Work

Increased age-associated B cells in patients with acquired aplastic anemia correlate with IFN-γ

Year: 2023

Type: article

Abstract: Acquired aplastic anemia (AA) represents a rare bone marrow failure syndrome characterized by pancytopenia in peripheral blood and empty bone marrow. 1 The increased interferon-gamma (IFN-γ) levels, contributed principally by circulating T cells in patients with AA, have a central role in the immune destruction of hematopoietic progenitors, leading to the clinical presentation of this rare and difficult to manage disease.We and others have previously shown that the transcription factor T-bet, a key regulator of Th1 development and function, is overexpressed in T cells from patients with AA. [2][3][4] It has also been shown that age-associated B cells (ABC), a subpopulation of peripheral CD11c + CD19 + CD21 -CD38-B cells, also express T-bet.[5][6][7] Such T-bet + ABC are reportedly increased in patients with autoimmune diseases (ie, systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis).6,[8][9][10][11] Stimulation of B cells with antigens, Toll-like receptor ligands and IFN-γ leads to the expansion of ABC; ABC in turn "talk" with T cells and stimulate them in order to produce IFN-γ.In a paracrine manner, IFN-γ may lead to the further expansion of T-bet + ABC.It has been proposed that the elimination of B-cell-intrinsic T-bet results in diminished T-cell activation and suppressed IFN-γ production.11 The molecular mechanisms controlling the expansion and function of ABC are not completely understood; IFN-γ and interleukin-21 (IL-21) promote B-cell T-bet expression, whereas IL-4 suppresses it.It has been shown that Ets-1 is an essential cofactor for STAT1 regulating of T-bet expression in ABC. 12 A small subset of CD4 + helper T cells circulating in the blood component of T follicular helper cells (cTfh) is also implicated in T-bet expression in ABC.11,13 cTfh are characterized by the surface expression of CXCR5, ICOS, and PD1, the transcription factor Bcl-6, and produce mainly IL-21, as well as IL-17, IL-4, and IFN-γ.Tfh represents the major population that helps B cells turn into plasma cells and is implicated in the pathogenesis of different diseases through excessive or insufficient antibody production.In patients with autoimmune diseases, cTfh cells are usually increased.[13][14][15] The expression of ABC and cTfh cells in patients with AA is not known.We enrolled 21 patients with AA (median age, 26 years; range, 8-50 years; 7 patients were children/adolescents; Table 1) and 20 healthy volunteers (median age, 29 years; range, 13-60 years).The diagnosis of AA was based on the criteria of the International Agranulocytosis and Aplastic Anemia Study.No patient underwent transfusion immediately before blood sampling.All blood samples were obtained after written informed consent was obtained in accordance with the Declaration of Helsinki and using protocols approved by the institutional review board of the University Hospital in Patras and the University of Patras Medical School, Rion, Greece.Peripheral blood mononuclear cells (PBMC) were separated by density gradient centrifugation immediately after blood sampling as previously described.16 At the time of sampling, 19 of the 21 patients included in the study were diagnosed but untreated, and 2 patients were in complete response and off

Source: Blood Advances

DOI: 10.1182/bloodadvances.2023010109