BACKGROUND: The impacts of chronic airway diseases on coronavirus disease 2019 (COVID-19) are far from understood. OBJECTIVE: To explore the influence of asthma and chronic obstructive pulmonary disease (COPD) comorbidity on disease expression and outcomes, and the potential underlying mechanisms in COVID-19 patients. METHODS: A total of 961 hospitalized COVID-19 patients with a definite clinical outcome (death or discharge) were retrospectively enrolled. Demographic and clinical information were extracted from the medical records. Lung tissue sections from patients suffering from lung cancer were used for immunohistochemistry study of angiotensin-converting enzyme II (ACE2) expression. BEAS-2B cell line was stimulated with various cytokines. RESULTS: In this cohort, 21 subjects (2.2%) had COPD and 22 (2.3%) had asthma. After adjusting for confounding factors, COPD patients had higher risk of developing severe illness (OR: 23.433; 95% CI 1.525-360.135; P < .01) and acute respiratory distress syndrome (OR: 19.762; 95% CI 1.461-267.369; P = .025) than asthmatics. COPD patients, particularly those with severe COVID-19, had lower counts of CD4+ T and CD8+ T cells and B cells and higher levels of TNF-α, IL-2 receptor, IL-10, IL-8, and IL-6 than asthmatics. COPD patients had increased, whereas asthmatics had decreased ACE2 protein expression in lower airways, compared with that in control subjects without asthma and COPD. IL-4 and IL-13 downregulated, but TNF-α, IL-12, and IL-17A upregulated ACE2 expression in BEAS-2B cells. CONCLUSION: Patients with asthma and COPD likely have different risk of severe COVID-19, which may be associated with different ACE2 expression.

Distinct effects of asthma and COPD comorbidity on disease expression and outcome in patients with COVID-19.

Chronically inflamed tissues commonly accrue lymphocyte aggregates that facilitate local T cell-B cell interactions. These aggregates can range from small, loosely arranged lymphocyte clusters to large, organized ectopic lymphoid structures. In some cases, ectopic lymphoid structures develop germinal centers that house prototypical T follicular helper (Tfh) cells with high expression of Bcl6, CXCR5, PD-1, and ICOS. However, in many chronically inflamed tissues, the T cells that interact with B cells show substantial differences from Tfh cells in their surface phenotypes, migratory capacity, and transcriptional regulation. This review discusses observations from multiple diseases and models in which tissue-infiltrating T cells produce factors associated with B cell help, including IL-21 and the B cell chemoattractant CXCL13, yet vary dramatically in their resemblance to Tfh cells. Particular attention is given to the PD-1hi CXCR5- Bcl6low T peripheral helper (Tph) cell population in rheumatoid arthritis, which infiltrates inflamed synovium through expression of chemokine receptors such as CCR2 and augments synovial B cell responses via CXCL13 and IL-21. The factors that regulate CD4+ T cell production of CXCL13 and IL-21 in these settings are also discussed. Understanding the range of T cell populations that can provide help to B cells within chronically inflamed tissues is essential to recognize these cells in diverse inflammatory conditions and to optimize either broad or selective therapeutic targeting of B cell-helper T cells.

/pdf/t-cells-that-help-b-cells-in-chronically-inflamed-tissues-3s67h9wlre.pdf

T Cells That Help B Cells in Chronically Inflamed Tissues.

Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by local inflammation of the upper airways and is historically divided into 2 main phenotypes: CRS with nasal polyps and CRS without nasal polyps. Inflammation in CRS is mainly characterized by 3 endotypes based on elevation of canonical lymphocyte cytokines: type (T) 1 (T1) by TH1 cytokine IFN-γ, T2 by TH2 cutokines IL-4, IL-5, and IL-13, and T3 by TH17 cytokines including IL-17. Inflammation in both CRS without nasal polyps and CRS with nasal polyps is highly heterogeneous, and the frequency of various endotypes varies geographically around the world. This finding complicates establishment of a unified understanding of the mechanisms of pathogenesis in CRS. Sinonasal epithelium acts as a passive barrier, and epithelial barrier dysfunction is a common feature in CRS induced by endotype-specific cytokines directly and indirectly. The sinonasal epithelium also participates in both innate immunity via recognition by innate pattern-recognition receptors and promotes and regulates adaptive immunity via release of chemokines and innate cytokines including thymic stromal lymphopoietin. The purpose of this review was to discuss the contribution of the epithelium to CRS pathogenesis and to update the field regarding endotypic heterogeneity and various mechanisms for understanding pathogenesis in CRS. 

Mechanisms and pathogenesis of chronic rhinosinusitis.

Allergic rhinitis (AR) is a chronic inflammatory immunoglobulin (Ig) E-mediated disease of the nasal mucosa that can be triggered by the inhalation of seasonal or perennial allergens. Typical symptoms include sneezing, rhinorrhea, nasal itching, nasal congestion and symptoms of allergic conjunctivitis. AR affects a quarter of the population in the United States of America and Europe. AR has been shown to reduce work productivity in 36–59% of the patients with 20% reporting deteriorated job attendance. Moreover, 42% of children with AR report reduced at-school productivity and lower grades. Most importantly, AR impacts the patient’s quality of life, due to sleep deprivation. However, a proportion of patients fails to respond to conventional medication and opts for the allergen immunotherapy (AIT), which currently is the only disease-modifying therapeutic option. AIT can be administered by either subcutaneous (SCIT) or sublingual (SLIT) route. Both routes of administration are safe, effective, and can lead to tolerance lasting years after treatment cessation. Both innate and adaptive immune responses that contribute to allergic inflammation are suppressed by AIT. Innate responses are ameliorated by reducing local mast cell, basophil, eosinophil, and circulating group 2 innate lymphoid cell frequencies which is accompanied by decreased basophil sensitivity. Induction of allergen-specific blocking antibodies, immunosuppressive cytokines, and regulatory T and B cell phenotypes are key pro-tolerogenic adaptive immune responses. A comprehensive understanding of these mechanisms is necessary for optimal selection of AIT-responsive patients and monitoring treatment efficacy. Moreover, it could inspire novel and more efficient AIT approaches.

/pdf/mechanisms-of-allergen-immunotherapy-in-allergic-rhinitis-3vqplawzu9.pdf

Mechanisms of Allergen Immunotherapy in Allergic Rhinitis.

Allergic diseases are characterized by overactive type 2 immune responses to allergens and immunoglobulin E (IgE)-mediated hypersensitivity. Emerging evidence suggests that follicular helper T (TFH ) cells, rather than type 2 T-helper (TH 2) cells, play a crucial role in controlling IgE production. However, follicular regulatory T (TFR ) cells, a specialized subset of regulatory T (TREG ) cells resident in B-cell follicles, restricts TFH cell-mediated help in extrafollicular antibody production, germinal center (GC) formation, immunoglobulin affinity maturation, and long-lived, high-affinity plasma and memory B-cell differentiation. In mouse models of allergic asthma and food allergy, CXCR5+ TFH cells, not CXCR5- conventional TH 2 cells, are needed to support IgE production, otherwise exacerbated by CXCR5+ TFR cell deletion. Upregulation of TFH cell activities, including a skewing toward type 2 TFH (TFH 2) and IL-13 producing TFH (TFH 13) phenotypes, and defects in TFR cells have been identified in patients with allergic diseases. Allergen immunotherapy (AIT) reinstates the balance between TFH and TFR cells in patients with allergic diseases, resulting in clinical benefits. Collectively, further understanding of TFH and TFR cells and their role in the immunopathogenesis of allergic diseases creates opportunities to develop novel therapeutic approaches.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/all.14639

Roles of follicular helper and regulatory T cells in allergic diseases and allergen immunotherapy.

Background Locally produced IgE contributes to the initiation and development of eosinophilic inflammation in eosinophilic nasal polyps independent of systemic atopy. However, whether CXCR5 + CD4 + T follicular helper (T FH ) cells are involved in local IgE production at mucosal sites remains unexplored. Objective We sought to explore the presence, phenotype, and function of CXCR5 + CD4 + T FH cells in eosinophilic nasal polyp tissues compared with noneosinophilic nasal polyp and control normal nasal tissues. Methods T FH cell-surface phenotypes and subsets and B-cell subsets in nasal tissues and peripheral blood were studied by means of flow cytometry. Immunohistochemistry was used to detect the tissue location of T FH cells. Sorted nasal T FH cells and CXCR5 − T cells were cultured with autologous naive B cells purified from blood. Results Nasal T FH cells expressed inducible costimulator, programmed cell death protein 1, and the transcription factor B-cell lymphoma 6 (Bcl-6) at an intermediate level when compared with bona fide T FH cells in tonsils and circulating T FH cells. Although counts of total T FH cells and IL-21 + , IFN-γ + , and IL-17 + T FH cells were increased in both eosinophilic and noneosinophilic nasal polyp tissues compared with those in normal nasal tissues, IL-4 + T FH cell counts were only increased in eosinophilic polyp tissues. IL-4 and IL-21 were involved in polyp T FH cell–induced IgE production from naive B cells, and nasal IL-4 + T FH cell counts correlated highly with local IgE levels in vivo . IL-4 + Bcl-6 + CD4 + T FH cells were identified in ectopic lymphoid structures in eosinophilic nasal polyps. T FH cells also positively correlated with germinal center B cells and plasma cells in nasal tissues. Conclusion Nasal IL-4 + T FH cells might be involved in local IgE production in eosinophilic nasal polyps.

Nasal IL-4+CXCR5+CD4+ T follicular helper cell counts correlate with local IgE production in eosinophilic nasal polyps

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Nasal IL-4+CXCR5+CD4+ T follicular helper cell counts correlate with local IgE production in eosinophilic nasal polyps