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1.  Human CD4+CD3− innate-like T cells provide a source of TNF and LTαβ and are elevated in Rheumatoid Arthritis‡ 
Journal of immunology (Baltimore, Md. : 1950)  2013;191(9):10.4049/jimmunol.1301672.
Innate lymphoid cells (ILCs) encompass a diverse array of lymphocyte subsets with unique phenotype that initiate inflammation and provide host defenses in specific microenvironments. In this report we identify a rare human CD4+CD3− innate-like lymphoid population with high TNF expression that is enriched in blood from patients with rheumatoid arthritis. These CD4+CD3− cells belong to the T cell lineage but the lack of antigen receptor at the cell surface renders them nonresponsive to TCR-directed stimuli. By developing a culture system that sustains survival, we show that CD4+CD3− innate-like T cells display IL-7-dependent induction of surface lymphotoxin-αβ (LTαβ) demonstrating their potential to modify tissue microenvironments. Furthermore, expression of CCR6 on CD4+CD3− population defines a CD127high subset that is highly responsive to IL-7. This CD4+CD3− population is enriched in the peripheral blood from rheumatoid arthritis patients suggesting a link to their involvement in chronic inflammatory disease.
doi:10.4049/jimmunol.1301672
PMCID: PMC3865291  PMID: 24078690
2.  Immunophenotype 
doi:10.1186/1546-0096-12-S1-I10
PMCID: PMC4184062
3.  Hydroxychloroquine preferentially induces apoptosis of CD45RO+ effector T cells by inhibiting autophagy: A possible mechanism for therapeutic modulation of T cells 
Although hydroxychloroquine is used for treatment of numerous autoimmune disorders the mechanism is unclear. We here demonstrate that hydroxychloroquine preferentially induces apoptosis of CD45RO+ memory and effector T cells by inhibiting the survival pathway of autophagy.
doi:10.1016/j.jaci.2013.02.026
PMCID: PMC3955204  PMID: 23541328
Hydroxychloroquine; autoimmunity; autophagy; apoptosis; T cells
4.  Discovery and characterization of 2-aminobenzimidazole derivatives as selective NOD1 inhibitors 
Chemistry & biology  2011;18(7):825-832.
NLR family proteins play important roles in innate immune response. NOD1 (NLRC1) activates various signaling pathways including NF-κB in response to bacterial ligands. Hereditary polymorphisms in the NOD1 gene are associated with asthma, inflammatory bowel disease, and other disorders. Using a high throughput screening (HTS) assay measuring NOD1-induced NF-κB reporter gene activity, followed by multiple downstream counter-screens that eliminated compounds impacting other NF-κB pathways, 2-aminobenzimidazole compounds were identified that selectively inhibit NOD1. Mechanistic studies of a prototypical compound, Nodinitib-1 (ML130; CID-1088438), suggest these small molecules cause conformational changes of NOD1 in vitro and alter NOD1 subcellular targeting in cells. Altogether, this inaugural class of inhibitors provides chemical probes for interrogating mechanisms regulating NOD1 activity and tools for exploring the roles of NOD1 in various infectious and inflammatory diseases.
doi:10.1016/j.chembiol.2011.06.009
PMCID: PMC3152441  PMID: 21802003
NOD1; NOD2; NLR; NF-κB; HTS
5.  Treating arthritis by immunomodulation: is there a role for regulatory T cells? 
Rheumatology (Oxford, England)  2010;49(9):1632-1644.
The discovery of regulatory T cells almost 15 years ago initiated a new and exciting research area. The growing evidence for a critical role of these cells in controlling autoimmune responses has raised expectations for therapeutic application of regulatory T cells in patients with autoimmune arthritis. Here, we review recent studies investigating the presence, phenotype and function of these cells in patients with RA and juvenile idiopathic arthritis (JIA) and consider their therapeutic potential. Both direct and indirect methods to target these cells will be discussed. Arguably, a therapeutic approach that combines multiple regulatory T-cell-enhancing strategies could be most successful for clinical application.
doi:10.1093/rheumatology/keq130
PMCID: PMC3203406  PMID: 20463189
Rheumatoid arthritis; Juvenile idiopathic arthritis; Regulatory T cells; Treatment; Pro-inflammatory cytokines; Effector T cells; Combination therapy
6.  Heat shock protein 60 reactive T cells in juvenile idiopathic arthritis: what is new? 
Juvenile idiopathic arthritis (JIA) is a disease characterized by chronic joint inflammation, caused by a deregulated immune response. In patients with JIA, heat shock proteins (HSPs) are highly expressed in the synovial lining tissues of inflamed joints. HSPs are endogenous proteins that are expressed upon cellular stress and are able to modulate immune responses. In this review, we concentrate on the role of HSPs, especially HSP60, in modulating immune responses in both experimental and human arthritis, with a focus on JIA. We will mainly discuss the tolerogenic immune responses induced by HSPs, which could have a beneficial effect in JIA. Overall, we will discuss the immune modulatory capacity of HSPs, and the underlying mechanisms of HSP60-mediated immune regulation in JIA, and how this can be translated into therapy.
doi:10.1186/ar2674
PMCID: PMC2714101  PMID: 19519922
7.  Heat Shock Protein-Derived T-Cell Epitopes Contribute to Autoimmune Inflammation in Pediatric Crohn's Disease 
PLoS ONE  2009;4(11):e7714.
Pediatric Crohn's disease is a chronic auto inflammatory bowel disorder affecting children under the age of 17 years. A putative etiopathogenesis of Crohn's disease (CD) is associated with disregulation of immune response to antigens commonly present in the gut microenvironment. Heat shock proteins (HSP) have been identified as ubiquitous antigens with the ability to modulate inflammatory responses associated with several autoimmune diseases. The present study tested the contribution of immune responses to HSP in the amplification of autoimmune inflammation in chronically inflamed mucosa of pediatric CD patients. Colonic biopsies obtained from normal and CD mucosa were stimulated with pairs of Pan HLA-DR binder HSP60-derived peptides (human/bacterial homologues). The modulation of RNA and protein levels of induced proinflammatory cytokines were measured. We identified two epitopes capable of sustaining proinflammatory responses, specifically TNF〈 and IFN© induction, in the inflamed intestinal mucosa in CD patients. The responses correlated positively with clinical and histological measurements of disease activity, thus suggesting a contribution of immune responses to HSP in pediatric CD site-specific mucosal inflammation.
doi:10.1371/journal.pone.0007714
PMCID: PMC2765612  PMID: 19888320
8.  Modulation of T Cell Function by Combination of Epitope Specific and Low Dose Anticytokine Therapy Controls Autoimmune Arthritis 
PLoS ONE  2006;1(1):e87.
Innate and adaptive immunity contribute to the pathogenesis of autoimmune arthritis by generating and maintaining inflammation, which leads to tissue damage. Current biological therapies target innate immunity, eminently by interfering with single pro-inflammatory cytokine pathways. This approach has shown excellent efficacy in a good proportion of patients with Rheumatoid Arthritis (RA), but is limited by cost and side effects. Adaptive immunity, particularly T cells with a regulatory function, plays a fundamental role in controlling inflammation in physiologic conditions. A growing body of evidence suggests that modulation of T cell function is impaired in autoimmunity. Restoration of such function could be of significant therapeutic value. We have recently demonstrated that epitope-specific therapy can restore modulation of T cell function in RA patients. Here, we tested the hypothesis that a combination of anti-cytokine and epitope-specific immunotherapy may facilitate the control of autoimmune inflammation by generating active T cell regulation. This novel combination of mucosal tolerization to a pathogenic T cell epitope and single low dose anti-TNFα was as therapeutically effective as full dose anti-TNFα treatment. Analysis of the underlying immunological mechanisms showed induction of T cell immune deviation.
doi:10.1371/journal.pone.0000087
PMCID: PMC1762388  PMID: 17183718
9.  Novel self-epitopes derived from aggrecan, fibrillin, and matrix metalloproteinase-3 drive distinct autoreactive T-cell responses in juvenile idiopathic arthritis and in health 
Juvenile idiopathic arthritis (JIA) is a heterogeneous autoimmune disease characterized by chronic joint inflammation. Knowing which antigens drive the autoreactive T-cell response in JIA is crucial for the understanding of disease pathogenesis and additionally may provide targets for antigen-specific immune therapy. In this study, we tested 9 self-peptides derived from joint-related autoantigens for T-cell recognition (T-cell proliferative responses and cytokine production) in 36 JIA patients and 15 healthy controls. Positive T-cell proliferative responses (stimulation index ≥2) to one or more peptides were detected in peripheral blood mononuclear cells (PBMC) of 69% of JIA patients irrespective of major histocompatibility complex (MHC) genotype. The peptides derived from aggrecan, fibrillin, and matrix metalloproteinase (MMP)-3 yielded the highest frequency of T-cell proliferative responses in JIA patients. In both the oligoarticular and polyarticular subtypes of JIA, the aggrecan peptide induced T-cell proliferative responses that were inversely related with disease duration. The fibrillin peptide, to our knowledge, is the first identified autoantigen that is primarily recognized in polyarticular JIA patients. Finally, the epitope derived from MMP-3 elicited immune responses in both subtypes of JIA and in healthy controls. Cytokine production in short-term peptide-specific T-cell lines revealed production of interferon-γ (aggrecan/MMP-3) and interleukin (IL)-17 (aggrecan) and inhibition of IL-10 production (aggrecan). Here, we have identified a triplet of self-epitopes, each with distinct patterns of T-cell recognition in JIA patients. Additional experiments need to be performed to explore their qualities and role in disease pathogenesis in further detail.
doi:10.1186/ar2088
PMCID: PMC1794523  PMID: 17129378
10.  Regulation of Peripheral Inflammation by Spinal p38 MAP Kinase in Rats 
PLoS Medicine  2006;3(9):e338.
Background
Somatic afferent input to the spinal cord from a peripheral inflammatory site can modulate the peripheral response. However, the intracellular signaling mechanisms in the spinal cord that regulate this linkage have not been defined. Previous studies suggest spinal cord p38 mitogen-activated protein (MAP) kinase and cytokines participate in nociceptive behavior. We therefore determined whether these pathways also regulate peripheral inflammation in rat adjuvant arthritis, which is a model of rheumatoid arthritis.
Methods and Findings
Selective blockade of spinal cord p38 MAP kinase by administering the p38 inhibitor SB203580 via intrathecal (IT) catheters in rats with adjuvant arthritis markedly suppressed paw swelling, inhibited synovial inflammation, and decreased radiographic evidence of joint destruction. The same dose of SB203580 delivered systemically had no effect, indicating that the effect was mediated by local concentrations in the neural compartment. Evaluation of articular gene expression by quantitative real-time PCR showed that spinal p38 inhibition markedly decreased synovial interleukin-1 and −6 and matrix metalloproteinase (MMP3) gene expression. Activation of p38 required tumor necrosis factor α (TNFα) in the nervous system because IT etanercept (a TNF inhibitor) given during adjuvant arthritis blocked spinal p38 phosphorylation and reduced clinical signs of adjuvant arthritis.
Conclusions
These data suggest that peripheral inflammation is sensed by the central nervous system (CNS), which subsequently activates stress-induced kinases in the spinal cord via a TNFα-dependent mechanism. Intracellular p38 MAP kinase signaling processes this information and profoundly modulates somatic inflammatory responses. Characterization of this mechanism could have clinical and basic research implications by supporting development of new treatments for arthritis and clarifying how the CNS regulates peripheral immune responses.
Inhibition of p38 MAP kinase in the CNS reduces peripheral inflammation and joint destruction in arthritic rats.
Editors' Summary
Background.
Rheumatoid arthritis is a disease marked by chronic inflammation, leading to joint pain and destruction. Pain and inflammation in the joints as well as other locations in the body (i.e., the “periphery”) are constantly monitored by the central nervous system (i.e., the brain and spinal cord). Scientists have long suspected that the central nervous system (CNS) can regulate inflammation and immune responses, but little is known about how the CNS does this. One potential player is a protein called p38 that is involved in a number of cellular processes critical to the development of rheumatoid arthritis. Several substances that block the action of p38 are effective in animal models of arthritis and are currently being tested in clinical trials in patients with rheumatoid arthritis. Originally, p38 was considered as a drug target that should mainly be blocked in the joints. But recent work has shown that pain in the periphery can lead to activation of p38 in the spinal cord, and that blocking p38 in the spinal cord might reduce peripheral pain.
Why Was This Study Done?
Based on the observation that p38 is activated in the CNS in response to peripheral pain, the researchers who did this study wondered whether it might be involved in the interaction between inflammation in the joints and the CNS.
What Did the Researchers Do and Find?
They induced inflammation in the joints of rats and then looked for responses in the spinal cord. They found that p38 was indeed activated in the spinal cord of these rats. This activation depended on another protein, called TNFα, which is another major regulator of inflammation. The scientists then blocked either p38 or the TNFα with drugs directly delivered to the spinal cord of the arthritic rats, they could substantially reduce inflammation, arthritis, and destruction of the joints, compared with rats that had undergone the same treatment but received no active drug. Treatment of arthritic rats with the same amount of drugs given directly under the skin (this is called “systemic treatment”) did not have any effect on the joints.
What Do These Findings Mean?
Blocking p38 and TNFα by giving drugs systemically is known to have beneficial effects in animal models and human patients with rheumatoid arthritis. However, the drugs tested in patients to date also have side effects. Given that much lower doses were needed to achieve beneficial effects in the rats when the drugs were administered directly into the spinal cord, it is possible that spinal cord administration might reduce the side effects (and possibly the costs) of the drugs without compromising the benefits to the patients. If future studies confirm that the action of these drugs on the CNS is essential to achieve a response even when administered as a systemic treatment, designing drugs that get into the CNS easier might improve the effectiveness and/or make it possible to use lower doses systemically.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030338.
MedlinePlus entry on rheumatoid arthritis
Rheumatoid arthritis pages from the US National Institute of Arthritis and Musculoskeletal and Skin Diseases
Rheumatoid Arthritis fact sheet from the American College of Rheumatology Description
Wikipedia entry on rheumatoid arthritis (note: Wikipedia is a free online encyclopedia that anyone can edit)
doi:10.1371/journal.pmed.0030338
PMCID: PMC1560929  PMID: 16953659

Results 1-10 (10)