Modulation of T-cell function by type I interferon

Production of type I interferon (IFN-α/β) is a common cellular response to virus infection. IFN-α/β has a dual role in combating infection, triggering innate antiviral mechanisms and stimulating the generation of an adaptive immune response. This review focuses on the effects of IFN-α/β on one particular immune cell type, the T cell, and the impact of IFN-α/β-mediated signalling in T cells on the immune response. The critical role of T-cell responsiveness to IFN-α/β for the generation of productive T-cell responses after infections with certain viruses in vivo is discussed in the context of in vitro experiments investigating the mechanisms by which IFN-α/β modifies T-cell function. These studies reveal complex effects of IFN-α/β on T cells, with the consequences of exposure to IFN-α/β depending on the context of other signals received by the T cell.     

Modulation of serotonin transporter function by interleukin-4

Serotonin (5-HT) is an important mediator of interactions between the nervous and immune systems. 5-HT signaling is regulated by the 5-HT transporter (5-HTT), which determines the magnitude and duration of serotonergic responses. Due to this important role, regulation of the 5-HTT by cytokines has been the focus of recent interest. A number of proinflammatory cytokines, including interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma, have been shown to upregulate the 5-HTT. In the present study we investigated the influence of interleukin-4 (IL-4), which acts as an anti-inflammatory cytokine in the central nervous system, on the 5-HTT. As a model system we used immortalized B lymphocytes, which not only express the 5-HTT, but also allow testing the co-modulatory influence of a recently described polymorphism in the 5-HTT gene promoter (5-HTTLPR) that is associated with anxiety- and depression-related behavioral traits. The results show that IL-4 induces a dose-dependent reduction of 5-HT uptake. This effect is preferentially seen in cell lines homozygous for the long, high-activity allele of the 5-HTTLPR. In conclusion, a picture of differential modulation of the 5-HTT by proinflammatory and anti-inflammatory cytokines is emerging, which may represent a fine-tuned mechanism to communicate the state of an immune response to the central nervous system.     

Interleukin-7 deficiency in rheumatoid arthritis

Interleukin-7 (IL-7) is a stromal factor that is crucial for the development of T lymphocytes in humans and mice, and also B lymphocytes in mice. IL-7 can act as a T cell growth factor as well as a critical anti-apoptotic survival factor. The essential non-redundant role of this cytokine for T cell development in vivo is indicated by the phenotype of murine knockout models as well as by humans with a T^-B⁺NK⁺ form of severe combined immunodeficiency (SCID) resulting from mutations in IL-7 receptor α chain. IL-7 deficiency has now been found in patients with rheumatoid arthritis, a finding that relates not only to the T-lymphocyte status in this disease but also to the ability of patients with rheumatoid arthritis to recover from therapy-induced lymphopenia.     

Interleukin-7 deficiency in rheumatoid arthritis

Interleukin-7 (IL-7) is a stromal factor that is crucial for the development of T lymphocytes in humans and mice, and also B lymphocytes in mice. IL-7 can act as a T cell growth factor as well as a critical anti-apoptotic survival factor. The essential non-redundant role of this cytokine for T cell development in vivo is indicated by the phenotype of murine knockout models as well as by humans with a T-B+NK+ form of severe combined immunodeficiency (SCID) resulting from mutations in IL-7 receptor alpha chain. IL-7 deficiency has now been found in patients with rheumatoid arthritis, a finding that relates not only to the T-lymphocyte status in this disease but also to the ability of patients with rheumatoid arthritis to recover from therapy-induced lymphopenia.     

Autonomic nervous system function in rheumatoid arthritis

The sympathoneural and the adrenomedullary systems are involved in regulation of immune processes. Their impairment has been suggested in patients with rheumatoid arthritis (RA). In this study, sympathetic response to orthostasis was evaluated in 22 RA females with <40 years of age and in 15 matched healthy controls. The testing consisted of stabilization period in supine position, legs-up position, 10 min of orthostasis and again supine position. In each of the body position blood samples were drawn, blood pressure and electrocardiogram was recorded. Plasma levels of epinephrine (EPI) and norepinephrine (NE) were measured and sympathoneural activity was evaluated by analysis of heart rate variability (HRV). During the testing, RA patients had similar EPI and NE concentrations compared to controls. Baseline diastolic blood pressure tended to be higher in RA patients compared to controls; however, blood pressure response to orthostasis was comparable between the groups. The RA and control groups did not differ in heart rate and HRV parameters. This study showed normal reactivity of the sympathoneural and the adrenomedullary systems during orthostatic challenge in RA patients younger than 40 years.     

Patterns of peripheral cellular immune disorders in severe rheumatoid arthritis

The study is focused on the correlated peripheral cellular immune disorders registered in a group of 23 patients with severe, progressive rheumatoid arthritis, on methotrexate therapy. We investigated a panel of peripheral immune parameters: leukocyte counts, the proportions of lymphocyte populations (T, Thelper, Tcytotoxic/suppressor, B lymphocytes and NK cells) and the polyclonal activation of lymphocytes. Results show that leukocytosis is due to simultaneously elevated values of monocytes, granulocytes and, to a lesser extent, lymphocytes. The registered high values of the Th to Tc/s ratio are mainly attributed to the abnormal low proportions of the Tc/s subpopulation. Inverse correlations were emphasized between B, Tc/s lymphocytes and NK cells or granulocytes. The unbalance of the lymphocyte to monocyte ratio or of the Th to Tc/s ratio does not impair the polyclonal activation of lymphocytes. In conclusion, we have characterized different patterns of correlated cellular peripheral immune disorders in rheumatoid arthritis, associated to pathological processes in conjunction with the immunsuppressive and anti-inflammatory action of methotrexate that might be relevant for further investigation of disease and further therapy outcome. We emphasize the special relation between the adaptive and innate immune system at the level of cell counts and proportions. The correlations between the peripheral abnormalities in the rheumatoid arthritis group are better highlighted by analyzing subgroups of patients characterized by particular values of the investigated parameters.     

The role of interleukin-17 in mediating joint destruction in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic, persistent inflammatory joint disease with systemic involvement that affects about 1% of the world’s population, that ultimately leads to the progressive destruction of joint. Effective medical treatment for joint destruction in RA is lacking because the knowledge about molecular mechanisms leading to joint destruction are incompletely understood. It has been confirmed that cytokine-mediated immunity plays a crucial role in the pathogenesis of various autoimmune diseases including RA. Recently, IL-17 was identified, which production by Th17 cells. IL-17 has proinflammatory properties and may promote bone and joint damage through induction of matrix metalloproteinases and osteoclasts. In mice, intra-articular injection of IL-17 into the knee joint results in joint inflammation and damage. In addition, it has been shown that blocking IL-17/IL-17R signaling is effective in the control of rheumatoid arthritis symptoms and in the prevention of joint destruction. In this article, we will briefly discuss the biological features of IL-17/IL-17R and summarize recent advances on the role of IL-17/IL-17R in the pathogenesis and treatment of joint destruction in RA.     

Notch signalling in the regulation of peripheral T-cell function

The Notch signalling pathway plays a highly-conserved role in regulating the cellular differentiation and proliferation events that characterise pattern formation in the embryo. As cells in the embryo respond to environmental signals, similarly T-cells in the peripheral immune system must monitor their environment for antigens and respond accordingly by entering one of several potential differentiation pathways. Recent studies have identified a role for the Notch pathway in regulating the responses of T-cells in the periphery. In this review, we discuss these findings in the context of the Notch signalling pathway's role as an orchestrator of cellular differentiation, and propose a central role for Notch as a regulator of immune system function.     

Dual role of interleukin-17 in pannus growth and osteoclastogenesis in rheumatoid arthritis

Introduction  

In a murine model, interleukin (IL)-17 plays a critical role in the pathogenesis of arthritis. There are controversies, however, regarding whether IL-17 is a proinflammatory mediator in rheumatoid arthritis (RA). We previously established an ex vivo cellular model using synovial tissue (ST)-derived inflammatory cells, which reproduced pannus-like tissue growth and osteoclastic activity in vitro. Using this model, we investigated the effects of IL-17 on pannus growth and osteoclastogenesis in RA.     

Imbalance of peripheral B lymphocytes and NK cells in rheumatoid arthritis

The study was focused on several cellular immune disorders correlated with the imbalance between peripheral blood B lymphocytes and NK cells in severe rheumatoid arthritis. By flow cytometry we calculated the proportions of T, T helper, T cytotoxic/suppressor, B lymphocytes and natural killer cells in peripheral blood. The mitogen-induced proliferation of peripheral lymphocytes was measured by tritium-labeld uridine incorporation. Experimental data highlight a connection between annomal values of the B to natural killer cells ratio and disorders of the peripheral mononuclear cells concentration. We also showed that the polyclonal proliferation capacity of peripheral lymphocytes in rheumatoid arthritis is solely related to the B to natural killer cells ratio or to the natural killer cells proportion. The study reveals a potential role of the imbalance between proportions of peripheral B lymphocytes and natural killer cells in the immune pathogenesis of rheumatoid arthritis, thus pointing out an interrelation between the adaptive and innate immune systems.     

Soluble interleukin-18 receptor complex is a novel biomarker in rheumatoid arthritis

Introduction

There has been no report in the literature of a soluble form of interleukin (IL)-18 receptor α (IL-18Rα). In this study, we evaluated the levels and characteristics of soluble IL-18Rα (sIL-18Rα) in the sera of patients with rheumatoid arthritis (RA) and compared these results to control populations.

Methods

The sIL-18Rα complex was isolated from pooled human blood serum using an anti-IL-18Rα monoclonal antibody affinity column. The purified sIL-18Rα was then examined using Western blot analysis and used in experiments to evaluate the effects on an IL-18-responsive natural killer (NK) human cell line, NK0. An enzyme-linked immunosorbent assay was developed, and sera from 145 patients with RA, 6 patients with adult-onset Still's disease, 31 patients with osteoarthritis (OA), 39 patients with systemic lupus erythematosus (SLE) and 67 controls were tested, along with levels of immunoglobulin M, rheumatoid factor, anticyclic citrullinated peptide antibody, IL-18, IL-13 and interferon (IFN)-γ. Area under the receiver operating characteristic curve (ROC-AUC) analysis was used to evaluate the diagnostic utility of the sIL-18Rα complex.

Results

The isolated sIL-18Rα complex can be associated with IL-18 and the soluble form of the IL-18Rβ chain. The sIL-18Rα complex bound to the surface to the NK0 cell line, antagonized the stimulatory effects of IL-18 and IL-2 on the NK0 cell line and inhibited IFN-γ production by the cells. The serum levels of sIL-18Rα complex in RA (186.0 ± 33.5 ng/mL, n = 145) and adult-onset Still's disease (98.2 ± 8.9 ng/mL, n = 6) were significantly (P < 0.001) higher than those in the healthy controls (52.3 ± 8.5 ng/mL, n = 67), OA (38.6 ± 5.4 ng/mL, n = 31), SLE (44.6 ± 3.2 ng/mL, n = 39). The serum level of sIL-18Rα complex was not significantly different between RA and adult-onset Still's disease patients. The serum levels of IL-18, IL-13 and IFN-γ in the RA patients were significantly (P < 0.01) higher than in OA and SLE patients as well as healthy controls. ROC-AUC analysis of the serum concentration of sIL-18Rα indicated that it was significantly diagnostic of RA. Moreover, a tumor necrosis factor inhibitor, etanercept, significantly (P < 0.0001) decreased levels of sIL-18Rα in the sera of 29 RA patients 6 months after treatment.

Conclusions

The sIL-18Rα complex could be a potentially useful biomarker for the diagnosis of RA.     

Inflammation,endothelial function and atherosclerosis in rheumatoid arthritis

Different techniques have proven to be useful in determining the presence of subclinical cardiovascular disease in patients with rheumatoid arthritis (RA). Doppler imaging with iontophoresis of acetylcholine and flow-mediated, endothelium-dependent vasodilation give information on endothelial dysfunction, an early step in the atherogenesis process. However, there is no good correlation between these two surrogate markers of cardiovascular disease in RA. A single determination of routine laboratory markers of inflammation does not seem to relate to endothelial function in RA. Further research is needed to determine whether microvascular endothelial function is a better predictor of cardiovascular outcome than macrovascular endothelial function in patients with RA.Endothelial dysfunction is an early step in the atherogenesis process of rheumatoid arthritis (RA). In the previous issue of Arthritis Research & Therapy, Sandoo and colleagues [1] reported a cross-sectional study performed on 99 unselected patients with RA to determine the presence of microvascular and macrovascular endothelial function in parallel with disease activity, individual cardiovascular (CV) disease risk factors, and global CV disease. The authors also longitudinally studied 23 patients who had RA and who started on anti-tumor necrosis factor-alpha (anti-TNFα) therapy [1]. In the cross-sectional study, markers of RA-related inflammation were not associated with microvascular or macrovascular endothelium-dependent function, and global CV disease risk inversely correlated with microvascular endothelium dependent function. In the longitudinal study, only microvascular endothelium-dependent function showed an improvement following 2 weeks of anti-TNFα treatment in comparison with baseline, but no association between change in endothelial function and change in inflammatory markers was evident. Considering these results, the authors concluded that classic CV disease risk may influence endothelial function more than disease-related markers of inflammation in RA. They stated that classic CV disease risk factors and anti-TNFα medication have different effects on microvascular and macrovascular endothelial function [1].This interesting study raises a series of points that deserve to be addressed. First, endothelial dysfunction in RA is the result of a complex effect mediated by classic CV risk factors, genetic predisposition, chronic inflammation, pro-oxidative stress, a prothrombotic status, and metabolic abnormalities (such as insulin resistance or dyslipidemia) that to a greater or lesser extent may influence the development of this systemic pathological state [2]. The results reported by Sandoo and colleagues suggest that systemic markers of inflammation - erythrocyte sedimentation rate, C-reactive protein (CRP), and disease activity score using 28 joint counts (DAS28) - and disease duration do not relate to endothelial function in microvascular and macrovascular vascular beds [1]. With respect to this, we feel that a single determination of routine laboratory markers of inflammation may not be useful to provide accurate information on the whole atherosclerotic burden associated with this chronic disease. In this regard, when we conducted a study to assess the association between inflammation measured by CRP values and carotid intima-media thickness (IMT)(another surrogate marker of CV disease) [3], we could not find a correlation between CRP at the time of disease diagnosis or at the time of the ultrasound study and the carotid IMT [4]. Nevertheless, the magnitude and chronicity of the inflammatory response measured by the average CRP values in patients with at least 5 years'' disease duration correlated directly with the presence of atherosclerosis determined by carotid IMT [4]. Therefore, considering the results observed using carotid IMT, we think that an overall assessment of the values of biomarkers of inflammation over a prolonged period of time (that is, the mean value of CRP over at least 5 years'' time), rather than a single determination of these biomarkers, might yield more useful information on the implication of these biomarkers of inflammation in the assessment of endothelial dysfunction of patients with RA.Another important result derived from the study [1] was the poor correlation between different surrogate markers of atherosclerosis. This result is expected given that, in a study we conducted to determine whether a correlation between flow-mediated, endothelium-dependent macrovascular vasodilation and carotid IMT values exists, a correlation between these two surrogate markers of atherosclerosis was observed only in RA patients with a long disease duration (more than 7 years) [5]. Therefore, different techniques may provide information on different stages of the atherosclerotic disease [3]. Unlike laser Doppler imaging with iontophoresis of acetylcholine or flow-mediated, endothelium-dependent vasodilation (which give functional information on endothelial function), carotid ultrasound allows the identification of structural morphological damage that was reported to predict CV events in RA [6,7].An unexpected result from the study by Sandoo and colleagues [1] was the absence of change of flow-mediated, macrovascular, endothelial-dependent function in response to 3 months of anti-TNFα treatment. This finding is in contrast to that of previous reports [8-10]. The authors'' explanation of a better baseline macrovascular endothelial-dependent function in their cohort compared with previous series of RA patients undergoing anti-TNFα therapy may be plausible, as treatment with anti-TNFα may have less impact in RA patients who have an endothelial function similar to that of healthy individuals.Finally, the authors highlight the importance of assessing endothelial function in more than one vascular bed. This conclusion is based on the observations that micro-vascular, but not macrovascular, endothelium-dependent function was associated with global CV disease risk algorithms and that only microvascular endothelium dependent function changed following treatment with anti-TNFα [1]. At this point, replication of these observations by other investigators would be of great help to shed light on this matter.Whether classic CV risk factors are more important than chronic inflammation to establish endothelial dysfunction in RA is, at this point, rather speculative. We feel that, as previously pointed out by Kitas and Gabriel [11], classic CV risk factors are important but not sufficient to explain all of the CV excess risk found in RA. We feel that additional research is needed to determine whether microvascular endothelial function is a better predictor of CV outcome than macrovascular endothelial function in patients with RA.     

Monocytes are essential for inhibition of synovial T-cell glucocorticoid-mediated apoptosis in rheumatoid arthritis

Introduction  

Rheumatoid arthritis (RA) is characterized by synovial inflammation with local accumulation of mononuclear cells such as macrophages and lymphocytes. We previously demonstrated that intra-articular glucocorticoids decrease the synovial tissue (ST) T-cell population and therefore aimed to investigate whether this is mediated through modulation of apoptosis.     

Induction of tumour necrosis factor receptor-expressing macrophages by interleukin-10 and macrophage colony-stimulating factor in rheumatoid arthritis

Despite its potent ability to inhibit proinflammatory cytokine synthesis, interleukin (IL)-10 has a marginal clinical effect in rheumatoid arthritis (RA) patients. Recent evidence suggests that IL-10 induces monocyte/macrophage maturation in cooperation with macrophage-colony stimulating factor (M-CSF). In the present study, we found that the inducible subunit of the IL-10 receptor (IL-10R), type 1 IL-10R (IL-10R1), was expressed at higher levels on monocytes in RA than in healthy controls, in association with disease activity, while their expression of both type 1 and 2 tumour necrosis factor receptors (TNFR1/2) was not increased. The expression of IL-10R1 but not IL-10R2 was augmented on monocytes cultured in the presence of RA synovial tissue (ST) cell culture supernatants. Cell surface expression of TNFR1/2 expression on monocytes was induced by IL-10, and more efficiently in combination with M-CSF. Two-color immunofluorescence labeling of RA ST samples showed an intensive coexpression of IL-10R1, TNFR1/2, and M-CSF receptor in CD68⁺ lining macrophages. Adhered monocytes, after 3-day preincubation with IL-10 and M-CSF, could produce more IL-1β and IL-6 in response to TNF-α in the presence of dibutyryl cAMP, as compared with the cells preincubated with or without IL-10 or M-CSF alone. Microarray analysis of gene expression revealed that IL-10 activated various genes essential for macrophage functions, including other members of the TNFR superfamily, receptors for chemokines and growth factors, Toll-like receptors, and TNFR-associated signaling molecules. These results suggest that IL-10 may contribute to the inflammatory process by facilitating monocyte differentiation into TNF-α-responsive macrophages in the presence of M-CSF in RA.