Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production.

Desai-Mehta, Ami; Lu, Liping; Ramsey‐Goldman, Rosalind; Datta, Somnath

doi:10.1172/jci118643

Cited by 481 publications

(361 citation statements)

References 69 publications

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“…These studies thus suggest that T cell CD70 is required for the abnormal B cell stimulation in lupus. The present studies also suggest that CD70 overexpression on lupus T cells might contribute to B cell stimulation, together with other molecules, such as CD40L (35), and that inhibiting any of the costimulatory molecules is sufficient to decrease the antibody response to normal levels. Furthermore, IL-10, which is elevated in the serum of patients with SLE (36), is synergistic with the effects of CD27-CD70 interactions, which may lead to further increases in immunoglobulin synthesis (37).…”

Section: Discussionsupporting

confidence: 59%

Overexpression of CD70 and overstimulation of IgG synthesis by lupus T cells and T cells treated with DNA methylation inhibitors

Oelke¹,

Lu²,

Richardson³

et al. 2004

Arthritis & Rheumatism

220

182

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Objective. Generalized DNA hypomethylation contributes to altered T cell function and gene expression in systemic lupus erythematosus (SLE). Some of the overexpressed genes participate in the disease process, but the full repertoire of genes affected is unknown. Methylation-sensitive T cell genes were identified by treating T cells with the DNA methyltransferase inhibitor 5-azacytidine and comparing gene expression with oligonucleotide arrays. CD70, a costimulatory ligand for B cell CD27, was one gene that reproducibly increased. We then determined whether CD70 is overexpressed on T cells treated with other DNA methylation inhibitors and on SLE T cells, and determined its functional significance.Methods. Oligonucleotide arrays, real-time reverse transcription-polymerase chain reaction, and flow cytometry were used to compare CD70 expression in T cells treated with 2 DNA methyltransferase inhibitors (5-azacytidine and procainamide) and 3 ERK pathway inhibitors known to decrease DNA methyltransferase expression (U0126, PD98059, and hydralazine). The consequences of CD70 overexpression were tested by coculture of autologous T and B cells with and without anti-CD70 and measuring IgG production by enzymelinked immunosorbent assay. The results were compared with those of T cells from lupus patients. Results. SLE T cells and T cells treated with

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Section: Discussionsupporting

confidence: 59%

Overexpression of CD70 and overstimulation of IgG synthesis by lupus T cells and T cells treated with DNA methylation inhibitors

Oelke¹,

Lu²,

Richardson³

et al. 2004

Arthritis & Rheumatism

220

182

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“…during lymphocytic choriomeningitis virus infection [49,50] and in autoimmune states [51,52]. It remains an open question on how CD40L expression is regulated on CD8 T cells, and how CD40L expression relates to the cytotoxic killing ability of CD8 T cells, or their ability to regulate DC or B cell responses [46,53].…”

Section: Discussionmentioning

confidence: 99%

CD40L‐expressing CD8 T cells prime CD8α⁺ DC for IL‐12p70 production

et al. 2008

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CD8a + DC are implicated as the principle DC subset for cross-presentation and crosspriming of cytotoxic CD8 T cell responses. In this study, we demonstrate another unique facet of the CD8a + DC and CD8 T cell relationship, by showing that CD8 T cells reciprocally activate CD8a + DC, but not CD8a -DC, for IL-12p70 production, the key Th1-promoting cytokine. This effect was observed during an antigen-specific interaction between DC and activated CD8 T cells, along with secondary TLR stimulation of DC by LPS. Activated CD8 T cells use a combination of IFN-c and CD40L, which is rapidly up-regulated poststimulation, to prime DC for IL-12p70 production during an antigen-specific response. Our results suggest that the interaction between CD8a + DC and antigen-primed CD8 T cells may form an important component of Th1-mediated immunity through the induction of IL-12p70. Key words: CD8 T cells Á Dendritic cells Á IL-12p70Introduction DC are essential for the activation and polarization of T cells during an adaptive immune response [1,2]. DC respond to stimulatory signals from microbes and inflammatory mediators and mature into professional antigen-presenting cells that prime the adaptive immune system [3,4]. DC activity is also influenced through direct and indirect interaction with other effector immune cells, which results in the delivery of "feedback" signals that can influence the activation status of the DC and thus the outcome of the adaptive immune response [5][6][7]. CD8 T cells are principally known for their role in cytotoxic killing. However, their ability to promote Th1 responses has also been described. In vivo, CD8 T cells have been shown to be essential for the induction of protective Th1 responses against microbial infections [8][9][10]. Likewise, CD8 T cells can also inhibit the development of allergic Th2 IgE responses [11,12]. CD8 T cells can have a direct impact on DC during their interaction, inducing DC to mature [13], and enhancing their Th1-polarizing capabilities by augmenting their ability to produce 14,15].IL-12p70 is a heterodimeric pro-inflammatory cytokine that plays a central role in Th1 immunity, acting on T cells and NK cells by inducing proliferation, cytotoxic function and IFN-c production [16]. IL-12p70 production by DC during T cell priming is crucial for the development of Th1 responses [16][17][18]. Hence, control of DC IL-12p70 production is important for the development of Th1 immunity.Previous reports on CD8 T cell-mediated IL-12p70 production utilized DC generated from monocytes or bone marrow progenitors using 14,15]. These DC are now thought to appear only under inflammatory conditions [19]. They differ markedly from DC that reside in lymphoid organs, and hence do not necessarily reflect events that occur with lymphoid resident DC. Splenic DC comprise of a heterogeneous population of cells with different phenotypes and functional characteristics [20]. It is unknown whether CD8 T cells could possibly modulate IL-12p70 production with splenic resident DC, or whether CD8 T cellme...

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“…However, CD40L expression may not be limited to CD4+ T cells since studies indicate that CD8+ T cells (41,44), mast cells (49, eosinophils (46), and B cells (47) also can express CD40L. Moreover, there is increased CD40L expression on peripheral blood CD4+ T cells, CD8+ T cells, and B cells in active SLE (48). Immunohistochemical studies are therefore in progress to identify the cellular lineage of infiltrating CD40L+ mononuclear cells in lupus GN.…”

Section: Discussionmentioning

confidence: 99%

Immunohistologic analysis of renal CD40 and CD40L expression in lupus nephritis and other glomerulonephritides

Yellin

D’Agati

Parkinson

et al. 1997

Arthritis & Rheumatism

148

115

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Objective. To investigate potential mechanisms by which CD40L-mediated signals may be involved in the pathogenesis of lupus glomerulonephritis (GN).Methods. Renal in situ CD40L and CD40 expression was examined in patient biopsy specimens. Immunohistochemical studies were performed on frozen sections utilizing anti-CD40L monoclonal antibody (MAb), anti-CD40 MAb, or control MAb. As controls, we analyzed normal kidney specimens and specimens obtained from patients with IgA nephropathy, focal segmental glomerulosclerosis, minimal change disease, idiopathic membranous GN, and antineutrophil cytoplasmic antibodypositive pauci-immune GN. Staining distribution was noted and staining intensity scored on a semiquantitative scale of 0 (no staining) to 3+ (intense staining).Results. In normal kidney, CD40 was expressed on parietal epithelial cells, mesangial cells, endothelial cells, and distal tubules but not proximal tubules. Glomerular and tubular CD40 expression was markedly up-regulated in class I11 and class IV lupus GN, where there was intense staining of crescents, proximal and distal tubules, and interstitial mononuclear cells. In contrast, CD40 expression in class V lupus GN was similar to that in normal kidney. Interstitial mononuclear cells expressing CD40L were present in class IV lupus GN. However, these findings were not unique to lupus GN: up-regulation of CD40 and CD40L expres- Submitted for publication June 3, 1996; accepted in revised form July 17, 1996. sion was similarly observed in other inflammatory renal diseases.Conclusion. This study shows that CD40 is expressed on a variety of renal parenchymal and nonparenchymal cells in normal kidney. Renal CD40 expression is up-regulated in class I11 and class IV lupus nephritis, as well as in other inflammatory renal diseases, and is associated with the presence of CD40L+ mononuclear cells.

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Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production.

Abstract: We investigated the role of the costimulatory molecules, CD40 and its ligand CD40L, in the pathogenesis of human SLE. In comparison to normal subjects or patients in remission, PBMC from active lupus patients had a 21-fold increase in the frequency of CD40L-expressing, CD4 ϩ T cells.

Cited by 481 publications

References 69 publications

Overexpression of CD70 and overstimulation of IgG synthesis by lupus T cells and T cells treated with DNA methylation inhibitors

Overexpression of CD70 and overstimulation of IgG synthesis by lupus T cells and T cells treated with DNA methylation inhibitors

CD40L‐expressing CD8 T cells prime CD8α⁺ DC for IL‐12p70 production

Immunohistologic analysis of renal CD40 and CD40L expression in lupus nephritis and other glomerulonephritides

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Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production.

Abstract: We investigated the role of the costimulatory molecules, CD40 and its ligand CD40L, in the pathogenesis of human SLE. In comparison to normal subjects or patients in remission, PBMC from active lupus patients had a 21-fold increase in the frequency of CD40L-expressing, CD4 ϩ T cells.

Cited by 481 publications

References 69 publications

Overexpression of CD70 and overstimulation of IgG synthesis by lupus T cells and T cells treated with DNA methylation inhibitors

Overexpression of CD70 and overstimulation of IgG synthesis by lupus T cells and T cells treated with DNA methylation inhibitors

CD40L‐expressing CD8 T cells prime CD8α+ DC for IL‐12p70 production

Immunohistologic analysis of renal CD40 and CD40L expression in lupus nephritis and other glomerulonephritides

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CD40L‐expressing CD8 T cells prime CD8α⁺ DC for IL‐12p70 production