A small-molecule enhancer of STAT1 affects herpes simplex keratitis prognosis by mediating plasmacytoid dendritic cells migration through CXCR3/CXCL10.

Aims/Purpose: Prior work from our group has demonstrated a role for plasmacytoid dendritic cells (pDCs) in corneal nerve homeostasis. Herein, we sought to determine if pDC‐derived secretome could be used for the treatment of neuropathic corneal pain.Methods: The BDCA2‐DTR transgenic mice, in which pDCs can be selectively depleted result in subsequent nerve degeneration, were utilized for ex vivo electrophysiology studies. Animals were treated with pDC secretome drops, beginning 1 day after initial depletion. Electrophysiologic recordings were taken at day 3 post‐depletion analysed. A ciliary nerve ligation model of neuropathic corneal pain (NCP), was used to assess the therapeutic potential of pDC secretome. Spontaneous and evoked pain responses were assessed by palpebral opening measurements and hyperosmolar saline, respectively.Results: There was a significant reduction in cooling threshold following pDC depletion, which was rescued by pDC secretome treatment (26.85 ± 0.65°C vs. 29.52 ± 0.42°C; p < 0.05), restoring the cooling threshold to control levels (29.21 ± 0.51). Furthermore, nerve terminal exhaustion was reduced following pDC depletion and rescued by pDC secretome treatment (0.55 ± 0.08 vs. 1.11 ± 0.10; p < 0.01). Spontaneous pain responses were worse in the vehicle‐treated compared to pDC secretome‐treated group (0.67 ± 0.03 vs. 0.85 ± 0.02; p < 0.001). Similarly, evoked pain responses were worse in the vehicle‐treated compared to pDC secretome‐treated group (30.25 ± 1.50 wipes/30 sec vs. 15.38 ± 1.29; p < 0.0001).Conclusions: Herein, we demonstrate that pDC secretome restores normal functioning of corneal cold receptors. Importantly, in a translational model of NCP, pDC secretome treatment improved both spontaneous and evoked pain responses. Thus, pDC secretome is a viable therapeutic modality for further development and may hold promise in treatment of NCP and other corneal nerve related diseases.Reference1. Jamali A, Kenyon B, Ortiz G, Abou‐Slaybi A, Sendra VG, Harris DL, Hamrah P. Plasmacytoid Dendritic Cells in the Eye. Prog Retin Eye Res 2021; 80: 100877.2. Jamali A, Hu K, Sendra VG, Blanco T, Qazi Y, Zheng L, Turhan A, Hamrah P. Characterization of Resident Corneal Plasmacytoid Dendritic Cells and Their Pivotal Role in Herpes Simplex Keratitis. Cell Rep 2020; 32: 108099.

PurposeTo determine the role of plasmacytoid dendritic cells (pDC) and myeloid dendritic cells (mDC) in priming effector T cells to induce allergy, and to evaluate the effect of immunostimulatory sequences (ISS, TLR9 agonist) on dendritic cells.MethodsCultured mDC and pDC with/without ISS were injected intratracheally into sensitized Balb/C mice. Mice were sacrificed, and then pulmonary function tests, bronchoalveolar lavage (BAL), cell counts, and cytokine levels were evaluated. Migration of dendritic cells was also evaluated after ISS administration.ResultsIn mice injected with mDC, airway hyperresponsiveness, eosinophil counts, and Th2 cytokine levels in BAL increased with increasing numbers of mDC injected. However, in mice injected with pDC, none of these changed, suggesting poor priming of T cells by pDC. In addition, mDC pulsed with ISS inhibited asthmatic reactions, and ISS administration inhibited migration of DC to the lung.ConclusionsWe suggest that pDC played a limited role in priming T cells in this asthma model and that mDC played a major role in inducing asthma. In addition, ISS inhibited migration of DC to the lung.

The role of plasmacytoid dendritic cells (PDC), the major producers of alpha interferon upon viral infection, in the nasal mucosa is largely unknown. Here we examined the presence of PDC together with myeloid dendritic cells (MDC) in the nasal epithelia of healthy individuals, of asymptomatic patients with chronic nasal allergy, of patients undergoing steroid therapy, and of patients with infectious rhinitis or rhinosinusitis. Considerable numbers of PDC and MDC could be detected in the nasal epithelium. Furthermore, we demonstrate the expression of SDF-1, the major chemoattractant for PDC, in the nasal epithelium. PDC levels were significantly lower for patients with allergies than for healthy individuals. Interestingly, PDC and MDC were almost absent from patients who received treatment with glucocorticoids, while very high numbers of PDC were found for patients with recent upper respiratory tract infections. Our results demonstrate for the first time a quantitative analysis of PDC and MDC in the healthy nasal epithelium and in nasal epithelia from patients with different pathological conditions. With the identification of PDC, the major target cell for CpG DNA or immunostimulatory RNA, in the nasal epithelium, this study forms the basis for a local nasal application of such oligonucleotides for the treatment of viral infection and allergy.

Plasmacytoid DCs and cancer: a new role for an enigmatic cell

T 26th International Symposium of the Sapporo Cancer Seminar was held at Hokkaido University, Sapporo, Japan, on July 21–23, 2006. More than 120 researchers from various countries participated in the meeting (Fig. 1). The weather was fine every day, and the participants enjoyed walks around the university campus and dining at Chara Restaurant and Kirin Beer Garden. The symposium consisted of seminars presented by leading researchers from Japan and overseas in the field of innate immunity. Oral presentations were given by 12 researchers and poster presentations were given by 21 researchers. The symposium was organized by Dr Tsukasa Seya (Hokkaido University, Japan), as the chairman, and committee members Drs Misako Matsumoto, Hirofumi Sawa, Tokiyoshi Ayabe, and Roberto Cattaneo. Ms Saoko Kume was particularly involved in the organization of this meeting.

To assess the impact of the IFIT3/TBK1 signalling pathway in activating plasmacytoid dendritic cells (pDCs) and its role in the development of SSc. Utilized single-cell RNA sequencing (scRNA-seq) and high-throughput transcriptome RNA sequencing to reveal the differential abundance of pDCs and the role of the key gene IFIT3 in SSc. Conducted in vitro cell experiments to evaluate the effect of IFIT3/TBK1 signalling pathway intervention on pDC activation cytokine release and fibroblast function. Constructed an IFIT3-/- mouse model using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene editing to assess the potential benefits of intervening in the IFIT3/TBK1 signalling pathway on skin and lung fibrosis in the SSc mouse model. The IFIT3/TBK1 signalling pathway plays a crucial role in activating pDCs, with IFIT3 acting as an upstream regulator of TBK1. Intervention in the IFIT3/TBK1 signalling pathway can inhibit pDC activation cytokine release and impact fibroblast function. The IFIT3-/- mouse model shows potential benefits of targeting the IFIT3/TBK1 signalling pathway in reducing skin and lung fibrosis in the SSc mouse model. This study provides new insights into potential therapeutic targets for SSc, highlighting the critical role of the IFIT3/TBK1 signalling pathway in SSc development. This study elucidates the pivotal role of plasmacytoid dendritic cells (pDCs) in systemic sclerosis (SSc). This study identified the key regulatory gene involved in systemic sclerosis (SSc) as IFIT3. This study has found that IFIT3 functions as an upstream regulatory factor, activating TBK1. This study provides Evidence of the regulatory effects of the IFIT3/TBK1 pathway on plasmacytoid dendritic cells (pDCs). This study validated the therapeutic potential using the IFIT3-/- mouse model.

Cutaneous distribution of plasmacytoid dendritic cells in lupus erythematosus. Selective tropism at the site of epithelial apoptotic damage

Biology of Lung Dendritic Cells at the Origin of Asthma

Purpose To report the quantitative effectiveness of photodynamic therapy (PDT) with verteporfin in reducing corneal neovascularization (CNV) and lipid keratopathy (LK) in patients with herpetic interstitial keratitis. Methods We retrospectively evaluated patients with secondary LK due to herpetic keratitis who underwent PDT with Verteporfin. We analyzed before and after PDT, visual acuity (VA) and the percentage of CNV, LK, and total pathological corneal areas. The number of stromal neo-vessels and its activity, and the severity of the corneal opacity were also analyzed. Results We studied nine consecutive patients. The CNV area, LK extent, pathological area, vessel count, vessel activity and corneal opacity all exhibited a statistically significant decrease (p < 0.05) in all patients following PDT. A second PDT was required in 3 patients. Complete vascular occlusion was observed in 5 eyes (55.5%), and partial occlusion in 3 eyes (33.5%). The mean post-treatment VA was 0.76 ± 0.32. VA improved by more than 1 line in 5 eyes (55.5%), with more than 2 line-improvement observed in 4 eyes (44.4%). It remain unchanged in 3 eyes (33.3%), while one patient (11%) worsened. No adverse effects were detected after a mean of 14.9 ± 3.9 years follow-up. There was no relapse of herpetic keratitis after discharging 88,8% patients (follow-up after discharged 8.1 ± 4.6 years). Conclusion PDT with verteporfin is a safe and effective treatment of herpetic CNV and LK, with long lasting efficacy. Additionally, after the treatment, our cases had a lower incidence of herpetic recurrences than expected.

ABSTRACTIntroduction: Cornea clarity is essential for optimal vision at any age. In childhood, loss of corneal transparency may also lead to amblyopia. Thus, proper management of the conditions that lead to corneal scarring and neovascularization in children is of utmost importance.Areas covered: Herein, we review the pathophysiology of the main causes of corneal inflammation, scarring and neovascularization in childhood. A review of the literature was performed using the keywords ‘herpetic keratitis’, ‘blepharokeratoconjunctivitis’, ‘ocular rosacea’, ‘phlyctenular conjunctivitis’, ‘vernal keratoconjunctivitis’, and ‘corneal neovascularization’ in combination with the words ‘children’ or ‘childhood’.Expert commentary: Regardless of the underlying cause of the inflammatory stimulus – viral infection, meibomian gland secretions, atopy – scarring and neovascularization occur when expression of pro-angiogenic factors outweighs that of anti-angiogenic ones. Proper control of the inflammation will restore the equilibrium between pro- and anti-angiogenic enzymes and cytokines and, in turn, limit the resulting scarring and neovessel formation. Early diagnosis and therapy for herpetic infection, blepharokeratoconjunctivitis, and atopic disease can preserve and/or restore corneal clarity in childhood keratitis.

We addressed the role of plasmacytoid dendritic cells (PDC) in protection against AIDS in nonpathogenic simian immunodeficiency virus (SIVagm) infection in African green monkeys (AGMs). PDC were monitored in blood and lymph nodes (LNs) starting from day 1 postinfection. We observed significant declines in blood during acute infection. However, PDC then returned to normal levels, and chronically infected AGMs showed no decrease of PDC in blood. There was a significant increase of PDC in LNs during acute infection. Blood PDC displayed only weak alpha interferon (IFN-alpha) responses to TLR9 agonist stimulation before infection. However, during acute infection, both blood and LN PDC showed a transiently increased propensity for IFN-alpha production. Bioactive IFN-alpha was detected in plasma concomitant with the peak of viremia, though levels were only low to moderate in some animals. Plasma interleukin 6 (IL-6) and IL-12 were not increased. In conclusion, PDC were recruited to the LNs and displayed increased IFN-alpha production during acute infection. However, increases in IFN-alpha were transient. Together with the lack of inflammatory cytokine responses, these events might play an important role in the low level of T-cell activation which is associated with protection against AIDS in nonpathogenic SIVagm infection.

To study the precise role of Plasmacytoid dendritic cells (PDCs) and mast cells (MC) in Sjögren's Syndrome (SS). Lip specimen (178 SS vs 7 Sicca) were performed on lymphocytes infiltration, acinar atrophy and intralobular fibrosis. MC, PDCs, CD68 and CXCL13 were detected by IHC or toluidine blue. CXCL13 gene was detected by PCR. Significant lymphocytes infiltration, acinar atrophy and intralobular fibrosis were observed in SS. PDCs and MC were increased in SS than Sicca (p=0.03/0.02). Positive correlation between PDCs with lymphocytes infiltration (p=0.02) and MC with intralobular fibrosis (p=0.03) in primary SS (pSS) was observed. Within the pSS, PDCs correlated with CXCL13+cells, especially CXCL13+macrophages. When macrophages were stimulated with IFN-a in vitro, CXCL13 gene was up-regulated.Our data suggests the specific role of PDCs in lymphocyte infiltration and MCs in intralobular fibrosis of pSS. Therefore, it is likely that PDCs in early stage inducing CXCL13 production from macrophages due to IFN-a contributing to lymphocyte infiltration further constructing germinal centers. In addition, MC seems to be involved in intralobular fibrosis which occurs in mid to late stage of SS.

The role of dendritic cells in asthma

Plasmacytoid dendritic cells are part of the dendritic cells family and are a relevant link between innate and adaptive immunity. They are the most potent producers of type 1 interferon, generating antiviral response, stimulating macrophages and dendritic cells and inducing activation and migration of natural killer cells. Plasmacytoid dendritic cells also exert a role as antigen-presenting cells, promote T-lymphocyte responses, immunoregulation, plasma cells differentiation and antibody secretion. Even though plasmacytoid dendritic cells are not usually present in normal skin, their presence is detected in healing processes, viral infections, and inflammatory, autoimmune, and neoplastic diseases. In recent years, the presence of plasmacytoid dendritic cells in several dermatological diseases has been described, enhancing their potential role in the pathogenesis of such conditions. Future studies on the role of plasmacytoid dendritic cells in dermatology may lead to new therapeutic targets.

Reestablishing immune tolerance and long-term suppression of disease represent major therapeutic goals in rheumatoid arthritis (RA). Dendritic cells (DCs) likely play a central role in such regulation via the expansion and/or induction of Treg cells. The present study was undertaken to explore the contribution of DCs to the development of Treg cells in a human autoimmune disease setting. DC subsets were characterized by flow cytometry in the peripheral blood and synovial fluid of patients with RA. Proliferation of and cytokine release by naive CD4+CD25- T cells were measured in cocultures of these cells with DCs from patients with RA and healthy controls. The suppressive capacity of DC-polarized T cells was explored in vitro by a standard suppression assay. Only very low numbers of both plasmacytoid DCs (CD303+) and myeloid DCs (CD1c+) were present in the peripheral blood of patients with active RA. In contrast, patients with therapy-induced remission of RA exhibited higher numbers of circulating plasmacytoid DCs. Mature plasmacytoid DCs from RA patients with low disease activity, but not those from healthy controls, expressed high levels of indoleamine 2,3-dioxygenase and promoted the differentiation of allogeneic naive CD4+CD25- T cells into interleukin-10-secreting Treg cells, or Tr1 cells, that showed poor proliferation in vitro. Importantly, these plasmacytoid DC-primed Treg cells potently suppressed the proliferation of autologous naive CD4+ T cells, in a dose-dependent manner. These results demonstrate, for the first time, that human plasmacytoid DCs may be educated within the rheumatoid microenvironment to acquire a tolerogenic phenotype. Modulation of the immune response by plasmacytoid DCs might provide novel immune-based therapies in autoimmunity and transplantation.