**3.3. Hepatitis B virus**

become infected by EBV and proliferate to become latently infected memory B cells. Since they express virus-encoded antiapoptotic molecules, these become resistant to normal B-cell homeostasis-associated apoptosis [34]. These impaired B cells activate autoreactive T cells which similarly fail to undergo apoptosis as they receive a costimulatory survival signal from infected B cells. The autoreactive T cells expand to produce cytokines, which recruit other inflammatory cells, resulting

The association of EBV with rheumatoid arthritis is less clear. Patients with RA have higher levels of anti-EBV antibodies than healthy controls. Additionally, EBV-specific suppressor T-cell function is defective in rheumatoid arthritis, and patients with rheumatoid arthritis have a higher EBV load in peripheral blood lymphocytes. However, there is no clear evidence for the creation of rheumatoid arthritis-specific autoantibodies [36]. It has been proposed that EBV can, perhaps, play a role in the citrullination of autoantigens or the formation of autoantibodies such as anticyclic citrullinated peptide, but this theory remains to be proven [37].

Graves' disease is another autoimmune disease which is the most common cause of hyperthyroidism. It has been hypothesized by Nagata et al. that the reactivation of persisting Epstein-Barr virus in B lymphocytes induces differentiation of host B cells into plasma cells [38]. B cells infected with EBV possess thyrotropin receptor antibodies (TRAbs) on the surface of immunoglobulins (Igs) [39]. EBV reactivation induces these TRAb+EBV+ cells to produce TRAbs. Activation of B cells infected with the virus by polyclonal B cell activation leads to the production of Igs through plasma cell differentiation. This may be induced by EBV reactivation. EBV-LMP1 enables B cells to produce every isotype of Ig. Thus, it has been hypothesized that EBV rescues autoreactive B cells to produce autoantibodies, which contribute to the development and exacerbation of autoimmune diseases including Graves' disease [38].

Human cytomegalovirus (HCMV) or cytomegalovirus (CMV) is a large double-stranded DNA prototypic pathogenic member of the beta-subgroup of the herpesvirus family. Certain features attributed to the cytomegalovirus, like lytic replication in several different tissues, its lifelong persistence through periods of latency and reactivation, an extraordinarily large proteome, considerable manipulation of adaptive and innate immune systems, and its worldwide prevalence in human populations, make it a prominent candidate for involvement and exacerbation of autoimmune abnormalities [40]. Cytomegalovirus is known to be a leading cause of mental retardation and congenital hearing loss, and CMV infection is known to induce several autoimmune disorders in mice that resemble abnormalities in SLE [41]. It has also been implicated in the development and/or progression of SLE in humans [42]. Additionally, CMV has been associated with many other autoimmune diseases such as inflammatory bowel disease [43], diabetes mellitus [44, 45], systemic sclerosis [46], antiphospholipid syndrome [47, 48], and rheumatoid arthritis. The relationship between CMV infection and accelerated atherosclerosis [49, 50] is unclear, as conflicting data have been reported, and thus requires further investigation. A clear relationship between HCMV seroprevalence and disease has not been established. A higher prevalence of HCMV IgG antibodies would be expected in patients suffering from specific types

in target-organ damage and chronic autoimmune disease [35].

**3.2. Cytomegalovirus**

94 Autoantibodies and Cytokines

Hepatitis B virus (HBV) is a small partially double-stranded circular DNA virus that replicates in the liver cells. This hepatotropic virus is classified in the Hepadnaviridae family. HBV remains one of the major causes of liver disease, varying in severity from person to person [53–56]. The most common autoimmune diseases associated with chronic HBV infection are membranous glomerulonephritis and systemic necrotizing vasculitis [57]. HBV uses active immune evasion strategies that target the adaptive response responsible for the elimination of HBV virus [55, 58]. CD4 T cells or helper T cells produce cytokines and are involved in the efficient development of effector cytotoxic CD8 T-cell antibody production by B cells. HBV-infected hepatocytes are cleared by CD8 T cells through both cytolytic and noncytolytic mechanisms, leading to a reduction in the levels of circulating virus. The B-cell antibody production neutralizes free viral particles and can also prevent infection or reinfection [55]. Liver injury during the acute and chronic phases of viral hepatitis may be caused by T-cell responses. HBV-specific CD8+ T cells play a double role. On the one hand, the HBV-specific CD8+ T cells are vital in the clearance and control of the virus, but on the other hand, when overall antiviral immunity is not robust enough to clear the viruses, liver tissue damage may occur through different pathways, including perforin-mediated cytotoxicity and Fas ligand/Fas-mediated apoptosis [59, 60]. Thus, liver damage in patients with chronic HBV infections may be a result of autoreactivity.

Antibodies against the asialoglycoprotein receptor-R have been reported in patients with chronic HBV [60]. The occurrence of antiasialoglycoprotein receptor-R antibodies in patients with moderate and severe chronic active hepatitis suggests that these antibodies are related to progressive liver damage development in patients with HBV infection rather than as simply a response to tissue damage. Either the host's immune response to virus-infected hepatocytes could result in liver damage [61] or this may be the effect of virus-induced apoptosis [21]. Autoantibodies produced as a direct result of this damage may be of various different kinds such as antiasialoglycoprotein receptor-R [60], antinuclear antibody [61], smooth muscle antibody [62, 63], antimitochondrial antibody [62], microsome antibody [62], rheumatoid factor [41], and proliferating cell nuclear antigen [61]. These autoantibodies bind to liver and kidney tissue and are directed against microsomal targets (expressed in estrogen receptor of these two organs) [64]. Further investigations are required to determine the cause-and-effect relationship between HBV and the generation of autoantibodies.
