Selective response of circulating CLA+ T cells to antigens involved in cutaneous disease triggering.
Focusing on the study of human memory CLA+ T cells to understand psoriasis pathology constitutes an innovative approach to explore the pathological mechanism of this chronic cutaneous inflammatory disease. CLA+ T cells can be considered peripheral cell biomarkers in the study of T-cell mediated human skin diseases. During the last few years, new evidences have been found that link streptococcal infection with IL-17 response in psoriasis by studying the interaction between Streptococcus pyogenes with CLA+ T cells and autologous epidermal cells. S. pyogenes constitutes the best clinically characterized trigger of psoriasis and by exploring its effect on CLA+ T cells and epidermal cells in psoriasis may allow understanding psoriasis by using patient’s clinical samples ex vivo.
- CLA+ T cells
- translational research
- Streptococcus pyogenes
1. CLA+ T cells and the regional cutaneous immune system
The adaptive immune responses taking place during cutaneous chronic inflammation in psoriasis preferentially involve a subset of memory T lymphocytes, which are related to the skin and that belong to the cutaneous immune system, and constitute one of the best characterized regional immune systems of the body and known for decades . In the humans, the cutaneous lymphocyte-associated antigen (CLA) is a surface cell marker that allows identifying T cells that belong to the cutaneous immune system. The CLA antigen is a carbohydrate expressed by 15% of human circulating T cells, and on most (>90%) skin-infiltrating T cells, contrary to other inflamed organs . CLA is expressed preferentially on memory antigen-experienced T cells.
The CLA is one of the adhesion molecule that, together with chemokine receptors, allows T cells to selectively migrate to the skin, in either homeostatic or inflammatory conditions, by binding to endothelial cell wall via adhesion molecules or ligands. The molecular interactions between CLA/E-selectin, very late antigen-4 (VLA-4)/vascular cell adhesion protein-1 (VCAM-1), lymphocyte function-associated antigen-1 (LFA-1)/intercellular adhesion molecule-1 (ICAM-1), and chemokine ligands for chemokine, C-C motif receptor (CCR) 10, CCR4, CCR6, and CCR8 constitute a code bar system enabling skin infiltration .
The importance of circulating CLA+ T cells for understanding the skin immune system is not only based on their capacity to selectively migrate to skin, but also on the fact that these circulating memory T cells are functionally related to the immune response taking place in the cutaneous inflamed lesions. This feature is based on the recirculating capacity of those cells between lesional skin and blood during cutaneous inflammation in psoriasis . The adhesive interaction between LFA-1 and ICAM-1 is one of the mechanisms involved in the transendothelial migration of CLA+ T cells . Interestingly, the blockade of LFA-1/ICAM-1 interaction in psoriasis patients with anti-LFA-1 in patients blocks extravasation and leads to CLA+ T cell lymphocytosis. Such accumulation of CLA+ T cells in the blood has clinical relevance since skin relapse may develop after stopping the anti-LFA-1 treatment .
The function and phenotype of circulating CLA+ T cells in T-cell mediated skin disease have been studied in many different human skin conditions. Those skin-seeking memory T cells respond to antigens, allergens, or superantigens that play a key role in disease triggering of different human T-cell mediated skin diseases, see Table 1. In addition, their phenotype and function are related to clinical status of the patient. For these reasons, those cells are considered peripheral cell biomarkers of T-cell mediated human cutaneous diseases [3, 5, 6].
2. Translational research and clinically relevant pathological mechanism of psoriasis
The innovation in psoriasis treatment has benefited from the continuous bidirectional flow of information from the bedside of clinic to the laboratory and vice versa . Innovative pathogenic concepts have been tested in patients through the use of targeted therapeutics leading to clinically validated mechanism of disease. Those mechanisms that started as a merely scientific hypothesis of disease that can be proven to be relevant in the clinic by specific biological treatments allow improvement in the therapeutic arsenal for patients. At present, it is possible to understand psoriasis from several of its clinically relevant mechanism/targets that has been validated in the clinic since that has provided clinical benefit in patient. The current clinically validated concept of psoriasis is summarized in Tables 2 and 3. During the last two decades approximately, it has been demonstrated the key role of the IL-23/Th17 axis in psoriasis . The journey to the current situation in psoriasis treatment started by evidencing that T-cell activity in psoriasis had real implications for the patients. Thus, depletion of T cells [9, 10], costimulation , and inhibition of their migration from blood to skin demonstrated improvement in the clinical severity . Not only memory T cells are of translational relevance in psoriasis, but also TNF-α is a key cytokine for this disease. Although originally thought not to be associated to T-cell function, lately it was demonstrated that TNF-α neutralization affects Th17 function . The introduction of ustekinumab, a monoclonal antibody that neutralizes both IL-12 and IL-23, cytokines involved in differentiation of Th1 and Th17 cells, respectively, marked the initiation of the IL-23/Th17 axis era . In contrast to the increased amounts of IL-23, there is no marked increase of IL-12 in psoriatic lesion in comparison to nonlesional or healthy . It became evident that the ustekinumab clinical efficacy was related to inhibition of the IL-23 biological effect.
|Biological treatment||Mechanism action||Target||Relevance|
|DAB389-IL-2||Toxin acting on cells expressing IL-2 receptor||CD25||T-cells are important in psoriasis |
|CTLA4-Ig||T cell costimulation blockade||CD80, CD86||Blocking T cell activation improve psoriasis |
|LFA-3-Ig||Memory T cell depletion||CD2||Memory T cells are relevant in psoriasis |
|Anti-LFA-1||T cell migration and T-cell costimulation inhibitor||LFA-1||Migration of T cells to psoriasis lesion is involved in disease |
|Anti-TNF-α||Neutralization of biological activity||TNF-α||Biological activity of TNF-α is involved in psoriasis |
|Neutralization of biological activity||p40|
|Cytokines involved in generating Th1 and Th17 are relevant in psoriasis |
|Anti-IL-17A||Neutralization of I biological activity||IL-17A||Other cytokines besides TNF play a role in psoriasis |
|Anti-IL-17RA||Blockade of receptor||IL-17RA||IL-17 signaling plays a relevant role in psoriasis |
|Anti-IL-23p19||Neutralization of biological activity||IL-23p19||IL-23/Th17 axis play essential role in psoriasis |
|Biological treatment||Mechanism of action||Target||Relevance|
|IL-8||Neutralization of biological activity||IL-8||IL-8 is not clinically validated in psoriasis |
|IFN-γ||Neutralization of biological activity||IFN-γ||IFN-γ is not clinically validated in psoriasis |
|IFN-α||Neutralization of biological activity||IFN-α||IFN-α is not clinically validated in psoriasis |
|IL-22||Neutralization of biological activity||IL-22||IL-22 is not clinically validated in psoriasis |
The next step was to translate the consequence of blocking the IL-23, a cytokine involved in the differentiation of T cells producing IL-17, into the clinic. The selective inhibition of the biological activity of IL-17A, or its receptor IL-17RA, has demonstrated an impressive clinical efficacy in patients in the clinical trials. The most innovative approach currently is to block selectively IL-23, which also has confirmed the clinical relevance of specifically blocking the IL-23/Th17 in psoriasis .
In contrast to the mediators or cells that have confirmed its relevance in psoriasis due to its clinical importance in reducing disease severity, there are several well-known mechanisms present in psoriasis that have not been validated in the clinic, since their biological neutralization in the patient has not brought clinical benefit, see Table 3. Mediators such us IFN-γ, IFN-α, IL-8, and IL-22 have been neutralized in patients without significant clinical improvement.
When studying psoriasis triggering factors from the translational point of view, perhaps the best characterized environmental factor is throat infection by β-hemolytic streptococci. As it is commented below, there is a great body of evidences that associate streptococcal infection with psoriasis flares or exacerbations in both guttate and plaque psoriasis. This can be considered a translational opportunity of studying psoriasis immune response from a different and innovative perspective.
Streptococcal pyogenesinfection and psoriasis
Throat infection by β-hemolytic streptococci has been associated with both the flare and exacerbation of psoriasis [17–19]. In guttate psoriasis, this infection precedes clinical cutaneous symptoms in 56–97% of the cases . Interestingly, chronic plaque psoriasis patients are more susceptible to throat infections by
An immunological model has been proposed to explain how an infection taking place in the throat can lead to a chronic inflammation in a distant tissue such as the skin. One interesting observation is to note that dendritic cells from tonsils and upper respiratory truck are capable of generating some skin-tropic CLA+ T cells , thus indicating that those cells can acquire antigen-specificity for microbes infecting noncutaneous sites. In this regard, streptococcal superantigens promote the expression of CLA on T cells , as well as the activation and expansion of CLA+ T cells, at least from guttate psoriasis. Guttate psoriasis is an acute form of psoriasis, which erupts as small drop-shaped papules, and is frequently associated with streptococcal throat infection. In particular, accumulation of Vβ2+ T cells in acute guttate lesions has been reported, a variable β chain expressed on T cells that are preferentially expanded through the streptococcal pyrogenic exotoxin (SPE)-C , which contained T cells with different junctional sequences in the CDR3 region, thus supporting a superantigen-driven expansion. However, as psoriasis progresses, such superantigen hypothesis does not seem to explain the presence of identical TCR rearrangements in plaque psoriasis patients, probably indicating that a stable antigen-specific T-cell response is involved for longer stages of the disease [30, 31]. Interestingly, T-cell lines isolated from psoriatic lesions have shown strong cross-reactivity to streptococcal antigens . Furthermore, restricted TCRVβ spectratypes shared by CLA+ T cells in streptococcal angina, but not by CLA− T cells, with T cells in psoriasis skin lesions supports the idea of the existence of a tonsillar source of antigen-driven T-cell expansion that then migrate to the skin . Altogether, streptococcal superantigens could facilitate at least early migration of tonsillar T cells to the skin by upregulating CLA expression and could be especially involved in guttate-type flares.
Despite the evidence of streptococcal involvement in psoriasis course, the use of antibiotics has not proven effectiveness in psoriasis . However, it might be explained by the fact that streptococci can exist in intracellular reservoirs in the tonsillar epithelia and macrophages, and that could not be affected by the use of antibiotics. Then, this quiescent load could be reactivated and cause disease symptoms again, whereas tonsillectomy, which has been associated to clinical improvement, might remove this hidden pool of streptococci [22, 37].
Other entry routes for
Streptococcus pyogenes: an innate trigger that induces IL-17 production through skin-related memory CLA+ T cells in psoriasis
Analyzing the antigen-specific immune responses with clinically relevant stimuli in responding patients allows identifying pathologic translational mechanisms of several immunologic diseases, including psoriasis. This experimental approach can be reproduced
Since the closest and clearest relationship between streptococcal infection and subsequent onset of lesions has been described for guttate-type psoriasis, the evaluation of immune responses in the context of
A second study based on this
The importance of Th17 role in initial steps of psoriasis development is also supported by other findings, such as the high levels in serum of IL-17 found in patients with early spreading guttate form . Even a bimodal immunopathology theory proposes that psoriasis is initiated by IL-1/Th17-dominated responses . In addition to the well-known association of preceding pharyngitis episode, guttate psoriasis onset is mostly confined to individuals carrying the HLA-Cw6 allele , a genetic risk factor for early psoriasis. Interestingly, when immune responses from guttate psoriasis samples were classified according with the simultaneous presence of both genetic and environmental factors, that is HLA-Cw6 allele and a prior pharyngitis episode, respectively, the Th17-associated response was higher than that exerted by samples from the other “nonpredisposed” guttate psoriatic individuals. In fact, significant higher levels of IL-17A, IL-17F, and even IL-6, which participates in Th17-differentiation, were found in those “predisposed” guttate psoriasis patients. Furthermore, the treatment of
Therapies targeting the IL-23/Th17-axis are showing the best efficacy rates in terms of percentage of patients reaching PASI improvement. The observation of rapid normalization of hundreds of psoriasis-related genes as soon as 2 weeks after the use of IL-17A or IL-17RA-blocking antibodies [53, 54] may partly explain the importance of IL-17A effects in psoriasis pathology, and why its blockade provides such impressive clinical improvement. Therefore, the characterization of IL-17-targeted transcripts that are rapidly normalized after these therapies could reveal relevant information regarding to the development of skin lesions.
In this regard, Ruiz-Romeu et al.  have taken advantage of the use of CLA+ T cell and epidermal cells activated by SE conditioned supernatants to activate normal keratinocytes and to evaluate gene expression of noncharacterized IL-17A targets. In their study, they characterize the expression of
The translational approach of developing an
The study was funded by FIS/ISCIII 2013 (Ministerio de Economía y Competitividad e Instituto de Salud Carlos III; PI09/2222, PI13/01845 and PI13/01716) and FIS/ISCIII 2016 (PI16/01573 and PI016/99532). This work was supported by European Regional Development Fund grants. E. R. R was granted by a PhD fellowship by the Ministerio de Educación, Cultura y Deporte of the Spanish Government (FPU13/02308).
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