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Viruses ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 147
Author(s):  
Abenaya Muralidharan ◽  
Md Bashir Uddin ◽  
Christopher Bauer ◽  
Wenzhe Wu ◽  
Xiaoyong Bao ◽  
...  

The susceptibility to respiratory syncytial virus (RSV) infection in early life has been associated with a deficient T-helper cell type 1 (Th1) response. Conversely, healthy adults generally do not exhibit severe illness from RSV infection. In the current study, we investigated whether Th1 cytokine IFN-γ is essential for protection against RSV and RSV-associated comorbidities in adult mice. We found that, distinct from influenza virus, prior RSV infection does not induce significant IFN-γ production and susceptibility to secondary Streptococcus pneumoniae infection in adult wild-type (WT) mice. In ovalbumin (OVA)-induced asthmatic mice, RSV super-infection increases airway neutrophil recruitment and inflammatory lung damage but has no significant effect on OVA-induced eosinophilia. Compared with WT controls, RSV infection of asthmatic Ifng−/− mice results in increased airway eosinophil accumulation. However, a comparable increase in eosinophilia was detected in house dust mite (HDM)-induced asthmatic Ifng−/− mice in the absence of RSV infection. Furthermore, neither WT nor Ifng−/− mice exhibit apparent eosinophil infiltration during RSV infection alone. Together, these findings indicate that, despite its critical role in limiting eosinophilic inflammation during asthma, IFN-γ is not essential for protection against RSV-induced exacerbation of asthmatic inflammation in adult mice.


2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Seong-A Ju ◽  
Quang-Tam Nguyen ◽  
Thu-Ha T. Nguyen ◽  
Jae-Hee Suh ◽  
Won G. An ◽  
...  

Sepsis is characterized by an initial net hyperinflammatory response, followed by a period of immunosuppression, termed immunoparalysis. During this immunosuppressive phase, patients may have difficulty eradicating invading pathogens and are susceptible to life-threatening secondary hospital-acquired infections. Due to progress in antimicrobial treatment and supportive care, most patients survive early sepsis. Mortality is more frequently attributed to subsequent secondary nosocomial infections and multiorgan system failure. 6-Gingerol is the major pharmacologically active component of ginger. Although it is known to exhibit a variety of biological activities, including anti-inflammation and antioxidation, the role of 6-gingerol in sepsis-induced immune dysfunction remains elusive. Thus, we investigated whether 6-gingerol improves septic host response to infections during sepsis. 6-Gingerol-treated mice showed significantly lower mortality in polymicrobial sepsis induced by cecal ligation and puncture LPS via enhanced bacterial clearance in the peritoneum, blood, and organs (liver, spleen, and kidney) and inhibited the production of TNF-α and IL-6 in TLR2 and/or TLR4-stimulated macrophages. In addition, we demonstrated that survival improvement of secondary infection following septic insult was associated with an initial response of enhanced neutrophil numbers and function at the infection site, reduced apoptosis of immune cells, and a shift from a T helper cell type 2 (Th2) to a T helper cell type 1 (Th1) cytokine balance in the hypoinflammation phase. Our overall findings suggest that 6-gingerol potentially restores sepsis-induced immune dysfunction by shifting the balance of Th1/Th2 and by regulating apoptosis of immune cells.


Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 4804
Author(s):  
Hyeji Shin ◽  
Yoo Kyong Han ◽  
Youngjoo Byun ◽  
Young Ho Jeon ◽  
Ki Yong Lee

Thymic stromal lymphopoietin (TSLP) plays an important role in the pathophysiology of various allergic diseases that are mediated by T helper cell type-2 (Th2) responses, including asthma and atopic dermatitis. The primary focus of this study was the identification of potent inhibitors of the TSLP signaling pathway for potential therapeutic use. The 80% methanol extract of Machilus thunbergii bark significantly inhibited the signal transducer and activator of transcription 5 (STAT5) phosphorylation in human mast cell (HMC)-1 cells. Through activity-guided isolation, three lignans (1–3) were obtained and identified as (+)-galbelgin (1), meso-dihydroguaiaretic acid (2), and machilin A (3). Among them, two lignans (1 and 2) significantly inhibited STAT5 phosphorylation and TSLP/TSLPR interaction, as determined by ELISA. Our results indicated that lignans isolated from M. thunbergii are a promising resource for the treatment of allergic diseases.


Pathogens ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 618
Author(s):  
T. Spencer Poore ◽  
Gina Hong ◽  
Edith T. Zemanick

Fungi are frequently recovered from lower airway samples from people with cystic fibrosis (CF), yet the role of fungi in the progression of lung disease is debated. Recent studies suggest worsening clinical outcomes associated with airway fungal detection, although most studies to date are retrospective or observational. The presence of fungi can elicit a T helper cell type 2 (Th-2) mediated inflammatory reaction known as allergic bronchopulmonary aspergillosis (ABPA), particularly in those with a genetic atopic predisposition. In this review, we discuss the epidemiology of fungal infections in people with CF, risk factors associated with development of fungal infections, and microbiologic approaches for isolation and identification of fungi. We review the spectrum of fungal disease presentations, clinical outcomes after isolation of fungi from airway samples, and the importance of considering airway co-infections. Finally, we discuss the association between fungi and airway inflammation highlighting gaps in knowledge and future research questions that may further elucidate the role of fungus in lung disease progression.


2021 ◽  
Vol 0 ◽  
pp. 1-5
Author(s):  
Eman Deif ◽  
Sheerja Bali ◽  
Asha Rajeev

Atopic dermatitis (AD) is a chronic inflammatory skin condition causing significant decline in quality of life. Moderate-to-severe AD is refractory to first-line topical therapy, while systemic immunosuppressants can have significant adverse effects. Dupilumab is a fully human monoclonal antibody and the first food and drug administration approved biologic therapy for the treatment of adults with moderate-to-severe AD. It inhibits the actions of both interleukin (IL)-4 and IL-13, two T helper cell type 2 cytokines involved in the pathogenesis of AD. Dupilumab has been found to be an efficacious treatment option in AD with its main adverse reactions being conjunctivitis, injection site reaction, and facial redness. Dupilumab is known to improve the severity and extent of AD, as measured by the eczema area severity index and dermatology life quality index. A similar observation was made by the authors in 30 patients. Thus, dupilumab represents a valuable new treatment option for moderate-to-severe AD, however, high cost remains a major consideration.


2020 ◽  
Author(s):  
Shunichi Shiozawa ◽  
Ken Tsumiyama ◽  
Keiichi Sakurai ◽  
Takahiko Horiuchi ◽  
Tsukasa Matsubara ◽  
...  

Abstract Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease of unknown cause. We show here that a novel T follicular helper cell type expressing the guanine nucleotide exchange factor DOCK8 on the cell surface causes SLE. These cells, which we have designated autoantibody-inducing CD4 T (aiCD4 T) cells, are generated after resuscitation from anergy following strong TCR stimulation by antigen. When mice normally not prone to autoimmune disease were repeatedly immunized with an antigen such as OVA, they generated DOCK8+ CD4 T cells. These DOCK8+ CD4 T cells, in vivo and also upon transfer to naïve mice, induced a variety of autoantibodies and lesions characteristic of SLE. TCR repertoire analyses showed that a substantial number of novel TCR repertoires were generated in the DOCK8+ CD4 T cells, which induced novel autoantibodies upon transfer to naïve mice. DOCK8+ CD4 T cells are localized in splenic red pulp, the space immunoreactive against a variety of antigens, and specifically increased in the peripheral blood of SLE patients in association with disease activity. Anti-DOCK8 antibody treatment ameliorated the lesions induced by DOCK8+ CD4 T cells and in lupus model (NZB x W) F1 mice. Thus, when CD4 T cells are overstimulated by an external disturbance, i.e., repeatedly stimulated with antigen, to levels that surpass the system’s self-organized criticality, these cells express DOCK8 on the cell surface and acquire autoreactivity via TCR re-revision at the periphery. These DOCK8+ CD4 T cells subsequently induce a variety of autoantibodies and SLE.


Circulation ◽  
2020 ◽  
Vol 142 (13) ◽  
pp. 1279-1293 ◽  
Author(s):  
Dennis Wolf ◽  
Teresa Gerhardt ◽  
Holger Winkels ◽  
Nathaly Anto Michel ◽  
Akula Bala Pramod ◽  
...  

Background: Throughout the inflammatory response that accompanies atherosclerosis, autoreactive CD4 + T-helper cells accumulate in the atherosclerotic plaque. Apolipoprotein B 100 (apoB), the core protein of low-density lipoprotein, is an autoantigen that drives the generation of pathogenic T-helper type 1 (T H 1) cells with proinflammatory cytokine secretion. Clinical data suggest the existence of apoB-specific CD4 + T cells with an atheroprotective, regulatory T cell (T reg ) phenotype in healthy individuals. Yet, the function of apoB-reactive T regs and their relationship with pathogenic T H 1 cells remain unknown. Methods: To interrogate the function of autoreactive CD4 + T cells in atherosclerosis, we used a novel tetramer of major histocompatibility complex II to track T cells reactive to the mouse self-peptide apo B 978-993 (apoB + ) at the single-cell level. Results: We found that apoB + T cells build an oligoclonal population in lymph nodes of healthy mice that exhibit a T reg -like transcriptome, although only 21% of all apoB + T cells expressed the T reg transcription factor FoxP3 (Forkhead Box P3) protein as detected by flow cytometry. In single-cell RNA sequencing, apoB + T cells formed several clusters with mixed T H signatures that suggested overlapping multilineage phenotypes with pro- and anti-inflammatory transcripts of T H 1, T helper cell type 2 (T H 2), and T helper cell type 17 (T H 17), and of follicular-helper T cells. ApoB + T cells were increased in mice and humans with atherosclerosis and progressively converted into pathogenic T H 1/T H 17-like cells with proinflammatory properties and only a residual T reg transcriptome. Plaque T cells that expanded during progression of atherosclerosis consistently showed a mixed T H 1/T H 17 phenotype in single-cell RNA sequencing. In addition, we observed a loss of FoxP3 in a fraction of apoB + T regs in lineage tracing of hyperlipidemic Apoe –/– mice. In adoptive transfer experiments, converting apoB + T regs failed to protect from atherosclerosis. Conclusions: Our results demonstrate an unexpected mixed phenotype of apoB-reactive autoimmune T cells in atherosclerosis and suggest an initially protective autoimmune response against apoB with a progressive derangement in clinical disease. These findings identify apoB autoreactive T regs as a novel cellular target in atherosclerosis.


2020 ◽  
Vol 83 (1) ◽  
pp. 63-70 ◽  
Author(s):  
Michelle S. Min ◽  
Jianni Wu ◽  
Helen He ◽  
Juan Luis Sanz-Cabanillas ◽  
Ester Del Duca ◽  
...  

2020 ◽  
Vol 6 (2) ◽  
pp. 74
Author(s):  
John Morgan Knight ◽  
Yifan Wu ◽  
Kelsey Mauk ◽  
Jill Weatherhead ◽  
Sara Anvari ◽  
...  

Filamentous fungi of the Aspergillus genus and others have long been linked to the induction of type 2 immunity that underlies IgE-mediated hypersensitivity responses. This unique immune response is characterized by the production of the allergy-associated T helper cell type 2 (Th2) and Th17 cytokines interleukin 4 (IL-4), IL-13, and IL-17 that drive IgE, eosinophilia, airway hyperresponsiveness and other manifestations of asthma. Proteinases secreted by filamentous fungi promote type 2 immunity, but the mechanism by which this occurs has long remained obscure. Through detailed biochemical analysis of household dust, microbiological dissection of human airway secretions, and extensive modeling in mice, our laboratory has assembled a detailed mechanistic description of how type 2 immunity evolves after exposure to fungi. In this review we summarize three key discoveries: (1) fungal proteinases drive the type 2 immune response; (2) the relationship between fungi, proteinases, and type 2 immunity is explained by airway mycosis, a form of non-invasive fungal infection of the airway lumen; and (3) the innate component of proteinase-driven type 2 immunity is mediated by cleavage of the clotting protein fibrinogen. Despite these advances, additional work is required to understand how Th2 and Th17 responses evolve and the role that non-filamentous fungi potentially play in allergic diseases.


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