Inflammatory Cytokine-Producing Cells and Inflammation Markers in the Synovium of Osteoarthritis Patients Evidenced in Human Herpesvirus 7 Infection

Abstract

A direct association between joint inflammation and the progression of osteoarthritis (OA) has been proposed, and synovitis is considered a powerful driver of the disease. Among infections implicated in the development of joint disease, human herpesvirus 7 (HHV-7) infection remains poorly characterized. Therefore, we assessed synovitis in OA patients; determined the occurrence and distribution of the HHV-7 antigen within the synovial membrane of OA-affected subjects; and correlated plasma levels of the pro-inflammatory cytokines tumor necrosis factor (TNF), interleukin-6 (IL-6), and TNF expressed locally within lesioned synovial tissues with HHV-7 observations, suggesting differences in persistent latent and active infection. Synovial HHV-7, CD4, CD68, and TNF antigens were detected immunohistochemically. The plasma levels of TNF and IL-6 were measured by an enzyme-linked immunosorbent assay. Our findings confirm the presence of persistent HHV-7 infection in 81.5% and reactivation in 20.5% of patients. In 35.2% of patients, virus-specific DNA was extracted from synovial membrane tissue samples. We evidenced the absence of histopathologically detectable synovitis and low-grade changes in the majority of OA patients enrolled in the study, in both HHV-7 PCR+ and HHV-7 PCR‒ groups. The number of synovial CD4-positive cells in the HHV-7 polymerase chain reaction (PCR)+ group was significantly higher than that in the HHV-7 PCR‒ group. CD4- and CD68-positive cells were differently distributed in both HHV-7 PCR+ and HHV-7 PCR‒ groups, as well as in latent and active HHV-7 infection. The number of TNF+ and HHV-7+ lymphocytes, as well as HHV-7+ vascular endothelial cells, was strongly correlated. Vascular endothelial cells, especially in the case of infection reactivation, appeared vulnerable. The balance between virus latency and reactivation is a long-term relationship between the host and infectious agent, and the immune system appears to be involved in displaying overreaction when a shift in the established equilibrium develops.

Healthy and Osteoarthritis-Affected Joints Facing the Cellular Crosstalk

“…Krenn et al proposed a histopathological grading system to evaluate the damage to the synovial membrane and define the synovitis grade in inflammatory and non-inflammatory arthritides by using light microscopy [ 54 ]. Patients with OA-related synovitis may have different levels of inflammation, but in most cases, it is a low-grade [ 26 , 27 ].…”

“…Furthermore, even though, it is acknowledged that changes within joint tissue during OA are mainly degenerative, recent studies underline the importance of chronic inflammation [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. The activation of the immune system, whether innate or adaptive, reflects local changes in the tissue.…”

From Low-Grade Inflammation in Osteoarthritis to Neuropsychiatric Sequelae: A Narrative Review

“…Currently, the contribution of chronic, low-grade inflammation (Figure 1) to the development of OA and the action of inflamed synovium as a trigger of the OA process has been suggested [25,[29][30][31]. The synovial intimal cells are essential producers of various pro-inflammatory cytokines that drive the OA process in the affected joint [32][33][34][35]. Furthermore, these inflammatory mediators may activate their corresponding receptors on different brain cells and initiate various pathways of molecular signaling in the CNS [36].…”

Research of Pathogenesis and Novel Therapeutics in Arthritis 2.0

“…Belluzzi and colleagues describe inflammatory and fibrotic changes in OA infrapatellar fat pad (IFP) characteristics, which suggests that targeting fibrosis could effectively counteract the disease progression and associated pain in patients with OA [11]. Groma and colleagues discuss their findings of persistent human herpesvirus 7 (HHV-7) infection in 81.5% of their study subjects with OA and reactivation in 20.5% of the subjects [12]. The study researchers discuss the significance of the immune system reaction to a foreign antigen and the impact on inflammatory cells in OA [12].…”

“…Groma and colleagues discuss their findings of persistent human herpesvirus 7 (HHV-7) infection in 81.5% of their study subjects with OA and reactivation in 20.5% of the subjects [12]. The study researchers discuss the significance of the immune system reaction to a foreign antigen and the impact on inflammatory cells in OA [12]. Chang and colleagues describe findings suggesting that electronegative low-density lipoprotein (LDL) may promote atherogenesis by augmenting macrophage foam cell formation, upregulating CD11c expression, and enhancing the expression levels of atherosclerosis-related mediators in RA [13].…”