IntroductionImmunologic self-tolerance is critical for the prevention of autoimmunity and maintenance of immune homeostasis. The ability of the immune system to discriminate between self and nonself is controlled by central and peripheral tolerance mechanisms. The former involves deletion of self-reactive T cells in the thymus at an early stage of development, 1,2 whereas peripheral tolerance involves several mechanisms, including T-cell anergy and ignorance. Since these mechanisms are not completely effective and potentially autoantigen-reactive lymphocytes escape into the periphery, additional mechanisms are involved in the maintenance of self-tolerance. A number of subsets of regulatory T cells play an important role in preventing activation of autoantigenreactive T cells. Among these are naturally occurring "professional" regulatory T cells (Tregs). In this regard, studies carried out during the past decade provided strong evidence for the existence of a unique CD4 ϩ CD25 ϩ population of naturally occurring regulatory/suppressor T cells that actively prevent both the activation and the effector function of autoreactive T cells that have escaped other mechanisms of tolerance. [3][4][5] Removal of this population from normal rodents leads to the spontaneous development of various autoimmune diseases, organ specific as well as systemic. Notably, the generation of CD4 ϩ CD25 ϩ T-regulatory cells in the immune system is developmentally and genetically controlled, as recent studies have demonstrated that the transcription factor, FoxP3, is essential for their thymic development 6 and is sufficient to activate a program of suppressor function in peripheral CD4 ϩ CD25 Ϫ T cells. 7 Genetic defects that affect the development or function of CD4 ϩ CD25 ϩ Tregs can be a primary cause of autoimmune and other inflammatory disorders in humans. 8 It has been proposed that during the initiation of an adaptive immune response, dendritic cells can induce effector CD4 ϩ T cells to become resistant to the suppressive effects of Tregs by secreting IL-6, thus allowing a productive immune response to take place. 9 Similarly, glucocorticoid-induced tumor necrosis factor-like receptor (GITR) engagement on effector T cells by its ligand (GITRL) expressed on antigen-presenting cells (APCs) has been claimed to render them resistant to suppression by CD4 ϩ CD25 ϩ Tregs, 10 and may also have an effect on the function of Tregs. 11 Recent studies have revealed the presence of CD4 ϩ CD25 ϩ Tregs in human peripheral blood, where they constitute up to 5% of the CD4 ϩ T cells. 12,13 These cells are similar to those described in the mouse in that they require cell-to-cell contact to exert their suppressive effect. Whether a soluble factor is involved depends on the experimental system used. 14,15 Tumor necrosis factor (TNF) is a pleiotropic cytokine critical for cell trafficking, inflammation, maintenance of secondary lymphoid organ structure, and host defense against various pathogens. 16 Because of this panoply of effects, TNF plays a critic...
CD4+CD25+ T regulatory cells (Tregs) play an essential role in maintaining immunologic homeostasis and preventing autoimmunity. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance to nuclear components. We hypothesized that altered function of CD4+CD25high Tregs might play a role in the breakdown of immunologic self-tolerance in patients with SLE. In this study, we report a significant decrease in the suppressive function of CD4+CD25high Tregs from peripheral blood of patients with active SLE as compared with normal donors and patients with inactive SLE. Notably, CD4+CD25high Tregs isolated from patients with active SLE expressed reduced levels of FoxP3 mRNA and protein and poorly suppressed the proliferation and cytokine secretion of CD4+ effector T cells in vitro. In contrast, the expression of FoxP3 mRNA and protein and in vitro suppression of the proliferation of CD4+ effector T cells by Tregs isolated from inactive SLE patients, was comparable to that of normal individuals. In vitro activation of CD4+CD25high Tregs from patients with active SLE increased FoxP3 mRNA and protein expression and restored their suppressive function. These data are the first to demonstrate a reversible defect in CD4+CD25high Treg function in patients with active SLE, and suggest that strategies to enhance the function of these cells might benefit patients with this autoimmune disease.
Cadherins are integral membrane proteins expressed in tissue-restricted patterns that mediate homophilic intercellular adhesion. During development, they orchestrate tissue morphogenesis and, in the adult, they determine tissue integrity and architecture. The synovial lining is a condensation of fibroblast-like synoviocytes (FLS) and macrophages one to three cells thick. These cells are embedded within the extracellular matrix, but the structure is neither an epithelium nor an endothelium. Previously, the basis for organization of the synovium into a tissue was unknown. Here, we cloned cadherin-11 from human rheumatoid arthritis (RA)-derived FLS. We developed L cell transfectants expressing cadherin-11, cadherin-11 fusion proteins, and anti–cadherin-11 mAb. Cadherin-11 was found to be expressed mainly in the synovial lining by immunohistologic staining of human synovium. FLS adhered to cadherin-11–Fc, and transfection of cadherin-11 conferred the formation of tissue-like sheets and lining-like structures upon fibroblasts in vitro. These findings support a key role for cadherin-11 in the specific adhesion of FLS and in synovial tissue organization and behavior in health and RA.
Maintenance of immune tolerance in the periphery can be envisioned as a balance between autoreactive lymphocytes and regulatory mechanisms that counteract them. The naturally occurring CD4(+)CD25(+) regulatory T cells (T(REGs)) have a major role in modulating the activity of self-reactive cells. The identification of Forkhead box P3 transcription factor (FoxP3) as the critical determinant of T(REG) development and function has provided new opportunities and generated expanded interest in studying the balance between autoimmunity and regulatory mechanisms in human autoimmune diseases. The identification of both human and mouse diseases resulting from the lack of FoxP3 expression, and consequently the absence of T(REGs), has rapidly expanded knowledge of T(REG) development and function during the past 5 years. Although it is still unclear how these regulatory cells function, they can inhibit the activation of potentially pathogenic T cells in vitro. Using in vitro functional assays and phenotypic analysis, T(REGs) isolated from patients with a variety of autoimmune diseases have been shown to exhibit reduced regulatory function as compared with those isolated from healthy controls. This Review will focus on the current state of knowledge on human T(REGs) and their association with specific autoimmune diseases.
There is an enhanced presence of sleep disorders in patients with SLE. The most frequent primary sleep disorders are respiratory and movement disorders.
Human CD1d molecules consist of a transmembrane CD1 (cluster of differentiation 1) heavy chain in association with  2 -microglobulin ( 2 m). Assembly occurs in the endoplasmic reticulum (ER) and involves the initial glycan-dependent association of the free heavy chain with calreticulin and calnexin and the thiol oxidoreductase ERp57. Folding and disulfide bond formation within the heavy chain occurs prior to  2 m binding. There are four N-linked glycans on the CD1d heavy chain, and we mutated them individually to ascertain their importance for the assembly and function of CD1d- 2 m heterodimers. None of the four were indispensable for assembly or the ability to bind ␣-galactosyl ceramide and to present it to human NKT cells. Nor were any required for the CD1d molecule to bind and present ␣-galactosyl ceramide after lysosomal processing of a precursor lipid, galactosyl-(␣1-2)-galactosyl ceramide. However, one glycan, glycan 2 at Asn-42, proved to be of particular importance for the stability of the CD1d- 2 m heterodimer. A mutant CD1d heavy chain lacking glycan 2 assembled with  2 m and transported from the ER more rapidly than wild-type CD1d and dissociated more readily from  2 m upon exposure to detergents. A mutant expressing only glycan 1 dissociated completely from  2 m upon exposure to the detergent Triton X-100, whereas a mutant expressing only glycan 2 at Asn-42 was more stable. In addition, glycan 2 was not processed efficiently to the complex form in mature wild-type CD1d molecules. Modeling the glycans on the published structure indicated that glycan 2 interacts significantly with both the CD1d heavy chain and  2 m, which may explain these unusual properties.The human CD1 5 (cluster of differentiation 1) family consists of five transmembrane glycoproteins encoded by linked genes (1). They are divided into two groups based on amino acid sequence homology; group 1 includes CD1a, -b, and -c, and group 2 consists of CD1d, the only isoform present in mice and rats. The fifth member of the family, CD1e, has an amino acid sequence intermediate between the two groups. CD1 heavy chains are structurally similar to MHC class I molecules and possess a short C-terminal cytosolic tail, a hydrophobic transmembrane region, and an extracellular region that interacts non-covalently with  2 -microglobulin ( 2 m). The role of CD1 molecules is to bind lipid antigens and present them to T cells, and the ␣1 and ␣2 domains of the extracellular region fold in a similar manner to the analogous domains in MHC class I molecules to generate the lipid binding site.CD1 heavy chain folding and association with  2 m occurs in the endoplasmic reticulum (ER). After exiting the ER, the assembled CD1 molecules pass through the secretory pathway and reach the plasma membrane. From there, with the exception of CD1a, they enter the endocytic system by adaptor protein (AP)-dependent internalization using tyrosine-based endocytic motifs (YXX⌽, X ϭ any amino acid and ⌽ ϭ bulky hydrophobic amino acid). Similar to MHC class II molecul...
Objective Interleukin‐20 (IL‐20) is implicated in the pathogenesis of rheumatoid arthritis (RA). The efficacy, safety, and tolerability of NNC0109‐0012, a selective anti–IL‐20 recombinant human monoclonal antibody (mAb), were assessed in patients with active RA who had an inadequate response to methotrexate therapy. Methods Sixty‐seven patients with RA were enrolled and randomized (2:1) to receive NNC0109‐0012 (3 mg/kg per week, subcutaneously) or placebo in a phase IIa, double‐blind, 12‐week trial with a 13‐week followup. The primary end point was change in the Disease Activity Score in 28 joints based on C‐reactive protein level (DAS28‐CRP) from baseline to week 12. Results In patients treated with NNC0109‐0012, the primary end point, improvement in the DAS28‐CRP at week 12, was achieved (estimated difference −0.88; P = 0.02), with significant improvement starting at week 1. A greater response was observed in seropositive patients (estimated difference −1.66; P < 0.001), which was sustained through 13 weeks of followup, whereas no improvement was noted in patients with seronegative RA. A significant proportion of patients with seropositive RA receiving NNC0109‐0012, compared to those receiving placebo, achieved treatment responses according to the American College of Rheumatology 20% (ACR20) (59% versus 21%), ACR50 (48% versus 14%), and ACR70 (35% versus 0%) levels of improvement, and showed greater improvements in the Health Assessment Questionnaire disability index (P = 0.047). The most frequent adverse events reported with NNC0109‐0012 were injection site reactions and infections (e.g., herpes, nasopharyngitis, respiratory, and urinary). No serious infections or discontinuations associated with NNC0109‐0012 were observed. Conclusion In this phase IIa trial, treatment with NNC0109‐0012 (anti–IL‐20 mAb) was effective in patients with seropositive RA as early as week 1, with further improvements to week 12. No safety or tolerability concerns were identified with weekly NNC0109‐0012 administration.
Objective. The 2-[18 F]-fluoro-2-deoxy-D-glucosepositron emission tomography (FDG-PET) technique provides information on uptake and metabolism of glucose in various tissues. Compared with resting cells, activated lymphocytes take up radioactively labeled glucose analog at a higher rate, which makes it possible to identify lymphoid organs with higher concentrations of activated lymphocytes. This study was undertaken to compare the pattern of PET images and quantitative FDG uptake in lymphoid organs of patients with active systemic lupus erythematosus (SLE) versus patients with inactive SLE and to correlate these findings with peripheral blood lymphocyte phenotypes.Methods. Ten patients with active SLE and 9 patients with inactive SLE were studied. FDG-PET images were obtained from the inguinal region to above the ear, starting at 60 minutes after injection of FDG. Standardized uptake values using lean body mass were determined over areas of interest.Results. Both patients with active lupus and those with inactive lupus had increased FDG uptake in lymph nodes when compared with healthy volunteers, and there was no statistically significant difference between the 2 groups of lupus patients. Thymic uptake was demonstrated in 5 of 10 patients with active lupus compared with 0 of 9 patients with inactive disease. Three of the 5 patients with active SLE who were over 29 years of age had thymic uptake. Of the activation markers tested, only the CD3/CD71 population of cells was significantly different between the patient groups, with an increased percentage in the active disease group (P ؍ 0.0247).Conclusion. Increased FDG uptake in lymph nodes of both patients with active SLE and patients with inactive SLE suggests that metabolic, and probably immunologic, activity is enhanced not only in active, but also in clinically quiescent, disease. The increased thymic uptake observed only in patients with active disease suggests that the thymus plays an important role during periods of disease activity.Peripheral blood lymphocytes (PBLs) from patients with systemic lupus erythematosus (SLE) often contain T cells that exhibit signs of activation (1). Compared with both T and B lymphocytes from patients with inactive disease, those from patients with active SLE express higher levels of activation markers and costimulatory molecules such as CD40 ligand. The correlation between disease activity and lymphocyte activation is further supported by studies showing that effective treatment leads to a decrease in activated lymphocytes (2).The 2-[ 18 F]-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) technique is an imaging method based on the uptake and metabolism of a specific radiopharmaceutical by various tissues. The glucose analog FDG competes with glucose for facili-
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