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ID PMID Title PublicationDate abstract
9720647 Functional properties of CD4+ CD28- T cells in the aging immune system. 1998 May 15 The aging immune system is characterized by a progressive decline in the responsiveness to exogenous antigens and tumors in combination with a paradoxical increase in autoimmunity. From a clinical viewpoint, deficiencies in antibody responses to exogenous antigens, such as vaccines, have a major impact and may reflect intrinsic B cell defects or altered performance of helper T cells. Here we describe that aging is associated with the emergence of an unusual CD4 T cell subset characterized by the loss of CD28 expression. CD28 is the major costimulatory molecule required to complement signaling through the antigen receptor for complete T cell activation. CD4+ CD28- T cells are long-lived, typically undergo clonal expansion in vivo, and react to autoantigens in vitro. Despite the deficiency of CD28, these unusual T cells remain functionally active and produce high concentrations of interferon-gamma (IFN-gamma) and interleukin-2 (IL-2). The loss of CD28 expression is correlated with a lack of CD40 ligand expression rendering these CD4 T cells incapable of promoting B cell differentiation and immunoglobulin secretion. Aging-related accumulation of CD4+ CD28- T cells should result in an immune compartment skewed towards autoreactive responses and away from the generation of high-affinity B cell responses against exogenous antigens. We propose that the emergence of CD28-deficient CD4 T cells in the elderly can partially explain age-specific aberrations in immune responsiveness.
10577962 Increased IgA rheumatoid factor and V(H)1 associated cross reactive idiotype expression in 1999 Dec OBJECTIVE: To investigate whether autoreactive mechanisms occur in Lyme disease (LD) by determining IgA, IgG and IgM rheumatoid factor (RF) concentrations and RF associated cross reactive idiotype (CRI) expression in the serum of LD patients, with comparison to patients with rheumatoid arthritis (RA). METHODS: The RF isotype profiles were determined in 59 patients with LD; erythema migrans (EM) (n=19), neuroborreliosis (NB) (n=20) and Lyme arthritis (LA) (n=20). Mouse monoclonal antibodies (mAbs) G6 and G8 (V(H)1 gene associated), D12 (V(H)3 gene associated) and C7 (V(kappa)III gene associated) were then used to determine the RF associated CRI expression on IgM antibodies in 16 of these LD patients (eight seropositive for RF); (EM (n=3), NB (n=6), LA (n=7)). RESULTS: Seven (18%) patients with either NB or LA had increased concentrations of IgA RF compared with none with EM. Significant differences in the number of patients with raised concentrations of IgG RF or IgM RF were not found between the LD patient groups. Five (3NB, 1LA and 1 EM) (31%) and three (2NB and 1LA) (19%) of LD patients had raised concentrations of the CRIs recognised by mAbs G6 and G8, respectively. These CRIs were detected in LD sera both with and without raised concentrations of RF and were not demonstrated on anti-Borrelia burgdorferi antibodies using ELISA. No LD sera tested had raised concentrations of the determinants recognised by mAbs C7 or D12. CONCLUSION: Significantly raised concentrations of IgA RF and increased use of V(H)1 germline gene associated CRIs are found on IgM antibodies in the serum of LD patients. These data indicate the recruitment of autoreactive B lymphocytes in some patients with the later stages of LD.
9209354 Models of HTLV-I-induced diseases. Infectious transmission of HTLV-I in inbred rats and HT 1997 Apr To examine the pathogenic roles of HTLV-I in HTLV-I-induced diseases, we developed two models; namely HTLV-I carrier rats and HTLV-I env-pX transgenic rats. Among life long HTLV-I carriers in seven rat strains, only WKAH rats with the RT1k haplotype developed chronic progressive myeloneuropathy, resembling HAM/TSP clinically and histologically in humans, designated as HAM rat disease and after long incubation periods. Apoptosis of myelin forming cells, oligodendrocytes and Schwann cells associated with HTLV-I infection appears to be the primary cause of HAM rat disease. Local activation of the pX gene and TNF alpha gene was evident in these rats. WKAH rats transgenic for HTLV-I env-pX gene were established and at age 5 weeks, swelling of the bilateral ankle joints began to develop and histological features of the affected joints resembled findings in cases of rheumatoid arthritis (RA): high-titers of rheumatoid factors were present in these rats. A series of vascular collagen diseases such as polyarteritis nodosa-like angiitis, polymyositis, myocarditis, and Sjögren's syndrome-like sialodenitis together with RA were present, even in one individual animal. These transgenic rats as well as HAM rats appear to be suitable animal models for elucidating pathogenic mechanisms implicated in HTLV-I-induced diseases and also various demyelinating vascular collagen diseases of unknown etiology.
11460154 Plasma cell differentiation requires the transcription factor XBP-1. 2001 Jul 19 Considerable progress has been made in identifying the transcription factors involved in the early specification of the B-lymphocyte lineage. However, little is known about factors that control the transition of mature activated B cells to antibody-secreting plasma cells. Here we report that the transcription factor XBP-1 is required for the generation of plasma cells. XBP-1 transcripts were rapidly upregulated in vitro by stimuli that induce plasma-cell differentiation, and were found at high levels in plasma cells from rheumatoid synovium. When introduced into B-lineage cells, XBP-1 initiated plasma-cell differentiation. Mouse lymphoid chimaeras deficient in XBP-1 possessed normal numbers of activated B lymphocytes that proliferated, secreted cytokines and formed normal germinal centres. However, they secreted very little immunoglobulin of any isotype and failed to control infection with the B-cell-dependent polyoma virus, because plasma cells were markedly absent. XBP-1 is the only transcription factor known to be selectively and specifically required for the terminal differentiation of B lymphocytes to plasma cells.
11465704 Localization of 3-nitrotyrosine to rheumatoid and normal synovium. 2001 Jul OBJECTIVE: To determine the localization of 3-nitrotyrosine (3-NT), a footprint marker of peroxynitrite (ONOO-) and other reactive nitrogen species, to the inflamed human synovium and to compare this with normal synovial and nonsynovial tissue of human and animal origin. METHODS: Monoclonal and polyclonal antibodies were used to investigate for 3-NT, inducible nitric oxide synthase (iNOS), macrophage marker CD68, and the vascular smooth muscle marker alpha-actin by avidin-biotin immunocytochemistry. RESULTS: In the inflamed synovium, 3-NT was found in the vascular smooth muscle and macrophages. In normal human synovium, 3-NT was present in the vascular smooth muscle and some lining cells and was not associated with immunoreactivity for iNOS. Similarly, 3-NT could be demonstrated in the vascular smooth muscle cells of normal rats and iNOS knockout mice. It was not present in the vascular smooth muscle of healthy, nonsynovial tissue. CONCLUSION: The synovial vasculature in histologically normal human and naive rodent synovium was alone among the normal tissues studied in exhibiting iNOS-independent immunoreactivity for 3-NT. These findings suggest a physiologic role for ONOO- in normal synovial vascular function.
9742508 Frequent N addition and clonal relatedness among immunoglobulin lambda light chains expres 1998 Aug BACKGROUND: In rheumatoid arthritis (RA), B-lineage cells in the synovial membrane secrete large amounts of immunoglobulin that contribute to tissue destruction. The CDR3 of an immunoglobulin light chain is formed by rearrangements of VL and JL gene segments. Addition of non-germline-encoded (N) nucleotides at V(D)J joins by the enzyme terminal deoxynucleotidyl transferase (TdT) enhances antibody diversity. TdT was previously thought to be active in B cells only during heavy chain rearrangement, but we and others reported unexpectedly high levels of N addition in kappa light chains. We also found clonally related kappa chains bearing unusually long CDR3 intervals in RA synovium, suggesting oligoclonal expansion of a set of atypical B lymphocytes. In this study, we analyzed lambda light chain expression to determine if N addition occurs throughout immunoglobulin gene rearrangement and to compare CDR3 lengths of lambda and kappa light chains in RA patients and normal individuals. MATERIALS AND METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) amplification of V lambda III transcripts was performed on RA synovia and peripheral blood lymphocytes (PBL) and normal PBL for which kappa repertoires were previously analyzed. Representative lambda + PCR products were cloned and sequenced. RESULTS: Analysis of 161 cDNA clones revealed that N addition occurs in lambda light chains of RA patients and normal controls. The lambda light chain repertoires in RA were enriched for long CDR3 intervals. In both RA and controls, CDR3 lengths were strongly influenced by which V lambda gene segment was present in the rearrangement. Five sets of clonally related sequences were found in RA synovia and PBL; one set was found in normal PBL. CONCLUSIONS: In humans, unlike mice, N addition enhances antibody diversity at all stages of immunoglobulin assembly, and the structural diversity of lambda CDR3 intervals is greater than that of kappa light chains. Clonally related V lambda gene segments in RA support an antigen-driven B-cell response.
11352233 Differential expression of chemokine receptors on peripheral blood, synovial fluid, and sy 2001 May OBJECTIVE: Since it is likely that monocytes utilize chemokines to migrate to the rheumatoid arthritis (RA) joint, we investigated the expression of C-C chemokine receptors (CCR) 1-6 and C-X-C receptor 3 (CXCR3) in the peripheral blood (PB), synovial fluid (SF), and synovial tissue of patients with RA as well as in the PB of normal subjects. METHODS: We compared chemokine receptor expression on CD14+ monocytes from normal PB, RA PB, and RA SF using 2-color flow cytometry. Correlations with patient clinical data were determined. Chemokine and receptor expression were investigated in RA synovial tissue by immunohistochemistry and 2-color immunofluorescence to identify CD68+ macrophages. RESULTS: Most normal PB monocytes expressed CCR1 (87%) and CCR2 (84%), but not CCRs 3, 4, 5, or 6 or CXCR3. RA PB monocytes expressed CCR1 (56%) and CCR2 (76%), with significantly more expressing CCR3 (18%), CCR4 (38%), and CCR5 (17%) compared with normal PB monocytes. Significantly fewer SF monocytes from RA patients expressed CCR1 (17%), CCR2 (24%), and CCR4 (6%) while significantly more expressed CCR3 (35%) and CCR5 (47%) compared with RA and normal PB monocytes; CCR6 and CXCR3 were rarely detected. Clinically, the erythrocyte sedimentation rate was inversely correlated with the expression of CCR1 and CCR4 by RA PB, and CCR5 expression by RA SF was correlated with the SF white blood cell count. CCR1-, CCR2-, and CCR5-immunoreactive cells were found in RA synovial tissue and colocalized with CD68+ macrophages. RA synovial tissue RANTES (regulated upon activation, normally T cell expressed and secreted chemokine)- and monocyte chemoattractant protein 1-immunoreactive cells colocalized with CCR1 and CCR2, respectively, on serial sections. Macrophage inflammatory protein 1alpha (MIP-1alpha) was principally restricted to vascular endothelium, and MIP-1beta+ macrophages were found throughout the sections. CONCLUSION: Monocytes mainly express CCR1 and CCR2 in normal and RA PB, CCR3 and CCR5 in RA PB and RA SF, and CCR4 in RA PB. The differential expression of chemokine receptors suggests that certain receptors aid in monocyte recruitment from the circulation while others are important in monocyte retention in the joint.
9676454 A comparison of alternative methods of measuring femoral anteversion. 1998 Jul PURPOSE: Although CT scans are widely believed to provide the most accurate measurements of femoral anteversion, any estimate of the anteversion of the femur depends on the accuracy of the calculated axis of the femoral neck. We devised a method to measure the anteversion of the femur precisely using a 3D femoral computer model reconstructed from digitized femoral contours. Using this method, we compared the accuracy of three popular methods of anteversion measurement based on CT scans. METHOD: The three popular CT methods were as follows: (a) the classic method of Weiner et al., based on a single CT image; (b) the method of Reikerås et al., in which the neck axis is defined by two superimposed images of the femoral head and neck; and (c) the method of Murphy et al., utilizing centroids of the head and the medullary canal. The accuracy of the single slice method was also examined using slices taken at four different neck slice levels within the proximal femur. CT scans of 30 femora were obtained using a helical CT scanner and reconstructed using custom software. RESULTS: Based on the 3D model, the true anteversion of the femora averaged 19.8 +/- 9.3 degrees (SD). Using the method of Weiner et al., the anteversion of the femora was underestimated by an average of 6.4 degrees (predicted value 13.4 +/- 10.4 degrees). Conversely, Murphy et al.'s method overestimated anteversion by an average of 6.3 degrees with an average value of 26.0 +/- 9.1 degrees. The difference between the true anteversion and the values predicted by both of these methods was statistically significant (p < 0.001). The average anteversion measured according to the method of Reikerås et al. was 17.8 +/- 8.9 degrees, 2.0 degrees less than the true anteversion of the sample (p < 0.005). Anteversion angles predicted from a slice just below the inferior edge of the head averaged 18.3 +/- 9.5 degrees, only 1.5-3.1 degrees less than the true anteversion of the femur (p = 0.14). CONCLUSION: The single slice CT method has sufficient accuracy for use, provided the slice is taken just below the femoral head. In cases with a femoral head deformity or a valgus neck or where difficulty is encountered in positioning the patient, 3D reconstruction appears essential for accurate measurement of anteversion.
9416849 Modulation of synovial cell function by somatostatin in patients with rheumatoid arthritis 1997 Dec OBJECTIVE: To elucidate the role of neurologic, endocrine, and immune system interactions in the development of pathologic responses in patients with rheumatoid arthritis (RA), we studied somatostatin (SOM) production and somatostatin receptor (SOMR) expression in RA synovium and its function in patients with RA. METHODS: The effects of SOM on proinflammatory cytokine (interleukin-6 [IL-6] and IL-8) and collagenase production by RA synovial cells were estimated by enzyme-linked immunosorbent assay, and their messenger RNA expression was assessed by reverse transcription-polymerase chain reaction (RT-PCR) using limiting dilutions of the complementary DNA. The expression of SOMR by RA synovial cells was also studied by RT-PCR. Local production of SOM was estimated by RT-PCR and immunohistochemical staining. RESULTS: Physiologic concentrations (approximately 10(-10)M) of SOM inhibited proliferation of RA synovial cells. The production of proinflammatory cytokines and matrix metalloproteinases by RA synovial cells was also modulated by SOM. SOMR subtypes 1 and 2 were expressed on fibroblast-like synovial cells, and the expression of SOMR-2 was up-regulated by proinflammatory cytokine treatment of the synovial cells from patients with RA. RA fibroblast-like cells synthesized SOM by themselves, suggesting that SOM acts as an autocrine regulator of synovial cell function in patients with RA. CONCLUSION: SOM inhibited aberrant synovial cell function in patients with RA, suggesting possible clinical applications of this neuropeptide.
10583179 Relapse of cutaneous leishmaniasis in a patient with an infected subcutaneous rheumatoid n 1999 Nov Cutaneous leishmaniasis is a protozoal infection generally considered to be limited to the skin. In Israel, the disease is common in geographically defined areas and is caused predominantly by Leishmania major. Sporotrichoid subcutaneous spread has been reported but is uncommon. We describe a patient with rheumatoid arthritis, treated with methotrexate and prednisone, in whom numerous rheumatoid nodules concomitant with cutaneous leishmaniasis were found, mimicking sporotrichoid spread of the disease. In a rheumatoid nodule that was examined by electron microscopy, Leishmania parasites were found at intracellular and extracellular locations. This observation supports the hypothesis that cutaneous leishmaniasis parasites persist after clinical cure of the disease and may re-emerge as a result of immunosuppression.
11642233 A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency. 2001 Oct 18 BACKGROUND: The Ehlers-Danlos syndrome is a heritable connective-tissue disorder caused by defects in fibrillar-collagen metabolism. Mutations in the type V collagen genes account for up to 50 percent of cases of classic Ehlers-Danlos syndrome, but many other cases are unexplained. We investigated whether the deficiency of the tenascins, extracellular-matrix proteins that are highly expressed in connective tissues, was associated with the Ehlers-Danlos syndrome. METHODS: We screened serum samples from 151 patients with the classic, hypermobility, or vascular types of the Ehlers-Danlos syndrome; 75 patients with psoriasis; 93 patients with rheumatoid arthritis; and 21 healthy persons for the presence of tenascin-X and tenascin-C by enzyme-linked immunosorbent assay. We examined the expression of tenascins and type V collagen in skin by immunohistochemical methods and sequenced the tenascin-X gene. RESULTS: Tenascin-X was present in serum from all normal subjects, all patients with psoriasis, all patients with rheumatoid arthritis, and 146 of 151 patients with the Ehlers-Danlos syndrome. Tenascin-X was absent from the serum of the 5 remaining patients with Ehlers-Danlos syndrome, who were unrelated. Tenascin-X deficiency was confirmed in these patients by analysis of skin fibroblasts and by immunostaining of skin. The expression of tenascin-C and type V collagen was normal in these patients. All five of these patients had hypermobile joints, hyperelastic skin, and easy bruising, without atrophic scarring. Tenascin-X mutations were identified in all tenascin-X-deficient patients; one patient had a homozygous tenascin-X gene deletion, one was heterozygous for the deletion, and three others had homozygous truncating point mutations, confirming a causative role for tenascin-X and a recessive pattern of inheritance. CONCLUSIONS: Tenascin-X deficiency causes a clinically distinct, recessive form of the Ehlers-Danlos syndrome. This finding indicates that factors other than the collagens or collagen-processing enzymes can cause the syndrome and suggests a central role for tenascin-X in maintaining the integrity of collagenous matrix.
10861675 New form of idiopathic osteolysis: nodulosis, arthropathy and osteolysis (NAO) syndrome. 2000 Jul 3 We describe 10 patients (6 females and 4 males) from 6 unrelated families with an autosomal recessive disease characterized by simultaneous presentation of nodulosis, arthropathy and osteolysis. They were followed up regularly at King Faisal Specialist Hospital and Research Center in Saudi Arabia for clinical evaluation, serial blood work-up, and evaluating radiological changes. Nodulosis and arthropathy were the clinical criteria for inclusion in this study, and the ten patients fulfilled these criteria. All patients had nodulosis and distal arthropathy. Eight patients (80%) presented with deformed hands and four (40%) with painful hands. All patients had parents who were first cousins and three families had more than one affected child, the finding suggesting autosomal recessive inheritance. Osteopenia and undertubulation of bones distally more than proximally, and upper limbs affected more often than lower limbs, were found in all patients. Osteolysis was seen in carpal and tarsal bones. Other common findings were sclerotic cranial sutures, brachycephaly, and broad medial clavicles. This novel phenotype should be considered in the differential diagnosis of chronic arthritis. Familial arthropathies are more often seen in communities where interfamilial marriage is common. Such a collection of patients is ideal for homozygosity mapping of the disease locus.
9182927 Epstein-Barr virus strain type and latent membrane protein 1 gene deletions in lymphomas i 1997 Jun OBJECTIVE: Recent studies have shown that immunomodulatory therapy for the treatment of rheumatic diseases can be associated with the development of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders. The present study was undertaken to determine the strain type of EBV in lymphoproliferative disorders that occur in patients with rheumatic disease and to investigate EBV latent membrane protein 1 (LMP-1) gene deletions that occur in these lymphoproliferative disorders. METHODS: Ten EBV-associated lymphoid neoplasms in patients with rheumatoid arthritis or dermatomyositis were analyzed by polymerase chain reaction to determine EBV strain type and to investigate for the presence of a previously characterized 30-basepair deletion in the LMP-1 gene. RESULTS: The results indicated that lymphoproliferative disorders in these patients can harbor EBV strain type A or B, with a predominance of type A infection (80%). It was also shown that both wild-type and mutated LMP-1 genes can be found in these neoplasms, with the deleted form of the LMP-1 gene occurring in one-third of cases in this series. CONCLUSION: LMP-1 deletions associated with certain aggressive lymphoid neoplasms are not required for the genesis of lymphoproliferative disorders in patients with rheumatic disease. The relative frequencies of type A and type B EBV strains in these lymphoproliferative disorders show similarities to the frequencies in patients with post-solid organ transplantation immunosuppression-associated lymphoproliferative disorders.
10591974 Long-term application of disease modifying antirheumatic drugs (DMARD). A single-center, o 1999 Oct OBJECTIVE: To study the long-term efficacy and safety of methotrexate (MTX), intramuscular gold, azathioprine (AZA), chloroquine (CQ), sulphasalazine (SASP), and D-penicillamine (DPA) in rheumatoid arthritis (RA) patients. METHODS: Between 1979 and 1994, clinical data were prospectively gathered in a single center. 1681 patients were followed-up for at least 4 years. A 50% reduction of the swollen joint count was required to continue therapy. In addition, a modified Lansbury index, the Keitel function test, and laboratory parameters were determined every six months. Side effects leading to the discontinuation of treatment were recorded as well. RESULTS: After an observation period of more than four years, 39.6% and 28.3% of patients were taking MTX and AZA, respectively; 18.2% were receiving gold, 16.9% remained on DPA. SASP and CQ were still applied in 13.5% and 6.6%. MTX, AZA and SASP had a drop-out rate due to toxicity of 15.9%, 15.3% and 17.7%, whereas 34.8% had to discontinue CQ (gold: 27.4%, DPA: 26.9%). The majority of dropouts occurred within the first year of treatment. Subgroups of seropositive patients and patients with rheumatoid nodules had a poorer treatment efficacy irrespective of the DMARD. CONCLUSION: In the long-term application, MTX was the most efficient compound, followed by AZA, whereas CQ had the poorest drug survival. Our results underline the value of long-term observations under the conditions of clinical practice as a supplement to controlled clinical trials.
10499071 Systemic vasculitis in adults in northwestern Spain, 1988-1997. Clinical and epidemiologic 1999 Sep The vasculitides constitute a heterogeneous group of diseases characterized by blood vessel inflammation and necrosis with different but frequently overlapping clinical and pathologic manifestations. The incidence of these conditions is frequently controversial. To further investigate the incidence and clinical manifestations of vasculitides, we reviewed the spectrum of these diseases in an unselected population of adults (age > 20 years) from northwestern Spain during a 10-year period. From January 1988 through December 1997, 267 adults were diagnosed as having vasculitis. The overall average annual incidence rate of vasculitis in the region of Lugo, Spain, between 1988 and 1997 for the population older than 20 years was 141.54/million. Primary vasculitis (115.04/million for the population older than 20 years; 81.3%), especially giant cell arteritis (GCA) was the most common group. Small vessel primary vasculitis (hypersensitivity vasculitis and Henoch-Schönlein purpura) was the second most common group. Both GCA and small vessel primary vasculitis had a good outcome. However, although less common, patients with medium and small vessel primary vasculitis, in particular those with polyarteritis nodosa, had a high mortality related to the systemic manifestations of the disease or to the immunosuppressive therapy. Among the group of adults with secondary vasculitis (26.51/million; 18.7%), rheumatic diseases and specifically those occurring in the context of rheumatoid arthritis were the most common group. Patients with secondary vasculitis had clinical or laboratory data that may suggest the presence of an underlying disease. In summary, systemic vasculitides are somewhat more common than previously considered. As in other western countries, GCA constitutes the most common type of vasculitis in northwestern Spain. Better physician awareness may contribute to the progressive increase in the recognition of these conditions.
11229457 Interferon-gamma-inducing activity of interleukin-18 in the joint with rheumatoid arthriti 2001 Feb OBJECTIVE: To examine the levels of interleukin-18 (IL-18) bioactivity within the rheumatoid arthritis (RA) joint, and the differential effects of IL-12 and IL-18 on interferon-gamma (IFNgamma) production by T cell infiltrates. METHODS: Expression of IL-18 protein and messenger RNA (mRNA) was determined by enzyme-linked immunosorbent assay and reverse transcriptase-polymerase chain reaction, respectively. The biologic activity of IL-18 was detected on the basis of IFNgamma secretion from IL-18-responding human myelomonocytic KG-1 cells. To determine the extent of inhibitory activity on binding of IL-18 to its receptor, a [125I]-IL-18 binding inhibition assay was performed, using a Chinese hamster ovary cell line transfected with a murine IL-18 receptor. RESULTS: The amount of IL-18 protein detected in both the serum and synovial fluid of RA patients was markedly larger than that detected in the serum and synovial fluid ofosteoarthritis (OA) patients, and serum IL-18 levels correlated with the levels of serum C-reactive protein. IFNgamma production by KG-1 cells was more strongly stimulated in synovial fluid samples from RA patients than in samples from OA patients, and this activity was largely diminished in the presence of anti-IL-18 antibody. In contrast, the activity of IL-18 binding inhibition in the serum and synovial fluid of RA patients was not significantly elevated compared with that in OA patients. RA synovial tissues showed increased expression of IL-18 mRNA and increased IL-18 protein synthesis compared with that in OA tissues. Purified CD14+ macrophages, but not activated fibroblast cell lines, from RA synovium were able to release mature IL-18, although both cell types expressed its transcripts. IL-18 alone showed a negligible effect on IFNgamma production by RA synovial tissue cells, in contrast to IL-12, which was directly stimulatory. However, IL-12-induced IFNgamma production was synergistically enhanced by IL-18, and yet was >50% reduced by neutralization of endogenous IL-18 with anti-IL-18 antibody. CONCLUSION: These results indicate that IL-18, produced predominantly by tissue macrophages, primarily potentiates IL-12-induced IFNgamma production by T cell infiltrates in RA synovium. Detection of significant IL-18 bioactivity in the joints, despite the presence of IL-18 binding inhibitors, supports an integral role of this cytokine in perpetuating the IFNgamma-dominant T cell cytokine response in RA.
9870868 Blockage of interleukin-6 receptor ameliorates joint disease in murine collagen-induced ar 1998 Dec OBJECTIVE: To clarify the role of interleukin-6 (IL-6) in the pathogenesis of collagen-induced arthritis (CIA). METHODS: CIA was induced by immunizing twice at a 3-week interval with bovine type II collagen (CII) emulsified with complete adjuvant. Rat anti-mouse IL-6 receptor (anti-IL-6R) monoclonal antibody MR16-1 or isotype-matched control antibody KH-5 was then injected once intraperitoneally. Symptoms of arthritis were evaluated with a visual scoring system, and serum anti-CII antibody and IL-6 levels were measured by enzyme-linked immunosorbent assay. In addition, the CII responsiveness of splenic lymphocytes from mice with CIA was examined. RESULTS: In mice with CIA, excess production of IL-6 in sera was observed within 24 hours after the first CII immunization, and then rapidly decreased. Serum IL-6 increased again beginning 14 days after immunization, in conjunction with the onset of arthritis. When MR16-1 was injected immediately after immunization with CII, it inhibited the development of arthritis in a dose-dependent manner. Furthermore, MR16-1-treated mice exhibited lower serum levels of IgG anti-CII antibody and reduced responsiveness of lymphocytes to CII. This suppressive effect was observed when MR16-1 was injected on day 0 or 3, but not when injected on day 7 or 14. CONCLUSION: IL-6 produced after CII immunization appears to play an essential role in the immunity to CII, and anti-IL-6R antibody reduces the development of CIA by suppressing IL-6 signal transduction.
11464341 Seeing the glass half full: living with Sjogren's Syndrome. 2001 Jul The purpose of this qualitative research was to explore the lived experiences of women with Sjogren's Syndrome (SS), a chronic autoimmune syndrome in which invading lymphocytes attack moisture-producing glands of the body. This syndrome, affecting 4 million Americans, involves extreme dryness of the eyes and mouth and other systemic complications such as fatigue and muscle and joint pain. Ten women, ranging in age from 27 to 83, with SS were interviewed to understand their coping strategies and attitudes. This study used Strauss' framework to view the quality of life of the chronically ill-specifically, those with SS. Nine questions were asked to elicit information on limitations with daily living, relationships, emotions about lifestyle changes, and comparisons with others living with chronic disease. In addition to SS, 8 of the 10 women also had fibromyalgia, and 4 had other conditions such as lupus and rheumatoid arthritis (secondary Sjogren's). Their responses were categorized into four groups: helping, hindering, hoping, and hurting. This led to the development of the 4H Model of Chronic Autoimmune Disease with subcategories such as: supporting, joining, comparing, coping, health promoting, fearing, becoming a chronic sufferer, feeling, wishing, appearing, impeding, restricting, isolating, suffering, doctoring, and diagnosing. J Prof Nurs 17:194-202, 2001.
9870907 Low density lipoprotein of synovial fluid in inflammatory joint disease is mildly oxidized 1998 Nov Oxidatively modified low density lipoprotein (LDL) has many biological activities which could contribute to the pathology of the atherosclerotic lesion. Because atherosclerosis has an inflammatory component, there has been much interest in the extent to which LDL could be oxidatively modified in vivo by inflammation. The present study examined LDL present in an accessible inflammatory site, the inflamed synovial joint, for evidence of compositional change and oxidative modification. LDL was isolated from knee joint synovial fluid (SF) from subjects with inflammatory arthropathies and also from matched plasma samples. SF and plasma LDL had similar free cholesterol and alpha-tocopherol content, but SF LDL had a lower content of esterified cholesterol. On electrophoresis, SF LDL was slightly more electronegative than LDL from matched plasma samples, but the changes were much less than those resulting from Cu2+-treatment of LDL. Oxidized cholesterol was not detected in any samples, but cholesterol ester hydroperoxide levels were greater in SF than in plasma LDL. When samples from three subjects were incubated with macrophages, the SF LDL did not cause significant loading of the cells with cholesterol or cholesterol esters, in contrast to the situation with acetylated LDL. Overall, the SF LDL displayed evidence of slightly increased oxidation by comparison with matched plasma samples. Despite their isolation from an environment with active inflammation, changes were modest compared with those resulting from Cu2+ treatment. Thus, extensive LDL oxidation is not a necessary correlate of location in a chronic inflammatory site, even though it is characteristic of atherosclerotic lesions.
11083284 Oral antibiotics as a novel therapy for arthritis: evidence for a beneficial effect of int 2000 Nov OBJECTIVE: The intestinal flora is thought to play an important role in regulation of immune responses. We investigated the effects of changing the intestinal flora on the course of adjuvant-induced arthritis (AIA) and on experimental autoimmune encephalomyelitis (EAE) by the use of oral antibiotics. METHODS: Oral treatment with either vancomycin or vancomycin, tobramycin, and colistin was started after AIA and EAE induction. Clinical symptoms of AIA and EAE were monitored, and microbial analysis of ileal samples was performed. RESULTS: Oral vancomycin treatment after disease induction significantly decreased clinical symptoms of AIA. Simultaneously, increased concentrations of Escherichia coli were detected in the distal ileum of vancomycin-treated rats. Ileal concentrations of E coli were inversely related to disease scores in rats with AIA. Coadministration of colistin/tobramycin to prevent the increase in E coli abrogated the beneficial effect of vancomycin on AIA. Vancomycin treatment also reduced the clinical symptoms of EAE. CONCLUSION: We propose oral vancomycin as a novel therapeutic strategy in autoimmune diseases.