Improvement of eosinophilic chronic rhinosinusitis after infection with severe acute respiratory syndrome corona virus 2 during dupilumab therapy: A case report.

Eosinophilic chronic rhinosinusitis (ECRS) is an intractable type 2 inflammatory disease of the paranasal sinuses that persists even after endoscopic sinus surgery (ESS) and systemic corticosteroid therapy. Dupilumab, a monoclonal antibody against the shared receptor components of interleukin (IL)-4 and IL-13, is a novel and effective treatment option for ECRS. Herein, an atypical case of ECRS that improved after infection with severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) during dupilumab therapy is reported. A 40-year-old man with a history of ESS for ECRS visited our hospital with complaints of nasal congestion and dysosmia. Nasal endoscopy revealed bilateral nasal polyps occupying the nasal cavity. Computed tomography (CT) revealed a soft tissue density lesion filling all sinuses on both sides. Based on these findings, ECRS recurrence was confirmed; however, 3 years of subsequent corticosteroid therapy did not improve disease activity. Accordingly, dupilumab therapy was initiated, although 6 months of therapy resulted in only slight improvement in ECRS. Eight months after the initiation of dupilumab therapy, the patient was infected with SARS-CoV-2; thereafter, he noticed an improvement in smell. Nasal endoscopy and sinus CT revealed a marked reduction in nasal polyps and soft tissue density lesions of the sinuses, respectively. With continued dupilumab therapy, no re-exacerbation of ECRS was confirmed at the 6-month follow-up from SARS-CoV-2 infection. Currently, there are no reports describing the impact of SARS-CoV-2 infection on ECRS. As such, careful follow-up and accumulation of cases are necessary.

Immunological status of the olfactory bulb in a murine model of Toll-like receptor 3-mediated upper respiratory tract inflammation.

BACKGROUND: Postviral olfactory dysfunction (PVOD) following a viral upper respiratory tract infection (URI) is one of the most common causes of olfactory disorders, often lasting for over a year. To date, the molecular pathology of PVOD has not been elucidated. METHODS: A murine model of Toll-like receptor 3 (TLR3)-mediated upper respiratory tract inflammation was used to investigate the impact of URIs on the olfactory system. Inflammation was induced via the intranasal administration of polyinosinic-polycytidylic acid (poly(I:C), a TLR3 ligand) to the right nostril for 3 days. Peripheral olfactory sensory neurons (OSNs), immune cells in the olfactory mucosa, and glial cells in the olfactory bulb (OB) were analyzed histologically. Proinflammatory cytokines in the nasal tissue and OB were evaluated using the quantitative real-time polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA). RESULTS: In the treated mice, OSNs were markedly reduced in the olfactory mucosa, and T cell and neutrophil infiltration therein was observed 1 day after the end of poly(I:C) administration. Moreover, there was a considerable increase in microglial cells and slight increase in activated astrocytes in the OB. In addition, qPCR and ELISA revealed the elevated expression of interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma both in the OB and nasal tissue. CONCLUSIONS: Taken together, the decreased peripheral OSNs, OB microgliosis, and elevated proinflammatory cytokines suggest that immunological changes in the OB may be involved in the pathogenesis of PVOD.

Caloric restriction reduces basal cell proliferation and results in the deterioration of neuroepithelial regeneration following olfactotoxic mucosal damage in mouse olfactory mucosa.

The effects of caloric restriction (CR) on cell dynamics and gene expression in the mouse olfactory neuroepithelium are evaluated. Eight-week-old male C57BL/6 mice were fed either control pellets (104 kcal/week) or CR pellets (67 kcal/week). The cytoarchitecture of the olfactory neuroepithelium in the uninjured condition and its regeneration after injury by an olfactotoxic chemical, methimazole, were compared between mice fed with the control and CR diets. In the uninjured condition, there were significantly fewer olfactory marker protein (OMP)-positive olfactory receptor neurons and Ki67-positive proliferating basal cells at 3 months in the CR group than in the control group. The number of Ki67-positive basal cells increased after methimazole-induced mucosal injury in both the control and the CR groups, but the increase was less robust in the CR group. The recovery of the neuroepithelium at 2 months after methimazole administration was less complete in the CR group than in the control group. These histological changes were region-specific. The decrease in the OMP-positive neurons was prominent in the anterior region of the olfactory mucosa. Gene expression analysis using a DNA microarray and quantitative real-time polymerase chain reaction demonstrated that the expression levels of two inflammatory cytokines, interleukin-6 and chemokine ligand 1, were elevated in the olfactory mucosa of the CR group compared with the control group. These findings suggest that CR may be disadvantageous to the maintenance of the olfactory neuroepithelium, especially when it is injured.

Successful Posterior Canal Wall Reconstruction with Tissue-Engineered Cartilage.

Difficulties are associated with reconstruction of middle ear bony structures in surgery for destructive lesions, including cholesteatoma. Although autologous cartilage appears to be the optimal choice because of its resistance to infection, the harvesting of sufficient volumes may be challenging. Therefore, regenerative medicine techniques to obtain sufficient material for reconstruction are awaited. We herein present a case of middle ear surgery for cholesteatoma with a sufficient volume of stick-shaped tissue-engineered cartilage produced from a piece of autologous auricular cartilage and autologous serum, with sufficient firmness to reconstruct bony structures. During surgery, sections of tissue-engineered cartilage were placed side by side to reconstruct the posterior canal wall. The postoperative course was uneventful. This is the first-in-human report of reconstructing middle ear bony structures with tissue-engineered cartilage. The results suggest a promising future for the satisfactory reconstruction of middle ear structures with minimal morbidity at the donor site.

Prolonged denervation induces remodeling of nasal mucosa in rat model of posterior nasal neurectomy.

BACKGROUND: The posterior nasal nerve is the dominant source of the parasympathetic, sympathetic, and sensory fibers that innervate the nasal respiratory mucosa. Therefore, a posterior nasal neurectomy (PNN) induces denervation of the nasal mucosa and relieves the nasal symptoms of intractable rhinitis. PNN depletes nerve fibers, choline acetyltransferase, and neuropeptides in nasal respiratory mucosa, and reduces nasal secretion. However, the histological and symptomatic changes over an extended period after PNN remain unknown. METHODS: Using a rat model of PNN via the transorbital approach, we investigated chronological changes of nasal morphology, innervation, and secretion over a 48-week postoperative period after PNN. RESULTS: The respiratory nasal mucosa exhibited squamous metaplasia, lymphocyte and plasma cell infiltration, basement membrane thickening, loss of cilia, and hyperplasia of the mucus gland in thickened epithelium with increased connective tissue from 24 weeks after PNN. These changes resemble the characteristics of remodeling in chronic rhinosinusitis. DNA microarray and quantitative polymerase chain reaction analysis revealed that mucin 5ac, interleukin 13, and brain-derived neurotrophic factor messenger RNA (mRNA) were upregulated in PNN-treated mucosa compared to untreated mucosa. During this period, nerve fibers including sensory, sympathetic, and parasympathetic fibers gradually reinnervated the mucosa from 12 weeks after PNN. However, nasal secretion was decreased even at 48 weeks after PNN probably due to the prolonged absence of choline acetyltransferase. CONCLUSION: Prolonged denervation induces remodeling of the nasal mucosa. Although the depleted nerves were partially reinnervated a few months after PNN, nasal secretion was still suppressed, partly due to a sustained deficiency of acetylcholine synthesis.

Longer latency of sensory response to intravenous odor injection predicts olfactory neural disorder.

A near loss of smell may result from conductive and/or neural olfactory disorders. However, an olfactory test to selectively detect neural disorders has not been established. We investigated whether onset latency of sensory response to intravenous odor injection can detect neural disorders in humans and mice. We showed that longer preoperative onset latency of odor recognition to intravenous odor in patients with chronic rhinosinusitis predicted worse recovery of olfactory symptoms following sinus surgery. The onset latency of the olfactory sensory neuron (OSN) response to intravenous odor using synaptopHluorin signals from OSN axon terminals was delayed in mice with reduced numbers of OSNs (neural disorder) but not with increased mucus or blocked orthonasal pathways (conductive disorders). Moreover, the increase in onset latency correlated with the decrease in mature OSN numbers. Longer onset latency to intravenous odor injection is a useful biomarker for presence and severity of olfactory disorders with neural etiology.

Denervation of nasal mucosa induced by posterior nasal neurectomy suppresses nasal secretion, not hypersensitivity, in an allergic rhinitis rat model.

The posterior nasal nerve is the dominant source of the parasympathetic, sympathetic, and sensory fibers that innervate the nasal respiratory mucosa. Therefore, a posterior nasal neurectomy (PNN) is thought to induce denervation of the nasal mucosa and relieve the nasal symptoms of allergic rhinitis. However, the underlying mechanisms and therapeutic action of PNN remain unknown. To investigate the impact of PNN-induced denervation of the nasal mucosa on allergic rhinitis, we developed a rat model of PNN and examined the effects of PNN on allergic rhinitis in ovalbumin-sensitized rats. This rat model of PNN was characterized by the depletion of nerve fibers, choline acetyltransferase, and neuropeptides (eg, substance P, calcitonin gene-related peptide, vasoactive intestinal peptide, and neuropeptide Y) in the nasal respiratory mucosa. These animals exhibited nasal gland and goblet cell hypertrophy in the septal mucosa and atrophy of the submucosal gland in the lateral nasal wall, as well as reduced nasal secretion due to deficient acetylcholine synthesis. In an ovalbumin-sensitized model of allergic rhinitis, PNN also induced the depletion of nerve fibers, choline acetyltransferase, and neuropeptides in the nasal mucosa and suppressed nasal secretion. However, PNN did not affect mucosal thickening, eosinophil and mast cell infiltration, interleukin-4 and interferon-γ mRNA expression, and allergic symptoms (ie, sneezing and nasal scratching). These results suggest that the peripheral nerves and corresponding neuropeptides regulate nasal secretion, but not hypersensitivity, in allergic rhinitis, and that allergic rhinitis-related mucosal reactions occur in a highly denervated mucosa after PNN. Posterior nasal neurectomy may be a therapeutic option for the treatment of hyperrhinorrhea, but not allergic rhinitis hypersensitivity.

BTB-ZF Protein Znf131 Regulates Cell Growth of Developing and Mature T Cells.

Many members of the BTB-ZF family have been shown to play important roles in lymphocyte development and function. The role of zinc finger Znf131 (also known as Zbtb35) in T cell lineage was elucidated through the production of mice with floxed allele to disrupt at different stages of development. In this article, we present that Znf131 is critical for T cell development during double-negative to double-positive stage, with which significant cell expansion triggered by the pre-TCR signal is coupled. In mature T cells, Znf131 is required for the activation of effector genes, as well as robust proliferation induced upon TCR signal. One of the cyclin-dependent kinase inhibitors, p21(Cip1) encoded by cdkn1a gene, is one of the targets of Znf131. The regulation of T cell proliferation by Znf131 is in part attributed to its suppression on the expression of p21(Cip1).

Ly49Q ligand expressed by activated B cells induces plasmacytoid DC maturation.

Ly49Q, a type II C-type lectin expressed on mouse plasmacytoid DC (pDC), contains a single carbohydrate recognition domain in its extracellular region and an ITIM in its cytoplasmic domain. We have identified the MHC class I molecule H-2K(b) as a Ly49Q ligand, confirming prior reports. Although H-2K(b) is expressed on essentially all hematopoietic cells, we found that only CpG-stimulated B cells were able to activate Ly49Q. This discovery correlated with our finding that although H-2K(b) forms clusters on CpG-activated B cells, it is diffusely expressed on resting B cells. Furthermore, CpG-stimulated, but not resting, B cells up-regulated co-stimulatory molecules on pDC. This finding was confirmed by the fact that binding by anti-Ly49Q mAb to Ly49Q led to pDC maturation in vitro. Our results suggest that clustered H-2K(b) on activated B cells act as ligands for Ly49Q and induce pDC maturation in vitro.

The role of CD11b in phagocytosis and dendritic cell development.

Activation of resting T cells is highly dependent on dendritic cells (DCs), which take up antigens and present antigenic peptides to T cells in the context of the major histocompatibility complex (MHC). In this study, we generated a monoclonal antibody, which we call 1C4 that recognizes integrin alpha(M)beta(2) (CD11b/CD18) on the surface of conventional DCs (cDCs) and is internalized after binding. Addition of 1C4 inhibited the ability of immature DCs to phagocytose apoptotic cells. 1C4 treatment also partially inhibited the generation of cDCs from bone marrow in the presence of granulocyte macrophage colony-stimulating factor (GM-CSF). Our findings suggest that not only CD11b is involved in the phagocytosis of apoptotic cells, but also that mAb such as 1C4 may be a useful tool for the delivery of specific proteins into the cytoplasm of immature DCs.

Type I interferon regulates pDC maturation and Ly49Q expression.

Ly49Q is expressed on peripheral mouse plasmacytoid dendritic cells (pDC). Immature Ly49Q-negative pDC precursors acquire Ly49Q in the bone marrow and then migrate into the periphery. While searching for molecules that regulate pDC maturation, we found that type I interferon (IFN) inhibited Ly49Q acquisition in vitro. Infections that induce type I IFN production by cells other than pDC (a condition mimicked by poly(I:C) injection in vivo) increase the prevalence of Ly49Q(-) pDC in the bone marrow and peripheral lymphoid organs in wild-type but not IFN-alpha/beta receptor knockout BALB/c mice. Moreover, in vivo exposure to type I IFN causes some Ly49Q(-), but not Ly49Q(+), pDC to convert to conventional DC, defined as B220(-) CD11c(+) CD11b(+) cells. These data suggest that type I IFN regulates pDC development and affects their distribution in the body.