Leukocyte Dysfunction and reduced CTLA-4 Expression are Associated with Perianal Crohn's Disease

Murillo Duarte-Silva; Rogério Serafim Parra; Marley Ribeiro Feitosa; Viviani Nardini; Sandra Regina Maruyama; José Joaquim Ribeiro da Rocha; Omar Feres; Cristina Ribeiro de Barros Cardoso

doi:10.1093/cei/uxae027

Leukocyte Dysfunction and reduced CTLA-4 Expression are Associated with Perianal Crohn's Disease

Clin Exp Immunol. 2024 Mar 22:uxae027. doi: 10.1093/cei/uxae027. Online ahead of print.

Authors

Murillo Duarte-Silva^{1

2}, Rogério Serafim Parra³, Marley Ribeiro Feitosa³, Viviani Nardini², Sandra Regina Maruyama⁴, José Joaquim Ribeiro da Rocha³, Omar Feres³, Cristina Ribeiro de Barros Cardoso⁴

Affiliations

¹ Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
² Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
³ Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
⁴ Department of Genetics and Evolution, Federal University of São Carlos, São Carlos - SP, Brazil.

PMID: 38517030
DOI: 10.1093/cei/uxae027

Abstract

Although perianal Crohn's disease (PCD) is highly associated with the exacerbated inflammation, the molecular basis and immunological signature that distinguish patients who present 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 detection of plasma cytokines and LPS. PBMC 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 IL-6 and LPS. However, their PBMC was characterized by decreased IL-6 production, while patients with history of PCD produced higher IL-6, IL-8 and IFN-γ, along with decreased TNF. CD patients had augmented FoxP3 and 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 in the disease management.

Keywords: CTLA-4; Crohn’s disease; Inflammatory bowel disease; Interleukin-6; Perianal disease.