B cells as under-appreciated mediators of non-auto-immune inflammatory disease

Abstract

B lymphocytes play roles in many auto-immune diseases characterized by unresolved inflammation, and B cell ablation is proving to be a relatively safe, effective treatment for such diseases. B cells function, in part, as important sources of regulatory cytokines in auto-immune disease, but B cell cytokines also play roles in other non-auto-immune inflammatory diseases. B cell ablation may therefore benefit inflammatory disease patients in addition to its demonstrated efficacy in auto-immune disease. Current ablation drugs clear both pro- and anti-inflammatory B cell subsets, which may unexpectedly exacerbate some pathologies. This possibility argues that a more thorough understanding of B cell function in human inflammatory disease is required to safely harness the clinical promise of B cell ablation. Type 2 diabetes (T2D) and periodontal disease (PD) are two inflammatory diseases characterized by little autoimmunity. These diseases are linked by coincident presentation and alterations in toll-like receptor (TLR)-dependent B cell cytokine production, which may identify B cell ablation as a new therapy for co-affected individuals. Further analysis of the role B cells and B cell cytokines play in T2D, PD and other inflammatory diseases is required to justify testing B cell depletion therapies on a broader range of patients.

Figure 1

Models explaining the clinically demonstrated association of T2D and PD. (A) Inflammation, mainly from immune system cells in the periphery and excess adipose tissue (in T2D patients) that secrete pro-inflammatory cytokines (and other mediators) to directly promote oral inflammation and the bone resorption characteristic of PD. The alternative, that T2D blunts the immune response to allow chronic infection with oral pathogens due to immune cell hypo-responsiveness, is not shown. Red indicates inflammatory cells/regions in all panels. (B) Metabolic and inflammatory changes occur concomitantly in the oral cavity, blood, and adipose tissue of T2D patients. Timing of T2D and PD diagnoses may differ either due to intrinsic differences in natural history of each disease, or due to differences in clinical diagnoses. Many endocrinologists and general practitioners who manage T2D patients do not focus on a PD diagnosis. (C) Alterations in adipose tissue metabolism elevates circulating pro-inflammatory molecules such as saturated fatty acids, which independently or interdependently activate inflammation in the oral cavity and periphery. (D) Unresolved bacterial infection in the oral cavity increases circulating levels of cytokines produced by resident oral cells, but also activates immune cells as they circulate through the gingiva. Because oral bacteria are also systemically elevated in PD patients (not shown), the bacteria may also activate immune cells at peripheral sites.