Whole transcriptional analysis identifies markers of B, T and plasma cell signaling pathways in the mesenteric adipose tissue associated with Crohn's disease

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da Silva, Francesca Aparecida Ramos ^[1] ; Pascoal, Livia Bitencourt ^[1] ; Dotti, Isabella ^[2] ; Setsuko Ayrizono, Maria de Lourdes ^[1] ; Aguilar, Daniel ^{[2, 3]} ; Rodrigues, Bruno Lima ^[1] ; Arroyes, Montserrat ^[2] ; Ferrer-Picon, Elena ^[2] ; Milanski, Marciane ^[4] ; Velloso, Licio Augusto ^[5] ; Fagundes, Joao Jose ^[1] ; Salas, Azucena ^[2] ; Leal, Raquel Franco ^[1]

Afiliação do(s) autor(es)

^[1] Univ Campinas UNICAMP, Sch Med Sci, IBD Res Lab, Colorectal Surg Unit, Dept Surg, Carlos Chagas St 420, Cidade Univ Zeferino Vaz, BR-13083878 Sao Paulo - Brazil

^[2] Hosp Clin Barcelona, Dept Gastroenterol, IDIBAPS, Barcelona - Spain

^[3] Biomed Res Networking Ctr Hepat & Digest Dis CIBE, Barcelona - Spain

^[4] Univ Campinas UNICAMP, Lab Metab Disorders, Sch Appl Sci, Sao Paulo - Brazil

^[5] Univ Campinas UNICAMP, Lab Cell Signaling, Sch Med Sci, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF TRANSLATIONAL MEDICINE; v. 18, n. 1 JAN 30 2020.
• Citações Web of Science: 0

Resumo

Background Crohn's disease (CD) is a multifactorial disease characterized by chronic intestinal inflammation. The increased visceral adiposity near the affected intestinal area, of which mesenteric adipose tissue (MAT) is the main component, is a feature of CD. Both protective and pathological roles have been attributed to this disease-associated tissue in CD. To understand the contribution of MAT to CD pathophysiology, a molecular and cellular signature of disease-associated MAT in CD patients was provided. Methods We performed an observational study with whole transcriptional analysis by RNA sequencing (RNA-seq) of MAT and ileal mucosa from CD patients with active disease and controls. qPCR and immunohistology were performed for validation analysis. Results RNA-seq identified 17 significantly regulated genes (|FC| > 1.5; FDR < 0.05) in CD-MAT compared to non-IBD controls, with a marked upregulation of plasma cell genes (i.e., IGLL5, MZB1, CD79A, POU2AF1, FCRL5, JCHAIN, DERL3, SDC1, PIM2). A less strict statistical cutoff value (|FC| > 1.5, nominal p <= 0.05) yielded a larger list of 651 genes in CD-MAT compared to controls. CD ileum showed the significant regulation compared to control ileum of 849 genes (|FC| > 1.5; FDR < 0.05) or 2654 genes (|FC| > 1.5, nominal p <= 0.05). Ingenuity Pathway Analysis revealed the significant regulation of pathways related to T- and B cell functionality in the MAT of CD patients. Despite the differences between the MAT and ileal signatures of CD patients, we identified a subset of 204 genes significantly modulated in both tissues compared to controls. This common signature included genes related to the plasma cell signature. Genes such as S100A8, S100A9 (calprotectin) and IL1B, which are associated with acute inflammatory response, were exclusively regulated in the ileal mucosa of CD disease. In contrast, some genes encoding for lymphocyte receptors such as MS4A1, CD3D and CD79A were exclusively regulated in CD-MAT, exhibiting a different pattern of immune cell activation compared to the ileal mucosa in CD patients. qPCR and immunohistology confirmed the presence of large infiltrates of CD3(+) CD20(+) lymphocytes and CD138(+) plasma cells in CD-MAT. Conclusion Our data strongly supports the role of CD-associated MAT as a site for T-, B- and plasma cell activation, and suggests that it could also act as a reservoir of memory immune responses. (AU)

• Processo FAPESP: 16/01638-7 - Análise transcricional de mucosa intestinal e tecido adiposo mesenterial de pacientes com doença de Crohn
• Beneficiário: Raquel Franco Leal
• Modalidade de apoio: Auxílio à Pesquisa - Regular