B cells in chronic obstructive pulmonary disease: moving to center stage

Abstract

Chronic inflammatory responses in the lungs contribute to the development and progression of chronic obstructive pulmonary disease (COPD). Although research studies focused initially on the contributions of the innate immune system to the pathogenesis of COPD, more recent studies have implicated adaptive immune responses in COPD. In particular, studies have demonstrated increases in B cell counts and increases in the number and size of B cell-rich lymphoid follicles in COPD lungs that correlate directly with COPD severity. There are also increases in lung levels of mediators that promote B cell maturation, activation, and survival in COPD patients. B cell products such as autoantibodies directed against lung cells, components of cells, and extracellular matrix proteins are also present in COPD lungs. These autoantibodies may contribute to lung inflammation and injury in COPD patients, in part, by forming immune complexes that activate complement components. Studies of B cell-deficient mice and human COPD patients have linked B cells most strongly to the emphysema phenotype. However, B cells have protective activities during acute exacerbations of COPD by promoting adaptive immune responses that contribute to host defense against pathogens. This review outlines the evidence that links B cells and B cell-rich lymphoid follicles to the pathogenesis of COPD and the mechanisms involved. It also reviews the potential and limitations of B cells as therapeutic targets to slow the progression of human COPD.

Keywords: B cells; COPD; cigarette smoke; immunity; lymphoid follicles.

Fig. 1.

B cell maturation and lymphoid follicle formation. 1: B cell activation and maturation. B cell activation is induced when a naive B cell binds via its B cell receptor to either a soluble antigen or to an antigen that is presented by macrophages or dendritic cells (DCs). T helper cells assist in the maturation of B cells into plasma cells and memory B cells. B cells then become mature memory B cells expressing CD20 and plasma cells. Only mature B lymphocytes can enter the lymphoid follicles and efficiently participate in the immune response. Within lymphoid follicles, B and T lymphocytes segregate into different areas but interact by the binding of cluster of differentiation (CD)40 expressed on B cells to CD40 ligand (CD40L) expressed on T cells. 2: Lymphoid follicle (LF) development. In response to environmental insults (e.g., bacteria and bacterial lipopolysaccharide), airway epithelium and macrophages express cytokines that recruit immature B and T cells and DCs. When inflammation becomes chronic due to persisting antigen exposure and/or tissue damage, lymphocyte aggregates will give rise to organized lymphoid follicles with separated B and T cell areas. B cell activating factor of the TNF family (BAFF), which is expressed by T cells, macrophages, and DCs activates B cells via the BAFF receptor (BAFFR). Mature lymphoid follicles contain high endothelial venules, follicular dendritic cells, and germinal centers. 3: Production of immunoglobulins by plasma cells. When B cells are activated following antigen binding, they proliferate to form plasma cells that produce antibodies that promote mucosal immunity (IgA) that increases clearance of pathogens.

Fig. 2.

B cells and B cell-rich lymphoid follicle expansion in COPD. In response to environmental insults (e.g., cigarette smoke and bacteria), airway epithelium and macrophages express cytokines that recruit immature B and T cells and DCs. When inflammation becomes chronic due to persisting antigen exposure and/or tissue injury, activated lymphocytes expressing lymphotoxin-α-β heterotrimer (LTα1β2) interact with the lymphotoxin-β receptor (LTβR) on neighboring stromal cells. Stromal cell stimulation induces the expression of lymphoid chemokines [CC-chemokine ligands (CCL)19 and CCL21, and CXC-chemokine ligands (CXCL)12 and CXCL13] and adhesion molecules that promote additional recruitment of naive B and T lymphocytes and DCs. B cell activating factor of TNF family (BAFF), which is expressed by T cells, macrophages, and DCs (and in advanced COPD by B cells themselves) activates B cells, leading to increases in B cell numbers in the lung and an expansion in pulmonary lymphoid follicles both in size and number. Activated B cells release interleukin 10 (IL-10), which activates macrophages to release matrix metalloproteinases-9 (MMP-9) and MMP-12, which degrade the lung extracellular matrix (ECM) proteins, leading to emphysema development and the generation of matrix fragments (matrikines) that recruit polymorphonuclear neutrophils (PMNs) into the lungs. Increased production of IL-17A by Th17 cells regulates the formation of LFs and the recruitment of PMNs into the lungs. PMNs release serine proteinases including neutrophil elastase that contribute to loss of alveolar walls. Activated B cells proliferate and mature into plasma cells. Plasma cells release antibodies to bacteria and/or autoantigens to lung components including proteolytic degradation products of the ECM and lung cells. Binding of autoantibodies to their target antigens induces complement activation, which recruits and activates inflammatory cells and induces immune complex-mediated injury to the lung. These processes contribute to the progression of air space enlargement. There are 2 monoclonal antibodies targeting B cells that potentially could limit COPD progression: 1) rituximab, which targets CD20 but was associated with increased risk of pulmonary infections when tested in COPD patients; and 2) belimumab, which targets BAFF but has not been tested in animal models of COPD or human COPD patients. In addition, a BAFFR-Fc fusion protein of the extracellular domain of murine BAFFR fused to a linker peptide and the Fc-portion of human IgG1 attenuated emphysema development in CS-induced mice but has not yet been tested in human COPD patients.