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

Arthritis Res Ther. 2017 Jan 19;19(1):8. doi: 10.1186/s13075-016-1213-9.

Abstract

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.

Keywords: IL-10; Regulatory B cells; Systemic sclerosis; TIM-1.

MeSH terms

  • Adult
  • B-Lymphocyte Subsets / immunology*
  • B-Lymphocytes, Regulatory / immunology*
  • Biomarkers / analysis
  • Cell Separation
  • Coculture Techniques
  • Female
  • Flow Cytometry
  • Hepatitis A Virus Cellular Receptor 1 / analysis
  • Hepatitis A Virus Cellular Receptor 1 / biosynthesis*
  • Hepatitis A Virus Cellular Receptor 1 / immunology
  • Humans
  • Interleukin-10 / immunology
  • Lymphocyte Activation / immunology
  • Male
  • Middle Aged
  • Scleroderma, Systemic / immunology*

Substances

  • Biomarkers
  • HAVCR1 protein, human
  • Hepatitis A Virus Cellular Receptor 1
  • IL10 protein, human
  • Interleukin-10