Human Cytomegalovirus and Autoimmune Diseases: Where Are We?

Abstract

Human cytomegalovirus (HCMV) is a ubiquitous double-stranded DNA virus belonging to the β-subgroup of the herpesvirus family. After the initial infection, the virus establishes latency in poorly differentiated myeloid precursors from where it can reactivate at later times to cause recurrences. In immunocompetent subjects, primary HCMV infection is usually asymptomatic, while in immunocompromised patients, HCMV infection can lead to severe, life-threatening diseases, whose clinical severity parallels the degree of immunosuppression. The existence of a strict interplay between HCMV and the immune system has led many to hypothesize that HCMV could also be involved in autoimmune diseases (ADs). Indeed, signs of active viral infection were later found in a variety of different ADs, such as rheumatological, neurological, enteric disorders, and metabolic diseases. In addition, HCMV infection has been frequently linked to increased production of autoantibodies, which play a driving role in AD progression, as observed in systemic lupus erythematosus (SLE) patients. Documented mechanisms of HCMV-associated autoimmunity include molecular mimicry, inflammation, and nonspecific B-cell activation. In this review, we summarize the available literature on the various ADs arising from or exacerbating upon HCMV infection, focusing on the potential role of HCMV-mediated immune activation at disease onset.

Keywords: autoimmune diseases; autoimmunity; human cytomegalovirus.

Figure 1

Schematic model summarizing the major aspects of HCMV modulation of the immune system. NK cells, CD8⁺ and CD4⁺ T-cells, and myeloid cells are the main protagonists of host immune control of HCMV infection. HCMV proteins are represented in blue. Black arrows indicate stimulation/activation; red lines represent inhibition.

Figure 2

The main mechanisms involved in HCMV-induced autoimmunity and associated ADs. (1) Autoantibodies production: the occurrence of viral epitopes, structurally similar to self-ones, can induce the activation of both T- and B-cells through their presentation by APCs; (2) increased inflammation: non-specific anti-HCMV immune response leads to the release of self-antigens and cytokines from the affected tissue; those self-antigens presented by APCs can stimulate autoreactive T-cells; (3) vascular damage: enduring HCMV infection triggers vascular damaging; the release of endothelial antigens and cytokines induces the activation of autoreactive T-cells and B-cells, culminating in aggression of endothelial cells via specific autoantibodies.