Chemokines and chemokine receptors in rheumatoid arthritis

Chemokines are chemotactic cytokines involved in a number of pathological processes, including inflammatory conditions. Chemokines play a role in the pathogenesis of various inflammatory diseases. Based on a burgeoning body of literature, RA was chosen as a prototype to discuss this issue. In this review, the authors give a detailed introduction to the classification and function of chemokines and their receptors. This is followed by a discussion of the role of chemokines and chemokine receptors in RA. Chemokines interact with other inflammatory mediators, such as cytokines. Thus, the regulation of chemokine production and the place of chemokines in the network of inflammatory mediators present in the rheumatoid synovium are also reviewed. Finally, potential strategies using anti-chemokine or anti-chemokine receptor biologicals in anti-rheumatic therapy are discussed.     

Chemokines: roles in leukocyte development,trafficking, and effector function

Chemokines, representing a large superfamily of 8- to 15-kd proteins, were originally discovered through their ability to recruit various cell types into sites of inflammation. It is now clear that these molecules play a much wider role in immune homeostasis, playing key roles in driving the maturation, homing, and activation of leukocytes. In this review we analyze the roles chemokines play in the development, recruitment, and activation of leukocytes. Because signaling from the receptors drives these processes, signal transduction from chemokine receptors will also be reviewed. Taken together, we highlight the various points at which chemokines contribute to allergic inflammation and at which their targeting might contribute to new therapies for type I hypersensitivity reactions.     

Chemokines and leukocyte traffic

Twenty years after the discovery of chemokines is an appropriate time to review leukocyte traffic and to assess the knowledge and opportunities that have arisen from countless studies of the large and tight-knit family of chemotactic proteins.     

Blood polymorphonuclear leukocyte migratory activities during rheumatoid arthritis

Blood polymorphonuclear leukocyte (PMN) migratory activity was investigated in adult rheumatoid arthritis (RA) patients and in healthy control subjects using fresh whole blood in a novel membrane filter assay. The PMNs migrated under FMLP stimulation and under blank control conditions (spontaneous migration). Essential evaluation criteria were the percentage of PMNs that migrated from the entire blood sample into the filters (TMI) and the penetration depth of the migrating cell bulk into the filters (DC). PMNs from healthy subjects penetrate deeper under FMLP stimulation than under blank control conditions. Migration depends on age and sex: the TMI decreases, while the DC and the reactivity towards FMLP increase with age. FMLP triggers a stronger DC reaction in females than in males. Compared with healthy subjects, patients with RA develop an increased PMN reaction, whereas FMLP inhibits migration in comparison with the blank controls. There is no correlation between disease activity estimated by joint functions and PMN migratory activity, while there are strong correlations between disease activity and the classical RA laboratory parameters WBC, platelets, BSR, CRP, hemoglobin and rheumatoid factor. PMNs therefore probably do not play a major role in joint injury. Gold therapy inhibits DC reactivity. PMN migration in RA differs markedly from the reactions in juvenile rheumatoid arthritis, where high disease activity is associated with high PMN migratory activity, and the correlations between classical laboratory parameters and disease activity follow other patterns than in RA.     

Chemokines in rapid leukocyte adhesion triggering and migration

Leukocyte subsets are recruited from the blood to lymphoid and non-lymphoid tissues via a multi-step process that involves distinct adhesive and activation steps. Chemokines, a family of chemotactic cytokines that signal through G-protein-coupled receptors, play critical roles in regulating the leukocyte recruitment cascade. Chemokines can be transported and immobilized on the surface of vascular endothelial cells, where they activate leukocyte subsets expressing specific receptors. Activation signals induce firm adhesion of rolling leukocytes by rapidly upregulating integrin affinity and/or avidity. Chemokines can also direct migration of adherent cells across the endothelium, and control segregation of cells into specific microenvironments within tissues. The regulated expression of chemokines and their receptors is a critical determinant for homing of specialized lymphocyte subsets, and controls both tissue and inflammation-specific immune processes.     

Circadian rhythms in leukocyte trafficking

A broad range of immunological processes oscillates over the course of a day. Recent findings have identified a molecular basis for the circadian clock in the regulation of the immune system. These rhythms manifest themselves in oscillatory behavior of immune cells and proinflammatory mediators, which causes a time-dependent sensitivity in the reaction to pathogens. This rhythmicity impacts disease manifestations and severity and provides an option for therapy that incorporates chronopharmacological considerations. This review will focus on the current knowledge and relevance of rhythmic immune cell trafficking. It will provide an overview of the molecular clock machinery and its interrelations with leukocyte migration and the immune response.     

Human leukocyte antigen-DQ and DR polymorphisms predict rheumatoid arthritis outcome better than DR alone.

Conflicting data have been published on the value of the shared epitope (SE) hypothesis in predicting disease outcome in rheumatoid arthritis (RA). Recently we have proposed an alternative hypothesis, referred to as the RA protection (RAP) model. In this model, the HLA-DQ loci carry predisposition while HLA-DRB1 alleles encoding the motif DERAA provide protection against severe RA. In the present study, we have compared the respective values of the models in predicting both remission and erosions in early RA patients. We made use of an early arthritis clinic in which 158 RA patients and 138 patients with undifferentiated arthritis were enrolled. Patients were typed for HLA-DQ and -DR using high resolution DNA typing methods. Homozygosity for predisposing HLA-DQ alleles was associated with no remission and high erosion score. The presence of DERAA-bearing DRB1 alleles was negatively associated with erosions in otherwise predisposed individuals and increased the chance of being in remission. We found that the RAP model was significantly better than the SE model in predicting remission rate and erosion scores at one and two years in early RA patients. We conclude that HLA polymorphism does not only affect RA susceptibility, but also protects against severe disease at early stage.     

Estrogens and rheumatoid arthritis.

Epidemiological and immunological evidence has suggested that female sex hormones may play a role in the etiology and course of autoimmune diseases such as rheumatoid arthritis (RA). In this review the present clinical data with regard to estrogens and RA are discussed, with emphasis on the possible preventive effect of oral contraceptives on the incidence of RA and on the possibility of using estrogens as adjuvant therapy in RA. It is concluded that oral contraceptives may mitigate or postpone the onset of RA slightly, but that estrogens are not able to alleviate the symptoms of RA. Presently there is no evidence to promote the use of estrogens in preventing or treating RA in females.     

Chemokines: directing leukocyte infiltration into allografts

Chemokines have been shown to play a critical role in the recruitment of leukocytes to transplanted organs. Animal models and clinical studies have demonstrated predictable temporal and spatial correlations between chemokine production and leukocyte infiltration into allografts. Antagonism of chemokines or chemokine receptors has been shown to delay leukocyte infiltration and prolong graft function, demonstrating an important role for chemokines in allograft rejection.     

Macrophage signaling, apoptosis, lectins and leukocyte trafficking.

The 10th International Symposium of the Molecular Cell Biology of Macrophages (Macrophages 2001) was held in Tokyo, Japan from 21-22 June 2001.     

Apoptosis in rheumatoid arthritis: p53 overexpression in rheumatoid arthritis synovium.

DNA damage induces p53 tumor suppressor gene expression and protein production, which in turn facilitates DNA repair or apoptosis. Wild-type p53 protein has a short half-life, so it is rarely detected in non-neoplastic tissue. Because DNA fragmentation is abundant in the intimal lining in rheumatoid arthritis (RA) synovial tissue (ST) using in situ end-labeling (Firestein GS, Yeo M, Zvaifler NJ: Apoptosis in rheumatoid arthritis synovium. J Clin Invest 1995, 96:1631-1638), we assessed ST p53 expression. Immunohistochemical analysis of fixed RA synovium using antibody PAb 1801 showed prominent p53 staining in the cytoplasm and nuclei of intimal lining cells. Noninflammatory and osteoarthritis (OA) ST had significantly less p53 in the lining. These data were confirmed by Western blot analysis of ST extracts, with abundant p53 found in RA compared with OA. p53 expression in cultured fibroblast-like synoviocytes (FLS) was then examined. Flow cytometry on permeabilized cells showed that RA FLS constitutively express p53 protein. Western blots showed that RA FLS expressed significantly more p53 than either OA FLS or dermal fibroblasts. Immunohistochemistry of FLS cultured in chamber slides localized the p53 to the cytoplasm of most resting FLS, with nuclear staining in only 10.7 +/- 2.4%. Exposure to hydrogen peroxide for increased nuclear staining to 70.7 +/- 12.8% after 8 hours (P = 0.003). These data indicate that p53 is overexpressed in RA ST in the intimal lining, which is the primary site of DNA damage, and is constitutively expressed by FLS.     

Chemokines: multiple levels of leukocyte migration control

The surge in interest in chemokines is explained by the recognition that numerous aspects of immunity are intimately related to leukocyte traffic. Chemokines are leukocyte attractants but also contribute to immune processes that do not directly involve leukocyte migration. Recent progress is most evident in the areas of lymphocyte development, immune response initiation and immune pathology. Important observations have also been reported on chemokine-receptor interactions, signal transduction and cellular responses. New insights into the role of chemokines in leukocyte attraction and relocation will be discussed, with emphasis on the distinct levels of leukocyte migration control that ultimately determine the performance of our immune defense system.     

Spotlight on etanercept in rheumatoid arthritis,psoriatic arthritis and juvenile rheumatoid arthritis

Etanercept (Enbrel) is a subcutaneously administered biological response modifier that binds and inactivates tumour necrosis factor-alpha, a proinflammatory cytokine. In patients with early active rheumatoid arthritis, etanercept 25mg twice weekly was associated with a more rapid improvement in disease activity and a significantly greater cumulative response than methotrexate over 12 months of treatment in a randomised, double-blind trial. In addition, etanercept recipients showed a slower rate of radiographic progression and a more rapid improvement in quality of life than methotrexate recipients. The efficacy of etanercept was maintained at 3 years' follow-up. Etanercept was also significantly better than placebo at reducing disease activity in patients who had an inadequate response to previous treatment with disease-modifying antirheumatic drugs (DMARDs) in several well controlled trials. At study end (after 3 or 6 months' treatment), the percentage of patients achieving an American College of Rheumatology 20% (ACR20) response with etanercept (25mg or 16 mg/m(2) twice weekly) was 59-75% as monotherapy and 71% in combination with methotrexate; corresponding placebo response rates were 11-14% and 27%, respectively. Response has been maintained in patients who continued treatment for up to 5 years. In patients with psoriatic arthritis, etanercept 25mg twice weekly significantly reduced disease activity and improved skin lesions in two double-blind, placebo-controlled, 12- to 24-week trials. In the 24-week study, ACR20 response rates (50 vs 13%), psoriatic arthritis response rates (70 vs 23%) and the median improvement in skin lesions (33 vs 0%) were significantly greater in etanercept than in placebo recipients. In patients with polyarticular-course juvenile rheumatoid arthritis, etanercept resulted in improvements in all measures of disease activity and was significantly more effective than placebo at reducing disease flare. Eighty percent of patients receiving etanercept achieved a > or =30% reduction in disease activity over 7 months of treatment, and this was maintained for up to 2 years in a trial extension. Etanercept was generally well tolerated in children and adults in clinical trials; the most commonly occurring adverse effects included injection site reactions, infection, headache, rhinitis and dizziness. In conclusion, etanercept has emerged as an important new treatment option in inflammatory arthritis. Etanercept provides rapid and sustained improvements in disease activity in patients with early and DMARD-refractory rheumatoid arthritis and has been shown to inhibit radiographic progression in those with early disease. Well controlled studies have also demonstrated the efficacy of etanercept in patients with psoriatic arthritis or polyarticular-course juvenile rheumatoid arthritis.     

Monoclonal gammopathies in rheumatoid arthritis.

A total of 2560 sera from patients with and without rheumatoid diseases were examined for the incidence of monoclonal proteins. The incidence of monoclonal protein was higher (3.3%) in patients with rheumatoid arthritis than with other non-rheumatoid diseases of connective tissue (0.7%). Of 16 monoclonal proteins found in rheumatoid arthritis, 15 were IgG and 1 IgA; 7 sera belonged to the kappa and 9 to lambda type.     

Immunotherapy for rheumatoid arthritis.

Recently published studies confirm that the long-term use of biological agents targeting TNF-alpha in therapy for rheumatoid arthritis (RA) gives rise to sustained improvement in symptoms and signs of disease, and in the quality of life. Furthermore, it has emerged that anti-TNF therapy protects joints from structural damage, which unexpectedly is also observed in the patient population showing no apparent benefit in control of signs and symptoms. Therapeutic benefit is observed in established disease that is unresponsive to conventional DMARDS and in early DMARDS-na?ve RA patients. Thus, for patients with RA, anti-TNF therapies set a new standard for symptom control and joint protection.