Elsevier

Autoimmunity Reviews

Volume 10, Issue 5, March 2011, Pages 244-247
Autoimmunity Reviews

Review
Do infections facilitate the emergence of systemic sclerosis?

https://doi.org/10.1016/j.autrev.2010.09.010Get rights and content

Abstract

Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular obliteration, excessive extracellular matrix deposition, and fibrosis of the connective tissues of the skin, lungs, gastrointestinal tract, heart, and kidneys.

Infections are believed to play a role in the immunopathogenesis of SSc.

A number of infectious agents have been proposed as possible triggering factors in SSc. Homology between viruses and autoantibody targets suggests that molecular mimicry may play a role in the initiation of antibody response in disorders characterized by diffuse vascular disease, mainly SSc. Four pathogenic hypotheses have been proposed: molecular mimicry, endothelial cell damage, super-antigens, and microchimerism.

Although several studies have provided important information linking infectious agents to SSc, a clear, direct association is still missing. It is very likely that the infectious agents are cofactors in a specific hormonal and environmental setting that mounts an immune reaction, which leads to the emergence of the disorder.

Introduction

Systemic sclerosis (SSc) is a connective tissue disorder characterized by vascular obliteration, immune dysfunction, excessive extracellular matrix deposition, and fibrosis of the connective tissue of the skin, lungs, gastrointestinal tract, heart, and kidneys [1]. Following an unknown triggering event, inflammatory cells are recruited into perivascular areas where they release inflammatory mediators that enhance fibroblast activation, collagen accumulation, and tissue hypoxia [2].

Taken separately, each of these elements share features with other disorders:

  • 1)

    Immune abnormalities: Humoral immunity is characterized by the generation of self-reactive antibodies such as anti-topoisomerase, anti-centromere, anti-fibrillin-1, anti-RNA polymerases I and III, and anti-endothelin antibodies.

    Cellular immunity is characterized by increase of CD4+ T-helper and TCR + lymphocytes, and decreased levels of CD8 cell in peripheral blood. These abnormalities can cause both microvascular damage and collagen over-production by fibroblasts [3].

  • 2)

    Endothelial dysfunction is characterized by both microvascular endothelial cell activation, and injury similar to that observed in allograft rejection vasculopathy, graft-versus-host disease, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura [4], [5].

  • 3)

    Fibroblast activation mimics chronic graft-versus-host reaction, porphyrias, and other examples of unregulated scar tissue formation [6].

    A number of infectious agents (bacterial and viral) have been found to be involved in the pathogenesis of systemic sclerosis [7].

Infections are believed to often play a role in the immunopathogenesis of systemic sclerosis, among other autoimmune disorders (Table 1). A study comparing serological samples against various infectious agents from patients with SSc with samples from healthy controls, found that patients with SSc had elevated IgM and IgG against Toxoplasma gondii and against CMV, as well as high titers against the hepatitis B core antigen and a significantly higher rate of IgM antibodies against the capsid antigen of EBV [8].

Section snippets

Viruses

A possible pathogenetic role of two viruses, human parvovirus B19 and human cytomegalovirus (HCMV) has been implicated in the emergence of SSc [9], [10].

Parvovirus B19 has been proposed as a causative agent in rheumatoid disease and other vascular injury syndromes, including Wegener's granulomatosis [11], microscopic polyarteritis nodosa [12], Henoch Schonlein purpura [13] and dermatomyositis [14]. Serum B19-related markers have been detected in SSc; B19 viremia was found in 4% of SSc patients,

Bacteria

Increased seroprevalence of Helicobacter pylori (HP) has been found in SSc (78%) [35] . Disturbed gastrointestinal motility in SSc patients may be linked to overlap with the occurrence of HP that has been correlated with a risk of coronary heart disease and seems associated to Reynaud's phenomenon [36]. The incidence of HP infection was 81% in 26 women with primary Reynaud's phenomenon [37]. It has been demonstrated that HP sheds extracellular products that elicit local and systemic immune

Pathogenesis hypotheses

There are several pathogenesis hypotheses linking infections with the development of SSc.

Molecular mimicry is a mechanism that may explain the pathogenicity of antibodies against viral proteins in SSc. Infection with HCMV may generate a host-antiviral response that is self-reactive toward autoantigens and endothelial cells.

Self-reactive antibodies against a virus may induce endothelial cell apoptosis through interaction with different integrins [40]. This can provide a pathogenic mechanism by

Conclusion

Three main physiological aspects are disrupted in SSc involving immune reactions, vascular function and fibrosis. A number of infectious agents have been implicated as possible triggering factors that facilitate these aberrations. It is believed that their pathogenetic impact is conveyed via molecular mimicry, endothelial cell damage, superantigens, and microchimerism.

Several studies have provided information linking infectious agents to SSc, but a direct association is still missing. Viral

Take-home messages

  • Direct and indirect evidence ties infection to the emergence of SSc. Several reports underline the finding of either antibodies against Parvo viruses, EBV, CMV and other in addition to the detection of viral RNA and DNA at higher frequencies in the blood and tissues of patients with SSc.

  • Higher rates of infection have also been reported with Helicobacter pylori and Chlamydial infections.

  • Infections may take part in the induction of SSc by diverse autoimmune mechanisms such molecular mimicry,

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