Toll-like receptor patterns in epidermodysplasia verruciformis-associated squamous cell carcinomas Cibele C A Pereira, Luis Alberto R Fróes, Lana Luiza C Silva, Maira G Saldanha, Naiura V Pereira, et al. Clinical and Experimental Dermatology, 2026 Background Epidermodysplasia verruciformis (EV) is a rare genetic condition characterized by viral warts and an increased risk of squamous cell carcinoma (SCC). It is particularly associated with specific human papillomavirus (HPV) types, notably β-HPV variants 5 and 8. Toll-like receptors (TLRs) are crucial for immune response regulation and may contribute to cancer development in EV. Objectives To assess the expression levels of TLR3, -4, -5 and -9 in SCC samples from patients with EV vs. those without EV to understand their potential roles in EV-related carcinogenesis. Methods We examined tumour samples from 18 patients with EV alongside samples from 90 participants without EV. Techniques included tissue microarray analysis and conventional histological evaluation, with immunohistochemistry performed to detect TLR expression. Controls were included to validate the specificity of the results, and statistical analyses employed the Kruskal–Wallis test with Dunn–Bonferroni post hoc comparisons. Results TLR3, -4, -5 and -9 were detected in both patient groups, with distinct expression patterns. TLR3 levels were higher in the healthy skin of patients with EV, while TLR9 was more prominent in tumours. In patients without EV, TLR3 and TLR4 expression varied with tumour stages. Invasive SCC showed increased TLR5 and TLR9 levels. EV samples showed significantly higher TLR4 and TLR9 expression than non-EV samples. Conclusions The differing TLR expression patterns indicate diverse immune mechanisms involved in EV-related carcinogenesis. This suggests that TLRs could be potential therapeutic targets, meriting further investigation into their roles in tumour growth regulation.
Reduced TLR3 and TLR9 Expression in Epidermodysplasia Verruciformis: Evidence From a Comparative Skin Study Luis Alberto Ribeiro Fróes, Cibele Conceição dos Apóstolos Pereira, Lana Luiza da Cruz Silva, Naiura Vieira Pereira, Walmar Roncalli Pereira de Oliveira, et al. Journal of Medical Virology, 2025 Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by lifelong β‐human papillomavirus (β‐HPV) persistence, extensive flat warts, and increased risk of cutaneous squamous cell carcinoma. While TMC6, TMC8, and CIB1 mutations are recognized as genetic drivers, innate immune mechanisms contributing to HPV persistence remain incompletely defined. This study quantified the expression of Toll‐like receptors (TLRs) 3, 4, 5, and 9 in normal skin and flat warts from patients with EV and immunocompetent individuals without EV (NEV). We performed immunohistochemical analysis on 135 formalin‐fixed, paraffin‐embedded specimens using standardized digital morphometry of epidermal keratinocytes. EV patients exhibited significantly reduced TLR3 and TLR9 expression in both normal skin and flat warts relative to controls, whereas TLR4 and TLR5 levels were comparable. Notably, flat warts from NEV individuals showed marked TLR3 upregulation relative to matched normal skin, whereas this response was absent in EV patients. These findings are consistent with an EV‐associated epithelial innate‐sensing phenotype. Our data suggest innate immune deficiencies may interact with previously described keratinocyte abnormalities, amplifying local immune dysfunction. These findings provide a framework for investigating TLR‐based therapeutic approaches in EV.
Leprosy in the 21st century: a comprehensive review of immunological mechanisms, diagnosis, and treatment Luis Alberto Ribeiro Froes Junior, Mirian Nacagami Sotto, Maria Angela Bianconcini Trindade Revista do Instituto De Medicina Tropical De Sao Paulo, 2025 Leprosy remains a significant public health challenge, with approximately 182,815 new cases annually. This review synthesizes current knowledge on pathogenesis, diagnosis, and treatment, emphasizing recent advances. We discuss the immunological spectrum, ranging from Th1-dominant tuberculoid forms to Th2/regulatory-dominant lepromatous forms, and highlight the roles of B-lymphocyte, inflammasome activation, and Schwann cell antigen presentation in granuloma formation and neural damage. Leprosy reactions—type 1 and 2—arise from distinct immunopathological mechanisms triggered by various factors, with emerging evidence pointing to the involvement of Th17 and regulatory B cells. Diagnostic advances include molecular techniques, nerve ultrasonography, monofilament testing, and serological assays that complement traditional approaches. Treatment is based on multidrug therapy, with country-specific adaptations such as Brazil’s PQT-U, although challenges with adherence and resistance persist. Alternative regimens may include minocycline, clarithromycin, and fluoroquinolones, with bedaquiline showing promising results. Prophylactic strategies include BCG vaccination and the debated use of single-dose rifampicin for contacts. Management of reactional states employs corticosteroids, thalidomide, with biologics and JAK inhibitors reserved for refractory cases. Genetic and epigenetic factors, including TLR polymorphisms and HLA variants, influence susceptibility and outcomes. Despite recent progress, delayed detection, stigma, and inadequate follow-up remain barriers. Comprehensive approaches integrating early diagnosis, active case finding, chemoprophylaxis, stigma reduction, and rehabilitation are essential. The elimination of leprosy requires sustained commitment, improved resource access, and ongoing research into host-pathogen interactions. This review offers clinicians and researchers an updated understanding to support global control strategies.
Bacterial, fungal and parasitic co-infections in leprosy: A scoping review Luis Alberto Ribeiro Fróes, Tereza Setsuko Toma, Marie Jachiet, Laurie Rousset, Rosana Evangelista Poderoso, et al. Plos Neglected Tropical Diseases, 2023 BackgroundIn leprosy patients, the most commonly reported non-viral co-infections are Tuberculosis, Leishmaniasis, Chromoblastomycosis and Helminths. The presence of a secondary infection is believed to increase the likelihood of leprosy reactions. The purpose of this review was to describe the clinical and epidemiological characteristics of the most reported bacterial, fungal, and parasitic co-infections in leprosy.Methodology/Principal findingsFollowing the PRISMA Extension for Scoping Reviews guidelines, a systematic literature search was conducted by two independent reviewers, resulting in the inclusion of 89 studies. For tuberculosis, a total of 211 cases were identified, with a median age of 36 years and male predominance (82%). Leprosy was the initial infection in 89% of cases, 82% of individuals had multibacillary disease, and 17% developed leprosy reactions. For leishmaniasis, 464 cases were identified, with a median age of 44 years and male predominance (83%). Leprosy was the initial infection in 44% of cases, 76% of individuals presented with multibacillary disease, and 18% developed leprosy reactions. Regarding chromoblastomycosis, we identified 19 cases with a median age of 54 years and male predominance (88%). Leprosy was the primary infection in 66% of cases, 70% of individuals had multibacillary disease, and 35% developed leprosy reactions. Additionally, we found 151 cases of co-infection with leprosy and helminths, with a median age of 43 years and male predominance (68%). Leprosy was the primary infection in 66% of cases, and 76% of individuals presented with multibacillary disease, while the occurrence of leprosy reactions varied from 37% to 81% across studies.ConclusionWe observed a male-dominated pattern of co-infections among working-age individuals with multibacillary leprosy. Unlike prior studies reporting increased leprosy reactions in chronic viral co-infections, our findings did not indicate any increase among bacterial, fungal, or parasitic co-infections. Rather, co-infections with tuberculosis and leishmaniasis appeared to reduce leprosy reactions.
Viral co-infections in leprosy: a scoping review Luis Alberto Ribeiro Fróes, Tereza Setsuko Toma, Rosana Evangelista Poderoso, Maria Ângela Bianconcini Trindade International Journal of Dermatology, 2023 ContextThe most reported viral co‐infections in leprosy are human immunodeficiency virus (HIV), human T‐cell lymphotropic virus (HTLV), hepatitis B virus (HBV), hepatitis C virus (HCV), and SARS‐CoV‐2. In co‐infections, the burden of an agent can be increased or decreased by the presence of others. To address this issue, we need to fully understand their prevalence, risk factors, immunology, clinical manifestations, and treatment. The purpose of this scoping review is to describe the clinical and epidemiological characteristics of the most reported viral co‐infections in leprosy to inform clinicians and guide future research.MethodsThe authors conducted a literature search of five databases for articles on each of the aforementioned co‐infections published prior to October 2022. Two independent reviewers conducted the selection process and identified 53 papers meeting the study inclusion criteria. The data extraction process and evidence synthesis were conducted by one reviewer and double‐checked by a second one, consistent with best practice recommendations for scoping reviews.ResultsFor all assessed viruses, most studies reported prevalence rates in leprosy patients higher than the general population. Studies found that HTLV, HBV, and HCV chronic infections were highest in multibacillary leprosy, whereas HIV was mostly found in paucibacillary leprosy, and SARS‐Cov‐2 affected leprosy subtypes equally. Overall, co‐infections were also associated with higher rates of leprosy reactions, except for COVID‐19. Forty‐six percent of the studies discussed issues related to treatment, which led to favorable outcomes for the most part.ConclusionsThis review summarizes the existing literature on viral co‐infections in leprosy patients, generating valuable insights and recommending areas for future research.
Immunology of leprosy Luis Alberto Ribeiro Froes, Maria Angela Bianconcini Trindade, Mirian Nacagami Sotto International Reviews of Immunology, 2022
Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families John Charles A. Lacson, Shawn A. Zamani, Luis Alberto Ribeiro Froes, Nandita Mitra, Lu Qian, et al. BMC Public Health, 2021 Background Individuals from melanoma-prone families have similar or reduced sun-protective behaviors compared to the general population. Studies on trends in sun-related behaviors have been temporally and geographically limited. Methods Individuals from an international consortium of melanoma-prone families (GenoMEL) were retrospectively asked about sunscreen use, sun exposure (time spent outside), sunburns, and sunbed use at several timepoints over their lifetime. Generalized linear mixed models were used to examine the association between these outcomes and birth cohort defined by decade spans, after adjusting for covariates. Results A total of 2407 participants from 547 families across 17 centers were analyzed. Sunscreen use increased across subsequent birth cohorts, and although the likelihood of sunburns increased until the 1950s birth cohort, it decreased thereafter. Average sun exposure did not change across the birth cohorts, and the likelihood of sunbed use increased in more recent birth cohorts. We generally did not find any differences in sun-related behavior when comparing melanoma cases to non-cases. Melanoma cases had increased sunscreen use, decreased sun exposure, and decreased odds of sunburn and sunbed use after melanoma diagnosis compared to before diagnosis. Conclusions Although sunscreen use has increased and the likelihood of sunburns has decreased in more recent birth cohorts, individuals in melanoma-prone families have not reduced their overall sun exposure and had an increased likelihood of sunbed use in more recent birth cohorts. These observations demonstrate partial improvements in melanoma prevention and suggest that additional intervention strategies may be needed to achieve optimal sun-protective behavior in melanoma-prone families.
RECENT SCHOLAR PUBLICATIONS
Avaliação da qualidade de vida em pacientes com vitiligo: estudo transversal NMN Simões, GC Franciscatti, LAR Froes Junior, MV Quaresma Anais Brasileiros de Dermatologia (Portuguese) 101 (2) , 2026 2026.0
Exames laboratoriais e avaliação funcional na hanseníase: indicações e interpretação na prática clínica LAR Fróes Júnior, MN Sotto, J Avancini, JA Garbino, MÂB Trindade Anais Brasileiros de Dermatologia 101 (2) , 2026 2026.0
Quality of life assessment in vitiligo patients: a cross-sectional study NMN Simões, GC Franciscatti, LARF Junior, MV Quaresma Anais Brasileiros de Dermatologia 101 (2), 501305 , 2026 2026.0
Laboratory and functional tests in leprosy diagnosis: a practical guide for clinical decision-making LARF Júnior, MN Sotto, JA Garbino, J Avancini, MÂB Trindade Anais Brasileiros de Dermatologia 101 (2), 501297 , 2026 2026.0
Toll-like receptor patterns in epidermodysplasia verruciformis-associated squamous cell carcinomas CCA Pereira, LAR Fróes Jr, LLC Silva, MG Saldanha, NV Pereira, ... Clinical and Experimental Dermatology 51 (3), 393-400 , 2026 2026.0
Leprosy in the 21 st century: a comprehensive review of immunological mechanisms, diagnosis, and treatment LAR Froes, MN Sotto, MAB Trindade Revista do Instituto de Medicina Tropical de São Paulo 67, e74 , 2025 2025.0 Citations: 3
Reduced TLR3 and TLR9 Expression in Epidermodysplasia Verruciformis: Evidence From a Comparative Skin Study LAR Fróes Jr, CCA Pereira, LLC Silva, NV Pereira, WRP de Oliveira, ... Journal of Medical Virology 97 (11), e70696 , 2025 2025.0
B-cell subsets in leprosy lesions: unraveling the complex interplay LARF Junior, C Pagliari, MAB Trindade, MN Sotto Anais Brasileiros de Dermatologia 100 (5), 501184 , 2025 2025.0 Citations: 2
Subpopulações de células B em lesões de hanseníase: desvendando a complexa interação LAR Fróes Junior, C Pagliari, MAB Trindade, MN Sotto Anais Brasileiros de Dermatologia 100 (5) , 2025 2025.0
Subconjuntos de linfócitos B nas lesões cutâneas da hanseníase tuberculoide, indeterminada, virchowiana e estados reacionais LAR Froes Junior, MN Sotto, MÂB Trindade 2024.0
Bacterial, fungal and parasitic co-infections in leprosy: A scoping review LAR Fróes Jr, TS Toma, M Jachiet, L Rousset, RE Poderoso, ... PLoS Neglected Tropical Diseases 17 (5), e0011334 , 2023 2023.0 Citations: 23
Viral co‐infections in leprosy: a scoping review LAR Fróes Jr, TS Toma, RE Poderoso, MÂB Trindade International Journal of Dermatology 62 (4), 547-557 , 2023 2023.0 Citations: 8
Hanseníase: características clínicas e imunopatológicas LAR Froes Junior, MN Sotto, MAB Trindade Anais Brasileiros de Dermatologia (Portuguese) 97 (3), 338-347 , 2022 2022.0 Citations: 20
Leprosy: clinical and immunopathological characteristics LARF Junior, MN Sotto, MAB Trindade Anais brasileiros de dermatologia 97 (3), 338-347 , 2022 2022.0 Citations: 142
Immunology of leprosy LAR Froes Jr, MAB Trindade, MN Sotto International Reviews of Immunology 41 (2), 72-83 , 2022 2022.0 Citations: 56
Anais Brasileiros de LARF Junior, MN Sotto, MAB Trindade Anais Brasileiros de Dermatologia 97 (3) , 2022 2022.0
Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families JCA Lacson, SA Zamani, LAR Froes Jr, N Mitra, L Qian, SH Doyle, E Azizi, ... BMC Public Health 21 (1), 692 , 2021 2021.0 Citations: 9
Protocolo: Coinfecções virais em pessoas com hanseníase: uma revisão de escopo LARF Júnior, TS Toma, RE Poderoso, MÂB Trindade
MOST CITED SCHOLAR PUBLICATIONS
Leprosy: clinical and immunopathological characteristics LARF Junior, MN Sotto, MAB Trindade Anais brasileiros de dermatologia 97 (3), 338-347 , 2022 2022.0 Citations: 142
Immunology of leprosy LAR Froes Jr, MAB Trindade, MN Sotto International Reviews of Immunology 41 (2), 72-83 , 2022 2022.0 Citations: 56
Bacterial, fungal and parasitic co-infections in leprosy: A scoping review LAR Fróes Jr, TS Toma, M Jachiet, L Rousset, RE Poderoso, ... PLoS Neglected Tropical Diseases 17 (5), e0011334 , 2023 2023.0 Citations: 23
Hanseníase: características clínicas e imunopatológicas LAR Froes Junior, MN Sotto, MAB Trindade Anais Brasileiros de Dermatologia (Portuguese) 97 (3), 338-347 , 2022 2022.0 Citations: 20
Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families JCA Lacson, SA Zamani, LAR Froes Jr, N Mitra, L Qian, SH Doyle, E Azizi, ... BMC Public Health 21 (1), 692 , 2021 2021.0 Citations: 9
Viral co‐infections in leprosy: a scoping review LAR Fróes Jr, TS Toma, RE Poderoso, MÂB Trindade International Journal of Dermatology 62 (4), 547-557 , 2023 2023.0 Citations: 8
Leprosy in the 21 st century: a comprehensive review of immunological mechanisms, diagnosis, and treatment LAR Froes, MN Sotto, MAB Trindade Revista do Instituto de Medicina Tropical de São Paulo 67, e74 , 2025 2025.0 Citations: 3
B-cell subsets in leprosy lesions: unraveling the complex interplay LARF Junior, C Pagliari, MAB Trindade, MN Sotto Anais Brasileiros de Dermatologia 100 (5), 501184 , 2025 2025.0 Citations: 2
Avaliação da qualidade de vida em pacientes com vitiligo: estudo transversal NMN Simões, GC Franciscatti, LAR Froes Junior, MV Quaresma Anais Brasileiros de Dermatologia (Portuguese) 101 (2) , 2026 2026.0
Exames laboratoriais e avaliação funcional na hanseníase: indicações e interpretação na prática clínica LAR Fróes Júnior, MN Sotto, J Avancini, JA Garbino, MÂB Trindade Anais Brasileiros de Dermatologia 101 (2) , 2026 2026.0
Quality of life assessment in vitiligo patients: a cross-sectional study NMN Simões, GC Franciscatti, LARF Junior, MV Quaresma Anais Brasileiros de Dermatologia 101 (2), 501305 , 2026 2026.0
Laboratory and functional tests in leprosy diagnosis: a practical guide for clinical decision-making LARF Júnior, MN Sotto, JA Garbino, J Avancini, MÂB Trindade Anais Brasileiros de Dermatologia 101 (2), 501297 , 2026 2026.0
Toll-like receptor patterns in epidermodysplasia verruciformis-associated squamous cell carcinomas CCA Pereira, LAR Fróes Jr, LLC Silva, MG Saldanha, NV Pereira, ... Clinical and Experimental Dermatology 51 (3), 393-400 , 2026 2026.0
Reduced TLR3 and TLR9 Expression in Epidermodysplasia Verruciformis: Evidence From a Comparative Skin Study LAR Fróes Jr, CCA Pereira, LLC Silva, NV Pereira, WRP de Oliveira, ... Journal of Medical Virology 97 (11), e70696 , 2025 2025.0
Subpopulações de células B em lesões de hanseníase: desvendando a complexa interação LAR Fróes Junior, C Pagliari, MAB Trindade, MN Sotto Anais Brasileiros de Dermatologia 100 (5) , 2025 2025.0
Subconjuntos de linfócitos B nas lesões cutâneas da hanseníase tuberculoide, indeterminada, virchowiana e estados reacionais LAR Froes Junior, MN Sotto, MÂB Trindade 2024.0
Anais Brasileiros de LARF Junior, MN Sotto, MAB Trindade Anais Brasileiros de Dermatologia 97 (3) , 2022 2022.0
Protocolo: Coinfecções virais em pessoas com hanseníase: uma revisão de escopo LARF Júnior, TS Toma, RE Poderoso, MÂB Trindade
