Impaired IgA mucosal immunity following lung transplantation: a potential trigger for bronchiolitis obliterans syndrome

Abstract

Rationale: Bronchiolitis obliterans syndrome (BOS) limits long-term survival after lung transplantation (LuTx) and may be triggered by infections. As immunoglobulin (Ig)A is crucial to ensure adequate mucosal immunity, we explored whether IgA-related mucosal immunity is impaired in BOS.

Methods: 60 LuTx recipients from the Cohort for Lung Transplantation (COLT) cohort were included retrospectively. All participants were in stable condition within the first year post-transplant. At 3.5 years post-LuTx, 30 remained stable and 30 had developed BOS. Bronchoalveolar lavage fluid (BALF) and sera collected pre-transplant and at 6 (M6) and 12 months (M12) post-transplant were assessed for monomeric IgA, secretory (S)-IgA, secretory component and cytokine profiling. Second, bronchiolar polymeric Ig receptor (pIgR) expression and subepithelial IgA-producing B-cell numbers were compared across graft tissue samples from 54 LuTx recipients classified as stable, pre-BOS, BOS or end-stage BOS.

Results: S-IgA levels in BALF decreased between M6 and M12 (p=0.0001) and were reduced in BOS patients at M12 (p=0.0018). Patients with lower S-IgA levels had higher infection rates. BOS patients exhibited elevated secretory component levels in serum (p<0.01). Both reduced S-IgA in BALF and increased secretory component in serum were associated with higher risk of BOS. Lastly, a reduction in bronchiolar pIgR expression was observed in BOS patients (p=0.0001), that paralleled BOS severity.

Conclusions: This study demonstrates an early impairment of mucosal IgA immunity in LuTx patients, which was linked to the later development of BOS, suggesting that IgA-related markers may serve as early predictors of BOS onset.

Overview of the study. S-IgA: secretory immunoglobulin A; d-IgA: dimeric immunoglobulin A; pIgR: polymeric immunoglobulin receptor; BOS: bronchiolitis obliterans syndrome; SC: secretory component.

FIGURE 1

Study flowchart. a) Cohort for Lung Transplantation (COLT) study population: This cohort included patients with longitudinal follow-up. Samples were collected prior to lung transplantation (LuTx) (serum only, M0), as well as 6 and 12 months following LuTx (serum and bronchoalveolar lavage fluid (BALF), M6 and M12, respectively). After a 3.5-year follow-up, patients were categorised into stable or bronchiolitis obliterans syndrome (BOS) groups based on their functional outcome. b) Foch cohort: this cohort consisted of tissue samples from LuTx recipients with various post-transplant outcomes: patients with stable evolution (n=20); those who were stable at the time of transbronchial biopsy, but later developed BOS within 1 year (pre-BOS, n=19); patients with definitive BOS grade >1 [4] (n=14); and those with end-stage BOS (explants, n=15). Notably, the 14 BOS samples were from patients who had been part of the pre-BOS group.

FIGURE 2

Concentrations of secretory immunoglobulin A (S-IgA) in bronchoalveolar lavage fluid (BALF) and secretory component (SC) in serum from lung transplant (LuTx) recipients. a) Absolute change in S-IgA levels in BALF from 6 months (M6) to 12 months (M12) in stable and bronchiolitis obliterans syndrome (BOS) LuTx recipients. A significant decrease in S-IgA levels was observed from M6 to M12 in BOS patients, while a slight increase was observed in stable recipients, showing a statistically significant difference between the two groups (p=0.0018). b) S-IgA levels in BALF at M6 and M12 post-LuTx in stable and BOS recipients. S-IgA levels were lower at M12 compared to M6 in BOS patients (p=0.0004), while stable recipients showed no significant decrease. c) SC levels in serum pre-LuTx (M0), M6 and M12 in stable and BOS patients. BOS patients exhibited higher SC levels at M6 and M12 compared to stable recipients (p=0.0085 and p=0.0062, respectively). No significant difference in SC levels was observed between groups at M0 (pre-LuTx). d) S-IgA levels at M12, but e) not the S-IgA difference between M6 and M12, directly correlated with an earlier occurrence of BOS. ns: nonsignificant. **: p<0.01; ***: p<0.001.

FIGURE 3

Immunoglobulin (Ig)A, IgA₁ and IgA₂ levels in serum in stable and bronchiolitis obliterans syndrome (BOS) patients (Cohort for Lung Transplantation). Levels were measured prior to lung transplantation (LuTx) (M0), at 6 months (M6) and at 12 months (M12) post-LuTx. a) Total IgA serum levels in stable and BOS LuTx recipients. Total IgA levels decreased similarly in both stable and BOS patients from M0 to M6 and from M0 to M12 (p<0.0001, for all four comparisons). b) IgA₁ and c) IgA₂ serum levels in stable and BOS LuTx recipients. Both groups showed decreased IgA₁ levels after LuTx at M6 and M12 compared to M0 (stable group: p=0.021 for M6 versus M0, and p=0.0022 for M12 versus M0; BOS group: p=0.0041 for M6 versus M0, and p=0.0032 for M12 versus M0), while IgA₂ levels remained unchanged. **: p<0.01; ***: p<0.001; ****: p<0.0001.

FIGURE 4

Freedom from bronchiolitis obliterans syndrome (BOS) depending on bronchoalveolar lavage fluid secretory immunoglobulin A (S-IgA) and serum secretory component (SC) levels. a) Freedom from BOS is higher for the high S-IgA groups as compared with the low S-IgA group, using a 12.59 µg·mL⁻¹ cut-off at 12 months (M12) (log-rank test, p<0.0001). b) Freedom from BOS is higher for the low SC group as compared with the high SC group, using a 90.99 ng·mL⁻¹ cut-off at M12 (log-rank test, p=0.0002). c) Freedom from BOS is higher in lung transplant (LuTx) recipients whose S-IgA levels increased at M12 versus 6 months, as compared to those whose levels decreased (log-rank test, p<0.0001).

FIGURE 5

Infection rates in stable and bronchiolitis obliterans syndrome (BOS) lung transplant (LuTx) recipients. The a) total number of infections, b) bacterial infections, c) fungal infections and d) viral infections recorded between 3 months and 3.5 years post-LuTx are presented. BOS recipients exhibited significantly higher infection rates across most categories compared to stable recipients (p=0.0049 for total infections, p=0.012 for bacterial infections, p=0.023 for fungal infections). e) LuTx recipients in the lowest secretory immunoglobulin A (S-IgA) quartile (Q) at 12 months post-LuTx (M12) showed an increased risk of infections during the follow-up period. p=0.014 for Q1 versus Q2, p=0.025 for Q1 versus Q3, p=0.049 for Q1 versus Q4. *: p<0.05; **: p<0.01.

FIGURE 6

Polymeric immunoglobulin receptor (pIgR) expression at the bronchiolar level is reduced in bronchiolitis obliterans syndrome (BOS) patients. a) pIgR expression levels were reduced in the airway epithelium from BOS and end-BOS patients as compared to stable and pre-BOS recipients (stable versus BOS p=0.012; stable versus end-BOS p<0.0001; pre-BOS versus BOS p=0.012; pre-BOS versus end-BOS p<0.0001; BOS versus end-BOS p=0.0257). b) In the 14 paired transbronchial biopsies (i.e. from the same 14 patients sampled both before and after BOS diagnosis), pIgR epithelial expression in the airway epithelium is decreased after BOS diagnosis (p=0.004). c) Absolute IgA⁺ plasma cell numbers (cells·mm⁻²) in airway epithelium were similar in stable, pre-BOS, BOS and end-BOS lung transplant (LuTx) recipients. d) The proportion of IgA⁺ plasma cells among total plasma cells were similar among the four groups. AU: arbitrary units. *: p<0.05; **: p<0.01; ****: p<0.0001.