Notch Signaling Pathway Expression in the Skin of Leprosy Patients: Association With Skin and Neural Damage

Abstract

Introduction: Leprosy is an infectious disease caused by Mycobacterium leprae, a debilitating disease that affects the skin and peripheral nerves. It is possible that tissue changes during infection with leprosy are related to alterations in the activity of the Notch signaling pathway, an innate signaling pathway in the physiology of the skin and peripheral nerves. Methods: This is a descriptive observational study. Thirty skin biopsies from leprosy patients and 15 from individuals with no history of this disease were evaluated. In these samples, gene expressions of cellular components associated with the Notch signaling pathway, Hes-1, Hey-1, Runx-1 Jagged-1, Notch-1, and Numb, were evaluated using q-PCR, and protein expression was evaluated using immunohistochemistry of Runx-1 and Hes-1. Results: Changes were observed in the transcription of Notch signaling pathway components; Hes-1 was downregulated and Runx-1 upregulated in the skin of infected patients. These results were confirmed by immunohistochemistry, where reduction of Hes-1 expression was found in the epidermis, eccrine glands, and hair follicles. Increased expression of Runx-1 was found in inflammatory cells in the dermis of infected patients; however, it is not related to tissue changes. With these results, a multivariate analysis was performed to determine the causes of transcription factor Hes-1 reduction. It was concluded that tissue inflammation was the main cause. Conclusions: The tissue changes found in the skin of infected patients could be associated with a reduction in the expression of Hes-1, a situation that would promote the survival and proliferation of M. leprae in this tissue.

Transcription Factor HES-1: How Is the Expression of This Transcriptional Factor in Paucibacillary Leprosy Patients?

“…Likewise, this finding is consistent and similar to the one reported by our research group on dermal nerves from MB leprosy patients. 5 The IHC results determined that HES-1 could have an efficiency comparable to that of S-100 as an auxiliary immunomarker in diagnosing MB leprosy. However, in PB forms, we observed that HES-1 had a lower sensitivity (66.7%) than S-100 (100%), even though this transcriptional factor is 100% specific in PB and MB leprosy.…”

“…5 Besides, this cell dedifferentiation would alter the keratinocytes' innate and adaptative immune response, affecting the antigenic presentation and the differentiation of CD4 + LT toward a Th1 and Th17 pattern. 5 Furthermore, in the eccrine and hair follicle cells, reducing HES-1 would alter the stem cell activity of these cutaneous annexes. 5 Conversely, we propose that these changes in HES-1 expression in PB and MB forms could be explained by a common inflammatory component in all clinical forms of leprosy, possibly related to alterations in the glycosylation of Notch receptors and their interaction mainly with Jagged-type ligands, 5,11 which would reduce the expression of HES-1 in the epidermis and skin appendages of these patients.…”

“…5 Furthermore, in the eccrine and hair follicle cells, reducing HES-1 would alter the stem cell activity of these cutaneous annexes. 5 Conversely, we propose that these changes in HES-1 expression in PB and MB forms could be explained by a common inflammatory component in all clinical forms of leprosy, possibly related to alterations in the glycosylation of Notch receptors and their interaction mainly with Jagged-type ligands, 5,11 which would reduce the expression of HES-1 in the epidermis and skin appendages of these patients. Furthermore, this biological hypothesis became more plausible when we observed that 3 of the 4 patients with indeterminate leprosy did not show relevant changes in the expression of HES-1 at these cutaneous structures.…”

“…Moreover, the visualization of HES-1 in the cutaneous structures, where it is expressed is simple and does not require great expertise from the evaluator. 5,15 Conversely, identifying cutaneous nerves requires more expertise from the evaluator, even using S-100 IHC. Specifically, 1 of our criticisms of S-100, as exposed in our previous study, 8 is that the nonvisualization of the nerve fiber in the dermal nerve is usually interpreted as a pathognomonic diagnostic sign of this disease.…”

“…Conversely, the staining of skin nerve fibers marked with anti-S-100 was classified using the pathological patterns described in Table 1S http://links.lww.com/AJDP/A128 (Supplementary material). 5,8…”