Inflammatory endotype of odontogenic sinusitis.

BACKGROUND: Odontogenic sinusitis (ODS) is distinct from non-odontogenic rhinosinusitis with regard to clinical features as well as diagnostic and therapeutic approaches. While numerous studies have explored immune profiles of chronic rhinosinusitis, very few studies have explored the inflammatory endotype of ODS. METHODS: Odontogenic sinusitis was diagnosed by confirming infectious sinusitis adjacent to infectious maxillary odontogenic pathology. Maxillary sinus cultures and mucosal biopsies were obtained during endoscopic endonasal surgery in ODS and control patients. Controls were patients undergoing endoscopic skull base surgery with no sinus disease. Specimens were snap frozen in liquid nitrogen and stored at -80°C. Analysis was performed using a multiplex assay to measure Th-1 (TNFα, IFNγ, IL-2,12,18), Th-2 (IL-4,5,9,13), Th-17 (IL-17A,17F,22), and innate (CCL5,CXCL9,CXCL10, IL-6,8,10,12,23,27) immune pathways. Groups were compared via independent sample t-tests; if assumptions were violated, nonparametric Wilcoxon ranked sum tests were performed. RESULTS: Specimens from 22 ODS patients were compared to nine controls. ODS mucosal tissue was sampled in the setting of the following dental pathologies: post-dental extraction (n = 15), untreated apical periodontitis (n = 2), apical periodontitis after root canal therapy (n = 2), and maxillary sinus bone grafting with or without dental implantation (n = 3). The following cytokines were significantly elevated in ODS compared to controls: IFNγ, TNFα, IL-6, 8, 10, 27, and CXCL9. IL-17 levels were similar in both ODS and controls. Therefore, ODS demonstrated heightened innate and Th1 immune activity. CONCLUSION: ODS demonstrated both innate immune and Th1 inflammatory endotypes. Further studies are needed to explore ODS immunopathobiology and its potential impact on ODS management.

IL-22, cell regeneration and autoimmunity.

IL-22 as a cytokine is described with opposing pro-inflammatory and anti-inflammatory functions. Cell regeneration, tissue remodelling and balance between commensal bacteria in the gut and host immune system are considered as anti-inflammatory features of IL-22, whereas production of IL-22 from Th17 cells links this cytokine to pro-inflammatory pathways. Th17 cells and group 3 innate lymphoid cells (ILC3) are two major producers of IL-22 and both cell types express ROR-γt and Aryl hydrocarbon receptor (AhR) transcription factors. Typically, the immune system cells are the main producers of IL-22. However, targets of this cytokine are mostly non-hematopoietic cells such as hepatocytes, keratinocytes, and epithelial cells of lung and intestine. Association of IL-22 with other cytokines or transcription factors in different cell types might explain its contrasting role in health and disease. In this review we discuss the regulation of IL-22 production by AhR- and IL-23-driven pathways. A clear understanding of the biology of IL-22 will provide new opportunities for its application to improve human health involving many debilitating conditions.

Vasostatin-1 antigenic epitope mapping for induction of cellular and humoral immune responses to chromogranin A autoantigen in NOD mice.

The chromogranin A (ChgA) 29-42 sequence is the antigenic epitope for the BDC2.5 CD4(+) T-cell receptor in NOD mice (H-2(g7) ). We have now characterized the binding register of the ChgA 29-42 peptide for the I-A(g7) molecule. Truncation of the peptide demonstrated that the KCVLEVISD sequence 34-42 is the binding register and extension of this sequence by flanking residues increased its binding affinity and antigenic capacity. We employed anti-ChgA peptide antibodies generated against different fragments of ChgA for immunostaining of pancreatic islet sections from NOD mice. A strong immuno-staining pattern was observed for the ChgA 17-38 peptide antibodies that overlap with the ChgA 29-42 sequence. Moreover, sera from diabetic NOD mice showed elevated titers of autoantibodies to the ChgA 29-42 peptide. These findings indicate that peptides from the N-terminal region of ChgA are able to induce cellular and humoral immune responses in NOD mice.

The involvement of interleukin-22 in the expression of pancreatic beta cell regenerative Reg genes.

BACKGROUND: In Type 1 diabetes, the insulin-producing ß-cells within the pancreatic islets of Langerhans are destroyed. We showed previously that immunotherapy with Bacillus Calmette-Guerin (BCG) or complete Freund's adjuvant (CFA) of non-obese diabetic (NOD) mice can prevent disease process and pancreatic ß-cell loss. This was associated with increased islet Regenerating (Reg) genes expression, and elevated IL-22-producing Th17 T-cells in the pancreas. RESULTS: We hypothesized that IL-22 was responsible for the increased Reg gene expression in the pancreas. We therefore quantified the Reg1, Reg2, and Reg3δ (INGAP) mRNA expression in isolated pre-diabetic NOD islets treated with IL-22. We measured IL-22, and IL-22 receptor(R)-α mRNA expression in the pancreas and spleen of pre-diabetic and diabetic NOD mice. Our results showed: 1) Reg1 and Reg2 mRNA abundance to be significantly increased in IL-22-treated islets in vitro; 2) IL-22 mRNA expression in the pre-diabetic mouse pancreas increased with time following CFA treatment; 3) a reduced expression of IL-22Rα following CFA treatment; 4) a down-regulation in Reg1 and Reg2 mRNA expression in the pancreas of pre-diabetic mice injected with an IL-22 neutralizing antibody; and 5) an increased islet ß-cell DNA synthesis in vitro in the presence of IL-22. CONCLUSIONS: We conclude that IL-22 may contribute to the regeneration of ß-cells by up-regulating Regenerating Reg1 and Reg2 genes in the islets.

Modulation of autoimmune diseases by interleukin (IL)-17 producing regulatory T helper (Th17) cells.

Following the discovery of interleukin (IL)-17 producing T helper (Th17) cells as a distinct lineage of CD4+ T helper cells it became clear that these cells play an important role in the host defense against extracellular fungal and bacterial pathogens and participate in the pathogenesis of multiple inflammatory and autoimmune disorders. Depending on the microenvironment, Th17 cells can alter their differentiation programme ultimately giving rise to either protective or pro-inflammatory pathogenic cells. We found that besides the conventional in vitro protocol for Th17 differentiation by transforming growth factor-beta (TGF-ß) plus IL-6 cytokines, a combination of IL-23 plus IL-6 can also induce Th17 cells. The Th17 cells induced by IL-23 plus IL-6 (termed as effector Th17, Teff17 cells) are pathogenic upon adoptive transfer into non-obese diabetic (NOD) mice contributing to the development of type 1 diabetes (T1D) while cells induced by TGF-ß plus IL-6 (termed as regulatory T cells, Treg17 cells) are non pathogenic and regulatory, and suppressed the pathogenic T cells in T1D. These cells differentially expressed a number of cytokines where Teff17 cells exhibited an increase in granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-22 whereas Treg17 cells demonstrated increased expression of IL-21 and immunosuppressive cytokine IL-10. Differentiation of Th17 cells is controlled by a transcription factor, RORγT although these cells also express variable levels of T-bet and FoxP3 transcription factors. This points to a dual functional role of Th17 subsets in autoimmune diseases particularly T1D. We suggest that similar to conventional regulatory T cells (Treg), induction of regulatory Treg17 cells could play an important role in modulating and preventing certain autoimmune diseases.