IFNα Serum Levels Are Associated with Endothelial Progenitor Cells Imbalance and Disease Features in Rheumatoid Arthritis Patients

Abstract

IntroductionIFNα has been largely implicated in the ethiopathogenesis of autoimmune diseases but only recently it has been linked to endothelial damage and accelerated atherosclerosis in autoimmunity. In addition, proinflammatory conditions are supposed to be implicated in the cardiovascular status of these patients. Since a role for IFNα in endothelial damage and impaired Endothelial Progenitor Cell (EPC) number and function has been reported in other diseases, we aimed to evaluate the potential associations of IFNα serum levels on EPC populations and cytokine profiles in Rheumatoid Arthritis (RA) patients.Methodspre-EPC, EPC and mature EPC (mEPC) populations were quantified by flow cytometry analyzing their differential CD34, CD133 and VEGFR2 expression in blood samples from 120 RA patients, 52 healthy controls (HC), and 83 systemic lupus erythematosus (SLE) patients as disease control. Cytokine serum levels were measured by immunoassays and clinical and immunological data, including cardiovascular (CV) events and CV risk factors, were retrospectively obtained by reviewing clinical records.ResultsLong-standing, but not recent onset RA patients displayed a significant depletion of all endothelial progenitor populations, unless high IFNα levels were present. In fact, the IFNhigh RA patient group (n = 40, 33%), showed increased EPC levels, comparable to SLE patients. In addition, high IFNα serum levels were associated with higher disease activity (DAS28), presence of autoantibodies, higher levels of IL-1β, IL-6, IL-10 and MIP-1α, lower amounts of TGF-β, and increased mEPC/EPC ratio, thus suggesting higher rates of endothelial damage and an endothelial repair failure. Finally, the relationship between high IFNα levels and occurrence of CV events observed in RA patients seems to support this hypothesis.ConclusionsIFNα serum marker could be used to identify a group of RA patients with increased disease activity, EPC imbalance, enhanced proinflammatory profile and higher cardiovascular risk, probably due, at least in part, to an impaired endothelial repair.

Regulator Versus Effector Paradigm: Interleukin-10 as Indicator of the Switching Response

“…With respect to systemic lupus erythematous (SLE), both the percentage of circulating Breg cells and the ability to produce IL-10 were elevated; the percentage of Breg cells increased during SLE flares and decreased following disease remission [115]. Endothelial damage, accelerated atherosclerosis, and endothelial repair failure in rheumatoid arthritis (RA) have been associated with higher disease activity, presence of autoantibodies, and higher level of both inflammatory (IL-1, IL-6) and immunosuppressive (IL-10) cytokines [116]. Björkbacka et al have proposed that, during early stages of atherosclerosis, Tregs and anti-inflammatory cytokine IL-10 can control autoimmune response against plaque antigens due to inhibition of the activity of autoreactive Th1 effector T cells [117].…”

“…Under resting conditions or at the initial time of response, the relatively low IL-10 production originates mainly from the cells of central immune system [159][160][161]. During the successive period, there is transient IL-10 induction, directly from the Bintact^immune system or under the manipulative effect of infective agents and tumor tissue [72,89,116,120,132,157,161]. Under such circumstances, the induced IL-10 functions at the crossroads of immune stimulation, whereas the outcome of this stimulation is mainly depended on the role of additional immune effectors [141].…”

“…In some circumstances like vaccinations against infectious agents, there is a reduction of IL-10 and FoxP3 along successive weeks, whereas in the case of treatments with immunosuppressor drugs or AIT, the increased T cell originating IL-10 level remains along many months (see Table 2) [94,97,134,155,167]. This suggests that IL-10 could play a key-role during immunity switch or prolonged exposure to immunomodulators (such as immunosuppressive drugs or long treatment with vaccines); in contrast to this, the initial increased IL-10 level seems to be replaced by lower levels, which suggests for reaching of an immune equilibrium (such as during vaccination with infectious agents or after installation of autoimmune pathologies) [94,116,155,160]. This agrees with the fact that IL-10 production by Treg and Breg cells is prevalently observed during early stages of RA and atherosclerosis [116,117].…”

“…This suggests that IL-10 could play a key-role during immunity switch or prolonged exposure to immunomodulators (such as immunosuppressive drugs or long treatment with vaccines); in contrast to this, the initial increased IL-10 level seems to be replaced by lower levels, which suggests for reaching of an immune equilibrium (such as during vaccination with infectious agents or after installation of autoimmune pathologies) [94,116,155,160]. This agrees with the fact that IL-10 production by Treg and Breg cells is prevalently observed during early stages of RA and atherosclerosis [116,117]. This point-of-view could also explain the presence of discrepant/antagonistic findings among similar studies on the same topic, the consideration of IL-10 both as pro-inflammatory and immunosuppressive cytokine, and its consideration as regulator and effector cytokine [2, 66, 81, 113-117, 154, 158, 168].…”

Characteristics of dendritic cells from patients with rheumatoid arthritis and different type of drug therapy

“…Кроме того, мощным ин-дукторами дифференцировки моноцитов ДК являются интерфероны I типа [14]. Учитывая важную патогенетическую роль интерферонов I типа (IFNα, IFNβ) и их повышенный уровень при аутоиммунной патологии [15,16], а также низкое содержании IL-4 в синовиальной жидкости и сы-воротке крови [17,18], логично полагать, что дифференцировка моноцитов в ДК у больных РА осуществляется с участием IFN-α. Соответствен-но, IFN-ДК (как и IL4-ДК) также могут являться мишенью терапевтических воздействий и пред-ставлять интерес в плане новых прогностических маркеров ýффективности терапии.…”