Mechanisms of lymphatic system-specific viral replication and its potential role in autoimmune disease

Abstract

Viral infections can be fatal because of the direct cytopathic effects of the virus or the induction of a strong, uncontrolled inflammatory response. Virus and host intrinsic characteristics strongly modulate the outcome of viral infections. Recently we determined the circumstances under which enhanced replication of virus within the lymphoid tissue is beneficial for the outcome of a disease. This enforced viral replication promotes anti-viral immune activation and, counterintuitively, accelerates virus control. In this review we summarize the mechanisms that contribute to enforced viral replication. Antigen-presenting cells and CD169 + macrophages exhibit enforced viral replication after infection with the model viruses lymphocytic choriomeningitis virus (LCMV) and vesicular stomatitis virus (VSV). Ubiquitin-specific peptidase 18 (Usp18), an endogenous type I interferon blocker in CD169 + macrophages, has been identified as a proviral gene, as are B cell activating factor (BAFF) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). Lymphotoxins (LT) strongly enhance viral replication in the spleen and lymph nodes. All these factors modulate splenic architecture and thereby promote the development of CD169 + macrophages. Tumor necrosis factor alpha (TNF-α) and nuclear factor kappa-light-chain-enhancer of activated B cell signaling (NF-κB) have been found to promote the survival of infected CD169 + macrophages, thereby similarly promoting enforced viral replication. Association of autoimmune disease with infections is evident from (1) autoimmune phenomena described during a chronic virus infection; (2) onset of autoimmune disease simultaneous to viral infections; and (3) experimental evidence. Involvement of virus infection during onset of type I diabetes is strongly evident. Epstein-Bar virus (EBV) infection was discussed to be involved in the pathogenesis of systemic lupus erythematosus.In conclusion, several mechanisms promote viral replication in secondary lymphatic organs. Identifying such factors in humans is a challenge for future studies.

Innate Immune Modulation Induced by EBV Lytic Infection Promotes Endothelial Cell Inflammation and Vascular Injury in Scleroderma

“…Although the mechanism responsible for the increase of the EBV DNA load in autoimmune diseases and SSc remains to be established, it is possible that impaired immune function could lead to an increase in EBV DNA replication in SSc patients, rendering these patients long-term viral carriers. Given the numerous HLA polymorphisms in the HLA-class-I/II-genes strongly associating with the risk of developing autoimmune diseases including SSc (2,59,108), it is also possible that SSc genetic susceptibility associated with the genetic variability in EBV strain might predispose SSc patients to an uncontrolled, persistent active EBV lytic infection (89,(109)(110)(111)(112)(113). An important aspect of this study is that SSc monocytes carry high levels of EBV DNA while monocytes from SLE patients do not.…”

Anti-Jo-1 Antibody-positive Interstitial Pneumonia in an Elderly Patient with Congenital Rubella Syndrome

“…Interstitial pneumonia with autoimmune features was diagnosed in our patient based on the serological and radiological findings (16). Previous studies have suggested that viral infection is involved in the development of connective tissue diseases (17)(18)(19). To clarify the relationship between interstitial pneumonia and CRS in adulthood, further investigations will be needed.…”

Functions of CD169 positive macrophages in human diseases (Review)

“…In addition, interfering with the CSF-1 signalling pathway in the spleen of mice could quickly inhibit the generation of this cell ( 27 , 28 ). The development of CD169 + macrophages also depends on lymphotoxin (LT)-α and LT-β secreted by B cells, and the deletion of B cells or LT can affect cell development directly ( 29 , 30 ). In the colon however, the development of CD169 + macrophages is dependent on vitamin A, rather than LT ( 26 ).…”

“…CD169 + macrophages transfer antigens to CD8a + DCs using the CD169 molecule, which preferentially participate in cell contact, eventually inducing an effective CD8 + T cell response ( 51 ). Moreover, CD169 + macrophages have been shown to enforce viral replication, resulting in the delivery of a large number of viral antigens, and the amplification of T and B lymphocyte responses ( 29 , 78 ). Type I IFN induced macrophages express CD169 molecules both in vivo and in vitro ( 50 ).…”