Sinonasal T-cell expression of cytotoxic mediators granzyme B and perforin is reduced in patients with chronic rhinosinusitis.

BACKGROUND: CD8+ T cells and natural killer (NK) cells are cytotoxic cells that use granzyme B (GrB) and perforin. Defective cytotoxic function is known to play a role in dysregulated immune response as seen in chronic sinusitis, also referred to as chronic rhinosinusitis (CRS). However, to our knowledge, in the United States, neither GrB or perforin expression has been reported in patients with CRS. OBJECTIVE: The aim of this study was to investigate sinonasal cytotoxic cells, their mediators, and cell-specific distribution of these mediators in patients with CRS with nasal polyp (CRSwNP) and in patients with CRS without nasal polyp (CRSsNP). METHODS: Blood and sinus tissue samples were taken from patients with CRSsNP (n = 8) and CRSwNP (n = 8) at the time of surgery. Control subjects (n = 8) underwent surgery for cerebrospinal fluid leak repair or to remove non-hormone-secreting pituitary tumors. The cells were analyzed via flow cytometry by using CD8 expression to identify cytotoxic T cells and CD56 expression to identify NK cells. Intracellular GrB and perforin expression were analyzed with flow cytometry. RESULTS: We observed no significant differences in plasma or peripheral blood immune cell numbers or specific levels of GrB or perforin among the groups. In the sinonasal mucosa of the patients with CRSsNP and the patients with CRSwNP, there was a significant decrease in GrB and perforin levels (p < 0.05) despite similar or increased numbers of cytotoxic cells when compared with the controls. The overall decrease in GrB and perforin in the sinonasal mucosa of the patients with CRSsNP and the patients with CRSwNP was due to decreased T cell production. There was no difference in total NK cell count or expression of perforin or GrB among all the groups. CONCLUSION: Total levels of sinonasal GrB and perforin were decreased in the sinonasal mucosa of both the patients with CRSwNP and the patients with CRSsNP compared with the controls, whereas sinonasal CD8+ T cells, (but not NK cells,), intracellular stores of GrB and perforin were reduced in the patients with CRSwNP compared with the controls.

Vitamin D3 as a novel regulator of basic fibroblast growth factor in chronic rhinosinusitis with nasal polyposis.

BACKGROUND: The immunopathogenesis of chronic rhinosinusitis (CRS) is largely unknown, but it is thought that different inflammatory profiles are responsible for the different CRS subtypes. 25-Hydroxyvitamin-D (25-VD3) has been shown to alter inflammatory mediators in other disease processes and 25-VD3 deficiency is associated with CRS with nasal polyps (CRSwNP), but it is unknown if 25-VD3 levels impact local inflammation in CRS. This study investigated the correlation between plasma 25-VD3 and sinonasal mucus monocyte chemoattractant protein-1 (MCP-1), regulated upon activation normal T cell expressed and secreted (RANTES), and basic fibroblast growth factor (bFGF) levels in patients with CRS. METHODS: Study subjects undergoing endoscopic sinus surgery (ESS) for CRS were prospectively enrolled from January 2012 to August 2014. Control subjects included patients undergoing ESS for noninflammatory pathology. Blood and sinonasal mucus were collected at the time of ESS. Plasma 25-VD3 was measured by enzyme-linked immunosorbent assay (ELISA) and mucus levels of MCP-1, RANTES, and bFGF by cytometric bead array (CBA). RESULTS: A total of 57 patients were enrolled and categorized as CRS without nasal polyps (CRSsNP) (n = 31), CRSwNP (n = 14), and controls (n = 12). No significant correlation was found between MCP-1 and 25-VD3. There was a significant negative correlation between 25-VD3 and RANTES (r = -0.612; p = 0.026) and bFGF (r = -0.578; p = 0.039) in CRSwNP patients; however, there was no significant correlation in CRSsNP patients. CONCLUSION: This data suggests that 25-VD3 may play a role in regulation of RANTES and bFGF expression in CRSwNP. This may occur through regulation of NP fibroblasts or other immune cells. Further investigation is warranted to better elucidate the role of RANTES, bFGF, and 25-VD3 in CRSwNP.

Vitamin D for the treatment of respiratory diseases: is it the end or just the beginning?

A large number of human, animal and in vitro studies have suggested that vitamin D3 (VD3) plays a critical role in inflammatory airway diseases such as asthma, chronic rhinosinusitis, and allergic rhinitis. VD3 acts upon a broad range of immune cells involved in the pathogenesis of these diseases including T-cells, dendritic cells (DCs), macrophages, and B-cells. In addition, VD3 can also regulate the functions of a number of non-immune cells including epithelial cells, fibroblasts, and smooth muscle cells. Given that VD3 has known effects on the immune system, it seems logical that supplementation with VD3 would prove efficacious in the treatment of these three diseases. While many studies, most of which are observational, have suggested that VD3 deficiency is associated with more severe disease, VD3 supplementation trials in humans have resulted in varied outcomes in terms of efficacy. In this review article we will discuss the role of VD3 in these three commonly associated respiratory diseases. We will explore the literature describing associations of VD3 deficiency with patient outcomes, cells in the respiratory microenvironment susceptible to VD3 regulation, conflicting results of VD3 supplementation trials, and potential gaps in our knowledge that may be limiting the widespread use of VD3 for the treatment of respiratory diseases such asthma, chronic rhinosinusitis and allergic rhinitis. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.

Characterization of B-cell subpopulations in patients with chronic rhinosinusitis.

BACKGROUND: Recent research suggest that B and plasma cells may play an important role in the pathogenesis of chronic rhinosinusitis with nasal polyposis (CRSwNP). The purpose of this study was to subcharacterize the B cell response in the sinus mucosa of control and CRS patients. METHODS: Representative tissue samples and peripheral blood samples were obtained from controls, CRS without nasal polyps (CRSsNP) and CRSwNP. Using single-cell suspension flow cytometry these samples were analyzed for overall and stage-specific B and plasma cell percentages. RESULTS: Both atopic and nonatopic CRSwNP patients showed an increase in local numbers of naive, active, and memory B cells compared to controls. CRSsNP patients only showed local elevations of naive B cells. Plasma cells were only significantly elevated in the sinus tissue of atopic CRSwNP patients. These local tissue increases did not correlate with increased numbers of circulating B cells. CONCLUSION: This study provides further evidence of an important role of B cells in CRSwNP patients. The local increase appears to be independent of a systemic response.

A systematic review of the endoscopic repair of cerebrospinal fluid leaks.

OBJECTIVES: To provide an up-to-date review of the literature on the safety and efficacy of the endoscopic technique for cerebrospinal (CSF) leak repairs. DATA SOURCES: PubMed, Medline/Old Medline, and Cochrane Central databases. REVIEW METHODS: Using the above outlined data sources, studies involving the endoscopic repair of CSF leaks were reviewed independently by 2 researchers. Studies included met the following criteria: full-text article written in the English language, at least 5 human patients undergoing purely endoscopic surgical repair of a CSF leak, and documented follow-up. Data extracted included leak etiology, presentation and location, the use of imaging, intrathecal fluorescein, and adjunctive measures as well as the success rate of the repair. RESULTS: Fifty-five studies, involving 1778 fistulae repairs, were included for analysis. Spontaneous leaks were most prevalent, with the ethmoid roof and sphenoid the most common sites involved. The overall success rate of repair was high at 90% for primary and 97% for secondary repairs. A low complication rate of less than 0.03% was reported. CONCLUSION: The endoscopic repair of CSF fistula is both safe and effective and should be considered the standard of care for most cases. Evidence supporting adjunctive measures such as lumbar drains and antibiotics remains limited despite their common use.