Elevated serum levels of soluble CD154 in children with juvenile idiopathic arthritis

Prahalad, Sampath; Martins, Thomas B.; Tebo, Anne E.; Whiting, April; Clifford, Bronte; Zeft, Andrew; McNally, Bernadette; Bohnsack, John F.; Hill, Harry R.

doi:10.1186/1546-0096-6-8

Cited by 27 publications

(39 citation statements)

References 31 publications

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“…In addition to its membranous form, CD154 is also released as a biologically active soluble molecule (sCD154) detectable in the serum of healthy individuals (Prahalad et al 2008;Tamura et al 2001). Platelets, which also express surface CD154, are the major source of sCD154 in the circulation, contributing more than 95% of plasma sCD154 (Andre et al 2002).…”

Section: Soluble Cd154 In Inflammatory and Immune Responsesmentioning

confidence: 99%

“…Macrophages can also produce sCD154 (Kilmon et al 2007). Moreover, elevated levels of sCD154 have been reported in the serum of patients with chronic lymphocytic leukemia (Younes et al 1998), HIV (Sipsas et al 2002), SLE (Goules et al 2006;Kato et al 1999;Urquizu-Padilla et al 2009) as well as other autoimmune diseases (Prahalad et al 2008;Tamura et al 2001;Toubi and Shoenfeld 2004). Besides the fact that excess sCD154 could be a contributing factor in many diseases, the therapeutic potential of this molecule has also been evaluated in cancer and transplantation (reviewed in Costello et al 1999;Quezada et al 2004).…”

Section: Soluble Cd154 In Inflammatory and Immune Responsesmentioning

confidence: 99%

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Tuning of CD40–CD154 Interactions in Human B-Lymphocyte Activation: A Broad Array of In Vitro Models for a Complex In Vivo Situation

Néron

Nadeau

Darveau

et al. 2011

Arch. Immunol. Ther. Exp.

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Naive and memory B-lymphocyte populations can be activated through the binding of CD154 to CD40, a receptor that is constitutively expressed on the surface of these cells. Models based on the in vitro stimulation of human B lymphocytes through CD40 have greatly contributed to our understanding of the human immune response in healthy individuals and patients suffering from immune disorders. The nature of the engineered CD40 ligands is as diverse as the in vitro models used in studies of CD40-activated B lymphocytes. Monoclonal anti-CD40 antibodies, recombinant CD154 proteins, soluble CD154(+) membranes as well as CD154(+) cell lines have turned out to be very useful tools, and are still in use today. As for any receptor-ligand interaction, parameters such as duration and strength of contact, timing, affinity, and receptor density are major determinants of CD40 binding by CD154 or anti-CD40. Furthermore, variation in the intensity of CD40 stimulation has been shown to influence proliferation, differentiation and immunoglobulin secretion of human hybridomas, B-cell lines, tonsil and blood B lymphocytes. The objective of this review is to present an overview of the great diversity of CD40 agonists used in in vitro models of B-lymphocyte activation, with a particular emphasis on variations in the resulting strength of CD40 signaling generated by these models. A better understanding of these models could open up new avenues for the rational use of human B lymphocytes as antigen-presenting cells in cellular therapies.

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Section: Soluble Cd154 In Inflammatory and Immune Responsesmentioning

confidence: 99%

Section: Soluble Cd154 In Inflammatory and Immune Responsesmentioning

confidence: 99%

Tuning of CD40–CD154 Interactions in Human B-Lymphocyte Activation: A Broad Array of In Vitro Models for a Complex In Vivo Situation

Néron

Nadeau

Darveau

et al. 2011

Arch. Immunol. Ther. Exp.

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“…Postactivation, CD40L is cleaved rapidly from the cell surface, providing an important feedback mechanism that keeps CD40 activation in check. Indeed, soluble CD40L (sCD40L) levels are enhanced in various autoimmune diseases in both preclinical models and human patients (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Moreover, the levels of sCD40L often track with disease severity or active versus quiescent stages of the disease; this is particularly evident in patients with systemic lupus erythematosus (5,6).…”

mentioning

confidence: 99%

Engineering of a Novel Anti-CD40L Domain Antibody for Treatment of Autoimmune Diseases

Xie

Yamniuk

Borowski

et al. 2014

The Journal of Immunology

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CD40–CD40L interactions play a critical role in regulating immune responses. Blockade of CD40L by Abs, such as the anti-CD40L Ab 5c8, demonstrated positive clinical effects in patients with autoimmune diseases; however, incidents of thromboembolism (TE) precluded further development of these molecules. In this study, we examined the role of the Fc domain interaction with FcγRs in modulating platelet activation and potential for TE. Our results show that the interaction of the 5c8 wild-type IgG1 Fc domain with FcγRs is responsible for platelet activation, as measured by induction of PAC-1 and CD62P. A version of 5c8 with a mutated IgG1 tail was identified that showed minimal FcγR binding and platelet activation while maintaining full binding to CD40L. To address whether Fc effector function is required for immunosuppression, a potent Ab fragment, termed a “domain Ab” (dAb), against murine CD40L was identified and fused to a murine IgG1 Fc domain containing a D265A mutation that lacks Fc effector function. In vitro, this dAb–Fc demonstrated comparable potency to the benchmark mAb MR-1 in inhibiting B cell and dendritic cell activation. Furthermore, the anti-CD40L dAb–Fc exhibited a notable efficacy comparable to MR-1 in various preclinical models, such as keyhole limpet hemocyanin–induced Ab responses, alloantigen-induced T cell proliferation, “heart-to-ear” transplantation, and NZB × NZW F1 spontaneous lupus. Thus, our data show that immunosuppression and TE can be uncoupled and that a CD40L dAb with an inert Fc tail is expected to be efficacious for treating autoimmune diseases, with reduced risk for TE.

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“…Furthermore, the soluble form of the protein (sCD154) exhibits cytokine-like properties [21]. In fact, CD40 and CD154 are members of the TNF-α receptor and TNF super-families, respectively [22].…”

mentioning

confidence: 99%

“…CD154, the ligand for CD40, is expressed on activated T cells and on platelets [16], and systemically elevated levels of CD154 are observed in both autoimmune and nonautoimmune diseases [17][18][19][20][21]. Furthermore, the soluble form of the protein (sCD154) exhibits cytokine-like properties [21].…”

mentioning

confidence: 99%

The co-evolution of our understanding of CD40 and inflammation

Wagner

2009

Diabetologia

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Elevated serum levels of soluble CD154 in children with juvenile idiopathic arthritis

Abstract: Serum levels of sCD154, IL1beta, IL6, IL8, sIL2R and TNFalpha are elevated in most JIA subtypes, suggesting a major role for sCD154, and these cytokines and cytokine receptors in the pathogenesis of JIA.

Cited by 27 publications

References 31 publications

Tuning of CD40–CD154 Interactions in Human B-Lymphocyte Activation: A Broad Array of In Vitro Models for a Complex In Vivo Situation

Tuning of CD40–CD154 Interactions in Human B-Lymphocyte Activation: A Broad Array of In Vitro Models for a Complex In Vivo Situation

Engineering of a Novel Anti-CD40L Domain Antibody for Treatment of Autoimmune Diseases

The co-evolution of our understanding of CD40 and inflammation

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