Elsevier

Autoimmunity Reviews

Volume 7, Issue 3, January 2008, Pages 256-261
Autoimmunity Reviews

Novel molecular targets in the treatment of systemic lupus erythematosus

https://doi.org/10.1016/j.autrev.2007.11.020Get rights and content

Abstract

T cells from patients with systemic lupus erythematosus (SLE) display a number of biochemical abnormalities which include altered expression of key signaling molecules, heightened calcium responses, and skewed expression of transcription factors. These defects are involved in the altered behavior of SLE T cells and are probably central in the disease pathogenesis. The aim of this communication is to review the defects that have been consistently documented in SLE T cells, highlighting molecules and pathways that represent therapeutic targets.

Section snippets

CD3ζ and FcRγ

CD3ζ is component of the CD3 complex and represents the main signaling partner of the T cell receptor (TCR). The levels of CD3ζ are significantly diminished in T cells from most patients with SLE [2]. Paradoxically, the defect is associated with increased calcium influx following TCR-mediated stimulation. The absent chain is replaced by a surrogate molecule normally absent in T cells: the Fc receptor (FcR) γ chain (originally identified as a component of FcɛRI) [3]. The substitution creates an

CD44 and pERM

The molecules that mediate signal transduction in lymphocytes are distributed in a non-random fashion throughout the cell membrane; they are primarily located within zones that are rich in cholesterol and gangliosides. The clustering of key molecules within these regions, called lipid rafts, facilitates their interactions allowing downstream signaling events to occur in a rapid and amplified fashion. When the T cell is stimulated, lipid rafts move and cluster at the zone of the membrane where

pCREB and CREM

A phenotypic hallmark of the T cells from patients with SLE is a failure to produce normal amounts of IL-2 upon activation [15]. Such deficiency could account for a number of abnormalities present in the immune system of SLE patients: hampered T cell responses, defective activation induced cell death, and altered regulatory T cell homeostasis and function.

IL-2 production is primarily controlled at the transcriptional level. The binding of transcription factors to promoter sites of the IL-2 gene

Potential therapeutic targets

The reviewed pathogenic pathways offer a number of potential molecules whose targeting might prove to be of therapeutic value in patients with SLE. As mentioned earlier, some of these molecules act as key mediators in SLE T cells, whilst being completely absent from normal T cells; the levels of others are conspicuously altered in SLE T cells. The targeting of these molecules would, at least in theory, offer the advantage of being relative selective for diseased cells.

The restoration of CD3ζ

Concluding remarks

The pathogenic mechanisms that underlie SLE are slowly being unraveled. As we progress in its understanding, potential therapeutic targets that will allow the design of specific treatments are emerging. Development of agents capable of inhibiting – or increasing – the expression of the mentioned molecules promises to be more effective and less toxic. The question that remains is to which extent the correction of the biochemical abnormalities of SLE T cells will lead to clinical improvement.

Take home messages

  • T cells are central in the SLE pathogenesis.

  • The decreased CD3ζ:FcRγ ratio that characterizes SLE T cells is associated with an abnormal response to TCR stimulation.

  • SLE T cells have increased levels of PP2A that suppresses CREB activity.

  • Sera from patients with SLE causes activation of CaMKIV that leads to increased binding of the repressor CREM to gene promoters.

  • SLE T cells exhibit a number of specific defects that represent potential therapeutic targets.

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