Peroxisome Proliferator-Activated Receptor γ B Cell-Specific–Deficient Mice Have an Impaired Antibody Response

Abstract

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. PPARγ, a ligand activated transcription factor, has important anti-inflammatory and anti-proliferative functions and it has been associated with diseases including diabetes, scarring and atherosclerosis among others. PPARγ is expressed in most bone marrow derived cells and influences their function. PPARγ ligands can stimulate human B cell differentiation and promote antibody production. A knowledge gap is that the role of PPARγ in B cells under physiological conditions is not known. We developed a new B cell-specific PPARγ (B-PPARγ) knockout mouse and explored the role of PPARγ during both the primary and secondary immune response. Here, we show that PPARγ deficiency in B cells decreases germinal center B cells and plasma cell development as well as the levels of circulating antigen-specific antibodies during a primary challenge. Inability to generate germinal center B cells and plasma cells is correlated to decreased MHC class II expression and decreased Bcl-6 and Blimp-1 levels. Furthermore, B-PPARγ-deficient mice have an impaired memory response, characterized by low titers of antigen-specific antibodies and low numbers of antigen-experienced antibody-secreting cells. However, B-PPARγ-deficient mice have no differences in B cell population distribution within neither primary nor secondary lymphoid organs during development. This is the first report to show under physiological conditions that PPARγ expression in B cells is required for an efficient B cell-mediated immune response as it regulates B cell differentiation and antibody production.

The Specialized Proresolving Mediator 17-HDHA Enhances the Antibody-Mediated Immune Response against Influenza Virus: A New Class of Adjuvant?

“…C57BL/6J male mice, 8–10 weeks old (The Jackson Laboratory, Bar Harbor, ME), were immunized by intraperitoneal (i.p.) injection (22). Mice were immediately given a second injection in the same site (i.p.)…”

“…Fluorescence minus one (FMO) controls were included in each staining protocol and used to set specific gates (22, 26, 27). 6-peak validation beads were used for calibration during the time course analysis.…”

“…Cells were then sorted using an 18-color FACSAria II (BD bioscience, San Jose, CA). Purified B cells were activated with CpG ODN 1826 (1 μg/mL) plus rabbit anti-mouse IgM antibody fragment (2 μg/mL) (Jackson ImmunoResearch Laboratories, West Grove, PA) and cultured for up to 6 days (22). 17-HDHA or vehicle control were added to cell culture 30 minutes before mitogen stimulation.…”

Corticosteroids inhibit anti-IgE activities of specialized proresolving mediators on B cells from asthma patients

“…In this context, some studies reported the beneficial effects of exogenous treatment of PPARγ ligands in preclinical mouse models of asthma, with reduced serum levels of Th2 cytokines that regulate B cell IgE production (48,49). However, our lab has previously shown direct effects of PPARγ ligands on human B cells by enhancing differentiation and promoting IgG antibody production (17). Here, we show that 17-HDHA in combination with dexamethasone promoted autologous PPARγ ligand production, which is associated with increased IgE production.…”

“…Therefore, we next investigated whether SPMs plus dexamethasone could affect B cell differentiation. One of the important signaling pathways involved in B cell differentiation is the activation of PPARγ by PPARγ ligands (17,18). We measured PPARγ binding activity activated by PPARγ ligands produced by B cells using a PPAR response element-luciferase (PPRE-luciferase) reporter assay.…”