Misc

It is anticipated that biomarkers support rheumatologists to judge a group of patients that can improve the diagnosis and prognosis, and further facilitate appropriate and precise treatment with targeted therapy. In particular, biomarkers for predicting and monitoring response to biological disease modifying anti-rheumatic drugs (DMARDs) are demanding. Given the mechanism action of biological DMARDs is much more simple than the conventional synthetic DMARDs, a variety of approaches to find such biomarkers has been taken recent years. In this article, I will summarize the background for biomarker research and introduce recent topics in the research and the possible clinical applications of biomarkers to guide treatment in rheumatoid arthritis (RA).

SLE is associated with a deficiency in cluster of differentiation 247 (CD247, also known as CD3 zeta chain), a component of the T-cell receptor (TCR)-CD3 complex. A comprehensive analysis showed that in more than half of SLE patients tested CD247 expression was either attenuated or absent. Recent evidence suggests that these variations in expression profiles may be due, at least in part, to polymorphisms in the CD247 gene. Aberrant CD247 transcript variants displaying either spliced exon 7 or short 3'-untranslated region have been detected in SLE T cells, and a recent genome-wide association study reported the existence of new CD247 single-nucleotide polymorphisms in SLE patients. Here, we review these unique and significant features of defective CD247 observed in SLE. © The Author 2013. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.

Interstitial lung disease (ILD) develops in 30-50% of patients with polymyositis/dermatomyositis (PM/DM) and negatively affects their prognosis. The progression of PM/DM-ILD may be acute, subacute, chronic, or chronic becoming acute. The histopathological classification of PM/ DM-ILD includes non-specific interstitial pneumonia (NSIP), organizing pneumonia (OP), diffuse alveolar damage (DAD), and usual interstitial pneumonia (UIP) or mixed variations. Some patients with acute/subacute interstitial pneumonia (A/SIP), typically with lung histology of OP or cellular NSIP, respond favorably to corticosteroid treatment, while others do not. Japanese patients with DM, especially those with clinically amyopathic DM (C-ADM) and palmar papules, seem to be at a greater risk of developing fulminant A/SIP with DAD histology resulting in pneumomediastinum and fatal outcome in a few months. An aggressive combination regimen including cyclosporine A (or tacrolimus) and cyclophosphamide should be immediately added to corticosteroid treatment for such patients. Sequential follow-up examination using high-resolution computed tomography (HRCT) of the chest and careful monitoring for bacterial and viral infections are essential. However, intensive immunosuppression alone may not be sufficient to control fulminant A/SIP, and other therapeutic targets, such as fibroblasts, should be considered. © 2006 Bentham Science Publishers Ltd.

It is now evident that biological agents targeting on the tumor necrosis factor (TNF) have not only induce a substantial clinical response, but also inhibit the structural damage in patients with Rheumatoid Arthritis (RA). Upon the great success of anti-TNF biologicals as the therapeutic modalities of choice in the treatment of inflammatory disorders of unknown etiology, the details of TNF, and anti-TNF biological agents are extensively reviewed, particularly, focusing on those used against RA. So far, nearly one million patients are expected to expose to these agents worldwide. In Japan, chimeric monoclonal antibody to TNFα, infliximab has been approved for Crohn's disease in 2002, RA in 2003, and TNF receptor 2-IgG Fc fusion protein, etanercept had just approved for RA in 2005. Full human anti-TNFa monoclonal antibody, adalimumab is now under clinical trials. Safety profiles of these agents, based on the exposure to one hundred million patients for up to ten years, are summarized. While the experiences using biological agents in Japan are rather limited, the unique circumstances in Asian countries should been taken into account. In this respect, the issues around the anti-TNF biologicals in Japan are finally discussed. ©2005 Japanese Society of Allergology.

SLE T cells may play a key role in autoantibody production in SLE B cells. In addition, accumulating evidence has shown that SLE T cells participate in the attack on target cells or tissues through the overproduction of pro-inflammatory cytokines or an increase in cell-to-cell adhesion. Thus, the functional abnormality of SLE T cells appears to be pivotal to an understanding of SLE pathogenesis. Accumulating evidence suggests that potential defects may reside in the proximal signal transduction around the TCR-CD3 complex. We have demonstrated that the expression of TCR ζ chain is significantly decreased in peripheral blood T cells from SLE patients. To explore the mechanism of defective expression of TCR ζ chain, we examined mRNA of TCR ζ, and found that two alternatively spliced variants such as exon 7 (-) and short 3′-UTR are detected in SLE. We review the possible role of the TCR ζ defects in autoimmunity and discuss how the splicing variants lead to downregulated protein expression of TCR ζ chain.

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 ζ chain was attenuated, or absent in more than half of SLE patients. Moreover, the aberrant transcripts of the TCR ζ 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 ζ chain is also observed in patients with cancers, infections and other autoimmune diseases, sustained attenuation of TCR ζ expression and aberrant transcripts are only observed in SLE. In this review we discuss the unique features of the TCR ζ defects in SLE. © 2005 Taylor & Francis.

It is widely accepted that T cells with defective function play a central role in the pathogenesis of systemic lupus erythematosus (SLE). The detailed molecular mechanism underlying the aberrant function of SLE T cells is now being revealed. The TCR zeta chain, transcription factor, elf-1, inflammation signal transducer NF-kB, and PKC theta have been identified as the responsible molecules. In contrast to the defective signal transduction molecules, surface structures such as adhesion molecules, and co-stimulators have been reported to increase in their expression and function. Glucocorticoids and immunosuppressive agents have greatly improved the outcome of acute diseases and 5-year survival rate. However, it is suggested that long-term survival and quality of life appears to be unsatisfactory. Although the medical management of SLE is not sufficient to warrant long-term survival of young patients, recent progress in anti-cytokine biologics therapy against rheumatoid arthritis (RA) has facilitated searching for the molecular targets of SLE. In this report, we briefly review the molecular basis of SLE pathogenesis, and discuss possible therapeutic targets in this disease, focusing particularly on signal transduction and adhesion molecules in T cells. © 2005 Bentham Science Publishers Ltd.

In the present study, we have investigated the molecular basis for immunoregulatory function of CD8 cells after autologous mixed lymphocyte reaction (AMLR) activation. We demonstrated that the CD8+CD45R+ but not the CD8+CD45R- subset of cells was a subpopulation, with the majority of suppressor activity after AMLR activation. In contrast, cytotoxic activity against alloantigens resided in both the CD8+CD45R+ and CD8+CD45R- subsets of cells. Importantly, the treatment of AMLR-activated CD8 cells with anti-CD45R antibody or anti-CD3 antibody abolished the suppressor function of these cells, which contrasts with earlier studies showing that treatment of AMLR activated CD4 suppressor inducer cells could be blocked with anti-CD45R but not with anti-CD3 antibody. The results suggest that the CD45R antigen as well as the CD3-T cell receptor (TCR) complex have an important role in the suppressor function of AMLR-activated cells.