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      Therapeutic Strategies for SLE Involving Cytokines: Mechanism-Oriented Therapies Especially IFN- γ Targeting Gene Therapy

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      Journal: Journal of Biomedicine and Biotechnology
      Publisher: Hindawi Publishing Corporation

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          Abstract

          Systemic lupus erythematosus (SLE: lupus) is a chronic complicated autoimmune disease and pathogenesis is still unclear. However, key cytokines have been recognized. Interferon (IFN)- γ and also IFN α/ β are of particular importance. Depending on the concept that lupus is a helper T(Th)1 disease and that dendritic cells (DCs) determine the direction of lupus, balance shift of Th1/Th2 and immunogenic/tolerogenic DCs is reviewed for therapy. (IFN)- γ- and IFN- α/ β-targeted (gene) therapies are introduced. These consist of Th1/Th2 balance shift and elimination of IFN- γ and IFN- γ-related cytokines such as (interleukin)IL-12 and IL-18. Other approaches include suppression of immunocompetent cells, normalization of abnormal T-cell function, costimulation blockade, B lymphocyte stimulator (Blys) blockade, and suppression of nephritic kidney inflammation. Moreover, balance shift of IFN- α/ β and tumor necrosis factor (TNF)- α together with regulatory T(Treg) cells are briefely introduced. Clinical application will be discussed.

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          Type I interferon in systemic lupus erythematosus and other autoimmune diseases.

          Jacques Banchereau, Virginia Pascual (2006)
          Different genetic alterations may lead to type I interferon (IFN) overproduction in human systemic lupus erythematosus (SLE). The increased bioavailability of type I IFN contributes to peripheral tolerance breakdown through the activation of immature myeloid dendritic cells (mDCs). IFN-matured mDCs activate autoreactive T cells. These cells, together with plasmacytoid DCs, help expand autoreactive B cells. IFN-matured DCs also activate cytotoxic CD8+ T cells, possibly increasing apoptotic cell availability. The capture of apoptotic cells by mDCs and of nucleic acid-containing immune complexes by plasmacytoid DCs and B cells amplifies the autoimmune reaction leading to disease manifestations. Genetic alterations in lineages other than B cells might explain other autoimmune syndromes where type I IFNs appear to be involved.
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            Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication.

            Prapaporn Pisitkun, Jonathan A Deane, Michael J. Difilippantonio … (2006)
            Antibodies against nuclear self-antigens are characteristic of systemic autoimmunity, although mechanisms promoting their generation and selection are unclear. Here, we report that B cells containing the Y-linked autoimmune accelerator (Yaa) locus are intrinsically biased toward nucleolar antigens because of increased expression of TLR7, a single-stranded RNA-binding innate immune receptor. The TLR7 gene is duplicated in Yaa mice because of a 4-Megabase expansion of the pseudoautosomal region. These results reveal high divergence in mouse Y chromosomes and represent a good example of gene copy number qualitatively altering a polygenic disease manifestation.
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              CD4+CD25high regulatory cells in human peripheral blood.

              Andrew Allan, David A. Hafler, Emery Brown … (2001)
              Thymectomy in mice on neonatal day 3 leads to the development of multiorgan autoimmune disease due to loss of a CD(+)CD25(+) T cell regulatory population in their peripheral lymphoid tissues. Here, we report the identification of a CD4(+) population of regulatory T cells in the circulation of humans expressing high levels of CD25 that exhibit in vitro characteristics identical with those of the CD4(+)CD25(+) regulatory cells isolated in mice. With TCR cross-linking, CD4(+)CD25(high) cells did not proliferate but instead totally inhibited proliferation and cytokine secretion by activated CD4(+)CD25(-) responder T cells in a contact-dependent manner. The CD4(+)CD25(high) regulatory T cells expressed high levels of CD45RO but not CD45RA, akin to the expression of CD45RB(low) on murine CD4(+)CD25(+) regulatory cells. Increasing the strength of signal by providing either costimulation with CD28 cross-linking or the addition of IL-2 to a maximal anti-CD3 stimulus resulted in a modest induction of proliferation and the loss of observable suppression in cocultures of CD4(+)CD25(high) regulatory cells and CD4(+)CD25(-) responder cells. Whereas higher ratios of CD4(+)CD25(high) T cells are required to suppress proliferation if the PD-L1 receptor is blocked, regulatory cell function is shown to persist in the absence of the PD-1/PD-L1 or CTLA-4/B7 pathway. Thus, regulatory CD4 T cells expressing high levels of the IL-2 receptor are present in humans, providing the opportunity to determine whether alterations of these populations of T cells are involved in the induction of human autoimmune disorders.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Biomed Biotechnol
                Journal ID (publisher-id): JBB
                Title: Journal of Biomedicine and Biotechnology
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 1110-7243
                ISSN (Electronic): 1110-7251
                Publication date (Print): 2010
                Publication date (Electronic): 17 August 2010
                Volume: 2010
                Electronic Location Identifier: 461641
                Affiliations
                Laboratory of Veterinary Pathology, Faculty of Agriculture, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8515, Japan
                Author notes

                Academic Editor: Brian Poole

                Article
                DOI: 10.1155/2010/461641
                PMC ID: 2933908
                PubMed ID: 20827419
                SO-VID: 4270b62d-f03c-4ccb-87f9-9cc059d3fc44
                Copyright © Copyright © 2010 Toshiharu Hayashi.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 25 January 2010
                Date accepted : 25 June 2010
                Categories
                Subject: Review Article

                ScienceOpen disciplines: Molecular medicine
                Data availability:
                ScienceOpen disciplines: Molecular medicine

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