Abstract
B-cells mediate humoral adaptive immune response via the production of antibodies and cytokines, and by inducing T-cell activation. These functions can be attributed to distinct B-cell subpopulations. Infection with Trypanosoma cruzi, the causative agent of Chagas disease, induces a polyclonal B-cell activation and lytic antibody production, critical for controlling parasitemia. Individuals within the chronic phase of Chagas disease may remain in an asymptomatic form (indeterminate), or develop severe cardiomyopathy (cardiac form) that can lead to death. Currently, there is no effective vaccine to prevent Chagas disease, and no treatment to halt the development of the cardiomyopathy once it is installed. The pathology associated with cardiac Chagas disease is a result of an inflammatory reaction. Thus, discovering characteristics of the host's immune response that favor the maintenance of favorable heart function may unveil important immunotherapeutic targets. Given the importance of B cells in antibody production and parasite control, we investigated T. cruzi-derived antigenic fractions responsible for B-cell activation and whether frequencies and functional characteristics of B-cell subpopulations are associated with different clinical outcomes of human Chagas disease. We stimulated cells from indeterminate (I) and cardiac (C) Chagas patients, as well as non-infected individuals (NI), with T. cruzi-derived protein- (PRO), glycolipid- (GCL) and lipid (LIP)-enriched fractions and determined functional characteristics of B-cell subpopulations. Our results showed that the frequency of B-cells was similar amongst groups. PRO, but not GCL nor LIP, led to an increased frequency of B1 B-cells in I, but not C nor NI. Although stimulation with PRO induced higher TNF expression by B1 B-cells from C and I, as compared to NI, it induced expression of IL-10 in cells from I, but not C. Stimulation with PRO induced an increased frequency of the CD11b+ B1 B-cell subpopulation, which was associated with better cardiac function. Chagas patients displayed increased IgM production, and activation of gamma-delta T-cells, which have been associated with B1 B-cell function. Our data showed that PRO activates CD11b+ B1 B-cells, and that this activation is associated with a beneficial clinical status. These findings may have implications in designing new strategies focusing on B-cell activation to prevent Chagas disease cardiomyopathy.
Highlights
B lymphocytes are instrumental for the establishment of adaptive immune response as they mediate humoral immunity, characterized by the production of antibodies that can recognize and neutralize specific antigens
B-cell responses are critical for human Chagas disease diagnosis and for parasite control [14, 15], little is known about the role of these cells in the immune response of chronic Chagas patients
We identified the T. cruzi-derived components responsible for the activation of human B cell subpopulations in chronic Chagas patients, and determined their contribution to the immune response observed in patients with polar clinical forms of the disease
Summary
B lymphocytes are instrumental for the establishment of adaptive immune response as they mediate humoral immunity, characterized by the production of antibodies that can recognize and neutralize specific antigens They can be classified into two major groups, B1 and B2 cells, according to their location, migration capacity and activation mechanisms [1, 2]. Murine B1 B-cells are present at low frequency (0.3–0.5%) in peripheral blood, display a polyspecific B cell receptor (BCR), secrete natural antibodies spontaneously, and are activated in a T-independent fashion [5]. They are self-renewing and proliferate for generations [1, 5]. Different antigenic components such as soluble peptides, carbohydrates and lipid antigens can lead to the activation of the distinct B cell subpopulations [11,12,13]
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