Nitric Oxide Regulates BAFF Expression and T Cell–Independent Antibody Responses

Abstract

While nitric oxide (NO) is known to regulate T cell responses, its role in regulating B cell responses remains unclear. Previous studies suggested that inducible NO synthase 2 (NOS2/iNOS) is required for normal IgA Ab responses but inhibits anti-viral IgG2a Ab responses. Here we used NOS2−/− mice to determine the role of NO in T cell-dependent (TD) and T cell-independent-2 (TI-2) Ab responses. While TD Ab responses were only modestly increased in NOS2−/− mice, IgM and IgG3 Ab responses as well as marginal zone (MZ) B cell plasma cell (PC) numbers and peritoneal B1b B cells were significantly elevated after immunization with the TI-2 Ag NP-Ficoll. The elevated TI-2 responses in NOS2−/− mice were accompanied by significant increases in serum levels of B cell activating factor (BAFF/BLyS) and by increases in BAFF-producing Ly6Chi inflammatory monocytes and monocyte-derived dendritic cells (Mo-DCs), suggesting that NO normally inhibits BAFF expression. Indeed, we found that NOS2−/− DCs produced more BAFF than WT DCs, and addition of a NO donor to NOS2−/− DCs reduced BAFF production. Bone marrow chimeric mice that lack NOS2 in either non-hematopoietic or hematopoietic cells, each had intermediate IgM and IgG3 Ab responses after NP-Ficoll immunization, suggesting that NOS2 from both hematopoietic and non-hematopoietic sources regulates TI-2 Ab responses. Similar to NOS2−/− mice, depletion of Ly6Chi inflammatory monocytes and Mo-DCs enhanced NP-specific IgM and IgG3 responses to NP-Ficoll. Thus, NO produced by inflammatory monocytes and their derivative DC subsets plays an important role in regulating BAFF production and TI-2 Ab responses.

The soluble pattern recognition receptor PTX3 links humoral innate and adaptive immune responses by helping marginal zone B cells

“…MZ B cells integrate signals from B cell receptors (BCRs), complement receptors, and TLRs to rapidly mount largely unmutated IgM and IgG responses against carbohydrate and lipid antigens through a T cell–independent (TI) pathway characterized by extrafollicular expansion of short-lived plasmablasts (PBs; Guinamard et al, 2000 ; Martin et al, 2001 ). The activation of this TI pathway further involves cytokines produced by DCs, macrophages, innate lymphoid cells (ILCs), and neutrophils ( Balázs et al, 2002 ; Puga et al, 2012 ; Xu et al, 2012 ; Giordano et al, 2014 ; Magri et al, 2014 ).…”

Pentablock Copolymer Micelle Nanoadjuvants Enhance Cytosolic Delivery of Antigen and Improve Vaccine Efficacy while Inducing Low Inflammation

“…Indeed, the activation of APCs through TLRs may not always be desirable, especially when TLR agonists induce excessive NO production, which can cause cellular stress and contribute to acute inflammatory state of the immune system 49,70,71 . Higher amounts of NO production by inflammatory immune cells has been linked to lower B cell activation, diminished antibody responses, lower class-switiching, and generation of more short-lived plasma cells then long-lived plasma cells 10,72 . In contrast, administration of PBC micelles did not lead to the production of NO or any cellular or mitochondrial ROS ( Figure 7 and SI Figure 3) while still enhancing antibody production ( Figure 1).…”

“…This leads to the induction of inflammatory signals, such as cytokines, superoxides, and nitric oxide (NO) 5 . However, due to immunosenescence in older adults, this cytokine milieu is highly imbalanced leading to a state of "inflamm-aging" and an overproduction of harmful oxide analytes 9,10 .…”

Role of nitric oxide in immune responses against viruses: beyond microbicidal activity

“…There is evidence that NO acts by inhibiting the expression of BAFF (B cell-activating factor), which is an important factor for the generation of antibodies against T-independent antigens. Thus, knockout iNOS mice produced two-to threefold more IgM and IgG3 in response to NP-Ficoll than wild-type mice [14]. In plasma, NO activated the PKG pathway via its second messenger cGMP, which regulates components of endoplasmic reticulum stress by increasing the survival of these cells [15].…”