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Summary: Neutrophil-derived bactericidal/permeability-increasing protein (BPI) is known for its bactericidal activity against gram-negative bacteria and neutralization of lipopolysaccharide. Here, we define BPI as a potent activator of murine dendritic cells (DCs). As shown in GM-CSF-cultured, bone-marrow-derived cells (BMDCs), BPI induces a distinct stimulation profile including IL-2, IL-6, and tumor necrosis factor expression. Conventional DCs also respond to BPI, while M-CSF-cultivated or peritoneal lavage macrophages do not. Subsequent to BPI stimulation of BMDCs, CD4+ T cells predominantly secrete IL-22 and, when naive, preferentially differentiate into T helper 22 (Th22) cells. Congruent with the tissue-protective properties of IL-22 and along with impaired IL-22 induction, disease severity is significantly increased during dextran sodium sulfate-induced colitis in BPI-deficient mice. Importantly, physiological diversification of intestinal microbiota fosters BPI-dependent IL-22 induction in CD4+ T cells derived from mesenteric lymph nodes. In conclusion, BPI is a potent activator of DCs and consecutive Th22 cell differentiation with substantial relevance in intestinal homeostasis.

The role of IL-22 in adult patients undergoing allogeneic stem cell transplantation (SCT) is of major interest since animal studies showed a protective and regenerative effect of IL-22 in graft versus host disease (GvHD). However, no clinical data exist on the tissue expression. Here we demonstrate that patients not suffering from transplant-related mortality (TRM) show significantly upregulated IL22 expression during histological and clinical GI-GvHD (p = 0.048 and p = 0.022, respectively). In contrast, in GvHD patients suffering from TRM, IL22 was significantly lower (p = 0.007). Accordingly, lower IL22 was associated with a higher probability of TRM in survival analysis (p = 0.005). In a multivariable competing risk Cox regression analysis, low IL22 was identified as an independent risk factor for TRM (p = 0.007, hazard ratio 2.72, 95% CI 1.32 to 5.61). The expression of IL22 seemed to be microbiota dependent as broad-spectrum antibiotics significantly diminished IL22 expression (p = 0.019). Furthermore, IL22 expression significantly correlated with G-protein coupled receptor (GPR)43 (r = 0.263, p = 0.015) and GPR41 expression (r = 0.284, p = 0.009). In conclusion, our findings reveal an essential role of IL22 for the prognosis of patients undergoing allogeneic SCT.

Early diagnosis of invasive pulmonary aspergillosis (IPA) is crucial to prevent lethal disease in immunocompromized hosts. So far, lipopolysaccharide binding protein (LBP) and bactericidal/permeability-increasing protein (BPI) levels have not been evaluated as biomarkers for IPA. IL-8, previously introduced as a biomarker for IPA, was also included in this study. Bronchoalveolar lavage fluid (BALF) of IPA patients and control patients with non-infectious lung disease was collected according to clinical indications. Measurements in BALF displayed significantly higher levels of LBP (p < 0.0001), BPI (p = 0.0002) and IL-8 (p < 0.0001) in IPA compared to control patients. Receiver operating characteristic curve analysis revealed higher AUC for LBP (0.98, 95% CI 0.95–1.00) than BPI (0.84, 95% CI 0.70–0.97; p = 0.0301). Although not significantly different, AUC of IL-8 (0.93, 95% CI 0.85–1.00) also tended to be higher than AUC for BPI (p = 0.0624). When the subgroup of non-hematological patients was analyzed, test performance of LBP (AUC 0.99, 95% CI 0.97–1.00), BPI (AUC 0.97, 95% CI 0.91–1.00) and IL-8 (AUC 0.96, 95% CI: 0.90–1.00) converged. In conclusion, LBP and—to a lesser extend—BPI displayed high AUCs that were comparable to those of IL-8 for diagnosis of IPA in BALF. Further investigations are worthwhile, especially in non-hematological patients in whom sensitive biomarkers for IPA are lacking.