Murillo Duarte-Silva

Although perianal Crohn’s disease (PCD) is highly associated with the exacerbated inflammation, the molecular basis and immunological signature that distinguish patients who present a history of perianal lesions are still unclear. This paper aims to define immunological characteristics related to PCD. In this cross-sectional observational study, we enrolled 20 healthy controls and 39 CD patients. Blood samples were obtained for the detection of plasma cytokines and lipopolysaccharides (LPS). Peripheral blood mononuclear cells (PBMCs) were phenotyped by flow cytometry. Leukocytes were stimulated with LPS or anti-CD3/anti-CD28 antibodies. Our results show that CD patients had augmented plasma interleukin (IL)-6 and LPS. However, their PBMC was characterized by decreased IL-6 production, while patients with a history of PCD produced higher IL-6, IL-8, and interferon-γ, along with decreased tumor necrosis factor alpha (TNF). CD patients had augmented FoxP3 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulatory markers, though the PCD subjects presented a significant reduction in CTLA-4 expression. CTLA-4 as well as IL-6 and TNF responses were able to distinguish the PCD patients from those who did not present perianal complications. In conclusion, IL-6, TNF, and CTLA-4 exhibit a distinct expression pattern in CD patients with a history of PCD, regardless of disease activity. These findings clarify some mechanisms involved in the development of the perianal manifestations and may have a great impact on the disease management.

Background: Adequate management of COVID-19 needs data that predict its outcomes in men and explain its sexual dimorphism. This study evaluated immunoendocrine mediators, gene expression profiles and their correlations in a large cohort of controls and COVID-19 patients with different clinical presentations. Methods: Analyses of a public databank confirmed the sex bias for unfavorable clinical outcomes in Brazilian men infected with SARS-CoV-2. A local cohort was then assessed for clinical outcomes and levels of steroids and immune mediators. This data and global gene expression profiles of blood leukocytes were correlated. Statistical analyses considered confounding factors in order to parse the role of androgens in COVID-19. Findings: In men infected with SARS-CoV-2, levels of inflammation mediators presented significant negative correlations with levels of testosterone, which were partially dependent of age and diabetes, comorbidities related to severe COVID-19. The androgen receptor signaling pathway was significantly upregulated in men presenting with severe COVID-19, including expression of TMPRSS2 and SRD5A1 genes, the products whereof provide for virus entrance and dihydrotestosterone production, respectively. Levels of dihydrotestosterone were significantly and positively associated with relative risk of death; in contrast, levels of testosterone were significantly and positively associated with protection against severe COVID-19. This study also identified combined sets of immune-endocrine parameters that predict progression from non-severe to severe COVID-19 in men. Interpretation: The data points to venues of investigation to determine mechanisms dictating outcomes of COVID-19 in men. Sex-specific management of disease, vaccination and sequelae should be considered when establishing measures to control the COVID-19 pandemic. Funding Information: This work was supported by The São Paulo Research Foundation (Fundação de Amparo à Pesquisa do Estado de São Paulo, FAPESP), under grants #2020/05207-6 for L.H.F., #2020/05270-0 for V.D.B and #2021/04590-3 for C.A.S. This study also had the financial support from National Council for Scientific and Technological Development (CNPq), #302514/2015-5-CNPq for L.H.F.; #303259/2020-5-CNPq for M.D.B. and #309583/2019-5-CNPq for C.R.B.C.; and from the Coordination for the Improvement of Higher Educational Personnel (CAPES-Finance Code 001), as well as Pró-Reitoria de Pesquisa da Universidade de São Paulo, grant-USP-VIDA. Declaration of Interests: All the authors declare no competing interests. Ethics Approval Statement: The study protocols were in accordance with the Brazilian national committee of ethics in research (CONEP), under code CAAE: 30525920∙7∙0000∙5403. Informed consent was obtained from the enrolled participants, as approved by CONEP.