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Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by excessive immune responses resulting in inflammation of the joints. Although current therapies can be successful in dampening inflammation, a long-lived state of tolerance is seldom achieved. Therefore, novel therapies are needed that restore and maintain tolerance in patients with RA. Targeting regulatory T cells (Tregs) is a successful strategy to achieve tolerance, as was shown in studies performed in animal models and in human clinical trials. The antigen-specificity of Tregs is crucial for their effectiveness and allows for very specific targeting of these cells. However, which antigen is suitable for autoimmune diseases such as RA, for which the autoantigens are largely unknown? Heat shock proteins (HSPs) are ubiquitously expressed and can be up-regulated during inflammation. Additionally, HSPs, or HSP-derived peptides are immunogenic and can be recognised by a variety of immune cells, including Tregs. Therefore, this review highlights the potential of HSP-specific Tregs to control inflammatory immune responses. Targeting HSP-specific Tregs in RA can be achieved via the administration of HSPs (derived peptides), thereby controlling inflammatory responses. This makes HSPs attractive candidates for therapeutic intervention in chronic autoimmune diseases, with the ultimate goal of inducing long-lasting tolerance.

Until recently, the immune system was seen solely as a defense system with its primary task being the elimination of unwanted microbial invaders. Currently, however, the functional significance of the immune system has obtained a much wider perspective, to include among others the maintenance and restoration of homeostasis following tissue damage. In this latter aspect, there is a growing interest in the identification of molecules involved, such as the so-called danger or damage-associated molecular patterns (DAMPs), also called alarmins. Since heat shock proteins are archetypical molecules produced under stressful conditions, such as tissue damage or inflammation, they are frequently mentioned as prime examples of DAMPs (Bianchi, J Leukoc Biol 81:1-5, 2007; Kono and Rock, Nat Rev Immunol 8:279-289, 2008; Martin-Murphy et al., Toxicol Lett 192:387-394, 2010). See for instance also a recent review (Chen and Nunez, Science 298:1395-1401, 2010). Contrary to this description, we recently presented some of the arguments against a role of heat shock protein as DAMPs (Broere et al., Nat Rev Immunol 11:565-c1, 2011). With this perspective and reflection article, we hope to elaborate on this debate and provide additional thoughts to further ignite this discussion on this critical and evolving issue.

Anim Genet. 2012 Sep 19. doi: 10.1111/age.12002. [Epub ahead of print] Tandem repeats modify the structure of the canine CD1D gene. Looringh van Beeck FA, Leegwater PA, Herrmann T, Broere F, Rutten VP, Willemse T, Van Rhijn I. Source Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL, Utrecht, The Netherlands. Abstract Among the CD1 proteins that present lipid antigens to T cells, CD1d is the only one that stimulates a population of T cells with an invariant T-cell receptor known as NKT cells. Sequencing of a 722 nucleotide gap in the dog (Canis lupus familiaris) genome revealed that the canine CD1D gene lacks a sequence homologous to exon 2 of human CD1D, coding for the start codon and signal peptide. Also, the canine CD1D gene contains three different short tandem repeats that disrupt the expected gene structure. Because canine CD1D cDNA lacks sequences homologous to human exon 2 and 3, the functionality of canine CD1d protein may be affected, and this could have consequences for the development and activation of canine NKT cells. © 2012 The Authors, Animal Genetics © 2012 Stichting International Foundation for Animal Genetics. PMID: 22988997 [PubMed - as supplied by publisher]

Anim Genet. 2012 Sep 19. doi: 10.1111/age.12002. [Epub ahead of print] Tandem repeats modify the structure of the canine CD1D gene. Looringh van Beeck FA, Leegwater PA, Herrmann T, Broere F, Rutten VP, Willemse T, Van Rhijn I. Source Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL, Utrecht, The Netherlands. Abstract Among the CD1 proteins that present lipid antigens to T cells, CD1d is the only one that stimulates a population of T cells with an invariant T-cell receptor known as NKT cells. Sequencing of a 722 nucleotide gap in the dog (Canis lupus familiaris) genome revealed that the canine CD1D gene lacks a sequence homologous to exon 2 of human CD1D, coding for the start codon and signal peptide. Also, the canine CD1D gene contains three different short tandem repeats that disrupt the expected gene structure. Because canine CD1D cDNA lacks sequences homologous to human exon 2 and 3, the functionality of canine CD1d protein may be affected, and this could have consequences for the development and activation of canine NKT cells. © 2012 The Authors, Animal Genetics © 2012 Stichting International Foundation for Animal Genetics. PMID: 22988997 [PubMed - as supplied by publisher]

The aim of this study was to identify new markers of mucosal T cells to monitor ongoing intestinal immune responses in peripheral blood.Expression of cell-surface markers was studied in mice on ovalbumin (OVA)-specific T cells in the gut-draining mesenteric lymph nodes (MLN) after OVA feed. The effect of the local mucosal mediators retinoic acid (RA) and transforming growth factor-β (TGF-β) on the induction of a mucosal phenotype was determined in in vitro T-cell differentiation assays with murine and human T cells. Tetramer stainings were performed to study gluten-specific T cells in the circulation of patients with celiac disease, a chronic small-intestinal inflammation.In mice, proliferating T cells in MLN were CD62L(neg)CD38(+) during both tolerance induction and abrogation of intestinal homeostasis. This mucosal CD62L(neg)CD38(+) T-cell phenotype was efficiently induced by RA and TGF-β in mice, whereas for human CD4(+) T cells RA alone was sufficient. The CD4(+)CD62L(neg)CD38(+) T-cell phenotype could be used to identify T cells with mucosal origin in human peripheral blood, as expression of the gut-homing chemokine receptor CCR9 and β(7) integrin were highly enriched in this subset whereas expression of cutaneous leukocyte-associated antigen was almost absent. Tetramer staining revealed that gluten-specific T cells appearing in blood of treated celiac disease patients after oral gluten challenge were predominantly CD4(+)CD62L(neg)CD38(+). The total percentage of circulating CD62L(neg)CD38(+) of CD4 T cells was not an indicator of intestinal inflammation as percentages did not differ between pediatric celiac disease patients, inflammatory bowel disease patients and respective controls. However, the phenotypic selection of mucosal T cells allowed cytokine profiling as upon restimulation of CD62L(neg)CD38(+) cells interleukin-10 (IL-10) and interferon-γ (IFN-γ) transcripts were readily detected in circulating mucosal T cells.By selecting for CD62L(neg)CD38(+) expression that comprises 5-10% of the cells within the total CD4(+) T-cell pool we are able to highly enrich for effector T cells with specificity for mucosal antigens. This is of pivotal importance for functional studies as this purification enhances the sensitivity of cytokine detection and cellular activation.

Rheumatoid arthritis (RA) is a chronic T-cell mediated autoimmune disease that affects primarily the joints. The induction of immune tolerance through antigen-specific therapies for the blockade of pathogenic CD4+ T cells constitutes a current focus of research. In this focus it is attempted to simultaneously activate multiple regulatory mechanisms, such as: apoptosis and regulatory T cells (Tregs). APL-1 is an altered peptide ligand derived from a novel CD4+ T-cell epitope of human heat-shock protein of 60kDa, an autoantigen involved in the pathogenesis of RA. Previously, we have reported that APL-1 induces CD4+ CD25(high)Foxp3+ Tregs in several systems. Here, we investigated the ability of APL-1 in inducing apoptosis in PBMCs from RA patients, who were classified as active or inactive according to their DAS28 score. APL-1 decreased the viability of PBMCs from active but not from inactive patients. DNA fragmentation assays and typical morphological features clearly demonstrated that APL-1 induced apoptosis in these cells. Activated CD4+ CD25+ T cells but not resting CD4+ CD25- T cells were identified as targets of APL-1. Furthermore, CD4+ T-cell responses to APL-1 were found to be dependent on antigen presentation via the HLA-DR molecule. Thus, APL-1 is a regulatory CD4+ T cell epitope which might modulate inflammatory immune responses in PBMCs from RA patients by inducing CD4+ CD25(high)Foxp3+ Tregs and apoptosis in activated CD4+ T cells. These results support further investigation of this candidate drug for the treatment of RA.

Tolerogenic dendritic cells (DCs) can induce regulatory T cells and dampen pathogenic T cell responses. Therefore, they are possible therapeutic targets in autoimmune diseases. In this study we investigated whether mouse tolerogenic DCs are induced by the phytonutrient carvacrol, a molecule with known anti-inflammatory properties, in combination with a physiological stress. We show that treatment of DCs with carvacrol and thermal stress led to the mRNA expression of both pro- and anti-inflammatory mediators. Interestingly, treated DCs with this mixed gene expression profile had a reduced ability to activate pro-inflammatory T cells. Furthermore, these DCs increased the proportion of FoxP3(+) regulatory T cells. In vivo, prophylactic injection of carvacrol-thermal stress treated DCs pulsed with the disease inducing antigen was able to suppress disease in a mouse model of arthritis. These findings suggest that treatment of mouse bone marrow derived DCs with carvacrol and thermal stress induce a functionally tolerogenic DC that can suppress autoimmune arthritis. Herewith carvacrol seems to offer novel opportunities for the development of a dietary based intervention in chronic inflammatory diseases.

Exploitation of antigen-specific regulatory T cells (Tregs) as critical regulators in the control of chronic inflammatory diseases is hampered by the obscure nature of most disease-relevant autoantigens. Heat shock proteins (Hsp) are possible targets for Tregs due to their enhanced expression in inflamed (stressed) tissues and there is evidence that Hsp can induce anti-inflammatory immunoregulatory T-cell responses.Recent publications showing that exogenous administration of stress proteins has induced immunoregulation in various models of inflammatory disease have also been shown to be effective in first clinical trials in humans. Now, in the light of a growing interest in T-cell regulation, it is of interest to further explore the mechanisms through which Hsp can be utilized to trigger immunoregulatory pathways, capable of suppressing such a wide and diversified spectrum of inflammatory diseases.Therapeutic approaches via exploitation of antigen-specific Tregs will benefit from tailor-made combination therapies. Combining current therapeutic approaches with Hsp-specific therapies thereby enhancing natural immune regulation might expedite the entry of antigen-specific regulatory T cells into the therapeutic arsenal of the anti-inflammatory therapeutics.