Obiekt
Tytuł: The expression of type 7,8,9 Toll-like receptors (TLR-7,8,9) in skin biopsies in patients with skin lesions in the course of lupus erythematosus (SCLE/DLE) and their importance in predicting the clinical response to hydroxychloroquine treatment
Abstrakt:
Introduction: Cutaneous lupus erythematosus (CLE) is a group of clinically diverse autoimmune diseases, primarily affecting the skin and mucosa, with complex and not fully understood pathogenetic mechanisms. Toll-like receptors (TLRs) belong to the main class of pattern recognition receptors (PRRs) of the innate immune response. They are involved in recognition of pathogenic microorganisms. In addition, Toll-like receptors initiate intracellular signaling cascades leading, inter alia, to translocation of the nuclear NF-κB molecule, which is a key transcription factor promoting the expression of genes encoding immune response molecules. Hydroxychloroquine is the first line of treatment for cutaneous lupus erythematosus (SCLE and DLE) when topical therapy is insufficient. However, not all patients achieve clinical remission of skin lesions. One of the postulated mechanisms of action of antimalarial drugs is inhibition of signaling pathways dependent on type 7 and 9 endosomal TLRs. Moreover, current scientific reports show the role of type 7, 8 and 9 TLRs in the pathogenesis of systemic lupus erythematosus. Their function in the development of cutaneous lupus erythematosus is not fully explained and is currently under investigation. Taking into account the above reports, the analysis of TLR receptor expression in skin biopsies in patients with subacute and discoid forms of lupus ; erythematosus was undertaken. Aims: a. Assessment of strength of type 7, 8 and 9 TLRs expression in the epidermis and within lymphocytes of the inflammatory infiltrate, expressed on a 3-point scale. b. Assessment of thickness of the epidermis and thickness of the epithelial part of hair follicles with a positive immunohistochemical reaction for type 7, 8, 9 TLRs. c. Assessment of the percentage of lymphocytes with a positive immunohistochemical reaction for TLRs 7, 8, 9. d. Analysis of a correlation between the level of expression of type 7, 8, 9 Toll-like receptors and the response to treatment with hydroxychloroquine, measured by the percentage reduction in CLASI index. e. Analysis of a correlation between the degree of disease severity assessed in the CLASI scale and selected laboratory and clinical parameters. Methods: Sixty-six patients with cutaneous lupus erythematosus (SCLE and DLE) who are patients of the Dermatology Clinic of the University Hospital in Krakow were enrolled. The control group was consisted of 4 healthy individuals from whom a biopsy of healthy skin, not exposed to UV radiation, was collected from the buttock area. Each patient enrolled in the study had a skin biopsy prior to the initiation of systemic immunomodulatory and immunosuppressive therapy, including hydroxychloroquine therapy. Then, expression of type 7, 8, 9 TLRs in skin biopsies in th ; e study and control group was determined using immunohistochemical methods. In addition, severity of skin lesions was also assessed using the CLASI scale in the study group, before the initiation of systemic immunomodulating and immunosuppressive therapy and after the 3-6-month treatment period. The analysis of correlation between the expression level of type 7, 8, 9 Toll-like receptors and the response to hydroxychloroquine treatment, measured by a percentage decrease in the CLASI index after 3-6 months of treatment, was performed. Correlation between severity of the disease, measured with the CLASI index before the initiation of systemic immunomodulating and immunosuppressive treatment, and selected parameters in the study group were also evaluated. Results: Patients with a higher CLASI index significantly more often presented symptoms in the form of: arthralgia in the hands and feet and/or knees and/or elbows, lymphopenia and anemia of chronic diseases. A relationship between the disease severity index assessed on the CLASI scale and the presence of thrombocytopenia in patients with CLE was at the border of statistical significance. There was no evidence of type 7 TLR expression in the epidermis in patients with CLE and in the control group. Skin biopsies of both healthy skin and CLE lesions were characterized by expression of type 8 and 9 TLRs in the epidermis, epithelial ; part of hair follicles and expression of type 7, 8 and 9 TLRs in the lymphocytic infiltrate in the dermis. Patients with CLE showed statistically significantly lower strength of expression of type 9 TLR in the epidermis, lesser thickness of the epidermis with positive expression of type 8, 9 TLRs, and a lower average percentage of lymphocytes with positive expression of type 8, 9 TLRs compared to the control group. Moreover, patients with SCLE showed significantly higher expression of type 8 TLR in the epidermis compared to patients with DLE. On the other hand, in patients with DLE, a significantly higher expression of type 9 TLR in the epidermis and epithelial part of hair follicles was observed compared to patients with SCLE. The strength of type 9 TLR expression in lymphocytes in patients with subacute and discoid lupus erythematosus correlated with the response to treatment with hydroxychloroquine and the percentage reduction in CLASI index after treatment. Patients with the best response to treatment (decrease in CLASI after treatment above 80%) showed the highest level of type 9 TLR expression in lymphocytes (grade 3 on a 0-3 scale). Moreover, patients whose dose of hydroxychloroquine was up-titrated to 400 mg, due to an insufficient response to treatment with hydroxychloroquine at the dose of 200 mg, presented significantly lower expression of type 9 TLRs in the epider ; mis (characterized by a smaller thickness of the epidermis with positive expression of type 9 TLRs) and a lower average percentage of lymphocytes with positive TLR9 expression compared to other patients treated with 200 mg hydroxychloroquine. Conclusions: Our investigation justifies the recommendation for evaluating skin lesions in CLE patients using CLASI index in wide clinical practice. In case of a high CLASI score we can preliminarily identify patients with possible extracutaneous involvement. In our research work, the expression of type 7 TLR in the epidermis of CLE patients, as well as in healthy skin, was not determined. This may indicate that type 7 TLR may not play an important role in CLE development. In turn, lower expression of type 8 and 9 TLR in the epidermis, in the lymphocytic infiltrate in the dermis and lower expression of type 9 TLR in epithelial part of hair follicles in CLE patients, compared to healthy skin, positively affect the development of this disease. Our results are consistent with the SLE studies on animal and in vitro models, in which high expressions of type 8 and 9 TLR play a protective role in the development of this disease. Lower expression of type 8 and 9 TLRs in the epidermis and a lower percentage of lymphocytes in the dermis with positive expression of type 8 and 9 TLRs in skin biopsies in CLE patients may constitute an unfavorable fa ; ctor in terms of disease activity. The effectiveness of hydroxychloroquine treatment depends on expression of type 9 TLR. Higher strength of expression of type 9 TLRs in the lymphocytic infiltrate in skin biopsies of CLE patients is associated with a better response to hydroxychloroquine treatment, as measured by a percentage reduction in CLASI index. Higher type 9 TLR expression in the epidermis and a higher percentage of lymphocytes with positive type 9 TLR expression in the dermis are associated with a lower dose of hydroxychloroquine necessary for clinical remission.
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Rada Dyscypliny Nauki medyczne
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7 maj 2024
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6 lut 2024
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| Nazwa wydania | Data |
|---|---|
| ZB-136749 | 7 maj 2024 |
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