C M Weyand

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..Natural killer T cells have proinflammatory properties and the capability of directly contributing to vascular injury...

..Recent data support the concept that the tissue organization in the rheumatoid joint fosters a breakdown in self-tolerance by promoting a phase transition from self-limited immune responses to self-perpetuating autoimmune responses...

..Understanding the mechanisms underlying the loss of T cell diversity and the emergence of pro-inflammatory CD4(+)CD28null T cell clonotypes may have implications for other autoimmune syndromes...

..B cells have a critical role in lymphoid organogenesis. Their contribution to synovial inflammation extends beyond antibody secretion and includes the activation and regulation of effector T cells...

..Follicle-sustaining CD8 T cells were located at the edge of or within the mantle zone. Cell-cell communication in the mantle zone, including CD8 T cells, appears to be critical for ectopic GC formation in rheumatoid synovitis...

..We propose that autoimmunity in rheumatoid arthritis is a consequence of immunodegeneration that is associated with age-inappropriate remodeling of the T-cell pool...

..The current study explored whether acetylsalicylic acid (ASA) had cytokine-repressing activity in GCA and could function as a steroid-sparing agent...

..Guidelines for the optimal use of corticosteroids that maximize relief of symptoms but minimize adverse effects of the therapy are needed...

..We propose that the emergence of CD28-deficient CD4 T cells in the elderly can partially explain age-specific aberrations in immune responsiveness...

..In general, the clinical outcome of giant-cell arteritis is excellent, and efforts must now concentrate on tailoring therapies to the needs of the individual patient...

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..Heterogeneity in the immune insult and the resulting arterial response patterns correlate with variations in clinical disease...

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..These results demonstrate that TNF-alpha directly influences CD28 gene transcription. We propose that the emergence of CD4(+)CD28(null) T cells in vivo is facilitated by increased production of TNF-alpha...

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..In vivo expanded CD4+CD28null and CD8+CD28null T cells uniformly lack alpha- and beta-bound complexes, resembling the pattern seen in chronically activated cells and not of senescent cells...

..Increased risk of autoimmunity, as a consequence of abnormal T-cell population dynamics, could be a common mechanism in chronic inflammatory diseases...

..IFN-gamma may derive from stimulated T lymphocytes, which implicates specific immune responses in the pathogenesis of acute coronary syndromes...

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..Frequencies of CD8(+) CD28(null) T cells are useful biological markers of compromised immunocompetence, identifying individuals at risk for insufficient antibody responses...

..The central role of B cells in synovial inflammation identifies them as excellent targets for immunosuppressive therapy...

..Specifically, KIR2DS2 in conjunction with the appropriate HLA-C ligand may have a role in vascular damage by regulating CD4(+)CD28(null) T cells...

..Rather, initiators can have a direct role in regulating the expression of specific genes. The gain or loss of initiator activity can be an important determinant of cell phenotypes...

..To determine what baseline factors might be associated with response to an initial mild treatment regimen in patients with early rheumatoid arthritis (RA)...

..Endotoxin contamination must be considered as a possible cause of eosinophil-active cytokine production by peripheral blood mononuclear cells...

..The purpose of this study was to compare HLA class II genes in patients with degenerative versus classic inflammatory AAAs and to quantify their impact as disease risk factors...

..The finding of a codominant function of HLA-DRB1 alleles suggests that the biological function of HLA-DR molecules in thymic selection might be important in the pathogenesis of RA...

..These therapeutic approaches can be classified as (1) immunomodulatory effects of existing therapies, (2) therapies targeting inflammatory triggers, and (3) agents inhibiting specific immune mechanisms...

..Expansion of CD4+CD28null T cells in these patients may contribute to the progression of atherosclerosis...

..CONCLUSION: Overproduction of TNFalpha in RA induces a global down-regulation of CD28 in CD4+ T cells and may cause reduced sensitivity to costimulatory signals in T cell responses...

..This confirms that SE genes contribute to RA disease severity and ExRA. Other genetic and environmental factors may have a more specific impact on individual ExRA manifestations...

..We propose that BLyS and APRIL regulate B cell as well as T cell function and have pro- and antiinflammatory activities in RA...

..Elucidation of the underlying mechanisms will allow for extending this turning point to later in life; ultimately, interventions have to aim at restoring thymic function and complementary modes of T cell reconstitution...

..Furthermore, studies of rheumatoid lesions implanted in immunodeficient mice suggest that T cell activation in synovitis is B cell dependent, indicating the role played by B cells in presenting antigens and providing survival signals...

..The collapse in CD4 T cell diversity during the seventh and eighth decades indicates substantial T cell loss and implies that therapeutic measures to improve vaccine responses will have to include strategies for T cell replenishment...

..We propose that rheumatoid synovitis can be suppressed by cell-based immunotherapy with immunoregulatory CD8(+) T cells...

..The presence of I249 not "balanced" by M280 confers an elevated risk of ACS. A FKN-mediated enhanced inflammatory activation might explain this increased risk...

..By virtue of their altered receptor profile, senescent CD4+ T cells receive strong stimulatory signals from nonprofessional antigen-presenting cells in the synovial microenvironment...

..These data identify tissue-residing DCs as gatekeepers in vasculitis and support the model that TLR ligands function as instigators of vessel wall inflammation...

..We suggest that the regulated expression of KIRs in T cells profoundly influences peripheral tolerance and antigen-specific immune responses...

..To define the kinetics and mechanisms of frank arteritis onset in patients with giant cell arteritis...

..By maintaining CCR7 expression, these end-differentiated T cells can home to lymphoid organs, enhance their survival, support clonal expansion, and perpetuate autoreactivity...

..The partially accessible promoter is sensitive to DNMT inhibition, which is sufficient to induce full transcription without further histone acetylation and methylation...

..The data show that CD8 T cells are age sensitive by at least two partially independent mechanisms: fragile homeostatic control and gene expression instability in a large set of regulatory cell surface molecules...

..These findings identify ICAM-2 as a potential therapeutic target to inhibit FLS activation in RA, allowing for a more selective intervention than broad LFA-1 inhibition...

..DCs are superior in sensing pathogen-derived motifs and are highly efficient in breaking T-cell tolerance, guiding T cells toward proinflammatory and tissue-invasive behavior...

..The aim of this study was to examine the mechanisms through which CD4 T cells, the dominant lymphocyte population in patients with rheumatoid synovitis, regulate synoviocyte proliferation...

..The data support a model in which CD70 expressed on T cells causes degeneracy in T cell responses and undermines tolerance mechanisms that normally control T cell autoreactivity...

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..Research efforts need to aim at understanding T-cell homeostatic control mechanisms to ultimately expand the time period of repertoire stability...

..To compare HLA-C genotypes and smoking habits in patients with vasculitis or other severe extraarticular manifestations of rheumatoid arthritis (ExRA) with those in RA patients without extraarticular disease...

..By acquiring a new set of regulatory receptors, senescent CD4 T cells become responsive to novel environmental cues and find ideal stimulatory conditions in the synovial microenvironment...

..Equally interestingly, accelerated T-cell aging combined with telomeric shortening may predispose for autoimmune responses and thereby explain the increased susceptibility for chronic inflammatory diseases in the elderly...

..To study lymphocyte markers in rheumatoid arthritis (RA)-associated interstitial pneumonitis (IP) compared with idiopathic IP...

..We propose that TSP2 is an endogenous regulator of angiogenesis and autoimmune inflammation in the synovium and represents a protective mechanism preventing ectopic lympho-organogenesis and persistent inflammation in this tissue site...

..Consequently, these T cells acquire cytolytic capability that can bypass the need for T-cell receptor triggering and, thus, impose a threat to self-tolerance...

..Studies exploring which mechanisms are functional in which subset of patients hold the promise of providing new and rational treatment approaches for autoimmune syndromes...

..Our data suggest that CD158j in T cells functions as a costimulatory molecule through the JNK pathway independent of KARAP/DAP12 and DAP10. Costimulation by CD158j may contribute to the autoreactivity of CD4(+)CD28(null) T cells in RA...

..The re-expressed CD28 was functional and restored the ability of CD4(+)CD28(null) T cells to express CD25 and CD40 ligand. Our data suggest that IL-12 may, in part, functionally rescue senescent CD4(+) T cells...

..The present data also provide evidence for INR-regulated transcription that is independent of the known components of the basal transcription complex...

..Heterogeneity of microvessels in NOS-3 regulation may be an additional determinant contributing to this compartmentalization and could explain the preferential targeting of newly generated capillary beds...

..We propose that CD8+ T cells regulate the structural integrity and functional activity of GCs in ectopic lymphoid follicles...

..The computer simulations favored a model in which KIR gene expression is inducible for a limited time during the initial stages of clonal expansion...

..The sensitizing effect of CRP suggests synergy between dysregulated T-cell function and acute phase proteins in acute coronary syndromes...

..Because TSP1 is abundantly expressed in the rheumatoid synovium, CD47-TSP1 interaction is proposed to be a key component of an FLS/T cell regulatory circuit that perpetuates the inflammatory process in the rheumatoid joint...

..These cells are under the regulatory control of nonconventional costimulatory molecules, display potent effector functions, and appear to be critical in the synovial and extra-articular manifestations of RA...

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..Because resident fibroblast-like synoviocytes (FLS) express receptors for LTbeta, we examined the consequences of FLS activation by LTbeta...

..T cell lines with transient expression of CD28 are invaluable in the dissection of the biochemical processes involved in the transactivation of the CD28 INR, the silencing of which is a key event in the ontogenesis of senescent T cells...

..This review summarizes recent insights in pathways that are functional in RA and that favor continuous and pathogenic T-cell activation...

..Indeed, studies on the molecular basis for the loss of CD28 are already providing information on methods to functionally rescue senescent T cells...

..How we translate the cellular and molecular details of this regulation into innovation and development of therapies for disease management remains a fundamental, but exciting, challenge...

..Immunologically most interesting is polymyalgia rheumatica, in which the systemic component is combined with aborted vasculitis, suggesting a role for artery-specific tolerance mechanisms...

..Activation of adventitial DCs initiates and maintains T cell responses in the artery and breaks tissue tolerance in the perivascular space...

..To identify prognostic markers that are predictive of progressive erosive disease in patients with early rheumatoid arthritis (RA)...

..We propose that HLA-DRB1*04 alleles or genes in linkage disequilibrium regulate stem cell replication and contribute to the accumulation of senescent and autoreactive T cells in rheumatoid arthritis...

..The outcome of the effects can be up-regulatory or down-regulatory, depending whether resistant or sensitive T cells are involved...