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      Expression of TLR-7, MyD88, NF-kB, and INF-α in B Lymphocytes of Mayan Women with Systemic Lupus Erythematosus in Mexico

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          Abstract

          Background

          Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease involving multiple organs. It is currently accepted that several genetic, environmental, and hormonal factors are contributing to its development. Innate immunity may have a great influence in autoimmunity through Toll-like receptors. TLR-7 recognizing single-strand RNA has been involved in SLE. Its activation induces intracellular signal with attraction of MyD88 and NF-kBp65, leading to IFN-α synthesis which correlate with disease activity.

          Objective

          To assess the expression of TLR-7, MyD88, and NF-kBp65 in B lymphocytes of Mayan women with SLE.

          Methods

          One hundred patients with SLE and 100 healthy controls, all of them Mayan women, were included. TLR-7 was analyzed on B and T lymphocytes, and MyD88 and NF-kB only in B lymphocytes. Serum INF-α level was evaluated by ELISA.

          Results

          Significant expression ( p < 0.0001) of TLR-7 in B and T lymphocytes and serum IFN-α increased ( p = 0.034) was observed in patients. MyD88 and NF-kBp65 were also increased in B lymphocytes of patients. TLR-7 and NF-kBp65 expression correlated, but no correlation with INF-α and disease activity was detected.

          Conclusion

          Data support the role of TLR-7 and signal proteins in the pathogenesis of SLE in the Mayan population of Yucatán.

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          Most cited references46

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          Toll-like receptors: critical proteins linking innate and acquired immunity.

          Recognition of pathogens is mediated by a set of germline-encoded receptors that are referred to as pattern-recognition receptors (PRRs). These receptors recognize conserved molecular patterns (pathogen-associated molecular patterns), which are shared by large groups of microorganisms. Toll-like receptors (TLRs) function as the PRRs in mammals and play an essential role in the recognition of microbial components. The TLRs may also recognize endogenous ligands induced during the inflammatory response. Similar cytoplasmic domains allow TLRs to use the same signaling molecules used by the interleukin 1 receptors (IL-1Rs): these include MyD88, IL-1R--associated protein kinase and tumor necrosis factor receptor--activated factor 6. However, evidence is accumulating that the signaling pathways associated with each TLR are not identical and may, therefore, result in different biological responses.
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            Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus.

            Systemic lupus erythematosus (SLE) is a complex, inflammatory autoimmune disease that affects multiple organ systems. We used global gene expression profiling of peripheral blood mononuclear cells to identify distinct patterns of gene expression that distinguish most SLE patients from healthy controls. Strikingly, about half of the patients studied showed dysregulated expression of genes in the IFN pathway. Furthermore, this IFN gene expression "signature" served as a marker for more severe disease involving the kidneys, hematopoetic cells, and/or the central nervous system. These results provide insights into the genetic pathways underlying SLE, and identify a subgroup of patients who may benefit from therapies targeting the IFN pathway.
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              Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication.

              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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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/229406
                URI : http://frontiersin.org/people/u/312262
                URI : http://frontiersin.org/people/u/232985
                URI : http://frontiersin.org/people/u/312289
                URI : http://frontiersin.org/people/u/312765
                URI : http://frontiersin.org/people/u/312280
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                02 February 2016
                2016
                : 7
                : 22
                Affiliations
                [1] 1Laboratorio de Hematología, Centro de Investigaciones Regionales Dr. Hideyo Noguchi, Universidad Autónoma de Yucatán , Mérida, Mexico
                [2] 2Facultad de Química, Universidad Autónoma de Yucatán , Mérida, Mexico
                [3] 3Hospital General Dr. Agustín O’Horán , Mérida, Mexico
                [4] 4Hospital General Regional ISSSTE, Servicios de Salud de Yucatán (SSY) , Mérida, México
                Author notes

                Edited by: Timothy B. Niewold, Mayo Clinic, USA

                Reviewed by: Geanncarlo Lugo-Villarino, Centre National de la Recherche Scientifique (CNRS), France; Philippe Georgel, Strasbourg University, France

                *Correspondence: Guillermo Valencia Pacheco, vpacheco@ 123456correo.uady.mx

                Specialty section: This article was submitted to Molecular Innate Immunity, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2016.00022
                4735402
                26870038
                1abe4ca9-d168-4574-9938-ec580809894c
                Copyright © 2016 Pacheco, Novelo Noh, Velasco Cárdenas, Angulo Ramírez, López Villanueva, Quintal Ortiz, Alonso Salomón, Ruz and Rivero Cárdenas.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 09 November 2015
                : 15 January 2016
                Page count
                Figures: 6, Tables: 1, Equations: 0, References: 57, Pages: 7, Words: 4945
                Funding
                Funded by: Consejo Nacional de Ciencia y TecnologÃ-a 10.13039/501100007350
                Award ID: FONSEC SALUD 2010-1-139788
                Categories
                Immunology
                Original Research

                Immunology
                innate immunity,toll-like receptor 7,interferon-α,systemic lupus erythematosus,pathogenesis

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