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      Pathogenesis of Systemic Sclerosis

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          Abstract

          Systemic scleroderma (SSc) is one of the most complex systemic autoimmune diseases. It targets the vasculature, connective tissue-producing cells (namely fibroblasts/myofibroblasts), and components of the innate and adaptive immune systems. Clinical and pathologic manifestations of SSc are the result of: (1) innate/adaptive immune system abnormalities leading to production of autoantibodies and cell-mediated autoimmunity, (2) microvascular endothelial cell/small vessel fibroproliferative vasculopathy, and (3) fibroblast dysfunction generating excessive accumulation of collagen and other matrix components in skin and internal organs. All three of these processes interact and affect each other. The disease is heterogeneous in its clinical presentation that likely reflects different genetic or triggering factor (i.e., infection or environmental toxin) influences on the immune system, vasculature, and connective tissue cells. The roles played by other ubiquitous molecular entities (such as lysophospholipids, endocannabinoids, and their diverse receptors and vitamin D) in influencing the immune system, vasculature, and connective tissue cells are just beginning to be realized and studied and may provide insights into new therapeutic approaches to treat SSc.

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          Most cited references 461

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          Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets.

          We predict regulatory targets of vertebrate microRNAs (miRNAs) by identifying mRNAs with conserved complementarity to the seed (nucleotides 2-7) of the miRNA. An overrepresentation of conserved adenosines flanking the seed complementary sites in mRNAs indicates that primary sequence determinants can supplement base pairing to specify miRNA target recognition. In a four-genome analysis of 3' UTRs, approximately 13,000 regulatory relationships were detected above the estimate of false-positive predictions, thereby implicating as miRNA targets more than 5300 human genes, which represented 30% of our gene set. Targeting was also detected in open reading frames. In sum, well over one third of human genes appear to be conserved miRNA targets.
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            Pathogen recognition and innate immunity.

            Microorganisms that invade a vertebrate host are initially recognized by the innate immune system through germline-encoded pattern-recognition receptors (PRRs). Several classes of PRRs, including Toll-like receptors and cytoplasmic receptors, recognize distinct microbial components and directly activate immune cells. Exposure of immune cells to the ligands of these receptors activates intracellular signaling cascades that rapidly induce the expression of a variety of overlapping and unique genes involved in the inflammatory and immune responses. New insights into innate immunity are changing the way we think about pathogenesis and the treatment of infectious diseases, allergy, and autoimmunity.
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              Toll-like receptor signalling.

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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/154950
                URI : http://frontiersin.org/people/u/241279
                URI : http://frontiersin.org/people/u/154464
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                08 June 2015
                2015
                : 6
                Affiliations
                1Department of Medicine, Division of Connective Tissue Diseases, The University of Tennessee Health Science Center , Memphis, TN, USA
                2Department of Veterans Affairs Medical Center , Memphis, TN, USA
                3Section of Pediatric Rheumatology, Department of Pediatrics, The University of Tennessee Health Science Center , Memphis, TN, USA
                Author notes

                Edited by: Giuseppe Alvise Ramirez, Università Vita-Salute San Raffaele, Italy

                Reviewed by: F. David Carmona, Instituto de Parasitología y Biomedicina “Lopez-Neyra” (CSIC), Spain; Enrico Tombetti, San Raffaele Scientific Institute, Italy

                *Correspondence: Arnold E. Postlethwaite, Department of Medicine, Division of Connective Tissue Diseases, The University of Tennessee Health Science Center, 956 Court Avenue, Room G326, Memphis, TN 38163-0001, USA, apostlet@ 123456uthsc.edu

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

                Article
                10.3389/fimmu.2015.00272
                4459100
                Copyright © 2015 Pattanaik, Brown, Postlethwaite and Postlethwaite.

                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.

                Page count
                Figures: 1, Tables: 5, Equations: 0, References: 468, Pages: 40, Words: 38838
                Funding
                Funded by: Merit Review
                Award ID: BX000671
                Funded by: Study of the genetic basis for fibrotic diseases in a mouse model
                Funded by: NIH
                Award ID: R01 AR052190-06A1
                Funded by: Novel biosynthetic pathway for secosteroids in the skin
                Categories
                Immunology
                Review

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