Increased IgA production by B-cells in COPDvialung epithelial interleukin-6 and TACI pathways

Abstract

Despite their relevance to mucosal defense, production of IgA and the function of lung B-cells remain unknown in chronic obstructive pulmonary disease (COPD).We assessed IgA synthesis in the lungs of COPD (n=28) and control (n=21) patients, and regulation of B-cells co-cultured with in vitro-reconstituted airway epithelium.In COPD lung tissue, synthesis of IgA1 was increased, which led to its accumulation in subepithelial areas. In vitro, the COPD bronchial epithelium imprinted normal human B-cells for increased production of IgA (mainly IgA1) and maturation into CD38 + plasma cells. These effects were associated with upregulation of TACI (transmembrane activator and CAML interactor) and were observed under resting conditions, while being partly inhibited upon stimulation with cigarette smoke extract. Interleukin (IL)-6 and BAFF (B-cell activating factor)/APRIL (a proliferation-inducing ligand) were upregulated in the COPD epithelium and lung tissue, respectively; the IgA-promoting effect of the COPD bronchial epithelium was inhibited by targeting IL-6 and, to a lower extent, by blocking TACI.These data show that in COPD, the bronchial epithelium imprints B-cells with signals promoting maturation into IgA-producing plasma cells through the action of two epithelial/B-cell axes, namely the IL-6/IL-6 receptor and BAFF-APRIL/TACI pathways, while cigarette smoke partly counteracts this IgApromoting effect. @ERSpublications COPD epithelium induces B-cell maturation of IgA-producing plasma cells via IL-6/IL-6R and BAFF-APRIL/TACI pathways

Relationships between Mucosal Antibodies, Non-Typeable Haemophilus influenzae (NTHi) Infection and Airway Inflammation in COPD

“…influenzae colonisation of the airways despite the presence of specific IgA and IgG in the serum and sputum of COPD patients. More recently, Polosukhin[7] described a defect in sIgA distribution in BAL fluid from severe COPD patients, whilst in contrast IgA synthesis and accumulation was shown to be increased in COPD lung tissue[12]. Our data of increased IgA and sIgA in the COPD airway compared to health would support the observations of Groeneveld[11] and Ledjemi[12].…”

“…There are conflicting previous reports of both decreased sIgA[7] and increased IgA[12] in the COPD airway. We therefore assessed both total and secretory IgA in BAL (Fig 2A and 2B).…”

“…More recently, Polosukhin[7] described a defect in sIgA distribution in BAL fluid from severe COPD patients, whilst in contrast IgA synthesis and accumulation was shown to be increased in COPD lung tissue[12]. Our data of increased IgA and sIgA in the COPD airway compared to health would support the observations of Groeneveld[11] and Ledjemi[12]. These observations may be a result of increased permeability of the mild-moderate COPD airway, rather than the impervious squamous metaplasic epithelium that has been demonstrated in more severe COPD[7], although we cannot rule out an increase in tissue resident B cells as previously described in COPD lung tissue[22].…”

“…However, a decrease in the amount of secretory (s)IgA in the bronchoalveolar lavage (BAL) of COPD patients, has been recently reported in advanced disease[7]. In contrast there have also been reports of increased IgA in COPD lung tissue[12], but to date no study has comprehensively analysed immunoglobulin levels in the human airway in the context of NTHi infection, or in earlier stages of disease. Indeed the immune correlates of protection against this un-encapsulated organism are not fully understood, but murine models of COPD have demonstrated impaired immunoglobulin class switching in disease with associated effects on NTHi clearance[13].…”

Interleukin-1α: a key player for epithelial-to-mesenchymal signalling in COPD?

“…It has also been shown in asthma that BECs may suppress constitutive and IgE-dependent histamine release by lung mast cells [10], further highlighting the central role of the epithelium in sensing and shaping mucosal danger signalling. We recently showed that BECs from COPD patients also imprint B-cells with signals promoting maturation into IgA-producing plasma cells, while cigarette smoke partly counteracts this IgA-promoting effect [11]. This effect was at least partly related to an intrinsic ability of COPD BECs to produce increased amounts of certain cytokines (IL-6 and BAFF; B-cell activating factor) and to induce B-cell expression of TACI (transmembrane activator and CAML interactor).…”