Elsevier

Cytokine

Volume 50, Issue 3, June 2010, Pages 234-242
Cytokine

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

https://doi.org/10.1016/j.cyto.2010.02.022Get rights and content

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.

Introduction

B cell depletion as an important therapy for an array of inflammatory diseases. Inflammation is a common underlying condition in many chronic diseases including auto-immune diseases like multiple sclerosis (MS), Crohnā€™s disease (CD), and type 1 diabetes (T1D). Inflammation also plays important roles in diseases that lack significant auto-immune components, including diseases characterized by inappropriate innate immune responses, such as type 2 diabetes (T2D) and periodontal disease (PD). The dominance of B cells in some of these inflammatory diseases, including lupus and rheumatoid arthritis, has been clinically exploited due to the availability and general safety of the B cell depletion drug Rituximab [1], [2], [3]. However, the ability of B cell depletion to induce remission of diseases more traditionally associated with T cell-mediated autoimmunity, such as MS [4], [5], suggests that even sub-dominant contributions of B cells can significantly alter disease pathogenesis. Although B cell depletion has promoted inflammatory disease in a small minority of case reports [6], [7], the overall acceptable safety profile of B cell depletion suggests that a wider array of inflammatory disease patients may benefit from this treatment [1] if timing and duration of treatment are properly controlled. Second generation B cell depletion drugs are under development that may benefit an even wider array of patients with B cell-influenced inflammatory disease [8]. The obvious first step towards comprehensively identifying inflammatory disease patients that might benefit from B cell depletion therapy is to more broadly identify the role B cells play in human inflammatory disease. This review will focus on the role B cells play in two clinically linked inflammatory diseases, T2D and PD, towards exploring the use of B cell depletion in a broader range of pathologies.

Section snippets

Inflammation may explain the clinical linkage between type 2 diabetes and periodontal disease

Unlike CD and other inflammatory diseases that occur in relative isolation, the link between T2D and PD is strong [9], [10], [11]. Foremost, the association of T2D and PD is supported by clinical evidence that shows about a 3-fold increased incidence of PD in T2D patients [12]. Multiple studies indicate that this linkage is largely due to the inflammation that precedes onset and promotes ongoing pathogenesis of both diseases. Several mechanisms may explain how inflammation in T2D patients

Lymphocytes promote systemic inflammation through multiple mechanisms

Lymphocytes can contribute to systemic inflammation in T2D, PD and co-affected patients by multiple mechanisms. First, the uncontrolled oral flora in PD lesions locally activates lymphocytes [18], [38], which may then re-circulate throughout the body, distributing inflammatory mediators along the way. Oral floral may also spread systemically [39], [40] to directly provide inflammatory signals to lymphocytes as they re-circulate through affected blood vessels. Although there is no parallel

B cell antibodies are implicated in inflammatory disease

B cells are activated by a variety of ligands that engage an array of surface receptors to trigger B cell responses. NaĆÆve B cells require a combination of ligands to achieve an activated phenotype. These ligands must engage a combination of surface immunoglobulin, the co-activator CD40, and a third signal, often provided by toll-like receptor (TLR) engagement [45]. Memory B cells, a subset set aside for rapid immune responses to subsequent antigen exposure, are more amenable to activation and

IL-10 is a protective B cell cytokine in inflammatory disease

B cells are demonstrated sources of cytokines both in healthy individuals and those with chronic, unresolved inflammatory disease. IL-10 is arguably the B cell cytokine most commonly implicated in inflammatory disease. IL-10 is generally considered anti-inflammatory, although it can have pro-inflammatory functions in some circumstances (i.e. up-regulation of surface TLR2; Ref. [86]). IL-10 producing human B cells arise upon stimulation through surface immunoglobulin alone or in combination with

Future directions

The roles of B cells in auto-immune and non-auto-immune inflammatory diseases have focused mainly on the ability of B cells to secrete auto-antibodies. More recently, B cells have been identified as important sources of pro-inflammatory and anti-inflammatory cytokines. B cells can either provide a quantitatively or functionally dominant source of cytokines. Alternatively, B cells may additively contribute to inflammation by skewing the overall pro-to-anti-inflammatory cytokine ratio past some

Acknowledgements

Supported by NIH R01 AI54611 and a Research Grant from the American Diabetes Association. The author thanks Madhumita Jagannathan, Ann Marshak-Rothstein, Rachel Ettinger, Lisa Ganley-Leal and Marie McDonnell for valuable conversations related to this work.

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