类风湿关节炎治疗药物的分子作用机制研究进展

类风湿关节炎是慢性自体免疫性疾病,文章从作用于细胞因子及其受体、针对T淋巴细胞的清除、影响G蛋白偶联受体信号转导和Ras-丝裂原激活的蛋白激酶信号转导四个方面阐述了消炎免疫药物治疗类风湿性关节炎的分子作用机制。     

Inflammation and collagenase production in rats with adjuvant arthritis reduced with 13-cis-retinoic acid

Oral administration of 13-cis-retinoic acid (40 or 160 milligrams per kilogram of body weight daily) significantly reduced the inflammation associated with developing and established adjuvant arthritis, an experimentally induced arthritis in rats that resembles human rheumatoid arthritis. The amount of collagenase secreted in tissue culture by adherent cells isolated from the inflamed joints of adjuvant rats treated with 13-cis-retinoic acid also decreased as compared to the amount secreted by cells from vehicle-treated adjuvant rats. Collagenase is important in the joint destruction accompanying rheumatoid arthritis. The successful use of retinoids in the treatment of this proliferative but nonmalignant disorder demonstrates a new application of these compounds.     

Substance P activation of rheumatoid synoviocytes: neural pathway in pathogenesis of arthritis

Several clinical features are consistent with nervous system involvement in the pathogenesis of rheumatoid arthritis. The neuropeptide substance P is one possible mediator of this interaction, since it can be released into joint tissues from primary sensory nerve fibers. The potential effects of the peptide on rheumatoid synoviocytes were examined. The results show that substance P stimulates prostaglandin E2 and collagenase release from synoviocytes. Furthermore, synoviocyte proliferation was increased in the presence of the neuropeptide. Similar effects were observed with a truncated form of substance P. Synoviocytes were sensitive to very small doses of the neuropeptide (10(-9) M), and its effects were inhibited by a specific antagonist. Thus, the specific stimulation of synoviocytes by the neuropeptide substance P represents a pathway by which the nervous system might be directly involved in the pathogenesis of rheumatoid arthritis.     

Cadherin-11 in synovial lining formation and pathology in arthritis

The normal synovium forms a membrane at the edges of joints and provides lubrication and nutrients for the cartilage. In rheumatoid arthritis, the synovium is the site of inflammation, and it participates in an organized tissue response that damages cartilage and bone. We identified cadherin-11 as essential for the development of the synovium. Cadherin-11-deficient mice have a hypoplastic synovial lining, display a disorganized synovial reaction to inflammation, and are resistant to inflammatory arthritis. Cadherin-11 therapeutics prevent and reduce arthritis in mouse models. Thus, synovial cadherin-11 determines the behavior of synovial cells in their proinflammatory and destructive tissue response in inflammatory arthritis.     

Blood sugar level following intravenous glucose in rheumatoid arthritis

Since the majority of patients with rheumatoid arthritis show a slower fall in the blood sugar level after the intravenous injection of glucose than do the normal controls, the alteration cannot be explained on the basis of gastrointestinal dysfunction. Differences in the renal threshold of glucose do not explain the altered glucose tolerance, since approximately the same amount of glucose is lost in the urine in both groups. Blood samples taken at 3 and 5 minutes following the injection of the glucose showed the height of the blood sugar level to be approximately the same in the patients with rheumatoid arthritis and in normals. The slower fall in the blood sugar level of the former is therefore not a simple function of a greater rise following the intravenous administration of the glucose. Although the patients with severe poliomyelitis had as much or more atrophy than the rheumatoid arthritic patients, there was no delay in rate of fall of the blood sugar level after the intravenous administration of glucose. In view of the fact that the hepatic homeostatic control regulates the blood sugar level, faulty utilization of glucose by extrahepatic tissues cannot be considered the primary factor responsible for the alteration of the glucose tolerance. The altered glucose tolerance in rheumatoid arthritis is explainable on the basis of an altered threshold of the hepatic homeostatic control of the blood sugar. Additional studies must be done to determine whether this derangement emanates directly from extrahepatic influences.     

Induction of inflammatory arthropathy resembling rheumatoid arthritis in mice transgenic for HTLV-I

Human T cell leukemia virus type-I (HTLV-I) is the etiologic agent of adult T cell leukemia and has also been suggested to be involved in other diseases such as chronic arthritis or myelopathy. To elucidate pathological roles of the virus in disease, transgenic mice were produced that carry the HTLV-I genome. At 2 to 3 months of age, many of the mice developed chronic arthritis resembling rheumatoid arthritis. Synovial and periarticular inflammation with articular erosion caused by invasion of granulation tissues were marked. These observations suggest a possibility that HTLV-I is one of the etiologic agents of chronic arthritis in humans.     

复方穿山龙颗粒治疗类风湿性关节炎临床观察

目的 观察复方穿山龙颗粒治疗类风湿性关节炎的临床疗效及不良反应。方法 将68例类风湿性关节炎患者随机分为治疗组（34例）和对照组（34例）,治疗组给予复方穿山龙颗粒,对照组给予来氟米特片和洛索洛芬钠片,疗程3个月。观察两组临床疗效以及血沉（ESR）、C-反应蛋白（CRP）、类风湿因子（RF）的变化。结果 治疗组临床疗效的总有效率为85.3%,ESR、CRP、RF较治疗前均明显降低（P<0.05）,与对照组比较差异无统计学意义（P>0.05）,但不良反应发生率明显低于对照组,差异有统计学意义（P<0.05）。结论 复方穿山龙颗粒治疗类风湿性关节炎具有疗效确切、不良反应少等优点,适合患者较长时间服用。     

类风湿关节炎患者关节液中IL-17的定量检测

目的探讨类风湿性关节炎（RA）患者关节液中IL-17的含量与关节炎症损伤的相关性,为研究RA的关节损伤机制提供科学依据.方法应用ELISA方法定量检测RA组40例和对照组40例关节液中IL-17的含量,应用t检验比较两组差异性.结果 RA组关节液中IL-17的含量显著高于对照组（P〈0.01）.结论 RA组关节液中具有较高的IL-17检测值,证实IL-17是RA患者关节滑膜损伤的重要因素之一.     

The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice

The growth factor progranulin (PGRN) has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation, but its receptors remain unidentified. We report that PGRN bound directly to tumor necrosis factor receptors (TNFRs) and disturbed the TNFα-TNFR interaction. PGRN-deficient mice were susceptible to collagen-induced arthritis, and administration of PGRN reversed inflammatory arthritis. Atsttrin, an engineered protein composed of three PGRN fragments, exhibited selective TNFR binding. PGRN and Atsttrin prevented inflammation in multiple arthritis mouse models and inhibited TNFα-activated intracellular signaling. Collectively, these findings demonstrate that PGRN is a ligand of TNFR, an antagonist of TNFα signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice. They also suggest new potential therapeutic interventions for various TNFα-mediated pathologies and conditions, including rheumatoid arthritis.     

A distinct endothelial cell recognition system that controls lymphocyte traffic into inflamed synovium

Lymphocytes are essential mediators of normal tissue inflammatory reactions and of pathologic tissue damage in, for example, rheumatoid arthritis and other autoimmune diseases. In a study of the mechanisms controlling lymphocyte entry into sites of inflammation from the blood, the function and specificity of lymphocyte-endothelial interactions were examined in inflamed joint tissue (synovium) from patients with rheumatoid arthritis. Synovial high endothelial venules (HEV) supported the binding of normal peripheral blood lymphocytes in vitro. The characteristics of this binding, which were similar to those of lymphocyte-HEV interactions controlling lymphocyte migration into organized lymphoid tissues, included a requirement for calcium ions, a dependence on metabolic activity, and a preferential adherence of circulating lymphocytes as opposed to immature thymocytes. However, the binding of lymphocytes to synovial HEV was not inhibited by a monoclonal antibody to lymphocyte receptors for lymph node HEV, and synovial HEV failed to bind either lymph node HEV-specific or mucosal HEV-specific B lymphoblastoid cells. The results suggest that a lymphocyte-endothelial cell recognition system that is distinct from such systems in organized lymphoid tissues directs the extravasation of normal lymphocytes as well as pathologically important effector cells into inflamed synovium.     

Autoantibodies to nucleosomal proteins: antibodies to HMG-17 in autoimmune diseases

The relative amounts of autoantibodies against defined nucleosomal proteins present in serums from patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and mixed connective tissue disease (MCTD) have been examined by an enzyme-linked immunoassay. Autoantibodies to nucleosomal proteins were detected in 45 percent of the patients with SLE, 18 percent of the MCTD patients, and none of the RA patients. The results suggest that, in SLE, antibodies are formed against a subset of nucleosomes which contain protein HMG-17.     

类风湿因子与抗环瓜氨酸肽抗体在诊断类风湿关节炎中的应用

目的通过对类风湿关节炎（RA）患者及非RA患者血清中的类风湿因子（RF）与抗环瓜氨酸肽抗体（抗-CCP抗体）水平测定,探讨抗-CCP抗体在RA的诊断价值．方法用酶联免疫吸附方法对49例RA、6l例非RA患者测定血清抗CCP抗体及RF,并对检测结果进行比较．结果49例RA患者中抗-CCP抗体阳性23例,61例非RA患者抗...     

NEW SERUM GROUP, GM(P)

The agglutination that occurs when rheumatoid arthritis serum Pond is added to erythrocytes sensitized with anti-D serum Moore is inhibited in the presence of some normal serums. The inhibitor, tentatively named Gm(p), is associated only with 7S gamma globulins and is apparently different from other previously defined serum groups. It is much more common in Caucasians than in Negroes, and probably is determined by a simple dominant gene.     

中药南蛇藤研究现状

近年来,国内外学者对南蛇藤（Celastrus orbiculatus）进行了广泛的研究,其在治疗类风湿性关节炎、抗肿瘤、抑制动脉硬化等方面取得了一定成果。随着南蛇藤活性成分研究的深入,其抗病毒、抗肿瘤、抗氧化活性等生物活性的研究必然成为国内外研究的热点。现仅对近10年来国内外有关南蛇藤方面的研究现状进行综述。     

A molecular basis for MHC class II--associated autoimmunity

Class II major histocompatibility (MHC) molecules have an immunoregulatory role. These cell-surface glycoproteins present fragments of protein antigens (or peptides) to thymus-derived lymphocytes (T cells). Nucleotide sequence polymorphism in the genes that encode the class II MHC products determines the specificity of the immune response and is correlated with the development of autoimmune diseases. This study identifies certain class II polymorphic amino acid residues that are strongly associated with susceptibility to insulin-dependent diabetes mellitus, rheumatoid arthritis, and pemphigus vulgaris. These findings implicate particular class II MHC isotypes in susceptibility to each disease and suggest new prophylactic and therapeutic strategies.     

Human collagenase: identification and characterization of an enzyme from rheumatoid synovium in culture

Synovial tissue from patients with rheumatoid arthritis produces lysis of gels of reconstituted collagen fibrils in culture and releases soluble collagenase when cultured in collagen-free medium. Collagen molecules in solution at neutral pH at 20 degrees and 27 degrees C are cleaved by the synovial enzyme into (3/4) and (1/4) length fragments. In this respect the action of synovial enzyme is similar to that of amphibian collagenase and distinct from that of bacterial collagenase. At 37 degrees C reconstituted collagen fibrils and native fibers are attacked by the enzyme and further degraded to polypeptides of low molecular weight. These polypeptides are produced only after denaturation of the larger fragments, which occurs at temperatures near 37 degrees C.     

三妙散合舒筋散治疗早期湿热阻络证类风湿性关节炎的疗效观察

目的 观察三妙散合舒筋散治疗早期湿热阻络证类风湿性关节炎的疗效。方法 将75例患者随机分为对照组和治疗组,对照组给予常规西药治疗,治疗组在对照组基础上给予三妙散合舒筋散治疗,观察比较2组总体疗效、临床症状、血清C反应蛋白（CRP）、红细胞沉降率（ESR）和类风湿因子（RF）变化。结果 治疗组总有效率92.10%,对照组总有效率72.97%,2组比较差异具有统计学意义（P<0.05）;治疗组的临床症状改善方面显著优于对照组（P<0.05）;治疗组的ESR、CRP和RF等血清指标较对照组明显降低,差异具有统计学意义（P<0.05）。结论 三妙散合舒筋散治疗早期湿热阻络证类风湿性关节炎疗效显著,值得临床推广应用。     

中医药通过调节Th17细胞分化在自身免疫性炎症性疾病中作用的研究进展

辅助性T淋巴细胞17（T helper 17,Th17）与多种炎症性疾病、自身免疫性疾病及肿瘤密切相关。在自身免疫性炎症性疾病中大多存在偏向Th17一侧的分化失衡,Th17细胞的分化程度往往决定了炎症程度及持续时间。中医药在治疗炎症性疾病方面积累了丰富的经验,具有一定的优势和潜力,许多中药及中药复方被证实有明显的免疫调节及抗炎作用。本文就Th17细胞的分化调节及中医药在类风湿性关节炎、溃疡性结肠炎、强直性脊柱炎及慢性前列腺炎等疾病中对Th17细胞的调节作用研究进展进行综述。     

Human lymphocytes making rheumatoid factor and antibody to ssDNA belong to Leu-1+ B-cell subset

B lymphocytes bearing the Leu-1 cell-surface antigen (Leu-1+), the human equivalent of mouse Ly-1+ B lymphocytes, have been detected in human peripheral blood, but there is little information on their frequency and properties. Analysis by fluorescence-activated cell sorter and double immunofluorescence showed that Leu-1+ B cells are consistently present in the peripheral blood and spleens of healthy subjects and constitute 17.0 +/- 5.0% (mean value +/- standard deviation) and 17.3 +/- 3.9%, respectively, of total B cells. When purified Leu-1+ and Leu-1- B lymphocytes were transformed into immunoglobulin-secreting cells by infection with Epstein-Barr virus and the culture fluids were tested for reactivity with self-antigens, at least two important autoantibodies, antibody to the Fc fragment of human immunoglobulin G (rheumatoid factor) and antibody to single-stranded DNA, were found to be made exclusively by Leu-1+ B cells. It is concluded that the Leu-1+ lymphocytes represent a major subset of the normal human B cell repertoire and include the B cells capable of making autoantibodies similar to those found in systemic lupus erythematosus and rheumatoid arthritis.