Ankylosing Spondylitis (AS) is a chronic inflammatory arthritis affecting primarily the spine and sacroiliac joints and belonging to Spondyloarthritis, a class of immune-mediated disorders. The AS strongest risk factor is the human leukocyte antigen class I gene, HLA-B*27. Recently, Endoplasmic Reticulum AminoPeptidases (ERAP) 1 and 2 genes have been identified by genome wide association studies as additional susceptibility factors. Some other autoimmune/autoinflammatory human diseases share a similar immunopathogenic ground. Accordingly, in all these polygenic disorders there is a principal risk factor which is a HLA class I gene: HLA-B*51 for Behçet's disease, HLA-A*2902 for Birdshot Chorioretinopathy and HLA-C*0602 for psoriasis, but a relevant role can also be attributed to ERAP1 and, in some cases, to ERAP2. Besides peculiar hallmarks imposed by different polygenic backgrounds, such disorders affect body sites undergoing physical stress at external barriers (oral mucosa, skin, gut, eye) or internal sites (joints, enthesis) implying a constant and multi-directional migration of pro-inflammatory cells of innate and adaptive immunity. The endogenous and/or exogenous aetiological triggers are usually unknown. Nevertheless, the co-occurring association of HLA class I and ERAP genes, involved in the peptide trimming, points at antigen processing and presentation pathway to CD8+ T cells as a putative pathogenic event.
A unifying concept proposes that aberrant innate immune reactions at mechanical stress sites or dysfunctions in environmental exposed organs could sustain secondary CD8+ T cell responses culminating in exacerbation and recurrence of such diseases. Thus, the aim of this project will be to study the migratory behaviour of CD8+ T cells in patients with AS by analysing: the chemokine receptor expression; the response to chemokine stimuli and the correlation with the immune-phenotype and senescence state evaluated by telomere shortening measurement.
This study will focus on the migratory behaviour and chemotactic properties of CD8+ T cells in AS. This is an important issue that deserves more attention since AS is a complex disease in which either innate or adaptive immunity concur to the chronic inflammation in the involved body sites. However, the pathogenic mechanisms underlying the crosstalk among immune cells and real leading cellular players are still poorly defined and further investigation is needed.
The observation that more 70% of AS patients have subclinical intestinal inflammation has pointed at gut microbiota as an important player in AS pathogenesis (4,9). Indeed, the intestinal dysbiosis would activate the innate immune system inducing the production of inflammatory cytokines: TNFalpha, IL23, IL17 and IL22 thus activating the pathologic gut-joint axis. Therefore, apart from tissue-resident immune cells there would be a fraction of cells migrating from one inflammatory site to the other but no data are available in this regard.
The role of CD8+ T cells in AS is still debated. HLA-B*27 transgenic rats develop a disease which recapitulates the human axial spondyloarthritis in which the involvement of CD4+ T cells but not of CD8+ T cells has been proven (16). On the contrary, the association of AS risk with genomic variants related to antigen presentation such as the HLA-B*27 and ERAP genes or even with other genes (EOMES, TBX21 and RUNX3) encoding for transcription factors implicated in the regulation of CD8+ T cell number and function points at this adaptive immune cell types as fully active in AS pathogenesis (4,7,13).
Noteworthy, total CD8+ T cell counts are lower in the peripheral blood of patients with AS in comparison to healthy individuals although the number of cytotoxic, perforin-secreting CD8+ T cells is increased in AS cases (4).
Several studies have documented the presence of CD8+ T cells with characteristic TCR beta motifs in the blood and their enrichment in synovial fluid of patients with AS but the phenotype and specific effector functions have not been investigated (19). It is important to mention that different subsets of human CD8+ T cells exist and some of them (CD8+CD122+ or CD8+CD28- T cells) are able to suppress conventional T cell responses. An impaired function or a lower number of these CD8+ Treg cells in the inflamed tissues would have a detrimental role in AS. In this regard, a recent study showed that the count of circulating CD8+ CD122+ T cells was significantly increased in AS patients compared to healthy controls (20). This fact could be interpreted as an effect of the defective homing of these CD8+ Treg subset to body sites including inflamed tissues which ends up increasing their count in the peripheral blood. Therefore, it is important to analyse the migratory capacity of these cells.
Our preliminary data showed that CD8+ T cells from patients with AS reveal an intrinsic hypermotility, independent from chemokine stimulation, which has not been found in patients with rheumatoid arthritis and in healthy controls. It will be interesting to correlate this behaviour with the analysis of the cytoskeleton machinery components and with the chemotaxis induced by specific chemokines. This could be relevant since intravital imaging of cytotoxic CD8+ T cells in pancreatic islets of diabetic mice has shown that the kinetics of cell homing to and between antigenic target sites is a stochastic process and argues against a dominant influence of chemotactic gradients (21).
Overall, this study could shed light on the potential relevance of CD8+ T cells in AS by correlating their migratory features with immune-phenotype, functions and senescence state. This information could be seminal to the identification of new disease biomarkers and therapeutic targets.
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