Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
16118939 [A 0,05% cyclosporine treatment of the advanced dry eye syndrome]. 2005 PURPOSE: The purpose of our study has been to present the results obtained from the treatment with 0.05% cyclosporine solution in drops in patients with severe aggravation of dry eye syndrome manifestations who otherwise did not suffer from any systemic disease (a three-month treatment). Another group in whom we used the same treatment were those who suffered from dry eye syndrome, which developed in the course of Sjogren's syndrome, and graft versus host disease following bone marrow transplantation (a six-month treatment). MATERIAL AND METHODS: The study comprised 15 dry eye syndrome patients (30 eyes), who were divided into three groups. In Group I were those with severe aggravation of dry eye syndrome manifestations without concomitant systemic diseases (3 women), aged 54 to 59 years (mean 57). Group II comprised the patients with Sjogren's syndrome (8 women, 1 man), aged 45 to 59 years (mean 55.5) with graft versus host disease. In Group III, there were 3 women, aged 52 to 59 years (mean 55) with graft versus host disease. All the patients were administered 0.05% cyclosporine topically twice daily. The Group I patients were given 0.05% cyclosporine solution for 3 months, those in Groups II and III for 6 months. Subjective complaints were classified according to the protocol of Dr. Mann Pharma/Bausch & Lomb. RESULTS: The effectiveness of the therapy with 0.05% cyclosporine solution was evaluated by the mean number of points in a five-point Schirmer II test score, measured before and after the treatment. The Group I patients (dry eye syndrome without systemic diseases) were found to have the highest mean number of points - 4. In the Sjogren's syndrome Group, the mean number of points was 3.1; and in Group III (graft vs host disease) the mean value was 2 points. Since the number of patients was different in particular groups, the findings have not been compared between themselves. CONCLUSIONS: Using 0.05% cyclosporine solution is effective in treating patients with dry eye syndrome but without systemic diseases. In such cases a short, three-month treatment is sufficient. The 0.05% cyclosporine treatment is just as effective in patients with dry eye syndrome and Sjogren's syndrome or graft versus host disease. Yet in such cases the treatment has to be longer and take six months. We observed a mean increase points in the five-point Schirmer II test score in all our patients.
15677968 Pseudorheumatoid nodules in adults: a juxta-articular form of nodular granuloma annulare. 2005 Feb Pseudorheumatoid nodules are considered a deep form of granuloma annulare. Most cases are described in children, occur mainly on the lower legs and scalp, and have favorable prognosis. Their appearance in adults is rare. In this series, fourteen women with pseudorheumatoid nodules were studied. The average age of onset was 36 years old. Lesions consisted of erythematous, violaceous, or skin-colored nodules located mainly on the small joints of the hands. None of the patients developed collagen vascular disease. Persistence was common. Biopsy specimens showed deep dermal nodules composed of epithelioid granulomata separated by thickened collagen bundles. In some areas eosinophilic material was surrounded by histiocytes in a palisaded array. Granuloma annulare was present at the periphery of eight cases. Special stains revealed that most of the eosinophilic material was collagen and mucin was present in eleven cases. In sum these findings demonstrate that pseudorheumatoid nodules in adults are a distinct clinical and pathologic entity, which may be mistaken for rheumatoid nodules. They are probably a juxta-articular variant of granuloma annulare.
17158115 Adult-onset Still's disease in a patient over 80 years old successfully treated with low-d 2007 Jan We report on an 83-year-old Japanese woman with adult-onset Still's disease (AOSD), with marked hypercytokinemia (serum levels of ferritin (Fer) and interleukin (IL)-18 were markedly high). On seeing older patients with fever of unknown origin (FUO), particularly Asians, AOSD should be considered. Reduced doses of oral prednisolone following intravenous methylprednisolone (mPSL) therapy caused a flare-up of AOSD and led to Pneumocystis carinii (jeroveci) pneumonia. Low-dose methotrexate (MTX) therapy was administered as a steroid-sparing agent with good response. Our case suggests that in very elderly people, as in younger patients, MTX is useful for controlling AOSD with marked hypercytokinemia, and avoiding corticosteroid-induced adverse effects.
15960170 [A case of brachial amyotrophic diplegia accompanied with Sjögren's syndrome presenting g 2005 May A 74-year-old woman suffered from progressive muscle atrophy and weakness of her arms since she was seventy two years old. Before referral to our department, she was diagnosed as having cervical spondylotic myeloradiculopathy and received spinal fusion. Though spinal decompression was successful, muscle weakness of her upper limbs were progressive even after the surgery. On admission, neurological examinations revealed marked atrophy and weakness of her bilateral upper limbs with absent deep tendon reflexes showing man-in-the-barrel syndrome. Her lower extremities had normal muscle strength, but fasciculations were seen in her all four limbs. Electrophysiologically, motor nerve conduction velocity was almost normal but the amplitude was remarkably decreased, conduction block was not detected, and electromyography showed neurogenic patterns on her all extremities. Spinal progressive musclar atrophy (SPMA) accompanied with Sjögren's syndrome was the likely diagnosis. Because 50 kDa anti-neuronal antibodies were found in her serum, we assumed that anterior horn cells were impaired by an autoimmune mechanism. Thus we treated her with corticosteroid pulse therapy, plasma exchange (PE) and intravenous immunoglobulin infusion therapy (IVIG). Although steroid pulse therapy only had a minimal effect, PE and IVIG promoted a remarkable improvement on her weakness, and the effect lasted for about three months. This is the first case of SPMA with Sjögren's syndrome which showed good response to PE and IVIG in the early course of the disease. We considered that some SPMA-like motor neuron syndrome accompanied with autoimmune features may require immunomodulating therapies.
15903025 Reproduction and gynaecological manifestations in women with primary Sjögren's syndrome: 2005 BACKGROUND: The impact of primary Sjögren's syndrome (pSS) on reproduction and gynaecological manifestations has seldom been explored. AIM OF STUDY: Assess gynaecological aspects, gynaecological interventions, and use of contraceptives in a population of pSS-patients versus controls. METHODS: In a case-control study, 58 pSS-patients and 157 controls answered a self-administered questionnaire, covering demographic data, reproductive events, gynaecological problems, and gynaecological interventions. RESULTS: Significantly more patients than controls reported episodes of amenorrhoea lasting for more than 3 months, and more patients suffered from menorrhagia/metrorrhagia compared with controls (54.5% versus 35.7%; p = 0.012). Complaints of vaginal dryness were common among the patients (52.9% versus 28.3%; p = 0.005). Endometriosis was reported to occur more frequently in the patients (8.5% versus 2.1%; p = 0.03), and 6.3% of pSS-patients reported having undergone surgical intervention for endometriosis versus 0.7% of the controls (p = 0.009). Positive information about surgery for endometriosis correlated with the presence of the autoantibodies anti-SSA (r = 0.322; p = 0.008) and anti-SSB (r = 0.313; p = 0.01). Among the pSS-patients, 5.9% had chosen not to have children due to the disease, but there was no indication of reduced fertility as judged by the number of pregnancies. CONCLUSION: Patients with pSS reported more gynaecological problems than controls, including vaginal sicca symptoms, endometriosis, several episodes of amenorrhoea, and menorrhagia/metrorrhagia.
15550934 Morphology of corneal nerves and corneal sensation in dry eye: a preliminary study. 2005 Dec PURPOSE: To evaluate the corneal sensitivity and nerve morphology in dry eyes. METHODS: A total of 32 eyes of 16 patients (10 Sjogren's syndrome and six non-Sjogren's syndrome) and 19 eyes of 10 age-matched controls were studied. Sensitivity of the central cornea was measured by the Cochet-Bonnet aesthesiometer. The morphology of corneal nerves was studied by in vivo confocal microscopy (ConfoScan 2.0, Fortune Technologies Srl, Vigonza (PD), Italy). Sub-basal epithelial nerve plexus, subepithelial nerve plexus, and stromal nerves were localized and evaluated for the number of nerves, thickness, reflectivity, and tortuosity for each frame. RESULTS: The mean corneal sensitivity of dry eye patients (5.6 mm/grs/S) was found significantly lower than that of the control (5.0 mm/grs/S) group (P<0.01). Although the subepithelial nerves were thicker in dry eyes (mean: 6.38+/-1.18 microm) than control eyes (mean: 5.72+/-1.27 microm), this difference was not significant (P>0.05). CONCLUSION: Decreased corneal sensitivity is not associated with morphological changes of corneal nerves in dry eyes.
16946104 R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling an 2006 Dec Recent compelling evidence has lead to renewed interest in the role of antibodies and immune complexes in the pathogenesis of several autoimmune disorders, such as rheumatoid arthritis. These immune complexes, consisting of autoantibodies to self-antigens, can mediate inflammatory responses largely through binding and activating the immunoglobulin Fc receptors (FcRs). Using cell-based structure activity relationships with cultured human mast cells, we have identified the small molecule R406 [N4-(2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine] as a potent inhibitor of immunoglobulin E (IgE)- and IgG-mediated activation of Fc receptor signaling (EC(50) for degranulation = 56-64 nM). Here we show that the primary target for R406 is the spleen tyrosine kinase (Syk), which plays a key role in the signaling of activating Fc receptors and the B-cell receptor (BCR). R406 inhibited phosphorylation of Syk substrate linker for activation of T cells in mast cells and B-cell linker protein/SLP65 in B cells. R406 bound to the ATP binding pocket of Syk and inhibited its kinase activity as an ATP-competitive inhibitor (K(i) = 30 nM). Furthermore, R406 blocked Syk-dependent FcR-mediated activation of monocytes/macrophages and neutrophils and BCR-mediated activation of B lymphocytes. R406 was selective as assessed using a large panel of Syk-independent cell-based assays representing both specific and general signaling pathways. Consistent with Syk inhibition, oral administration of R406 to mice reduced immune complex-mediated inflammation in a reverse-passive Arthus reaction and two antibody-induced arthritis models. Finally, we report a first-inhuman study showing that R406 is orally bioavailable, achieving exposures capable of inhibiting Syk-dependent IgE-mediated basophil activation. Collectively, the results show R406 potential for modulating Syk activity in human disease.
17101948 Cognitive deficits in patients with antiphospholipid syndrome: association with clinical, 2006 Nov 13 BACKGROUND: Antiphospholipid syndrome (APS) is a multisystem disorder characterized by arterial and venous thromboses, pregnancy morbidity, and various neuropsychiatric manifestations. Cognitive dysfunction in APS has been poorly recognized. We examined for the first time, to our knowledge, the presence of cognitive dysfunction in patients with APS and its association with clinical, laboratory, and cerebral magnetic resonance imaging characteristics. METHODS: Sixty patients (39 with primary APS and 21 with systemic lupus erythematosus-related APS) and 60 healthy individuals matched for age, sex, and education were examined by means of a comprehensive 3-hour battery of neuropsychological tests. Twenty-three patients had a history of central nervous system involvement. Fifty-nine of 60 patients underwent brain magnetic resonance imaging at the time of neuropsychological assessment. A disease control group not fulfilling criteria for APS (15 patients with systemic lupus erythematosus and 10 with rheumatoid arthritis) was also included. The demographic, clinical, and laboratory characteristics of patients were recorded. RESULTS: Twenty-five (42%) of the 60 patients with APS had cognitive deficits compared with 11 (18%) healthy control subjects (P = .005). No patient was diagnosed as having dementia. The most commonly involved cognitive domains were complex attention and verbal fluency. No difference was found in cognitive performance between patients with primary APS and those with systemic lupus erythematosus-related APS. No relationship was detected between cognitive dysfunction and prior central nervous system disease. We noted a significant association between cognitive dysfunction and livedo reticularis (P = .004) as well as between cognitive dysfunction and the presence of white matter lesions on the findings of brain magnetic resonance imaging (P=.01). No difference was detected in cognitive performance between the disease control group and healthy individuals (P=.86). CONCLUSIONS: Cognitive deficits may often be found among patients with APS, independent of any history of central nervous system involvement. Livedo reticularis and the presence of white matter lesions on brain magnetic resonance imaging are associated with an increased risk for cognitive dysfunction in APS.
16803639 Functional inhibition of NF-kappaB signal transduction in alphavbeta3 integrin expressing 2006 In order to selectively block nuclear factor kappaB (NF-kappaB)-dependent signal transduction in angiogenic endothelial cells, we constructed an alphavbeta3 integrin specific adenovirus encoding dominant negative IkappaB (dnIkappaB) as a therapeutic gene. By virtue of RGD modification of the PEGylated virus, the specificity of the cell entry pathway of adenovirus shifted from coxsacki-adenovirus receptor dependent to alphavbeta3 integrin dependent entry. The therapeutic outcome of delivery of the transgene into endothelial cells was determined by analysis of cellular responsiveness to tumor necrosis factor (TNF)-alpha. Using real time reverse transcription PCR, mRNA levels of the cell adhesion molecules E-selectin, vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1, the cytokines/growth factors IL-6, IL-8 and vascular endothelial growth factor (VEGF)-A, and the receptor tyrosine kinase Tie-2 were assessed. Furthermore, levels of ICAM-1 protein were determined by flow cytometric analysis. RGD-targeted adenovirus delivered the dnIkappaB via alphavbeta3 to become functionally expressed, leading to complete abolishment of TNF-alpha-induced up-regulation of E-selectin, ICAM-1, VCAM-1, IL-6, IL-8, VEGF-A and Tie-2. The approach of targeted delivery of dnIkappaB into endothelial cells presented here can be employed for diseases such as rheumatoid arthritis and inflammatory bowel disease where activation of NF-kappaB activity should be locally restored to basal levels in the endothelium.
15634914 Resolution of a 16.8-Mb autoimmunity-regulating rat chromosome 4 region into multiple ence 2005 Jan 15 To investigate effects of a 16.8-Mb region on rat chromosome 4q42-43 on encephalomyelitis, we performed a high-resolution mapping using a 10th generation advanced intercross line between the susceptible DA strain and the MHC identical but resistant PVG.1AV1 strain. Clinical signs of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) developed in 29% of 772 F(10) rats. Three regions controlling disease, Eae20, Eae21, and Eae22, were mapped using 15 microsatellite markers spanning 16.8 Mb. Eae20 was a major genetic determinant within the region whereas Eae21 modified disease severity. Eae22 was identified as an epistatic region because it only displayed an effect together with Piebald Virol Glaxo (PVG) alleles on Eae20. Disease down-regulation by PVG alleles in the telomeric part of Eae20 was also demonstrated in DA rats made congenic for a approximately 1.44-Mb chromosomal region from PVG. As the region containing Eae20-Eae22 also regulates arthritis, together with the fact that the syntenic mouse 6F(2)-F(3) region regulates experimental lupus and diabetes, and the syntenic human 12p13.31-13.2 region regulates multiple sclerosis and rheumatoid arthritis, the present data point to genes that control several inflammatory diseases. The pairscan analyses of interaction, which here identified Eae22, are novel in the encephalomyelitis field and of importance in the design of further studies of this region in other diseases and species. The limited number of genes identified in Eae20, Eae21, and Eae22 enables focused examination of their relevance in mechanistic animal studies and screening of their association to human diseases.
15942917 The benefit/risk profile of TNF-blocking agents: findings of a consensus panel. 2005 Jun OBJECTIVE: To review the benefits and risks associated with the use of the tumor necrosis factor (TNF)-blockers in various indications (eg, rheumatoid arthritis [RA], Crohn's disease [CD], psoriasis). METHODS: The members of the consensus panel were selected based on their expertise. Centocor, Inc provided an educational grant to the Center for Health Care Education to facilitate the consensus panel. Peer-reviewed articles discussing clinical studies and clinical experiences with TNF-blockers form the basis of this review. Emerging data that have not been peer-reviewed are also included. RESULTS: The TNF-blockers infliximab, etanercept, and adalimumab are all approved for treatment of RA. All 3 are effective, and there are currently no published data from head-to-head clinical trials to support using 1 agent over another. Preliminary data from small, retrospective studies indicate that switching among agents to overcome inadequate efficacy or poor tolerability is beneficial in some patients. The only TNF-blocker currently approved for the induction and maintenance of remission in CD is infliximab. Preliminary data indicate that etanercept and infliximab are effective in treating psoriasis. Some risks associated with TNF-blockers have become apparent, including congestive heart failure, demyelinating diseases, and systemic lupus erythematosus, but in most cases can be identified and managed. Several of these risks (eg, lymphoma and serious infections) are associated with either the condition per se or the concomitant medication use. Simple screening procedures help manage the risk of tuberculosis infection; however, it is recommended that physicians and patients be alert to the development of any new infection so that appropriate treatment may be initiated promptly. Rare infusion reactions, particularly with infliximab, may also be effectively managed. CONCLUSION: TNF-blockers are effective and may be safely used for short- and long-term management of RA or CD. TNF-blockers also show efficacy in other emerging indications.
16320343 Decreased Lyn expression and translocation to lipid raft signaling domains in B lymphocyte 2005 Dec OBJECTIVE: B lymphocytes from patients with systemic lupus erythematosus (SLE) are hyperactive and produce anti-double-stranded DNA (anti-dsDNA) autoantibodies. The cause or causes of B cell defects in SLE are unknown. In this study, we determined the level and subcellular distribution of Lyn protein, a key negative regulator of B cell receptor signaling, and assessed whether altered Lyn expression is characteristic of B cells in the setting of SLE. METHODS: Negative selection was used to isolate B lymphocytes from blood. Lipid raft signaling domains were purified from B cells obtained from 62 patients with SLE, 15 patients with rheumatoid arthritis, and 31 healthy controls, by gradient ultracentrifugation. The total Lyn protein level was determined by Western blotting, confocal microscopy, and fluorescein-activated cell sorting (FACS). The distribution of Lyn into lipid raft and nonlipid raft domains was determined by Western blotting and confocal microscopy. Lyn content in B cell subpopulations was determined by FACS. In order to assess B lymphocyte activity, we used (3)H-thymidine incorporation and enzyme-linked immunosorbent assay to measure spontaneous proliferation and IgG and cytokine production by B cells. RESULTS: This study revealed that B lymphocytes from a majority of patients with SLE have a reduced level of Lyn and manifest altered translocation to lipid rafts. An investigation into the mechanisms of Lyn reduction suggested that increased ubiquitination is involved. This was evident from increased ubiquitination of Lyn and translocation of c-Cbl into lipid rafts. Studies of B cell responses showed that altered Lyn expression was associated with heightened spontaneous proliferation, anti-dsDNA autoantibodies, and increased interleukin-10 production. CONCLUSION: This study provides evidence for altered Lyn expression in B cells from a majority of patients with SLE. Altered Lyn expression in SLE may influence the B cell receptor signaling and B cell hyperactivity that are characteristic of the disease.
17083971 Physiology, pharmacology, and therapeutic relevance of urocortins in mammals: ancient CRF 2007 Apr Urocortins, three paralogs of the stress-related peptide corticotropin-releasing factor (CRF) found in bony fish, amphibians, birds, and mammals, have unique phylogenies, pharmacologies, and tissue distributions. As a result and despite a structural family resemblance, the natural functions of urocortins and CRF in mammalian homeostatic responses differ substantially. Endogenous urocortins are neither simply counterpoints nor mimics of endogenous CRF action. In their own right, urocortins may be clinically relevant molecules in the pathogenesis or management of many conditions, including congestive heart failure, hypertension, gastrointestinal and inflammatory disorders (irritable bowel syndrome, active gastritis, gastroparesis, and rheumatoid arthritis), atopic/allergic disorders (dermatitis, urticaria, and asthma), pregnancy and parturition (preeclampsia, spontaneous abortion, onset, and maintenance of effective labor), major depression and obesity. Safety trials for intravenous urocortin treatment have already begun for the treatment of congestive heart failure. Further understanding the unique functions of urocortin 1, urocortin 2, and urocortin 3 action may uncover other therapeutic opportunities.
16537805 TNF downmodulates the function of human CD4+CD25hi T-regulatory cells. 2006 Jul 1 CD4+CD25+ T-regulatory cells (Tregs) play an essential role in maintaining immunologic homeostasis and preventing autoimmunity. However, little is known about the exogenous factors that regulate their differentiation and function. Here, we report that TNF inhibits the suppressive function of both naturally occurring CD4+CD25+ Tregs and TGFbeta1-induced CD4+CD25+ T-regulatory cells. The mechanism of this inhibition involves signaling through TNFRII that is constitutively expressed selectively on unstimulated Tregs and that is up-regulated by TNF. TNF-mediated inhibition of suppressive function is related to a decrease in FoxP3 mRNA and protein expression by the Tregs. Notably, CD4+CD25hi Tregs isolated from patients with active rheumatoid arthritis (RA) expressed reduced levels of FoxP3 mRNA and protein and poorly suppressed the proliferation and cytokine secretion of CD4+ effector T cells in vitro. Treatment with anti-TNF antibody (infliximab) increased FOXP3 mRNA and protein expression by CD4+CD25hi Tregs and restored their suppressive function. Thus, TNF has a novel action in modulating autoimmunity, by inhibiting CD4+CD25+ Treg activity.
16466022 Isolation and structures of novel fungal metabolites as chemokine receptor (CCR2) antagoni 2005 Nov The chemokine receptor, CCR2, is predominantly expressed on monocytes/macrophages, and on a subset of memory T cells. It binds to several CC type chemokines of the monocyte chemoattractant protein (MCP) family of which MCP-1 exhibits the highest affinity. CCR2/MCP-1 expression/association in monocyte/macrophage/T cells has been associated with inflammatory processes such as rheumatoid arthritis, multiple sclerosis and atherosclerosis. Neutralization of CCR2 with either a peptide or receptor antagonist results in the prevention of joint swelling in rodent models of arthritis. In this paper, bioassay-guided discovery of CCR2 receptor antagonists derived from natural product extracts are reported. These antagonists belong to two main classes exemplified by bisthiodiketopiperazines and cytochalasins. Six compounds, including emestrin, two new emestrin analogs, and chaetomin represent the first group of compounds. These compounds inhibited the binding of MCP-1 to CCR2 (CHO membrane) with IC50 values of 0.8 to 9 microM and exhibited good activity in a whole cell assay using MCP-1 and human monocytes with IC50's ranging from 4-9 microM. Cytochalasins A and B represented the second group and inhibited the binding activity with IC50 values of 5 and 188 microM, respectively. This is the first report of natural product antagonists of the CCR2 receptor.
16398617 Vascular endothelial growth factor in thyroid cancers. 2005 Dec Vascular endothelial growth factor (VEGF) is an essential peptide in new vessel growth in physiology (endometrial growth, embryonic development); pathological conditions (diabetic retinopathy, rheumatoid arthritis); as well as in tumor cell growth, particularly distant metastases. This study focused on VEGF structure, receptors, and angiogensis in tumors, especially their roles in thyroid cancer. The VEGF mRNA undergoes alternative splicing events that generate four homodimeric isoforms, including VEGF121, VEGF165, VEGF189, or VEGF206. Using VEGF purified from a culture medium conditioned by A-431 human epidermoid carcinoma cells, VEGF-binding site complexes of 230, 170, and 125 kDa were detected on human umbilical vein endothelial cells. The VEGF specifically induced the tyrosine phosphorylation of a 190-kDa polypeptide, which had similar mass to the largest binding site detected through affinity cross-linking. A transmembrane receptor belongs to the tyrosine kinase family, fms-like tyrosine kinase (FLT). These receptor tyrosine kinases encoded by the FLT gene family have distinct functions in regulating blood vessel growth and differentiation. Regulation of VEGF is a complex, multistep mechanism in various kinds of cells and tissues. Hypoxia-dependent and -independent mechanisms are illustrated in different cancer tissues. Hypoxic tumor cells may switch to a proangiogenic phenotype, which increases VEGF transcription. Clinical applications of VEGF in cancer have included diagnosis, prediction of prognosis, and treatment in different solid tumors, including thyroid tumors. Studies involving thyroid cancer cell lines, serum level determination, immunohistocytochemical staining, molecular biological studies, and gene therapy to the in vivo clinical trials, have shown that antiangiogensis therapy can provide another treatment modality for thyroid cancer. Future studies focused on recombinant human anti-VEGF research involving patients with advanced thyroid cancer, and investigation of the protection of high-risk patients by using novel antiangiogenic vaccines, are warranted.
17100636 Glycolipids as immune modulatory tools. 2006 Nov NKT cells are a subset of regulatory lymphocytes characterized by co-expression of the NK cell receptor-CD161 and an invariant TCR-alpha chain (Valpha14-Jalpha28). They are most abundant in the liver, spleen, and bone marrow. NKT lymphocytes have been implicated in the regulation of autoimmune processes in both mice and humans. Activation of NKT lymphocytes leads to rapid amplification of either IFNgamma or IL4, endowing these cells with the capability to mediate both pro-inflammatory and anti-inflammatory immune responses. Activation of this subset of cells is associated with significant liver damage in the Concanavalin A immune mediated hepatitis model. Administration of CD1d ligand has a protective role in collagen-induced arthritis in mice. Disease amelioration was associated with a shift in the immune balance from a pathological Th1 type response towards a protective Th2 type response. In humans, patients with SLE, scleroderma, diabetes, multiple sclerosis, and rheumatoid arthritis have lower numbers of peripheral NKT cells. NKT lymphocytes promote tumor rejection in experimental models of tumor immunotherapy. In contrast, NKT lymphocyte-related anti-tumor activity is associated with pro-inflammatory Th1-type immune responses. NKT cells were shown to have a role in suppression of hepatocellular carcinoma (HCC) via immune regulation towards tumor derived antigens, and adoptive transfer of dendritic cells pulsed ex vivo with the same antigens. NKT lymphocytes are activated by interaction of their TCR with glycolipids presented by CD1d, a nonpolymorphic, MHC class I-like molecule expressed by antigen presenting cells, and also by hepatocytes. Several possible ligands for NKT cells have recently been suggested including CD1d bound Glucocerebroside. Glucocerebroside (GC, beta-glucosylceramide), a naturally occurring glycolipid, is a metabolic intermediate in the anabolic and catabolic pathways of complex glycosphingolipids. Its synthesis from ceramide is catalyzed by the enzyme glucosylceramide synthase. Inherited deficiency of glucocerebrosidase, a lysosomal hydrolase, results in Gaucher's disease. Patients with Gaucher's disease have altered humoral and cellular immune profiles and increased peripheral blood NKT lymphocytes. CD1d-bound glucocerebroside does not activate NKT cells directly, and may inhibit activation of NKT cells by alpha-GalCer. On the other hand, glucosylceramide-synthase deficiency was shown to lead to defective ligand presentation by CD1d, with secondary inhibition of NKT cell activation. Recent studies have suggested that a number of glycolipids, including GC, have an immune modulatory effect in several immune mediated disorders. The ability to alter NKT lymphocyte function in various settings and the potential application of natural glycolipids for treatment are discussed.
16464986 Lack of association between the protein tyrosine phosphatase non-receptor 22 (PTPN22)*620W 2006 Sep The minor allele of the R620W missense single-nucleotide polymorphism (SNP; rs2476601) in the PTPN22 (protein tyrosine phosphatase non-receptor 22) gene has been reported to be associated with multiple autoimmune diseases, including type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, juvenile idiopathic arthritis, autoimmune thyroiditis and vitiligo. Systemic sclerosis (SSc) is a connective tissue disease with some autoimmune abnormalities. The aim of our study was to test for association of the PTPN22*620W allele with SSc in a French Caucasian cohort with a case-control study of 121 patients with SSc and 103 controls. All patients and controls were genotyped for the PTPN22*R620W SNP. No association was found between the PTPN22*620W allele and SSc (7% v 9.2%, p = 0.39). The frequency of genotypes carrying at least one 620W allele was similar in both groups (13% v 17%, p = 0.38). The PTPN22*620W allele was also not associated with autoantibody patterns. Thus, the PTPN22*R620W polymorphism cannot be regarded as a genetic susceptibility factor for SSc in the French Caucasian population.
16313349 Interplay between interferon and other cytokine systems in bone metabolism. 2005 Dec Interferons (IFNs) play crucial roles in the regulation of a wide variety of innate and adaptive immune responses. Type I interferons (IFN-alpha/beta) are central to the host defense against pathogens such as viruses, whereas type II interferon (IFN-gamma) mainly contributes to the T-cell-mediated regulation of the immune responses. Studies of bone destruction associated with rheumatoid arthritis have highlighted the importance of the interaction between the immune and skeletal systems. Recently, a new research area, termed osteoimmunology, has been spawned by a series of studies focusing on the signaling networks between IFN and other cytokines in bone metabolisms. It has been revealed that IFN-gamma interferes with the osteoclast differentiation induced by receptor activator of nuclear factor-kappaB ligand (RANKL), and this mechanism is critical for the suppression of pathological bone resorption associated with inflammation. In addition, RANKL induces the IFN-beta gene in osteoclast precursor cells, and this induction constitutes a critical aspect of the negative feedback regulation mechanisms of RANKL signaling to suppress excessive osteoclastogenesis. Furthermore, a novel function of signal transducer and activator of transcription 1 (Stat1), the essential transcription factor for both type I and type II IFN responses, was revealed in the regulation of osteoblast differentiation. Collectively, these studies unveil novel aspects of the IFN system and indicate the operation of the intricate signaling network among IFN and other cytokine systems in bone remodeling, which might offer a molecular basis for the treatment of bone diseases.
16918261 Epratuzumab (humanised anti-CD22 antibody) in autoimmune diseases. 2006 Sep B cells play an important role in the pathogenesis of many autoimmune diseases. Different approaches targeting the B cell compartment are under investigation. Selective modulation of B cells has been recently achieved using a humanised monoclonal antibody against the B cell surface marker CD22. This antibody (epratuzumab) was originally developed for the treatment of non-Hodgkin's lymphoma and was found to be effective, with a very good safety profile. Recent studies have demonstrated the efficacy and safety of epratuzumab in several autoimmune diseases, including systemic lupus erythematosus and primary Sjögren's syndrome.