类风湿性关节炎发病机理

类风湿性关节炎（ＲＡ）是一种原因不明的慢性炎性多系统疾病。ＲＡ病变特征是持续性进行性的滑膜炎，通常累及对称的周围关节。滑膜炎能引起软骨破坏和骨侵蚀，继而引起关节畸形而作为该病的标志。ＲＡ病程可表现多种多样。基因和环境因素控制着炎性反应的进程、范围和类...     

Different Therapeutic and Bystander Effects by Intranasal Administration of Homologous Type II and Type IX Collagens on the Collagen-Induced Arthritis and Pristane-Induced Arthritis in Rats

To assess the efficiency of nasally administered cartilage-specific collagens as vaccination against development of arthritis and to ameliorate already established chronic arthritis, experimental models which develop chronic arthritis, pristane-induced arthritis (PIA), and homologous collagen-induced arthritis (CIA) in the rat were selected. Cartilage-specific collagens type IX (CIX) and type II (CII) were used for vaccination intranasally. A single dose of 250 μg CII instilled intranasally in rats with established PIA ameliorated the disease. For the prevention of disease, the same dose given before immunization was found to be most effective. Most importantly, the disease was more severe if this dose was given three times. For treatment of PIA, CIX was found to be more effective than CII, whereas for treatment of CIA only CII was effective. The amelioration of CIA was associated with a marked suppression of delayed type hypersensitivity and the flare reaction to CII and lower levels of IgG2b anti-CII antibodies in serum, i.e., with suppression of the TH1 rather than the TH2 response to CII. These findings, that cartilage proteins, if given intranasally, can both prevent and ameliorate established chronic arthritis in rats, are of significant importance for possible use in rheumatoid arthritis. The identification of two different cartilage-specific proteins (CII and CIX) effective against a disease induced with a well-defined nonimmunogenic adjuvant such as pristane will be of value for enhancing the effectiveness of the treatment.     

Role of B Cells in the Pathogenesis of Rheumatoid Arthritis

In patients with rheumatoid arthritis, chronic inflammation in affected joints may lead to the development of tertiary lymphoid tissue. A micro-environment is generated in the synovial membrane which supports the activation and differentiation of B cells into plasma cells. Through a process of affinity maturation, plasma cells may be generated locally which secrete antibodies of high affinity. Rheumatoid arthritis is characterised by autoantibodies specific for self immunoglobulin. These rheumatoid factors form large antigen/antibody complexes which may enhance the process of joint destruction. The poor prognosis of rheumatoid factor-positive patients is indicitive of the critical role of immunoglobulin complexes in the continuous stimulation of the immune system and thus of the inflammatory processes. In general, treatment of patients with rheumatoid arthritis aims at suppressing inflammation. The currently most successful reagents are those which interfere with the network of cytokines, such as tumour necrosis factor or interleukin-1 receptor antagonists. Only recently have immunosuppressive therapies targeted directly at the B cell response been developed. These first studies suggest that therapies which directly affect the humoral immune response are of great therapeutic potential in the treatment of patients with rheumatoid arthritis.     

IL‐23 in the Pathogenesis of Rheumatoid Arthritis

Interleukin‐23 (IL‐23) is a heterodimeric cytokine belonging to the IL‐6/IL‐12 family that plays a key role in several of autoimmune and inflammatory disorders. This family contains the 34 type I cytokine receptor chains and 27 ligands, which share structural and functional similarities, but on the other hand they display distinct roles in shaping Th cells responses. IL‐12 family cytokines have not only proinflammatory effects but they also promote inflammatory responses. IL‐23 is composed of the p40 subunit in common with IL‐12, and with a unique p19 subunit. IL‐23 binding to an IL‐23 receptor expressed on dendritic cells, macrophages and monocytes triggers the activation of Jak2 and Tyk2, which in turn phosphorylates STAT1, STAT3, STAT4 and STAT5 as well as induce formation of STAT3‐STAT4 heterodimers. IL‐23 is one of the essential factors required for the survival and/or expansion of Th17 cells, which produce IL‐17, IL‐17F, IL‐6 and TNF‐α. Th17 cells stimulated by the IL‐23 promote osteoclastogenesis through production of IL‐17, which induce receptor activator of NF‐kappa B ligand on mesenchymal cells. The IL‐23‐IL‐17 axis includes Th17 cells and plays a key role in the development of autoimmune arthritis.     

Role of Endoplasmic Reticulum Stress in Rheumatoid Arthritis Pathogenesis

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by abnormal proliferation of synoviocytes, leukocyte infiltration, and angiogenesis. The endoplasmic reticulum (ER) is the site of biosynthesis for all secreted and membrane proteins. The accumulation of unfolded proteins in the ER leads to a condition known as ER stress. Failure of the ER''s adaptive capacity results in abnormal activation of the unfolded protein response. Recently, we have demonstrated that ER stress-associated gene signatures are highly expressed in RA synovium and synovial cells. Mice with Grp78 haploinsufficiency exhibit the suppression of experimentally induced arthritis, suggesting that the ER chaperone GRP78 is crucial for RA pathogenesis. Moreover, increasing evidence has suggested that GRP78 participates in antibody generation, T cell proliferation, and pro-inflammatory cytokine production, and is therefore one of the potential therapeutic targets for RA. In this review, we discuss the putative, pathophysiological roles of ER stress and GRP78 in RA pathogenesis.     

Prospective Immunological Assessment of Arthritis Induced by Rubella Vaccine

A prospective study was carried out to correlate the development of joint symptoms after rubella immunization with pre- and post-immunization rubella-specific immunological responses. Arthralgia or arthritis or both occurred in 10 of 37 adult female volunteers at a mean time of 17.0 days after immunization with the RA 27/3 rubella vaccine. All individuals studied before immunization were seronegative for rubella by either the hemagglutination inhibition or the single radial hemolysis technique. In contrast, rubella enzyme-linked immunosorbent assay or lymphoproliferative responses or both were positive in 27 of 37 (73%) individuals tested before receiving the vaccine. Rubella enzyme-linked immuno-sorbent assays carried out before immunization were positive at high levels (mean E = 0.536) in four individuals who developed recurrent episodes of arthritis after administration of the vaccine while remaining at low levels preimmunization in subjects who developed transient arthralgia (E = 0.238) or no joint manifestations at all (E = 0.288). These data provide preliminary evidence suggesting that rubella vaccine-associated arthritis may occur as a consequence of secondary, rather than primary, infection with rubella virus and that the presence of circulating, nonneutralizing rubella antibody may enhance the development or severity (or both) of the associated postinfection joint manifestations. Assessment of rubella hemagglutination inhibition, hemagglutination inhibition (immunoglobulin M), and enzyme-linked immunosorbent assay serological responses at 6 weeks and 6 months post-immunization revealed no significant differences between patients who developed and those who did not develop joint manifestations. Rubella lymphoproliferative responses were elevated at 6 weeks post-immunization in the group developing arthralgia or arthritis or both, with no difference between the groups observed at 6 months post-immunization.     

Role of SLAM-Associated Protein in the Pathogenesis of Autoimmune Diseases and Immunological Disorders

Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) is an adaptor molecule containing a Src homology 2 (SH2) domain. SAP is expressed in T cells and natural killer (NK) cells and binds to the cytoplasmic domains of SLAM family receptors, resulting in the subsequent recruitment of Fyn. The SAP (SH2D1A) gene is located on the X chromosome and is responsible for X-linked lymphoproliferative disease, characterized by higher susceptibility to Epstein-Barr virus infection. The SAP-mediated signal is not only essential for the development of NKT cells, i.e. unconventional CD1d-restricted T cells with invariant Vα14 T cell receptors, but also for the regulation of the function of NK cells and conventional T cells. The role of SAP-mediated signaling in the induction of autoimmune diseases has been analyzed using animal models such as lupus, hepatitis, and graft-versus-host disease and is considered important in their pathogenesis in humans. In this review we highlight the current findings on SAP-mediated signaling in hematopoietic cells and discuss its importance in autoimmune diseases and immunological disorders.     

Muscle Involvement in Rheumatoid Arthritis: An Ultrastructural Study

An electron microscopic investigation has been carried out on muscle bioptic samples from patients affected by rheumatoid arthritis (RA). This study was undertaken to seek further ultrastructural alterations affecting striated muscles in RA pathology. Bioptic samples were collected on a total of 30 surgical interventions of hip (10), knee(8), and foot (12). This yielded three muscle types: gluteus maximus, vastus lateralis, and extensor digitorum communis. Muscle samples from 12 patients with no RA stigmata, selected to match RA patients by age and gender, constituted the control group. Tissue samples were prepared both for conventional histochemical methods and according to conventional electron microscopic procedures, including morphometric analysis. Although to a different extent in each sample, in muscles from RA vs. controls the authors observed the simultaneous presence of discrete muscular alterations such as wider separation of myofibrils, myelin figures, dilated sarcotubular system, pleomorphic mitochondria, myofibril flaking, and lipofuscin deposition in the subsarcolemmal region. In addition to a progressive atrophy, the above findings are suggestive of rheumatoid myositis and lend further support to the still poorly documented presence of an idiopathic inflammatory myopathy and inclusion body myositis associated with RA.     

Role of Biological Mimicry in the Pathogenesis of Rat Arthritis Induced by Mycoplasma arthritidis

Complement fixation (CF), immunofluorescence, and agar gel double-diffusion tests were used to demonstrate an antigenic relationship between rat tissues and Mycoplasma arthritidis. Rabbit antisera against six strains of M. arthritidis exhibited positive reactions in the CF test with an ethyl alcohol-saline extract of rat muscle, whereas only 6 of 18 antisera against other Mycoplasma species were positive. With the use of gel diffusion techniques, absorption of various M. arthritidis antigens with antiserum against rat muscle removed at least one precipitin band when the absorbed mycoplasma antigens were reacted against homologous antisera. Rabbit antiserum against M. arthritidis was conjugated with fluorescein isothiocyanate and reacted against frozen sections of muscle tissues of various animals. As controls, unlabeled normal rabbit serum and rabbit anti-M. arthritidis serum were included to determine the specificity of the reaction. Rat, hamster, and mouse skeletal muscle exhibited specific fluorescence, whereas chicken, beef, frog, and turtle muscles exhibited no specific fluorescence. Mice injected at birth with rat lymphocytes were found to be more susceptible to subsequent infection by M. arthritidis than were normal mice or mice injected at birth with mouse lymphocytes. These results indicate the occurrence of a heterogenetic antigen(s) common to M. arthritidis and rat tissues. Preliminary evidence suggests that this heterogenetic antigen(s) may enable the mycoplasmas to become established in their host.     

The Role of Microparticles in the Pathogenesis of Rheumatoid Arthritis and Systemic Lupus Erythematosus

Microparticles (MPs) are small membrane‐bound vesicles with potent biological activities that can promote the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus (SLE). These particles contain diverse cellular components and are shed from cells during apoptosis or activation. MPs can drive inflammation and autoimmunity by multiple mechanisms reflecting their content of bioactive molecules and ability to engage multiple receptor systems simultaneously. In the rheumatoid joint, particles can stimulate synovitis via their display of cytokines, chemokines, complement and angiogenesis factors. In SLE, particles can serve as an important source of extracellular nuclear molecules to signal ‘danger’ and form pathogenic immune complexes. Future studies will define the pathways by which particles promote pathogenesis, strategies to block their activity and their utility as biomarkers to assess disease activity and the response to therapy.     

Immunological Characterization of Lymphocytes in Synovial Fluid from Patients with Rheumatoid Arthritis

Lymphocytes separated from synovial fluid in rheumatoid arthritis by means of gradient centrifugation were characterized with regard to B- and T-lymphocyte properties. Membrane-bound Ig detectable with immunofluorescence technique was utilized as a marker of B-lymphocytes, while the ability to bind sheep erythrocytes and form rosettes was interpreted as a T-lymphocyte characteristic. In 9 out of 18 patients studied no Ig-positive lymphocytes were found in synovial fluid, while the remaining 9 patients had 1% or less. Appropriate control experiments indicated that the absence of membrane-bound Ig on lymphocytes was not due to in vivo induced redistribution with subsequent endocytosis of Ig receptors. The percentages of B-lymphocytes in peripheral blood from patients (mean 11% and range 3–19%) were not significantly different from those of 54 normal individuals (mean 10% and range 3–22%). Rosette-forming lymphocytes were found in synovial fluid of 11 patients studied, with mean 29.6% and range 19.0–60.2%, which are significantly higher than the corresponding values in peripheral blood, 22.7% and 0.9–41.1%. The latter values were also significantly higher than those of peripheral blood from 32 normals (mean 14.8% and range 0.9–34.7%). The increased proportions of T-lymphocytes in synovial fluid in rheumatoid arthritis in contrast to the absence or very low numbers of B-lymphocytes may indicate an important role for the former in the pathogenesis of rheumatoid inflammation.     

The Immunologic Role of IL-17 in Psoriasis and Psoriatic Arthritis Pathogenesis

Psoriasis is a chronic, immune-mediated, inflammatory disease that is pathogenically driven by proinflammatory cytokines. This article reviews the immunologic role of interleukin (IL)-17, the major effector cytokine in the pathogenesis of psoriatic disease, along with the rationale for targeting the IL-17 cytokine family (IL-17A, IL-17F, and IL-17 receptor A) in the treatment of psoriasis and psoriatic arthritis. Emerging evidence indicates that major sources of IL-17A in patients with psoriatic disease are mast cells, γδ T cells, αβ T cells, and innate lymphoid cells in lesional skin and synovial fluid. Within the skin and joints, IL-17A acts on cellular targets, including keratinocytes, neutrophils, endothelial cells, fibroblasts, osteoclasts, chondrocytes, and osteoblasts, to stimulate production of various antimicrobial peptides, chemokines, and proinflammatory and proliferative cytokines, which, in turn, promote tissue inflammation and bone remodeling. The critical importance of the IL-23/IL-17A axis to the pathogenesis of psoriatic disease has resulted in many new biologic treatments targeting these cytokines. These biologics dramatically improve skin and joint symptoms in patients with moderate-to-severe psoriasis and psoriatic arthritis.