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ID PMID Title PublicationDate abstract
17639199 Immunization of Balb/c mice with modified auto-antigens for induction of autoimmune sialoa 2007 Sjögren's syndrome is an autoimmune disease characterized by sialoadenitis and elevated titers of autoantibodies. To assess whether it is possible to induce inflammatory changes in salivary gland tissues, a series of immunizations in Balb/c mice have been undertaken, using salivary gland extract, modified or not, added to several adjuvants. Mice's humoral immune response to salivary gland antigens was monitored by ELISA. Inflammatory cells infiltrating gland tissue were seen 3 months after immunization with salivary gland extract modified with pepsin (AgGp) and metaperiodate (AgGMp). Although pathological progression was not observed, the histopathological picture was similar to the initial phase of Sjögren's syndrome. In addition, a monoclonal antibody reactive with 3 gland polypeptides and anhydrase carbonic II was rescued among B cells from immunized mice. Thus, immunizations with modified autoantigens were able to initiate pathological damage to glandular tissue and stimulate the proliferation of auto-reactive B cells.
17054769 NOD mouse model for Sjögren's syndrome: lack of longitudinal stability. 2006 Nov OBJECTIVES: The non-obese diabetic (NOD) mouse is not only a widely used model for diabetes mellitus type I, but also for the chronic autoimmune disease Sjögren's syndrome (SS), mainly affecting salivary and lacrimal glands. We studied the efficacy of local recombinant serotype 2 adeno-associated viral (rAAV2) vector transfer of immunomodulatory transgenes to alter the SS-like disease in NOD mice. Data collected over a 2-year period indicated a changing SS phenotype in these mice and this phenomenon was investigated. METHODS: 10(10) particles rAAV2LacZ/gland were delivered to both submandibular glands (SMGs) of NOD/LtJ mice at 8 weeks (before sialadenitis onset) of age. Salivary flow rates were determined at 8 weeks and time of killing. Blood glucose levels and body weights were measured weekly. After killing, saliva and SMGs were harvested. Analyses of salivary output, inflammatory infiltrates (focus score), SMG cytokine profile, body weight, and diabetes mellitus status were performed. Data from six different experimental studies over 2 years were analyzed and compared. RESULTS: Salivary flow rate, focus score, and SMG cytokines interleukin (IL)-2, IL-4, IL-6, IL-10, IL-12(p70), tumor necrosis factor-alpha and IFNgamma showed changes over time. There were no differences for body weight, diabetes mellitus prevalence, or blood glucose level of non-diabetic mice. CONCLUSION: This retrospective report is the first to describe longitudinal variability in the NOD mouse as a model for SS. We advise other investigators to continuously monitor the SS phenotype parameters and include appropriate controls when studying this disease in NOD mice.
16547229 Desiccating stress induces T cell-mediated Sjögren's Syndrome-like lacrimal keratoconjunc 2006 Apr 1 Chronic dry eye syndrome affects over 10 million people in the United States; it is associated with inflammation of the lacrimal gland (LG) and in some cases involves T cell infiltration of the conjunctiva. We demonstrate that environmental desiccating stress (DS) elicits T cell-mediated inflammation of the cornea, conjunctiva, and LG, but not other organs in mice. The lacrimal keratoconjunctivitis (LKC) was mediated by CD4(+) T cells, which, when adoptively transferred to T cell-deficient nude mice, produced inflammation in the LG, cornea, and conjunctiva, but not in any other organ. Adoptively transferred CD4(+) T cells produced LKC even though recipients were not exposed to DS. LKC was exacerbated in euthymic mice depleted of CD4(+)CD25(+)forkhead/winged helix transcription factor(+) regulatory T cells. The results suggest that DS exposes shared epitopes in the cornea, conjunctiva, and LG that induce pathogenic CD4(+) T cells that produce LKC, which under normal circumstances is restrained by CD4(+)CD25(+)forkhead/winged helix transcription factor(+) regulatory T cells.
19035167 [The clinical significance of autoantibodies against acetylcholine muscarinic 3 receptor i 2008 Jul OBJECTIVE: To detect anti-M3 receptor antibodies in primary Sjögren's syndrome (pSS) patients and to explore its association with clinical manifestations. METHODS: Anti-M3 antibodies were tested in 70 patients with pSS , 50 patients with systemic lupus erythematosus (SLE) and 76 normal controls with ELISA and Western blot. The correlation between anti-M3 antibodies and other clinical manifestations was analyzed. RESULTS: (1) The positive rate of anti-M3 antibodies in pSS was 47.14% using ELISA and 60.00% using Western blot in SLE 4.00% using ELISA and 12.00% using Western blot and in normal controls 14.47% using ELISA and 15.79% using Western blot. (2) The incidence of schirmer test, tear break-up time (BUT), whole saliva flow rate, punctate epithelial erosions (PEE) on the corneas and external eye examination were not significantly different between the anti-M3 positive and negative groups. (3) The incidences of IgG, rheumatoid factor, SSB and fluorescence index (FI) > 3 were higher in the positive group than in the negative group using ELISA. CONCLUSION: The positive rate of anti-M3 antibodies is higher in pSS than in SLE and normal controls and in some degree it has correlation with the lesion in salivary gland.
19016805 Involvement of REG Ialpha protein in the regeneration of ductal epithelial cells in the mi 2009 Jan The regenerating gene (Reg) was originally isolated from regenerating rat pancreatic islets and revealed recently to constitute a multi-gene family in humans. REG Ialpha protein is known to be overexpressed not only in various human inflammatory diseases but also in various experimental models of inflammation in animal tissues. However, its involvement in pathophysiology of the minor salivary gland (MSG) is not clear. We investigated REG Ialpha expression in the MSG of patients with primary Sjögren's syndrome (SS) and assessed its role in ductal epithelial cell proliferation in such tissues. Lip biopsy specimens were obtained from 40 patients with primary SS and examined using immunohistochemistry for REG Ialpha protein, Ki67 and single-strand DNA (ssDNA). The relationships among clinicopathological factors and expression of REG Ialpha protein, Ki67 and ssDNA in the MSG were then analysed. REG Ialpha protein was expressed rarely in ductal epithelial cells of the normal MSG but was apparently overexpressed in those of patients with SS. The labelling indices for both Ki67 and ssDNA in the ductal cells of the MSGs were significantly higher in SS patients than in controls. Moreover, these labelling indices were significantly higher in REG Ialpha-positive than in negative SS patients. REG Ialpha protein may play a role in the regeneration of ductal epithelial cells in the MSGs of patients with SS.
17928968 [Fulminate liver failure in a 39-year-old female patient with leukocytosis, unclear fever, 2007 Oct 15 BACKGROUND: Fulminate liver insufficiency can have many causes and is a challenge for differential diagnosis. CASE REPORT: A 39-year-old woman was admitted because of a nonitching macular-papular exanthema on both thighs with spreading to the trunk. In addition, the patient complained of dysphagia, symmetrical arthralgias, myalgias, fever of 38 degrees C, and night sweats. An outpatient treatment with nonsteroidal antirheumatics, antihistamines and penicillin was started for 3 days before admission. On admission, a neutrophilic leukocytosis (23.6 Gpt/l), an increase in C-reactive protein (185 mg/l), and a ferritin level of 1,740 microg/l were found. Liver enzymes were increased (alanine aminotransferase 1.03 micromol/l.s, aspartate aminotransferase 1.06 micromol/l.s, gamma-glutamyltransferase 2.73 micromol/l.s, and lactate dehydrogenase 12.48 micromol/l.s). Sonographic examination showed a mild hepatosplenomegaly, but otherwise normal findings. X-rays of the lungs, hands, and ankles were normal. An echocardiography was within normal limits. Extensive serologic investigations including assays for hepatitides A, B and C as well as repeated blood cultures were negative. Antibiotic therapy was continued without any improvement. In addition, acetaminophen (4 x 1,000 mg/day) and ibuprofen (3 x 600 mg/day) were given. Liver function worsened and an icterus developed. The patient was transferred to the authors' university hospital. Because of the clinical findings of fever episodes, a typical macular exanthema, lymphadenopathy, hepatosplenomegaly, arthralgias, myalgias, dysphagia, and the presence of neutrophilic leukocytosis, fever, an increase in ferritin, but negative serologic titers and no bacteremia, a working diagnosis of Still's disease was made. The patient was treated with high-dose methylprednisone (250 mg/day for 3 days, then 100 mg/day). Liver biopsy revealed subacute hepatitis with necrosis and accompanying cholangitis. The prednisone therapy induced a fast remission and improvement of liver function, liver transplantation was not necessary. The patient is, 16 months after the incident, without symptoms under prednisone 3 mg/day, and the liver function is normal. CONCLUSION: The etiology of Still's disease is unknown and the disease is characterized by fever episodes, a typical macular-papular exanthema, lymphadenopathy, hepatosplenomegaly, and arthralgias. A mild to moderate increase in liver enzymes is often found as part of this disease. Rarely, a fulminate liver failure has been described, particularly in the presence of co-administration of nonsteroidal antirheumatics or acetaminophen. Still's disease must be considered as part of the differential diagnosis of acute liver failure, because an early diagnosis and consequent therapy with prednisone may prevent the need for liver transplantation.
16756750 A new approach to managing oral manifestations of Sjogren's syndrome and skin manifestatio 2006 May 31 Sjogren's syndrome (SS) is an autoimmune disorder that affects the salivary glands, leading to xerostomia, and the lacrimal glands, resulting in xerophthalmia. Secondary SS is associated with other autoimmune disorders such as systemic rheumatic diseases and systemic lupus erythematosis (SLE), which can affect multiple organs, including the epidermis. Recent studies have demonstrated that green tea polyphenols (GTPs) possess both anti-inflammatory and anti-apoptotic properties in normal human cells. Epidemiological evidence has indicated that, in comparison to the United States, the incidence of SS, clinical xerostomia and lupus is considerably lower in China and Japan, the two leading green tea-consuming countries.Thus, GTPs might be responsible, in part, for geographical differences in the incidence of xerostomia by reducing the initiation or severity of SS and lupus. Consistent with this, molecular, cellular and animal studies indicate that GTPs could provide protective effects against autoimmune reactions in salivary glands and skin. Therefore, salivary tissues and epidermal keratinocytes could be primary targets for novel therapies using GTPs. This review article evaluates the currently available research data on GTPs, focusing on their potential application in the treatment of the oral manifestations of SS and skin manifestations of SLE.
16688999 [Effects of Chinese herbal medicine for Yiqi Yangyin Quyu in treating Sjögren's syndrome 2006 Apr OBJECTIVE: To investigate the immuno-regulatory and therapeutic effects of Chinese herbal medicine for Yiqi Yangyin Quyu (YYQ, supplementing qi, nourishing yin, removing blood stasis) on Sjögren's syndrome (SS). METHODS: Sixty-two patients were randomly divided into the treated group (37 cases) treated with Chinese medicine and prednisone, and the control group (25 cases) treated with prednisone alone, and another 20 healthy persons were taken as the normal control group. Curative effects was observed, and immunoglobulin (Ig) and T lymphocyte subsets were detected before and after 3 months' treatment. RESULTS: Immunoglobulin (IgG, IgM and IgA) before treatment in SS patients were higher, while the proportion of natural killer (NK) cell and CD4 were lower as compared with those in the normal control group. After treatment, IgG, IgM and IgA lowered to normal levels (P < 0.05), the proportion of NK cell and CD4 rose in both groups (P < 0.05), but CD3 in the control group was still lower than that in the treated group (P < 0.05). The total curative effective rate in the treated group was 91.9%, better than that in the control group (76.0%, chi-squared = 3.92, P < 0.05). CONCLUSION: Chinese herbal medicine for YYQ could improve clinical curative effective rate and regulate immune function in SS patients.
17599763 Clinical criteria for systemic lupus erythematosus precede diagnosis, and associated autoa 2007 Jul OBJECTIVE: Specific events that occur during the development of systemic lupus erythematosus (SLE) can be quite variable among individual patients. The aim of this study was to identify patterns that distinguish early clinical events in SLE and to assess whether the presence of associated autoantibodies precedes the fulfillment of clinical criteria. METHODS: Through a retrospective chart review of military medical records, 130 patients who met the American College of Rheumatology (ACR) criteria for the classification of SLE were identified. The initial time at which each criterion was fulfilled was recorded. Autoantibody analysis was performed on serum samples, using enzyme-linked immunosorbent assays or immunofluorescence. RESULTS: The clinical features that were observed earliest were discoid rash and seizures, which developed a mean 1.74 and 1.70 years, respectively, before the diagnosis of SLE; however, arthritis was the criterion that was most commonly observed before diagnosis. The presence of IgG rheumatoid factor (IgG-RF) preceded the development of arthritis in 15 (94%) of the 16 patients who were positive for IgG-RF and in whom arthritis developed (Z = 10.2, P < 0.0001). Analogously, IgM-RF appeared before the development of arthritis in 13 (76%) of 17 patients. Anti-double-stranded DNA antibodies were associated with renal disease and appeared before evidence of nephritis in most patients (92%) (Z = 13.3, P < 0.0001). An analysis of the appearance of autoantibodies compared with the appearance of clinical criteria not associated with them revealed no significant temporal relationship. CONCLUSION: Symptoms associated with the ACR criteria for classification of SLE are commonly present before the diagnosis of SLE, and development of organ-associated autoantibodies generally precedes the appearance of their associated clinical features.
18767411 Antiphospholipid antibodies and migraine: a retrospective study of 428 patients with infla 2007 The antiphospholipid syndrome (APS) is defined by the presence of antiphospholipid antibodies (aPL), associated with thrombosis or recurrent spontaneous abortions. APS can occur alone or secondary to other conditions, especially associated to inflammatory systemic autoimmune diseases. Among the neurological manifestations associated with aPL, only ischemic stroke is recognized by the actual classification criteria for APS. Other neurological manifestations have been, however, repeatedly reported in case studies of APS patients. Headache, and especially migraine, was commonly reported in APS patients and is one of the classical features described by Hughes as related to aPL, but studies failed to confirm this association. We studied retrospectively the association between headache syndromes and aPL in 428 patients with inflammatory connective tissue diseases admitted in the Neurology and Internal Medicine Departments of Colentina Hospital-Bucharest. We found that migraine alone, not headache of all types, is significantly associated with aPL in patients with systemic immune disease. We studied the presence of cerebral ischemia in patients with headache and aPL. In SLE patients, headache (all types) is significantly associated with positive titers of aPL, and cerebral ischemic lesions are significantly encountered. Even if both migraine and aPL are conditions with high frequency in patients with immune systemic disease and their association may be coincidental, the presence of ischemic lesions in patients showing this association suggests the need to define a sub-group at risk, for whom headache can be a marker and anticoagulants can be discussed.
18709690 Prevalence and longterm course of primary biliary cirrhosis in primary Sjögren's syndrome 2008 Oct OBJECTIVE: To study the prevalence of primary biliary cirrhosis (PBC) and its progression in patients with primary Sjögren's syndrome (SS). METHODS: We investigated 410 patients with primary SS, without history of liver disease, for the presence of PBC based on a retrospective review of clinical, biochemical, immunologic, and histologic data. RESULTS: Thirty-six (8.8%) patients had cholestatic liver biochemistry. Of them, 21 (5.1%) had positive antimitochondrial autoantibodies (AMA) detected by indirect immunofluorescence, while 15 were AMA-negative. Ten of the 21 AMA-positive patients and 7 of the 15 AMA-negative patients were further investigated with liver biopsy, the result of which was compatible with PBC in all but one (AMA-negative) patient. Overall, 27 (6.6%) patients had definite (n=10), probable (n=11), or AMA-negative (n=6) PBC. Pathologically, most PBC lesions were stage 1. Five patients had a second liver biopsy, with no significant histological deterioration. CONCLUSION: PBC is a rather uncommon development in patients with primary SS. The disease appears to be pathologically mild, with a propensity for slow progression, as assessed clinically, biochemically, and histologically.
18600435 IkappaBalpha promoter polymorphisms in patients with primary Sjögren's syndrome. 2008 Sep INTRODUCTION: To investigate the association of IkBalpha promoter polymorphisms with the development of primary Sjögren's syndrome in Taiwan, 98 patients with primary Sjögren's syndrome and 110 unrelated healthy controls were enrolled in this study. MATERIALS AND METHODS: The IkappaBalpha -881 A/G, IkappaBalpha -826 C/T, IkappaBalpha -550 A/T, IkappaBalpha -519 C/T, and IkappaBalpha -297 C/T polymorphisms were determined by the methods of polymerase chain reaction/restriction fragment length polymorphism. RESULTS: This study demonstrated that the genotype frequencies of IkappaBalpha -826 C/T and IkappaBalpha -826 T/T, in comparison with that of IkappaBalpha -826 C/C, were significantly higher in the patients with primary Sjögren's syndrome than in the controls. The allele frequency of IkappaBalpha -881 G was significantly decreased in the patients with primary Sjögren's syndrome compared with that of the controls. In contrast, the allele frequency of IkappaBalpha -826 T was significantly higher in the patients with primary Sjögren's syndrome than in the controls. The similar findings could also be found in the allele carriage frequencies. The patients with primary Sjögren's syndrome had lower allele carriage frequencies of IkappaBalpha -881 G and IkappaBalpha -826 C, and a higher allele carriage frequency of IkappaBalpha -826 T. We also found that the estimated haplotype frequency of IkappaBalpha -881A-826T-550A-519C-297C was significantly increased in the patients with primary Sjögren's syndrome in comparison with that of the controls. DISCUSSION: This study demonstrated that the IkBalpha -826T allele and IkBalpha -881A-826T-550A-519C-297C haplotype were associated with susceptibility to primary Sjögren's syndrome in Taiwan. However, these findings may not be disease-specific but may be related to inflammatory responses.
17912146 Siögren's syndrome: anti-Ro and anti-La autoantibodies trigger apoptotic mechanism in the 2007 Sep AIM: The Sjögren's syndrome (SS) is an autoimmune rheumatic disease that targets salivary and lacrimal glands, characterized by a high concentration of autoantibodies in the serum. The anti-Ro and anti-La autoantibodies are present in approximately 70-90% of the patients with primary SS and this presence is correlated to extraglandular manifestations. The objective of this work was to explore the cellular apoptotic pathway triggered by binding and penetration of anti-Ro and anti-La autoantibodies, isolated from the total IgG fraction of patients with primary SS, in the human salivary gland cell line A-253. METHODS: The sera were obtained from 13 healthy volunteers and 13 patients with primary SS. The IgG was obtained from sera through precipitation with ammonium sulfate and the anti-La and anti-Ro autoantibodies were purified using Sepharose 4B-Ro and Sepharose 4B-La affinity columns. The methods used to evaluate the apoptosis were: DNA fragmentation, immunofluorescence and immunoenzymatic tests. RESULTS: In the salivary gland cells, the anti-Ro and anti-La autoantibodies: 1) are able to penetrate; 2) induce DNA fragmentation and cleavage and activation of the effector caspase-3. In the same experimental condition, IgG purified from healthy sera did not have any apoptotic effect on the human salivary gland cell line. CONCLUSION: Anti-Ro and anti-La autoantibodies mediate the apoptosis the human salivary gland cells A-253 in a caspase-3 dependent manner.
17878210 Epistasis between the MHC and the RCA alpha block in primary Sjögren syndrome. 2008 Jun OBJECTIVE: The RCA alpha block (Regulators of Complement Activation, 1q32) contains critical complement regulatory genes such as CR1 and MCP. This study examined RCA alpha block haplotype associations with both disease susceptibility and diversification of the anti-Ro/La autoantibody response in primary Sjögren syndrome (pSS). METHODS: 115 patients with pSS and 98 controls were included in the study. 93 of 109 (85%) of the patients with pSS were seropositive for Ro/La autoantibodies. The Genomic Matching Technique (GMT) was used to define RCA alpha block ancestral haplotypes (AH). RESULTS: RCA alpha block haplotypes, AH1 and AH3, were both associated with autoantibody-positive pSS (p = 0.0003). Autoantibody associations with both HLA DR3 and DR15 have been previously defined. There was an epistatic interaction (p = 0.023) between RCA alpha AH1 and HLA DR3, and this genotypic combination was present in 48% of autoantibody-positive patients with pSS compared with 8% of controls. This epistasis is most simply attributable to an interaction between C4 and its receptor, CR1, encoded within the RCA alpha block. Both DR3 and a relative C4 deficiency are carried on the major histocompatibility complex 8.1 ancestral haplotype. Only four of 92 (4%) autoantibody-positive patients with pSS did not carry any risk RCA alpha or HLA haplotype, compared with 36 of 96 (38%) controls, and there were differences in haplotype frequencies within autoantibody subsets of pSS. CONCLUSIONS: Normal population variation in the RCA alpha block, in addition to the major histocompatibility complex, contributes genetic susceptibility to systemic autoimmune disease and the autoantibody response. This finding provides evidence for the role of regulation of complement activation in disease pathogenesis.
16595521 Quantitative ultrasonometry of the calcaneus in children with juvenile idiopathic arthriti 2006 Oct OBJECTIVES: To evaluate bone quality by means of quantitative ultrasonometry (QUS) in children with juvenile idiopathic arthritis (JIA). METHODS: Seventy children [37 with oligoarticular JIA, mean age (+/-s.d.) 10.54 +/- 3.42 yr; and 33 with polyarticular rheumatoid factor negative JIA, mean age (+/- s.d.) 11.33 +/- 2.88 yr] were enrolled. Quantitative ultrasonometry was measured on both heels with a Cuba Clinical portable device. Body height, weight and body mass index were recorded together with disease duration and cumulative dose of prednisone. RESULTS: The lowest QUS parameters were observed in children with polyarticular JIA (P< 0.001 and 0.01 when compared with reference data and oligoarticular JIA, respectively). In children with oligoarticular JIA, the QUS values were also significantly lower in comparison with the reference data (P< 0.002). The QUS parameters were strongly influenced by body height, and to a lesser degree by body weight. In children with polyarticular JIA, there were significant inverse correlations between QUS parameters and disease duration [r=-0.57, P< 0.01 for broadband ultrasound attenuation (BUA) and r = - 0.67, P< 0.01 for velocity of sound (VOS)]. Similarly, there were inverse correlations between QUS and cumulative dose of prednisone (r = - 0.48, P< 0.05 for BUA and r =- 0.50, P < 0.01 for VOS, respectively). Similar results were obtained when BUA and VOS were adjusted for height. CONCLUSIONS: Disease duration and cumulative dose of prednisone in children with polyarticular JIA are risk factors of stunted growth and decreased QUS values of bone quality.
16947419 Soluble human p55 and p75 tumor necrosis factor receptors reverse spontaneous arthritis in 2006 Sep OBJECTIVE: The roles of the transmembrane and secreted forms of tumor necrosis factor alpha (TNFalpha) in rheumatoid arthritis (RA) remain unclear. Agents used to inhibit TNFalpha have shown varying efficacy in RA patients, suggesting that anti-TNFalpha agents possess dissimilar mechanisms of action, including the ability to neutralize transmembrane (tmTNFalpha) and secreted TNFalpha. In this study, TNFalpha-knockout (TNFalpha-KO) mice that were genetically altered to express elevated levels of tmTNFalpha were constructed to further understand the roles of the 17-kd secreted, trimeric, and 26-kd transmembrane forms of TNFalpha. METHODS: A speed-congenic mating scheme was used to generate 3 unique strains of mice: 1) transgenic tmTgA86 mice overexpressing 26-kd tmTNFalpha and also secreting 17-kd trimeric TNFalpha (tmTNFalpha-transgenic), 2) TNFalpha-/- mice (TNFalpha-KO), and 3) transgenic mice overexpressing tmTNFalpha backcrossed to TNFalpha-KO mice (tmTNFalpha-transgenic/TNFalpha-KO). Mice were treated with phosphate buffered saline (as vehicle control), dexamethasone (as positive control), or modified recombinant human soluble TNF receptor (sTNFR) p55 or p75, and were assessed clinically and histopathologically for signs of inflammation and development of arthritis. RESULTS: The tmTNFalpha-transgenic/TNFalpha-KO mice were born with crinkled tails and spinal deformities similar to those in ankylosing spondylitis. By 2-4 weeks, these mice developed symmetric inflammatory arthritis, characterized by tissue swelling, pannus formation, and bone deformities. The tmTNFalpha-transgenic mice also developed spontaneous-onset arthritis, but at a slower rate (100% incidence by 10-12 weeks). Clinical and histologic progression of arthritis in the tmTNFalpha-transgenic/TNFalpha-KO mice was reduced by treatment with dexamethasone or with the p55 or p75 sTNFR (69% and 63% reduction in total histologic score, respectively). CONCLUSION: These data show that arthritis is sufficiently initiated and maintained in tmTNFalpha-transgenic/TNFalpha-KO mice, and that it can be neutralized by recombinant human p55 or p75 sTNFR, resulting in amelioration of the biologic and subsequent histologic destructive effects of tmTNFalpha.
16770519 Arthritis in a child secondary to congenital insensitivity to pain and self-aggression. Wh 2007 Jul A 9 year-old female child presented with recurrent arthritis of ankles, left knee and unequal leg length. Clinical examination revealed mild valgus deformity in her left knee with grade 2 effusion, arthritis of both ankles and deformity in her left wrist. Examination of the affected joints showed no evidence of tenderness upon active or passive movements and the patient did not show any limping upon gait analysis. Past history of the patient revealed evidence of previous dislocation of her left hip and previous fibular fracture. Revision of her previous x-rays showed left hip dislocation, fracture left fibula and fracture of right metatarsal bone after repetitive trauma which pass unnoticed. Recent x-ray of her left knee showed osteochondral injury. Laboratory investigations were done to rule out common causes of childhood arthritis and revealed: ESR 12 1st hours, CRP negative, negative rheumatoid factor, and negative ANA. Neurological evaluation of the patient documented congenital insensitivity to pain and EMG studies confirmed evidence of sensory neuropathy. Traumatic arthritis resulting from congenital insensitivity to pain with self-aggression is rarely encountered in children but should be considered in the differential diagnosis specially if radiological features point to repetitive trauma with attempts of healing.
18815286 CD44-specific antibody treatment and CD44 deficiency exert distinct effects on leukocyte r 2008 Dec 15 CD44, the leukocyte adhesion receptor for hyaluronan, has been considered a therapeutic target on the basis of the robust anti-inflammatory effect of CD44-specific antibodies in animal models of immune-mediated diseases. However, CD44 deficiency does not provide substantial protection against inflammation. Using intravital video microscopy in a murine model of rheumatoid arthritis, we show that CD44 deficiency and anti-CD44 antibody treatment exert disparate effects on leukocyte recruitment in inflamed joints. Leukocyte rolling, which is increased in CD44-deficient mice, is promptly abrogated in anti-CD44-treated wild-type mice. CD44-specific antibodies also trigger platelet deposition on granulocytes and subsequent depletion of this leukocyte subset in the circulation. These in vivo effects require CD44 cross-linking and are reproducible with an antibody against Gr-1, a molecule that, like CD44, is highly expressed on granulocytes. Anticoagulant pretreatment, which prevents platelet deposition, mitigates both granulocyte depletion and the suppressive effect of CD44-specific antibody on joint swelling. Our observations suggest that cross-linking of prominent cell surface molecules, such as CD44 or Gr-1, can initiate a rapid self-elimination program in granulocytes through engagement of the coagulation system. We conclude that the robust anti-inflammatory effect of CD44-specific antibodies in arthritis is primarily the result of their ability to trigger granulocyte depletion.
17223654 Ectopic lymphoid neogenesis in psoriatic arthritis. 2007 Jun BACKGROUND: Ectopic lymphoid neogenesis (LN) occurs in rheumatoid synovium, where it is thought to drive local antigen-dependent B cell development and autoantibody production. This process involves the expression of specific homing chemokines and the development of high endothelial venules (HEV). OBJECTIVE: To investigate whether these mechanisms occur in psoriatic arthritis (PsA) synovium, where autoantibodies have not been described and the organisation and function of B cells is not clear, and to analyse their clinical correlates. METHODS: Arthroscopic synovial biopsy specimens from patients with PsA before and after tumour necrosis factor alpha blockade were characterised by immunohistochemical analysis for T/B cell segregation, peripheral lymph node addressin (PNAd)-positive HEV, and the expression of CXCL13, CCL21 and CXCL12 chemokines in relation to the size of lymphoid aggregates. RESULTS: Lymphoid aggregates of variable sizes were observed in 25 of 27 PsA synovial tissues. T/B cell segregation was often observed, and was correlated with the size of lymphoid aggregates. A close relationship between the presence of large and highly organised aggregates, the development of PNAd+ HEV, and the expression of CXCL13 and CCL21 was found. Large organised aggregates with all LN features were found in 13 of 27 tissues. LN in PsA synovitis was not related to the duration, pattern or severity of the disease. The synovial LN pattern remained stable over time in persistent synovitis, but a complete response to treatment was associated with a regression of the LN features. CONCLUSIONS: LN occurs frequently in inflamed PsA synovial tissues. Highly organised follicles display the characteristic features of PNAd+ HEV and CXCL13 and CCL21 expression, demonstrating that the microanatomical bases for germinal centre formation are present in PsA. The regression of LN on effective treatment indicates that the pathogenic and clinical relevance of these structures in PsA merits further investigation.
16567388 Neutrophil-derived leukotriene B4 is required for inflammatory arthritis. 2006 Apr 17 Neutrophils serve as a vanguard of the acute innate immune response to invading pathogens. Neutrophils are also abundant at sites of autoimmune inflammation, such as the rheumatoid joint, although their pathophysiologic role is incompletely defined and relevant effector functions remain obscure. Using genetic and pharmacologic approaches in the K/BxN serum transfer model of arthritis, we find that autoantibody-driven erosive synovitis is critically reliant on the generation of leukotrienes, and more specifically on leukotriene B4 (LTB4), for disease induction as well as perpetuation. Pursuing the cellular source for this mediator, we find via reconstitution experiments that mast cells are a dispensable source of leukotrienes, whereas arthritis susceptibility can be restored to leukotriene-deficient mice by intravenous administration of wild-type neutrophils. These experiments demonstrate a nonredundant role for LTB4 in inflammatory arthritis and define a neutrophil mediator involved in orchestrating the synovial eruption.