Memory T Cell Subpopulations as Early Predictors of Remission to Vedolizumab in Ulcerative Colitis.

Background: Vedolizumab is a humanized monoclonal antibody targeting the α4ß7 integrin used for the treatment of ulcerative colitis. Few biomarkers related to vedolizumab response have been identified. The aim of this work was to assess whether baseline circulating CD4+ and CD8+ memory T-lymphocyte subpopulations could help to identify patients with response to vedolizumab treatment in ulcerative colitis. Methods: Prospective pilot study in 15 patients with active ulcerative colitis and previous failure to anti-TNFα starting vedolizumab treatment. Peripheral blood samples were obtained before the first dose of vedolizumab and at week 6 and 14 of treatment. Clinical remission was defined as a Mayo Clinic partial score of ≤2 points without any concomitant dose of steroids. Biochemical remission or endoscopic improvement was defined as fecal calprotectin <250 mcg/g or Mayo endoscopic subscore ≤1. Results: At week 14, nine patients achieved clinical remission and eight patients achieved biochemical remission or endoscopic improvement. Patients in clinical remission presented higher baseline CD8 α4ß7 + memory T cells concentration when compared with patients with no remission. In addition, patients with biochemical remission or endoscopic improvement at week 14 presented higher baseline concentration of CD8 α4ß7 + memory T cells. No differences were identified according to flare severity, extent of disease or type of anti-TNFα failure. There were no significant differences regarding changes in T cell subsets during vedolizumab induction. Conclusion: CD8+ α4ß7 + memory T cells before starting vedolizumab therapy could be an early predictor of remission in ulcerative colitis patients and therefore help to select a subset of responders.

Human CLA+ Memory T Cell and Cytokines in Psoriasis.

Psoriasis is a common inflammatory skin condition resulting from the interplay between epidermal keratinocytes and immunological cellular components. This sustained inflammation is essentially driven by pro-inflammatory cytokines with the IL-23/IL-17 axis playing a critical central role, as proved by the clinical efficacy of their blockade in patients. Among all the CD45R0+ memory T cell subsets, those with special tropism for cutaneous tissues are identified by the expression of the Cutaneous Lymphocyte-associated Antigen (CLA) carbohydrate on their surface, that is induced during T cell maturation particularly in the skin-draining lymph nodes. Because of their ability to recirculate between the skin and blood, circulating CLA+ memory T cells reflect the immune abnormalities found in different human cutaneous conditions, such as psoriasis. Based on this premise, studying the effect of different environmental microbial triggers and psoriatic lesional cytokines on CLA+ memory T cells, in the presence of autologous epidermal cells from patients, revealed important IL-17 cytokines responses that are likely to enhance the pro-inflammatory loop underlying the development of psoriatic lesions. The goal of this mini-review is to present latest data regarding cytokines implicated in plaque and guttate psoriasis immunopathogenesis from the prism of CLA+ memory T cells, that are specifically related to the cutaneous immune system.

The Translational Relevance of Human Circulating Memory Cutaneous Lymphocyte-Associated Antigen Positive T Cells in Inflammatory Skin Disorders.

Circulating memory T cells are heterogeneous in their tissue tropism. The skin-seeking T cell subset expresses the cutaneous lymphocyte-associated antigen (CLA) on their surface. CLA+ memory T cells not only migrate from blood to skin but also recirculate between blood and skin. Studying CLA+ memory T cells in cutaneous diseases has allowed a better understanding of immune-inflammatory mechanisms that take place. The analysis of the phenotypical features of these cells, their antigen specificity, cytokine production profile, and changes in relationship to clinical status and therapies among other characteristics have led to the concept that they constitute peripheral cellular biomarkers in T cell-mediated cutaneous conditions. CLA+ memory T cells are of relevance in the pathogenesis of several cutaneous diseases, such as psoriasis (PSO), atopic dermatitis, vitiligo, and drug-induced allergic reactions, to name a few. The interaction of circulating CLA+ T cells with skin-resident cells has been investigated in different ex vivo coculture models made out of clinical samples. Interestingly, microbes that are present in the skin or related with human skin diseases are preferentially recognized by CLA+ T cells. Thus, the interaction of Streptococcus pyogenes with CLA+ T cells in PSO is providing novel concepts that help to understand disease immunopathogenesis. The goal of this review is to present latest results in the field of CLA+ T cells in T cell-mediated inflammatory skin diseases and their translational relevance for human immunodermatology.

Interplay between Humoral and CLA+ T Cell Response against Candida albicans in Psoriasis.

Candida albicans (CA) infections have been associated with psoriasis onset or disease flares. However, the integrated immune response against this fungus is still poorly characterized in psoriasis. We studied specific immunoglobulins in plasma and the CA response in cocultures of circulating memory CD45RA- cutaneous lymphocyte antigen (CLA)+/- T cell with autologous epidermal cells from plaque and guttate psoriasis patients (cohort 1, n = 52), and also healthy individuals (n = 17). A complete proteomic profile was also evaluated in plaque psoriasis patients (cohort 2, n = 114) regarding their anti-CA IgA levels. Increased anti-CA IgA and IgG levels are present in the plasma from plaque but not guttate psoriasis compared to healthy controls. CA cellular response is confined to CLA+ T cells and is primarily Th17. The levels of anti-CA IgA are directly associated with CLA+ Th17 response in plaque psoriasis. Proteomic analysis revealed distinct profiles in psoriasis patients with high anti-CA IgA. C-C motif chemokine ligand 18, chitinase-3-like protein 1 and azurocidin were significantly elevated in the plasma from plaque psoriasis patients with high anti-CA levels and severe disease. Our results indicate a mechanism by which Candida albicans exposure can trigger a clinically relevant IL-17 response in psoriasis. Assessing anti-CA IgA levels may be useful in order to evaluate chronic psoriasis patients.

IL-15 and IL-23 synergize to trigger Th17 response by CLA+ T cells in psoriasis.

IL-15 has emerged as a potentially relevant target in the IL-17 response in psoriasis. However, its mechanism is poorly characterized in humans. IL-15 and IL-23 are constitutively expressed in the psoriatic lesion. Also, IL-15 is considered a susceptibility-associated gene in psoriasis, as are IL-23R, and HLACW6. Here, we studied the effect of IL-15 and IL-23 stimulation on the cytokine response of CLA+/CLA- T cells from 9 psoriasis patients and 3 healthy control subjects. To this end, CLA + and CLA- T cells from blood samples were cultured with epidermal cells from skin biopsies and treated with IL-15 and IL-23. After five days of culture, cytokines in supernatant were measured by ELISA or fluorescent bead-based immunoassay. There was a statistically significant increase in IL-17F and IL-17A production (P < .001) in cocultures of psoriasis skin-homing CLA + T cells with epidermal cells when stimulated with IL-15 and IL-23, but this effect was not observed in the cells of healthy controls. Interestingly, this response was reduced by around 50 to 80% by blocking HLA class I and II molecules. Our results point to the synergic action of IL-15 and IL-23 selectively for CLA + cells in psoriasis, leading to the induction of Th17 cell-related cytokines.

Specific IgA and CLA+ T-Cell IL-17 Response to Streptococcus pyogenes in Psoriasis.

Streptococcus pyogenes tonsillar infection is well known to trigger and exacerbate psoriasis lesions in both guttate and plaque forms of the disease. Although mucosal and cutaneous tissues are closely involved in psoriasis pathology, the interaction between their specific immune responses has not been deeply explored. This work aims to address and characterize the presence of humoral responses against S. pyogenes in patients with psoriasis and its putative association with cytokine responses detected in vitro in our psoriasis ex vivo model, based on the coculture of cutaneous lymphocyte-associated antigen+/- T cells with autologous epidermal cells. Patients with psoriasis presented increased IgA response to S. pyogenes when compared with control subjects. In patients with plaque psoriasis, despite being negative for anti-streptolysin O antibody titer, IgA plasma levels against S. pyogenes correlated with cutaneous lymphocyte-associated antigen+ T-cell-dependent IL-17F response in vitro. No association is observed for IgG levels in plaque psoriasis. Similar association is observed for IgA anti-S. pyogenes extract and IL-17A in patients with guttate psoriasis. We propose S. pyogenes-specific IgA as a potential new perspective for better understanding the role of S. pyogenes in psoriasis development.

Analysis of the PD-1/PD-L1 axis in human autoimmune thyroid disease: Insights into pathogenesis and clues to immunotherapy associated thyroid autoimmunity.

Autoimmune thyroid diseases (AITDs), i.e., Graves' disease (GD) and Hashimoto thyroiditis (HT), are the most prevalent organ-specific autoimmune diseases, but their pathogenesis is still incompletely understood. The PD-1/PD-L1 pathway is an important mechanism of peripheral tolerance that has not been investigated in AITDs. Here, we report the analysis of the expression of PD-1, PD-L1 and PD-L2 in PBMCs, infiltrating thyroid lymphocytes (ITLs) and in thyroid follicular cells (TFCs) in GD, HT and multinodular goiter (MNG) patients and healthy controls PBMCs (HC). By combining flow cytometry, tissue immunofluorescence and induction experiments on primary and thyroid cell line cultures, we show that: 1) while PD-1+ T cells are moderately expanded in PBMCs from GD vs HC, approximately half of T cells in the infiltrate are PD-1+ including some PD-1hi; 2) PD-L1, but not PD-L2, is expressed by 81% of GD glands and in 25% of non-autoimmune glands; 3) PD-L1, was expressed by TFCs in areas that also contain abundant PD-1 positive T cells but; 4) co-localization in TFCs indicated only partial overlap between the smaller areas of the PD-L1+ and the larger areas of HLA class II+ expression; 5) IFNγ is capable of inducing PD-L1 in >90% of TFCs in primary cultures and cell lines. Collectively these results indicate that the PD-1/PD-L1 axis is operative in AITD glands and may restrain the autoimmune response. Yet the discrepancy between easy induction in vitro and the limited expression in vivo (compared to HLA) suggests that PD-L1 expression in vivo is partially inhibited in GD and HT glands. In conclusions 1) the PD-1/PD-L1 pathway is activated in AITD glands but probably not to the extent to inhibit disease progression and 2) Thyroid autoimmunity arising after PD-1/PD-L1 blocking therapies in cancer patients may result from interfering PD-1/PD-L1 tolerance mechanism in thyroid with minimal (focal) thyroiditis. Finally acting on the PD-1/PD-L1 pathway could be a new approach to treat AITD and other organ-specific autoimmunity in the future.

CLA+ T Cell Response to Microbes in Psoriasis.

Streptococcus pyogenes throat infection is a clinically relevant trigger of both guttate and chronic plaque psoriasis, and it provides an ideal context in which to study the pathogenesis of these diseases using an antigen-dependent approach. Circulating cutaneous lymphocyte-associated antigen (CLA) positive (+) memory T cells are a subset of peripheral lymphocytes whose phenotype and function are related to immunological mechanisms in the skin. These cells are considered peripheral biomarkers of T-cell-mediated skin diseases. The coculture of autologous epidermal cells with CLA+ T cells from psoriasis patients activated by S. pyogenes allows the reproduction of the ex vivo initial molecular events that occur during psoriatic lesion formation. With cooperation of autologous epidermal cells, S. pyogenes selectively activates CLA+ T cells both in guttate and plaque psoriasis, inducing key mediators, including an IL-17 response. Here, we explore potential new mechanisms of psoriasis development including the influence of HLA-Cw6 on S. pyogenes CLA+ T cell activation in guttate psoriasis, the relevance of IL-9 on microbe induced IL-17 response in guttate and plaque psoriasis, and novel effector functions of Candida albicans. This review will summarize recent knowledge of psoriatic mechanisms elicited by microbes that have been studied through an innovative translational perspective based on CLA+ T cell-mediated cutaneous immune response.

Microbe-Dependent Induction of IL-9 by CLA+ T Cells in Psoriasis and Relationship with IL-17A.

IL-9 is present in psoriatic lesions and is produced by lymphocytes. However, it is not known whether this cytokine is induced by relevant pathogenic triggers of psoriasis, such as Streptococcus pyogenes. Here we addressed the production of IL-9 in response to various pathogens in a psoriatic ex vivo model. Extracts of S. pyogenes and Candida albicans triggered the production of IL-9 and also IL-17A and IFN-γ. This induction was dependent on the interaction between CLA+ T cells and epidermal cells. Neutralization of IL-9 reduced S. pyogenes-induced IL-17A production by CLA+ T cells but had no effect on IFN-γ production. Also, IL-9 increased the survival of circulating psoriatic CLA+ T cells. Co-cultures from patients with guttate or plaque psoriasis with S. pyogenes produced similar amounts of IL-9. High cytokine responses in streptococcal-driven guttate patients paralleled peaks in Psoriasis Area Severity Index and anti-streptolysin O levels. Our results confirm that IL-9 promotes inflammation in psoriasis by up-regulating IL-17A production and support the clinical association of the immune response by streptococcal-sensitized CLA+ T cells with this cytokine, especially in guttate psoriasis.