Prolactin deficiency in rheumatoid arthritis.

Prolactin and growth hormone were determined from the sera of 48 patients with rheumatoid arthritis (RA) and 23 controls by radioimmunoassay and by the Nb2 lymphoma proliferation bioassay. A highly significant deficiency was found in the bioactivity of circulating prolactin (PRL) in patients with RA, whereas immunoactive PRL was near normal. Only age matched male patients showed significantly lower serum PRL levels by radioimmunoassay. Patients with RA with anemia and high reticulocyte counts had bioactivity of PRL elevated and those with anemia and low reticulocyte counts had a decreased bioactivity of PRL when compared to patients without anemia. Prolactin isolated from the sera of 5 patients with RA showed decreased bioactivity in comparison with PRL separated from 5 sex matched controls. Serum factors capable of enhancing or inhibiting the response of Nb2 cells to ovine PRL were also discovered. Our results indicate that RA is associated with PRL deficiency.     

New roles for estrogens in rheumatoid arthritis

Sex hormones appear to play an important role as modulators of autoimmune disease onset/perpetuation. Steroid hormones are implicated in the immune response, with estrogens as enhancers at least of humoral immunity, and androgens and progesterone (and glucocorticoids) as natural immune suppressors. Serum levels of estrogens have been found to be normal in rheumatoid arthritis (RA) patients. Synovial fluid levels (SF) of proinflammatory estrogens relative to androgens are significantly elevated in both male and female RA patients as compared to controls, which is most probably due to an increase in local aromatase activity. Thus, available steroid pre-hormones are rapidly converted to proinflammatory estrogens in the synovial tissue in the presence of inflammatory cytokines (i.e. TNF alpha, IL-1, IL-6). The increased estrogen concentrations observed in RA SF of both sexes are characterized mainly by the hydroxylated forms, in particular 16 alpha-hydroxyestrone, showing a mitogenic stimulating role. Indeed, recent studies by us indicate that 17-beta estradiol (E2) clearly enhanced the expression of markers of cell growth and proliferation, whereas testosterone (T) induced an increase in markers indicating DNA damage and apoptosis. In particular, our data further shows that the enhancing role of estrogens on the immune/inflammatory response is exerted by activating the NFkB complex. In conclusion, locally increased estrogens may exert activating effects on synovial cell proliferation, including macrophages and fibroblasts, suggesting new roles for estrogens in RA.     

Animal models of rheumatoid arthritis

Experimental animal models of arthritis, including type II collagen-induced arthritis, proteoglycan-induced arthritis, adjuvant arthritis, pristane-induced arthritis, and streptococcal cell wall-induced arthritis have contributed to recent advances in the understanding of the immunopathology of arthritis. The dissection of the T-cell populations regulating the autoimmune response is currently the most active area of investigation. Research into the mechanism underlying the association of specific class II major histocompatibility complex antigens with arthritis has focused attention on the interaction of particular V beta T-cell subsets with antigens presented in context of permissive major histocompatibility complex antigens. Several models indicate that both the structure of the major histocompatibility complex antigen and the T-cell receptor may be critical in the development of autoimmunity, while the MIs antigen system appears to regulate the availability of T cells with self-reactivity specificities. Studies on the role of heat-shock proteins in experimental arthritis have prompted research into the role of gamma/delta T cells in joint disease, while the availability of recombinant cytokines has permitted the direct analysis of soluble factors. In addition to providing basic insights into autoimmune disease, animal models continue to provide the means to test novel experimental approaches to the treatment of rheumatoid arthritis.     

Selective lymphocyte deficiency in seronegative rheumatoid arthritis

Prior studies have shown that in vitro infection with the Epstein Barr virus (EBV) is able to induce IgM rheumatoid factor production by normal lymphocytes, with a higher degree of production by seropositive rheumatoid arthritis lymphocytes. The present investigation demonstrates that EBV-infected lymphocytes from patients with seronegative rheumatoid arthritis produce in vitro significantly less IgM rheumatoid factor than do normal lymphocytes. The results suggest that the peripheral blood of seronegative patients is deficient in the rheumatoid factor precursor B cells responsive to stimulation by Epstein Barr virus.     

Dendritic cell subsets: their roles in rheumatoid arthritis

Dendritic cells (DC) are now known to influence many different classes of lymphocytes (T, B, NK cells) and many types of T cell responses (Th1/Th2/Th17, regulatory T cells, peripheral T cell deletion). In rheumatoid arthritis (RA) DC have been described and their roles in RA pathogenesis have been implicated. This review summarizes the data obtained so far concerning the functional characterization of several DC subsets in human RA. Moreover, the effect of TNF-alpha blockade on DC phenotype and function is also discussed. As most of the studies on DC in experimental arthritis have been conducted using (immunomodulated/tolerogenic) DC as tools to ameliorate experimental arthritis, we give some examples of how these cells may induce tolerance in vivo. Although a lot of work has been performed so far, the specific and functional roles of DC subsets in human RA and in CIA remain to be established. Achieving a detailed understanding of specific DC functions in RA holds potential for modulating DC for immunotherapy by down-regulating the autoimmune response.     

类风湿关节炎中尿激酶型纤溶酶原激活物及其受体蛋白和基因的表达

目的　检测尿激酶型纤溶酶原激活物 (uPA)及其受体 (uPAR)蛋白和mRNA在类风湿关节炎 (RA)的表达 ,探讨uPA、uPAR基因在RA细胞外基质降解中的作用。方法　采用免疫组化和cDNA mRNA原位分子杂交技术分别检测了 2 4例RA、18例骨关节炎 (OA)和 6例正常滑膜组织中uPA、uPAR蛋白和mRNA的分布及表达情况。结果　 2 4例RA滑膜组织均呈uPA、uPAR蛋白和mRNA的阳性表达 ,uPA、uPAR蛋白的强阳性率高于mRNA。uPA、uPAR蛋白和mRNA阳性信号主要分布在RA滑膜衬里细胞、滑膜下层单核细胞、巨噬细胞样细胞及血管内皮细胞 ;18例OA滑膜组织中 ,uPA、uPAR蛋白和mRNA的表达部位类似于RA ,但阳性率、阳性程度及分布范围均明显低于RA滑膜组织 ,两组之间蛋白和mRNA表达的差异均有显著性 (P <0 0 1或P <0 0 0 1)。 6例正常滑膜组织呈阴性反应。结论　RA滑膜组织存在高水平uPA、uPAR蛋白和mRNA的表达 ,提示在RA的发生发展过程中 ,uPA和uPAR基因起着重要作用 ;RA和OA中uPA、uPAR基因表达水平的差异 ,可能与这两种疾病软骨和骨基质降解的程度及进程等临床表现密切相关     

Experimental animal models resembling rheumatoid arthritis

Summary The experimental animal models of arthritis which in certain aspects share similarities to human rheumatoid arthritis are reviewed. Various methods have been applied to induce in animals experimental models of arthritis which would provide important insights into the aetiopathogenetic mechanisms of human RA. Immunological methods and infectious agents induced the most interesting models. The histology of the synovial tissue, regardless of the inducing mechanisms, is similar to the lesions of RA. Yet, none of these experimental models of arthritis reflects all the articular and systemic features, the immunological profile and the genetic factors which characterize the human disease. The animal models of arthritis reported here and the development of new ones may ultimately offer the information necessary for the understanding of the mechanisms involved in the aetiopathogenesis of human rheumatoid disease.     

Elevations in synovial fluid plasminogen activator in patients with rheumatoid arthritis

Plasminogen activator (PA) activity in synovial fluid (SF) obtained from patients with rheumatoid arthritis (RA) is elevated when compared to SF obtained from patients with osteoarthritis (OA). Immunological studies and lack of evidence for a decrease in PA inhibitors, or an increase in PA stimulators, suggest that elevations in RA SF PA activity reflect increases in PA level. Although the origin(s) of SF PA was not identified, the enzyme resembles urokinase and RA synovium may be a contributing source. These observations are consistent with a possible active role of PA in the pathogenesis of RA.     

Contrasting roles of IFN-gamma in murine models of autoimmune thyroid diseases.

Interferon-gamma (IFN-gamma), a prototypic proinflammatory cytokine produced by several different cell types, including the Th1 subset of CD4(+) T cells, plays an important role in inflammation and autoimmune diseases. This review focuses on the varied and often contrasting roles of IFN-gamma in three murine models of autoimmune thyroid disease, experimentally induced autoimmune thyroiditis, the model of iodine-induced spontaneous autoimmune thyroiditis in NOD.H-2h4 mice and several different murine models of Graves' disease.     

Tissue plasminogen activator,plasminogen activator inhibitor-1 and von willebrand factor in rheumatoid arthritis

Summary Tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) and von Willebrand factor (vWF), all of endothelial origin and active in the haemostasis, were analysed in 74 patients with rheumatoid arthritis. The concentrations were related to extra-articular disease and to the incidence of thromboembolic events (TE) registered in a 2-year follow-up period. Patients with extra-articular disease had a significant increase in PAI-1 activity and reduced tPA release in the venous occlusion test. von Willebrand factor, PAI-1 and also haptoglobin and triglycerides were significantly increased in the group of patients who later suffered from TE. In a multiple regression model, in which cholesterol, triglycerides and lipoprotein (a) showed significant association with TE, vWF had the strongest additive explanatory value. No distinct acute phase pattern of PAI-1 was found in any patient subgroup.     

Cartilage autoimmunity in experimental models for rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a disease characterized by a chronic and erosive inflammation of cartilaginous joints without evidence for persisting infectious agents. The association with HLA class II genes, autoimmune responses to cartilage proteins and the arthritogenicity of cartilage proteins in experimental animals suggest that cartilage autoimmunity plays an important role in the disease process. In the present review T cell recognition of type II collagen (CII) and its consequences for development of collagen-induced arthritis (CIA) is discussed. Susceptibility to disease is associated with major histocompatibility complex (MHC) genes; the important gene in the H-2^q haplotype has been shown to be coding for the A^q molecule. An immunodominant peptide from CII located at position 256–270 has been defined and recognition of the A^q/CII256–270 peptide complex is essential for the development of arthritis. Interestingly, the structures recognized by T cells are mainly post-translational modifications of lysine at position 264 (K264). The majority of the CII-reactive T cells recognize a β-galactose O-linked to K264. In addition, it has recently been shown that the MHC class II molecules associated with RA, i.e. HLA-DR4 (DRB1*0401/DRA) and the HLA-DR1, possess peptide binding pockets with a very similar structures to the A^q molecule. Consequently DR1 and DR4 transgenic mice are highly susceptible to CIA and bind peptides derived from the same region of CII. The most interesting area for further investigation will be to understand how the recognition of this immunodominant CII peptide will normally induce tolerance in the immune system and how this tolerance is modulated or broken to allow the development of arthritis. Since the same structural interactions most likely occur also in humans, these questions have high relevance for solving the RA enigma.     

Cartilage autoimmunity in experimental models for rheumatoid arthritis

Rheumatoid arthritis (RA) is a disease characterized by a chronic and erosive inflammation of cartilaginous joints without evidence for persisting infectious agents. The association with HLA class II genes, autoimmune responses to cartilage proteins and the arthritogenicity of cartilage proteins in experimental animals suggest that cartilage autoimmunity plays an important role in the disease process. In the present review T cell recognition of type II collagen (CII) and its consequences for development of collagen-induced arthritis (CIA) is discussed. Susceptibility to disease is associated with major histocompatibility complex (MHC) genes; the important gene in theH-2 ^q haplotype has been shown to be coding for the A ^q molecule. An immunodominant peptide from CII located at position 256–270 has been defined and recognition of the A ^q /CII256–270 peptide complex is essential for the development of arthritis. Interestingly, the structures recognized by T cells are mainly post-translational modifications of lysine at position 264 (K264). The majority of the CII-reactive T cells recognize a β-galactoseO-linked to K264. In addition, it has recently been shown that the MHC class II molecules associated with RA, i.e. HLA-DR4 (DRB1^*0401/DRA) and the HLA-DR1, possess peptide binding pockets with a very similar structures to the A ^q molecule. Consequently DR1 and DR4 transgenic mice are highly susceptible to CIA and bind peptides derived from the same region of CII. The most interesting area for further investigation will be to understand how the recognition of this immunodominant CII peptide will normally induce tolerance in the immune system and how this tolerance is modulated or broken to allow the development of arthritis. Since the same structural interactions most likely occur also in humans, these questions have high relevance for solving the RA enigma.     

The potential roles for novel biomarkers in rheumatoid arthritis assessment

Comprehensive management of rheumatoid arthritis (RA) requires regular monitoring of disease activity, functional status, and structural damage to facilitate optimal patient outcomes. Tight control strategies have been successfully used in other diseases including diabetes and hypertension. Tight control requires frequent disease activity measurements in order to tailor treatment for individual patients, resulting in improved patient outcomes. Current monitoring measures used in clinical practice are largely driven by subjective evaluation of signs and symptoms, which are critical but limited by assessor variability and may not reflect true biological change in a timely manner. Research suggests that novel biomarkers may provide quantitative, objective assessments of disease activity and structural damage risk in RA, which are not captured by current measures. The simultaneous use of multiple biomarkers in a single test algorithm may provide a more comprehensive quantitative representation of the overall complex heterogeneous biology of RA. This article reviews the current management strategies for monitoring RA and the potential impact that multi-biomarker assays may have on RA assessment, which may further improve clinical outcomes.     

Does sulphasalazine cause folate deficiency in rheumatoid arthritis?

Sulphasalazine impairs folic acid absorption and metabolism but rarely leads to folate deficiency in inflammatory bowel disease (IBD). In rheumatoid arthritis (RA), however, serum and red cell folate concentrations are often low and sulphasalazine might stress folate metabolism. In a prospective study, 2 g sulphasalazine was compared with 500 mg penicillamine daily in 30 patients over 24 weeks. Pre-treatment serum and red cell folate concentrations were low-normal. Improvements in disease activity and haemoglobin occurred in both treatment groups, but MCV increased only in patients taking sulphasalazine. Serum and red cell folate concentrations did not change in either group. Increased MCV with sulphasalazine might therefore reflect reticulocytosis secondary to drug-induced haemolysis. The mechanisms by which sulphasalazine antagonizes folate metabolism are dose-dependent and, consequently, higher doses might precipitate folate deficiency.     

Persistent and transient IgA deficiency in juvenile rheumatoid arthritis

Twenty-five children with serum IgA levels of less than 0.1 g/l (below the 2.5% confidence limit at 2 years of age) were found among approximately 350 cases of juvenile rheumatoid arthritis (JRA). During follow-up, 10 of them proved to have persistent IgA deficiency, 13 were classified as having transient IgA deficiency, and 2 had consistently low serum IgA. Transient IgA deficiency occurred during treatment, in 9 cases with gold and in 2 with antimalarials. The gold-induced IgA deficiency usually developed abruptly soon after institution of gold therapy, and its duration varied from a few months (4 cases) to several years (3 cases). In 6 cases a low IgA level has returned to normal despite continuing gold therapy. In half the patients with persistent IgA deficiency the course has been mild and oligoarticular, and after a mean duration of 8.8 years only one has active disease. In contrast, in the patients with transient IgA deficiency the disease was characterized by early onset (mean age 3.0 years), a polyarticular course (10/13) and prolonged activity (7/13, mean duration 9.6 years). Coeliac disease was diagnosed in 2 patients, both with persistent IgA deficiency.     

Functional disability in rheumatoid arthritis: two different models in early and established disease.

A hypothesis that the development of functional disability in rheumatoid arthritis (RA) would be more rapid at the beginning than in established disease was studied in a group of 82 patients with RA referred to the Rheumatology Unit of Nancy, France. The relationship between disease activity, articular destruction and functional disability indicated a significant interaction (moderating effect) of disease duration. Two different models are proposed to explain functional disability. A model for early RA (less than 5 years duration) includes biological activity, and a model for established disease (more than 5 years) includes disease duration, extraarticular lesions and radiographic damage. These models could be useful in designs of therapeutic trials.     

Advances in research on animal models of rheumatoid arthritis

At present, rheumatoid arthritis (RA) is considered a type of autoimmune disease. Its pathology is not certain, and effective drugs with less toxicity have not been established. The establishment and application of animal models are effective methods for RA research, especially using animal models similar to humans. Arthritis is more heterogeneous, and this is an important starting point when discussing animal models for arthritis. Animal models are instrumental in understanding the etiology and pathogenetic mechanisms of RA. Appropriate animal models should be selected according to experiments because they have different traits. Various methods have been applied to induce arthritis in animal experimental models, which have provided important insights into the etiopathogenetic mechanisms of human RA. This review was written to give a broad introduction of the current stage of RA model and hope to offer beneficial help for RA-related research.     

Prevalence of IgA deficiency in children with juvenile rheumatoid arthritis

The purpose of this study was to investigate any association between IgA deficiency (IgAD) and juvenile rheumatoid arthritis (JRA) among Iranian children.This case-control study was carried out on 83 children who were diagnosed as JRA according to American College of Rheumatology (ACR) criteria; Patients were admitted at the rheumatology clinic of Children's Medical Center, (Tehran). Serum immunoglobulins concentrations were determined by nephelometry method. Control group was 112 healthy children who were matched for age and gender. Informed consent obtained from all parents.Selective IgA deficiency (sIgAD) was found only in a boy (1.2%) among JRA children; however, partial IgA deficiency was found in 6(7.1%) of patients with JRA and in 12(10.7%) of control subjects, this difference was not statistically significant (p=0.46). Immunoglobulins levels in patients with JRA (IgM: 126.7±57.2, IgG: 1182.3±351 and IgA:169.3±98) were significantly higher than their controls (IgM: 104±52, IgG:802±220 and IgA: 94.6±47) (p<0.05). Patients with growth failure had higher IgM, IgG and IgA levels in comparison with patients without growth failure; however, this difference was significant about IgM and IgG levels (p<0.05).In contrast to other similar studies, the number of IgAD did not differ significantly between JRA patients and their control counterpart; this might be partly due to the high rate of consanguineous marriages in Iran that resulted in increased prevalence of clinically undiagnosed partial IgAD in general population. Hence, future epidemiological studies are warranted to make it clear.     

Animal models of rheumatoid arthritis and related inflammation

The major, extensively studied, experimentally-induced rat and mouse models of arthritis with features resembling rheumatoid arthritis are reviewed here. Etiopathogenetic studies that were recently published are emphasized. In summary, multiple triggering stimuli can induce disease in genetically-prone strains of inbred rats and mice. Multiple genetic loci, including both MHC and non-MHC, regulate disease expression in these animals. By comparison with other models of autoimmune disease, clustering of regulatory loci within and among species is increasingly becoming evident. At the cellular level, both innate and acquired immune systems are involved in the disease manifestations. At the molecular level, unbalanced chronic production of tumor necrosis factor-a (TNF-a), interleukin (IL)-1, IL-6 and IL-12, as opposed to IL-4 and IL-10, is correlated with arthritis disease susceptibility and severity.