T cell abnormalities in systemic lupus erythematosus

Abstract

Because of the consensus that T cells play a central role in the pathogenesis of systemic lupus erythematosus (SLE), we explored the molecular basis of the defective function of SLE T cells for expression of signal transduction molecules, as well as surface structures such as adhesion molecules, by extensively testing peripheral blood T cells from SLE patients. Upregulated expression and function of adhesion molecules was observed in T cells from patients with active SLE who had specific clinical manifestations such as vasculitis, epithelitis and arthritis, but proximal signal transduction was defective. Comprehensive analysis to identify the molecules responsible for the defects showed the expression of the TCR zeta chain was attenuated, or absent in more than half of SLE patients. Moreover, the aberrant transcripts of the TCR zeta chain, including spliced variants lacking exon 7 and with a short 3' UTR, were detected in SLE T cells. Although attenuated expression of the TCR zeta chain is also observed in patients with cancers, infections and other autoimmune diseases, sustained attenuation of TCR zeta expression and aberrant transcripts are only observed in SLE. In this review we discuss the unique features of the TCR zeta defects in SLE.

The role of protein kinase C isoenzymes in the regulation of calcineurin activity in human peripheral blood mononuclear cells

“…A number of signalling molecules in SLE T cells have been reported to malfunction, including transcription factor elf-1, inflammation signal transducer NF-κB and PKC θ (18). It has been shown that the treatment of the healthy and lupus T cells with GCS decreased the activity of calcineurin and elevated the expression of most isoforms of PKC close to the normal values (19,26).…”

“…In SLE various abnormalities affecting signal transduction pathways have been reported, for example abnormal NF-κB (nuclear factor-κB) activity and intracellular distribution of NFAT1, overproduction of proinflammatory cytokines, decreased expression of TCR ζ chain and PKC θ, and decreased PKC-dependent protein phosphorylation (13)(14)(15)(16)(17)(18). Previously, we studied the activity of calcineurin in healthy and lupus T cells treated with activating agents of PKC (5 μM of Ca-ionophore, A23187 and 80 nM phorbol-ester, PMA, phorbol-12-myristate-13-acetate) in the presence or the absence of glucocorticosteroid (GCS) mostly used for the treatment of SLE in the active period of the disease.…”

Genetic risk factors for sclerotic graft-versus-host disease

“…HLA-matched related 374 (44) 91 (46) 283 (44) HLA-matched unrelated 326 (38) 86 (43) 240 (37) HLA-mismatched related 13 (2) 1 (1) 12 (2) HLA-mismatched unrelated 134 ( (41) 67 (34) 281 (43) #450 cGy 297 (35) 78 (39) 219 (34) .450 cGy 202 (24) 53 (27) 149 (23) Prior grade 2-4 acute GVHD, no. (%) 619 (73) 137 (69) 482 (74) CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; MDS, myelodysplastic syndrome; MM, multiple myeloma; MPN, myeloproliferative neoplasm.…”

Stimulation of T cells up-regulates expression of Ifi202, an interferon-inducible lupus susceptibility gene, through activation of JNK/c-Jun pathway

“…For example, compared with normal controls, in which a balance of T cell functions exists, diverse T cell dysfunctions are known to result in an imbalance in the functions of T cell subsets in SLE [15]. Moreover, studies have provided evidence for abnormal T cell signal transduction in SLE [16,17]. The molecular mechanisms that cause T cell dysfunctions in SLE remain largely unknown.…”

“…T cells are thought to play a central role in the pathogenesis of both human and murine lupus [15][16][17]. For example, compared with normal controls, in which a balance of T cell functions exists, diverse T cell dysfunctions are known to result in an imbalance in the functions of T cell subsets in SLE [15].…”