Rheumatoid Arthritis: Guo B

Rothstein TL, Guo B. · Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA. · J Intern Med. · Pubmed #19493057 No free full text.

Abstract: Receptor crosstalk: reprogramming B cell receptor signalling to an alternate pathway results in expression and secretion of the autoimmunity-associated cytokine, osteopontin (Review). J Intern Med 2009; 265: 632-643.Intracellular signalling emanating from the B-cell antigen receptor is considered to follow a discrete course that requires participation by a set of mediators, grouped together as the signalosome, in order for downstream events to occur. Recent work indicates that this paradigm is true only for naïve B cells. Following engagement of the IL-4 receptor, a new, alternate pathway for B-cell receptor (BCR)-triggered intracellular signalling is established that bypasses the need for signalosome elements and operates in parallel with the classical, signalosome-dependent pathway. Reliance on Lyn and sensitivity to rottlerin by the former, but not the latter, distinguishes these two pathways. The advent of alternate pathway signalling leads to production and secretion by B cells of osteopontin (Opn). As Opn is a polyclonal B-cell activator that is strongly associated with a number of autoimmune diseases including lupus and rheumatoid arthritis, this novel finding is likely to be clinically relevant. Our results highlight the potential role of B-cell-derived Opn in immunity and autoimmunity and suggest that stress-related IL-4 expression might act to strengthen immunoglobulin secretion at the risk of autoantibody formation. Further, these results illustrate receptor crosstalk in the form of reprogramming, whereby engagement of one receptor (IL-4R) produces an effect that persists after the original ligand (IL-4) is removed and results in alteration of the pathway, and outcome, of signalling via a second receptor (BCR) following its activation.

Oganesyan G, Saha SK, Pietras EM, Guo B, Miyahira AK, Zarnegar B, Cheng G. · Department of Microbiology, Immunology and Molecular Genetics, University of California at Los Angeles, California 90095, USA. · J Biol Chem. · Pubmed #17925397 links to  free full text

Abstract: Hypomethylated CpG oligonucleotides (CpG) are not only potent adjuvants for enhancing adaptive immune responses but may also play a critical role in the development of autoimmune diseases such as Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). Here we provide evidence that, in addition to dendritic cells, murine B lymphocytes also exhibit a type I IFN response to CpG-B. Unlike dendritic cells, B cell-mediated type I IFN induction depended on the transcription factor IRF3, but similar to dendritic cells this pathway was independent of the IRF3 kinase TBK1. Utilizing type I IFN receptor-deficient mice, we were able to demonstrate that this IFN pathway enhanced Syndecan-1 expression and IgM production and was required for IgG2a production following CpG-B stimulation. Overall, our findings identify a unique IFN pathway in B cells that may play a central role in mediating B cell biology in response to CpG, potentially implicating this pathway in autoantibody production and the pathogenesis of certain autoimmune diseases.

Li C, Guo B, Ding S, Rius C, Langa C, Kumar P, Bernabeu C, Kumar S. · Department of Pathology, Medical School, University of Manchester, Manchester M13 9PT, U.K. · Anticancer Res. · Pubmed #12820370 No free full text.

Abstract: The vascular endothelium participates in angiogenesis, inflammation and the immune response, which are modulated by vasoactive cytokines such as tumour necrosis factor-alpha (TNF alpha) and transforming growth factor-beta 1 (TGF beta 1). CD105 is a component of the TGF beta receptor complex and is abundantly expressed in activated/injured endothelium where it is implicated in multiple cellular processes. Up-regulation of CD105 in synovial cells of rheumatoid arthritis and psoriatic lesions implies a possible role in the pathogenesis of such inflammatory disorders. The pro-inflammatory cytokine, TNF alpha, and anti-inflammatory cytokine, TGF beta 1, regulate multiple cellular processes such as proliferation, differentiation and apoptosis. Our hypothesis is that CD105 gene expression in endothelial cells is regulated by the multifunctional cytokines TNF alpha and TGF beta 1. By using human dermal microvascular endothelial cells the present study has shown that long-term treatment with TNF alpha (0.1-5 ng/ml) elicited a concentration- and time-dependent significant suppression (over 50% reduction) in CD105 protein levels. The observations that no significant alterations in the CD105 mRNA levels or in the CD105 promoter activity were found and that the potent inhibitor of NF kappa B, PDTC, did not affect the TNF alpha action suggest that CD105 down-regulation by TNF alpha is not at the transcriptional level. In contrast to TNF alpha, TGF beta 1 significantly elevated CD105 protein and mRNA expression (approximately 2-fold increase) through activation of its promoter activity. From these data we conclude that TNF alpha and TGF beta 1 exert opposing effects on CD105 expression in human vascular endothelial cells and that CD105 is enmeshed in the network of signal pathways modulating multiple cellular functions.