cellular elimination through apoptosis.Emerging evidence indicates that a recently defined member of the TNF superfamily, LIGHT (TNFSF14), plays a key role in T cell homeostasis. Studies by Wang et al. (2), in this issue of the JCI, and Shaikh et al. (3) reveal that sustained expression of LIGHT causes profound inflammation and loss of tolerance leading to autoimmune syndromes. These new findings validate LIGHT as an important T cell regulatory molecule and suggest its candidacy as a pharmaceutical target for diseases involving T cells.LIGHT is structurally and functionally an integral member of the immediate TNF family, defined by a close structural homology and a communal pattern of receptor-ligand pairing with lymphotoxin-αβ (LTαβ), LTα, and Fas ligand (4, 5). LIGHT is a type II transmembrane protein, produced by activated T cells and immature dendritic cells, that signals through two distinct cellular receptors: the herpesvirus entry mediator (HVEM), which is expressed prominently on T cells, and the LTβ receptor (LTβR), which is expressed on stromal cells but absent from lymphocytes. LIGHT has been proposed to mediate T cell activation, survival, or death, and also -by analogy with LTαβ -to help organize lymphoid tissues (6). Indeed, results in tissue culture models appear to support a role for LIGHT in T cell activation (7,8), although the responses of T cells to LIGHT signaling in vitro are rather subtle. The phenotype of mice expressing ectopic LIGHT is anything but subtle.The studies by Wang et al. (2) and Shaikh et al. (3) demonstrate that constitutive expression of LIGHT leads to profound inflammation caused by activated T cells. Normally, LIGHT is transiently expressed on the surface of T cells following activation, but in the studies highlighted here, the proximal lck (2) or CD2 (3) promoters drive the constitutive expression of LIGHT in T cells. At several months of age, both lines of LIGHT transgenic mice show lymphoid tissue abnormalities, including splenomegaly, lymphadenopathy, and pronounced inflammation in the intestine, consisting of expanded populations of conventional CD4 + and CD8 + αβ T cells. The inflamed intestines show signs of chronic processes including loss of goblet cells, distortion and hyperplasia of crypts, villous atrophy, and mononuclear cell infiltrates. Remarkably, an LTβR-Fc decoy receptor (a chimera of the receptor's ligand-binding domain for LIGHT fused with the Fc region of IgG that neutralizes both LIGHT and LTαβ) prevents colitis in a CD4 T cell-dependent transfer model (9). In this model, expression of LTαβ in...

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supporting

confidence: 64%

Turning on LIGHT

Granger

Ware

2001

J. Clin. Invest.

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“…Treatment with LT␤R-Ig can also reverse established insulitis and prevent diabetes (38). Because LT␤R is expressed on several cell types in the LN, including HEV and lymphatic vessel endothelial cells, dendritic cells, and stromal cells (28,(39)(40)(41), LT␤R-Ig treatment can have extensive effects on LN.…”

Section: Discussionmentioning

confidence: 99%

Transgenic LacZ under control of Hec-6st regulatory sequences recapitulates endogenous gene expression on high endothelial venules

Liao

Bentley

Lebrun

et al. 2007

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

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Hec-6st is a highly specific high endothelial venule (HEV) gene that is crucial for regulating lymphocyte homing to lymph nodes (LN). The enzyme is also expressed in HEV-like vessels in tertiary lymphoid organs that form in chronic inflammation in autoimmunity, graft rejection, and microbial infection. Understanding the molecular nature of Hec-6st regulation is crucial for elucidating its function in development and disease. However, studies of HEV are limited because of the difficulties in isolating and maintaining the unique characteristics of these vessels in vitro. The novel pClasper yeast homologous recombination technique was used to isolate from a BAC clone a 60-kb DNA fragment that included the Hec-6st (Chst4) gene with flanking sequences. Transgenic mice were generated with the ␤-galactosidase (LacZ) reporter gene inserted in-frame in the exon II of Hec-6st within the isolated BAC DNA fragment. LacZ was expressed specifically on HEV in LN, as indicated by its colocalization with peripheral node vascular addressin. LacZ was increased in nasal-associated lymphoid tissue during development and was reduced in LN and nasal-associated lymphoid tissue by LT␤R-Ig (lymphotoxin-␤ receptor human Ig fusion protein) treatment in a manner identical to the endogenous gene.The transgene was expressed at high levels in lymphoid accumulations with characteristics of tertiary lymphoid organs in the salivary glands of aged mice. Thus, the Hec-6st-LacZ construct faithfully reproduces Hec-6st tissue-specific expression and can be used in further studies to drive expression of reporter or effector genes, which could visualize or inhibit HEV in autoimmunity.lymphoid organ ͉ pClasper ͉ peripheral node vascular addressin ͉ sulfotransferase ͉ lymphotoxin H igh endothelial venules (HEV) are the site of entry of naïve lymphocytes into the lymph node (LN) parenchyma from the blood stream. Lymphocyte tethering along HEV in LN is mediated by the interaction of L-selectin expressed on the surface of lymphocytes and L-selectin ligands expressed on HEV.

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“…In most autoimmune diseases, activation of dendritic cells and the subsequent presentation of autoantigens seem to be crucial steps in the breakdown of tolerance and development of local autoimmune inflammation (2)(3)(4). There is evidence that in tissue-specific autoimmune diseases, the process of dendritic cell activation and antigen presentation occurs in the target organ itself and is often associated with local neoformation of lymphoid structures (5)(6)(7). In this context, the formal demonstration of local autoantigen presentation in the target organ is of major interest, because it may be a specific event characterizing the development of tissue-specific autoimmune inflammation.…”

mentioning

confidence: 99%

Detection of major histocompatibility complex/human cartilage gp‐39 complexes in rheumatoid arthritis synovitis as a specific and independent histologic marker

Baeten¹,

Steenbakkers²,

Rijnders³

et al. 2004

Arthritis & Rheumatism

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Clinically, there were no correlations between mAb 12A staining and clinical or biologic parameters in RA. However, positive staining was observed in 61.5% of the inflamed RA synovial samples compared with only 3.0% of the control samples (P < 0.001). This mAb 12A staining was not related to intracellular citrullinated peptides, which are another specific histologic marker for RA.Conclusion. Presentation by synovial dendritic cells of the immunodominant epitope of HC gp-39, in the context of the shared epitope, is associated with characteristic histologic features of follicular synovitis and is highly specific for RA. This suggests a contribution to the autoimmune-related tissue inflammation and provides a new and independent tool for the immunopathologic diagnosis of RA.

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Reversal of Spontaneous Autoimmune Insulitis in Nonobese Diabetic Mice by Soluble Lymphotoxin Receptor

Cited by 117 publications

References 21 publications

Turning on LIGHT

Turning on LIGHT

Transgenic LacZ under control of Hec-6st regulatory sequences recapitulates endogenous gene expression on high endothelial venules

Detection of major histocompatibility complex/human cartilage gp‐39 complexes in rheumatoid arthritis synovitis as a specific and independent histologic marker

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