TIM-1 defines a human regulatory B cell population that is altered in frequency and function in systemic sclerosis patients

• Published in: Arthritis research & therapy Vol. 19; no. 1; p. 8
• Main Authors: Aravena, Octavio, Ferrier, Ashley, Menon, Madhvi, Mauri, Claudia, Aguillón, Juan Carlos, Soto, Lilian, Catalán, Diego
• Format: Journal Article
• Language: English
• Published: London BioMed Central 19.01.2017; BioMed Central Ltd
• Subjects: Adult; Arthritis; B cells; B-Lymphocyte Subsets - immunology; B-Lymphocytes, Regulatory - immunology; Biological markers; Biomarkers - analysis; Cell Separation; Coculture Techniques; Development and progression; Female; Flow Cytometry; Health aspects; Hepatitis A Virus Cellular Receptor 1 - analysis; Hepatitis A Virus Cellular Receptor 1 - biosynthesis; Hepatitis A Virus Cellular Receptor 1 - immunology; Humans; Interleukin-10; Interleukin-10 - immunology; Lymphocyte Activation - immunology; Male; Medicine; Medicine & Public Health; Middle Aged; Orthopedics; Physiological aspects; Research Article; Rheumatology; Scleroderma (Disease); Scleroderma, Systemic - immunology; Systemic scleroderma; Chile; Regulatory B cells; Systemic sclerosis; TIM-1; IL-10
• ISSN: 1478-6362; 1478-6354; 1478-6362
• DOI: 10.1186/s13075-016-1213-9

Background Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by excessive production of extracellular matrix by fibroblasts on skin and internal organs. Although Th2 cells have been involved in fibroblast stimulation, hyperactivated B cells may also play an important role. Regulatory B cells (Bregs) are cells capable of inhibiting inflammatory responses and controlling autoimmune diseases. Although many Breg populations have in common the ability to produce high amounts of IL-10, a unique surface marker defining most human Bregs is lacking. It has been described in mice that T cell Ig and mucin domain protein 1 (TIM-1) is an inclusive marker for Bregs, and that TIM-1+ B cells are able to prevent the development of autoimmunity. The aim of this work was to evaluate TIM-1 as a marker for human IL-10 + Bregs, and to determine whether TIM-1+ B cells are defective in SSc patients. Methods SSc patients (n = 39) and 53 healthy subjects were recruited. TIM-1 and IL-10 expression was assessed in resting or activated peripheral blood CD19 + B cells by flow cytometry. The regulatory function of TIM-1 + or activated B cells from SSc patients and healthy subjects was assessed in autologous and allogenic co-cultures with CD4 + T cells, where T cell proliferation and IFN-γ, IL-17, TNF-α and IL-4 production by T cells was measured by flow cytometry. Results TIM-1 and IL-10 were preferentially expressed in transitional B cells, but were upregulated in naïve and memory B cells upon stimulation. The frequency of transitional TIM-1 + IL-10 + B cells was significantly decreased in SSc patients compared to healthy controls. In addition, activated B cells from SSc patients induced stronger allogenic Th1 and Th2 responses than activated B cells from healthy controls. Finally, TIM-1 + B cells, including transitional and non-transitional cells, exhibited a higher CD4 + T cell suppressive ability than TIM-1 − B cells in healthy controls, but not in SSc patients. Conclusions TIM-1 is a unique marker for the identification of a human IL-10 + Breg subpopulation which is partially superimposed with transitional B cells. Alterations in TIM-1 + B cells could contribute to the development of autoimmune diseases such as SSc.