CD40‐CD40 ligand interaction in autoimmune disease

Datta, Somnath; Kalled, Susan L.

doi:10.1002/art.1780401002

Cited by 101 publications

(70 citation statements)

References 123 publications

(115 reference statements)

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“…The possibility remains, however, that epitope spreading may occur later in the response and account for subsequent progression of the polyreactivity of the serum response. This observation is consistent with a study by Goodnow and colleagues (7) demonstrating that autoreactive B cells are less susceptible to tolerance induction that autoreactive T cells.…”

Section: Discussionsupporting

confidence: 93%

“…Production of autoantibodies by B cells requires T cell help (34) and athymic MRL-lpr and NZB/NZW mice do not develop SLE (27,35,36). In addition, interference with T cell activation by blocking MHC class II TCR (2, 4), CD28-B7 (5, 6), or CD40-CD40 ligand interactions in several mouse models of SLE abrogates disease (7,8). Although doublenegative as well as CD8 ϩ T cells capable of providing the necessary signals for autoantibody production have been isolated from lupus patients, CD4 ϩ cells seem to be the primary cells responsible for initiating the autoimmune response.…”

Section: Discussionmentioning

confidence: 99%

“…The serum response in systemic lupus erythematosus (SLE) 2 contains autoreactivities to a variety of nuclear Ags, of which antidsDNA reactivity is the most important prognostic factor (1). In murine lupus models, disruption of T cell activation (2)(3)(4)(5)(6)(7)(8) or an absence of T cells (9,10) abrogates autoantibody production and glomerulonephritis. In addition, nephritogenic anti-dsDNA Abs are high affinity, somatically mutated IgG Abs, all of which are features of a T cell-dependent, Ag-driven immune response (11,12).…”

Section: T Cell Studies In a Peptide-induced Model Of Systemic Lupus mentioning

confidence: 99%

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T Cell Studies in a Peptide-Induced Model of Systemic Lupus Erythematosus

Khalil

Inaba

Steinman

et al. 2001

The Journal of Immunology

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We have previously reported that immunization with a peptide mimetope of dsDNA on a branched polylysine backbone (DWEYSVWLSN-MAP) induces a systemic lupus erythematosus-like syndrome in the nonautoimmune BALB/c mouse strain. To understand the mechanism underlying this breakdown in self tolerance, we examined the role of T cells in the response. Our results show that the anti-foreign and anti-self response induced by immunization is T cell dependent and is mediated by I-Ed-restricted CD4+ T cells of the Th1 subset. In addition, generation of the critical T cell epitope requires processing by APCs and depends on the presence of both DWEYSVWLSN and the MAP backbone. The breakdown in self tolerance does not occur through cross-reactivity between the T cell epitope of DWEYSVWLSN-MAP and epitopes derived from nuclear Ags. In this induced-model of SLE, therefore, autoreactivity results from the activation of T cells specific for foreign Ag and of cross-reactive anti-foreign, anti-self B cells. Despite the fact that tissue injury is mediated by Ab, the critical initiating T cell response is Th1.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: T Cell Studies In a Peptide-induced Model Of Systemic Lupus mentioning

confidence: 99%

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T Cell Studies in a Peptide-Induced Model of Systemic Lupus Erythematosus

Khalil

Inaba

Steinman

et al. 2001

The Journal of Immunology

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“…This expression would still have to be tightly regulated, because continued or prolonged CD154 expression contributes to autoimmunity in the form of SLE and other autoimmune disorders. 3,31,32 A better understanding of the cis-and trans-acting factors that participate in CD154 expression should assist in identifying those factors involved in CD154 dysregulation in autoimmune states. 14 or a dominant-negative version of GATA-3 (KRR mutant; full bars).…”

Section: Discussionmentioning

confidence: 99%

A T-cell-specific CD154 transcriptional enhancer located just upstream of the promoter

Brunner

Genin

et al. 2008

Genes Immun

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CD154 (CD40-ligand) is a critical immune regulator. CD154 expression is tightly regulated and largely restricted to activated CD4 T cells. Using DNase I hypersensitivity site (HSS) mapping, we identified two novel HSS mapping to the human CD154 promoter element and just upstream. Both HSS were activation independent and CD4 T-cell specific. Approximately 350 bp of DNA sequence flanking the upstream HSS site was highly conserved between mouse and man, and was rich in binding sites for GATA and NFAT proteins. Gel shift and chromatin immunoprecipitation assays demonstrated both NFAT1 and the Th2 factor, GATA-3, bound this enhancer element in vitro and in vivo, respectively. A PstI/XbaI 345 bp fragment of this region acted as a transcriptional enhancer of the CD154 promoter in primary human CD4 T cells. Overexpression of repressor of GATA and a dominant negative GATA-3 protein independently inhibited transcription, whereas overexpression of wild-type GATA-3 enhanced transcriptional activity, by this element in primary CD4 T cells. Moreover, more interleukin-4-producing CD4 T cells expressed CD154 following activation than interferon-g-producing CD4 T cells. Thus, we identified a novel T-cell-specific, GATA-3 responsive, CD154 transcriptional enhancer, which may contribute to increased propensity of Th2 cells to express CD154.

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“…Thus, we propose that EBV-induced CD40L͞CD40 signaling cooperates with LMP1 in B cell survival and transformation, as they can cooperate for B cell activation (24). On the other hand, it is noteworthy that several autoimmune diseases, such as systemic lupus erythematosus, are asso- ciated with EBV infection and the ectopic expression of CD40L on B cells (25,26). Because transgenic mice expressing CD40L on their B cells display symptoms of lupus-like disease, EBVinduced CD40L may be one of the etiologic agents for such human autoimmune diseases (27).…”

Section: Ebv Infection Of T Cells Is Associated With Ectopic Expressimentioning

confidence: 99%

CD40 ligand is a critical effector of Epstein–Barr virus in host cell survival and transformation

Imadome

Shirakata

Shimizu

et al. 2003

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

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Epstein-Barr virus (EBV),E pstein-Barr virus (EBV), a ubiquitous human lymphotropic herpesvirus, is a cause of lymphoproliferative diseases in immunosuppressed patients and infectious mononucleosis and is tightly associated with lymphoid malignancies such as Burkitt's lymphoma and T cell͞natural killer cell lymphoma (1). EBV infection is also associated with epithelial malignancies such as nasopharyngeal carcinoma and gastric carcinoma. An important biological property of EBV, which rationalizes its tight link to cancer, is an ability to transform peripheral B cells in terms of their continuous growth in vitro and to establish latently infected lymphoblastoid cell lines (LCLs), which eventually become immortalized (1). LCLs express nine viral proteins: six EBV nuclear antigens (EBNA1-EBNA6) and three latent membrane proteins (LMP1, LMP2A, and LMP2B). Among them, an integral membrane protein, LMP1, is believed to be a key regulator of the B cell transformation, mainly because it transforms fibroblasts or epithelial cells and also induces B cell lymphoma in transgenic mice (1, 2). However, LMP1 expression is insufficient to maintain B cell proliferation, which needs, at least, a second signal (3).CD40 is a membrane-bound protein of the tumor necrosis factor (TNF) receptor family and is expressed on many cell types including B cells. Its ligand, CD40 ligand (CD40L), is a member of the TNF family and expressed mainly on activated T cells. CD40-CD40L interaction is crucial to B cells for their proliferation, survival, Ig istotype switching, and germinal center reaction upon stimulation by activated T cells (4). For instance, mutations in the CD40L gene were identified as the cause of X-linked hyper IgM syndrome (XHIM), a disease associated with drastic, if not complete, inhibition in T cell-dependent humoral immune responses (4, 5). Mice null for CD40 or CD40L had severe defects not only in their Ig isotype switching, but also in germinal center formation and establishment of B cell memory (4, 6). That we had very few LCLs from XHIM B cells upon EBV infection led us to investigate whether CD40L and CD40 play a role in EBV infection and͞or subsequent B cell transformation. Materials and MethodsReagents. For flow cytometry, mAbs to CD40 (5C3, PharMingen), CD40L (TRAP1, PharMingen), CD3 (Leu-4, PharMingen), and CD19 (HD37, DAKO) and isotype-matched control Ig (PharMingen) were used. For immunoblot analysis, mAb to LMP1 (S12, a gift from E. Kieff, Harvard Medical School, Boston) (7, 8) and a goat polyclonal antibody to ␤-actin (I-19, Santa Cruz Biotechnology) were used. For CD40 stimulation in LCL analysis, an agonistic mAb to CD40 (mAb89, Immunotech, Luminy, France) was used (9). For CD40L blocking, CD40Ig, a fusion protein of mouse CD40 (amino acids 1-193) and the Fc region of mouse IgG 2a , was used. The CD40Ig was expressed in Sf9 cells by using the baculovirus vector plasmid pFastBacmCD40͞m␥2a (a gift from M. R. Kehry, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT) and purified to homogeneity (Ͼ95%) with prot...

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CD40‐CD40 ligand interaction in autoimmune disease

Cited by 101 publications

References 123 publications

T Cell Studies in a Peptide-Induced Model of Systemic Lupus Erythematosus

T Cell Studies in a Peptide-Induced Model of Systemic Lupus Erythematosus

A T-cell-specific CD154 transcriptional enhancer located just upstream of the promoter

CD40 ligand is a critical effector of Epstein–Barr virus in host cell survival and transformation

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