scholarly journals Comparative Transcriptomics of IBD Patients Indicates Induction of Type 2 Immunity Irrespective of the Disease Ideotype

2021 ◽  
Vol 8 ◽  
Author(s):  
Miguel Gonzalez Acera ◽  
Jay V. Patankar ◽  
Leonard Diemand ◽  
Britta Siegmund ◽  
Markus F. Neurath ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Mouse Models ◽  
Intestinal Inflammation ◽  
Mucosal Healing ◽  
Th2 Cells ◽  
Parasitic Infections ◽  
Inflammatory Conditions ◽  
Elevated Type ◽  
Type 2 Cytokines

Inflammatory cytokines initiate and sustain the perpetuation of processes leading to chronic inflammatory conditions such as inflammatory bowel diseases (IBD). The nature of the trigger causing an inflammatory reaction decides whether type 1, type 17, or type 2 immune responses, typically characterized by the respective T- helper cell subsets, come into effect. In the intestine, Type 2 responses have been linked with mucosal healing and resolution upon an immune challenge involving parasitic infections. However, type 2 cytokines are frequently elevated in certain types of IBD in particular ulcerative colitis (UC) leading to the assumption that Th2 cells might critically support the pathogenesis of UC raising the question of whether such elevated type 2 responses in IBD are beneficial or detrimental. In line with this, previous studies showed that suppression of IL-13 and other type 2 related molecules in murine models could improve the outcomes of intestinal inflammation. However, therapeutic attempts of neutralizing IL-13 in ulcerative colitis patients have yielded no benefits. Thus, a better understanding of the role of type 2 cytokines in regulating intestinal inflammation is required. Here, we took a comparative transcriptomic approach to address how Th2 responses evolve in different mouse models of colitis and human IBD datasets. Our data show that type 2 immune-related transcripts are induced in the inflamed gut of IBD patients in both Crohn's disease and UC and across widely used mouse models of IBD. Collectively our data implicate that the presence of a type 2 signature rather defines a distinct state of intestinal inflammation than a disease-specific pathomechanism.

scholarly journals Maintenance of Type 2 Response by CXCR6-Deficient ILC2 in Papain-Induced Lung Inflammation

2019 ◽  
Vol 20 (21) ◽  
pp. 5493 ◽  
Author(s):  
Meunier ◽  
Chea ◽  
Garrido ◽  
Perchet ◽  
Petit ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Nk Cell ◽  
Lymphoid Cells ◽  
Inflammatory Conditions ◽  
Airway Diseases ◽  
Type 2 Cytokines ◽  
Lymphoid Organogenesis ◽  
Deficient Mice

Innate lymphoid cells (ILC) are important players of early immune defenses in situations like lymphoid organogenesis or in case of immune response to inflammation, infection and cancer. Th1 and Th2 antagonism is crucial for the regulation of immune responses, however mechanisms are still unclear for ILC functions. ILC2 and NK cells were reported to be both involved in allergic airway diseases and were shown to be able to interplay in the regulation of the immune response. CXCR6 is a common chemokine receptor expressed by all ILC, and its deficiency affects ILC2 and ILC1/NK cell numbers and functions in lungs in both steady-state and inflammatory conditions. We determined that the absence of a specific ILC2 KLRG1+ST2– subset in CXCR6-deficient mice is probably dependent on CXCR6 for its recruitment to the lung under inflammation. We show that despite their decreased numbers, lung CXCR6-deficient ILC2 are even more activated cells producing large amount of type 2 cytokines that could drive eosinophilia. This is strongly associated to the decrease of the lung Th1 response in CXCR6-deficient mice.

Retinoic Acid Is Elevated in the Mucosa of Patients With Active Ulcerative Colitis and Displays a Proinflammatory Role by Augmenting IL-17 and IFNγ Production

2020 ◽  
Vol 27 (1) ◽  
pp. 74-83 ◽  
Author(s):  
Ritika Rampal ◽  
Nahidul Wari ◽  
Amit Kumar Singh ◽  
Ujjwalkumar Das ◽  
Sawan Bopanna ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
T Cells ◽  
Retinoic Acid ◽  
Crucial Role ◽  
Intestinal Inflammation ◽  
Γδ T Cells ◽  
Inflammatory Conditions ◽  
Invariant T Cells ◽  
Active Disease

Abstract Background All-trans retinoic acid (RA) plays a crucial role in promoting Foxp3+ Treg generation while reciprocally inhibiting Th1/Th17 generation. Our previous research highlighted that in the face of inflammatory conditions, RA plays a contrary role where it aggravates intestinal inflammation by promoting interferon (IFN) γ and interleukin (IL)-17 differentiation in vitro. Methods In this study we translated our in vitro results into a clinical setting where we estimated mucosal and serum RA levels along with the immunophenotypic profile (IL-17, IFNγ, Foxp3, IL-10) in adaptive (CD4, CD8) and innate-like T cells (mucosal associated invariant T cells and γδ T cells) in patients with ulcerative colitis in remission or with active inflammation. Results This is the first study to estimate RA levels in the human gut and shows that patients with active disease had increased mucosal RA levels as compared with patients in remission (4.0 vs 2.5 ng/mL; P < 0.01) and control patients (3.4 vs 0.8 ng/mL; P < 0.0001). This effect was accompanied by significantly elevated IL-17 and IFNγ in tissue CD4+, CD8+, mucosal associated invariant T+ cells, and γδ + T cells. Moreover, the raised RA levels in patients with active disease showed a positive correlation with proinflammatory cytokines (IL-17, IFNγ) and a negative correlation with IL-10. We also found that RA negatively correlated with IL-9, thereby reinstating our previous finding that RA inhibits Th9 differentiation. Conclusions These data confirm our previous in vitro results that in the presence of inflammation, RA plays a crucial role in maintaining gut inflammation by upregulating proinflammatory markers.

scholarly journals Dual vaccination against IL-4 and IL-13 protects against chronic allergic asthma in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Eva Conde ◽  
Romain Bertrand ◽  
Bianca Balbino ◽  
Jonathan Bonnefoy ◽  
Julien Stackowicz ◽  
...  
Keyword(s):  
Allergic Asthma ◽  
Mouse Models ◽  
Cost Effective ◽  
Interleukin 4 ◽  
Mucus Production ◽  
Post Vaccination ◽  
Type 2 Cytokines ◽  
Therapeutic Monoclonal Antibodies

AbstractAllergic asthma is characterized by elevated levels of IgE antibodies, type 2 cytokines such as interleukin-4 (IL-4) and IL-13, airway hyperresponsiveness (AHR), mucus hypersecretion and eosinophilia. Approved therapeutic monoclonal antibodies targeting IgE or IL-4/IL-13 reduce asthma symptoms but require costly lifelong administrations. Here, we develop conjugate vaccines against mouse IL-4 and IL-13, and demonstrate their prophylactic and therapeutic efficacy in reducing IgE levels, AHR, eosinophilia and mucus production in mouse models of asthma analyzed up to 15 weeks after initial vaccination. More importantly, we also test similar vaccines specific for human IL-4/IL-13 in mice expressing human IL-4/IL-13 and the related receptor, IL-4Rα, to find efficient neutralization of both cytokines and reduced IgE levels for at least 11 weeks post-vaccination. Our results imply that dual IL-4/IL-13 vaccination may represent a cost-effective, long-term therapeutic strategy for the treatment of allergic asthma as demonstrated in mouse models, although additional studies are warranted to assess its safety and feasibility.

scholarly journals Reduction of Allergic Lung Disease by Mucosal Application of Toxoplasma gondii-Derived Molecules: Possible Role of Carbohydrates

2021 ◽  
Vol 11 ◽  
Author(s):  
Elke Korb ◽  
Mirjana Drinić ◽  
Angelika Wagner ◽  
Nora Geissler ◽  
Aleksandra Inic-Kanada ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Spleen Cell ◽  
Cell Cultures ◽  
Ex Vivo ◽  
Inflammatory Cells ◽  
Heat Inactivation ◽  
Parasitic Infections ◽  
Type 2 Cytokines

BackgroundThe hygiene hypothesis suggests a link between parasitic infections and immune disorders, such as allergic diseases. We previously showed that infection with Toxoplasma gondii or systemic application of T. gondii tachyzoites lysate antigen (TLA) in a prophylactic, but not therapeutic protocol, prevented allergic airway inflammation in mice. Here we tested the effect of prophylactic and therapeutic application of TLA via the mucosal route.MethodsMice were intranasally treated with TLA either i) prior to sensitization, ii) during sensitization and challenge, or iii) after sensitization with ovalbumin (OVA). Recruitment of inflammatory cells to the lung, cytokine levels in restimulated lung and spleen cell cultures as well as levels of OVA-specific antibodies in serum were measured. In parallel, the effect of native TLA, heat-inactivated (hiTLA) or deglycosylated TLA (dgTLA) on sensitized splenocytes was evaluated ex vivo.ResultsWhen applied together with OVA i) during systemic sensitization and local challenge or ii) exclusively during local challenge, TLA reduced infiltration of eosinophils into the lung, OVA-specific type 2 cytokines in restimulated lung cell cultures, and partially, type 2 cytokines in restimulated spleen cell cultures in comparison to allergic controls. No beneficial effect was observed when TLA was applied prior to the start of sensitization. Analysis of epitope sugars on TLA indicated a high abundance of mannose, fucose, N-acetylglucosamine, and N-acetylgalactosamine. Deglycosylation of TLA, but not heat-inactivation, abolished the potential of TLA to reduce type 2 responses ex vivo, suggesting a significant role of carbohydrates in immunomodulation.ConclusionWe showed that mucosal application of TLA reduced the development of experimental allergy in mice. The beneficial effects depended on the timing of the application in relation to the time point of sensitization. Not only co-application, but also therapy in sensitized/allergic animals with native TLA reduced local allergic responses. Furthermore, we show that TLA is highly glycosylated and glycoconjugates seem to play a role in anti-allergic effects. In summary, given the powerful modulatory effect that TLA exhibits, understanding its exact mechanisms of action may lead to the development of novel immunomodulators in clinical application.

scholarly journals Imunopatogenesis Asma

2019 ◽  
Vol 3 (1) ◽  
pp. 26
Author(s):  
Resti Yudhawati ◽  
Desak Putu Agung Krisdanti
Keyword(s):  
Immune Response ◽  
Mast Cells ◽  
Cell Activation ◽  
Airway Remodeling ◽  
Th2 Cells ◽  
Lower Airway ◽  
Type 2 Cytokines ◽  
Type 2 Immune Response ◽  
Slow Type

Asthma is a chronic inflammatory disease of the airways characterized by recurrent wheezing, shortness of breath, chest tightness and cough especially at night and or early morning. Airflow resistance in asthma were caused by changes in the airways include bronchoconstriction, airway edema, hyperresponsiveness and airway remodeling. The inflammatory response in asthma patients varies among individuals, whether it can be immediate or late (slow-type) response. Different types of cells are known to play role in this process, especially mast cells, eosinophils, T lymphocytes, macrophages, neutrophils and epithelial cells. Degranulation of mast cells in the airways release inflammatory mediators and various metabolites that directly lead to smooth muscle hypersponsive resulting in airway obstruction. While eosinophil cells, mast cells and lymphocytes associated with slow-type responses, will release various mediators including leukotriene, prostaglandins and a number of proinflammatory cytokines. Type 2 immune response in the lower respiratory tract is a central immunologic process in asthma. This type 2 immune response is mediated by Th2 cells of CD4 + and IgE. The CD4 + Th2 cell is characterized by the large amount of transacting T-cell-specific transcription factor GATA-3 and the secretion of type 2 cytokines (IL-4, IL-5, IL-9 and IL-13). Excessive type 2 cytokines in the lower airway will trigger IgE-mediated hypersensitivity, epithelial cell activation, inflammatory cell inflation mediation into the airways, and cause remodeling responses in the epithelium and subepithelial matrices. This inflammatory cascade of type 2 cytokines is the pathological basis of the main symptoms of asthma.

Possible Involvement of Type 2 Cytokines in Alloknesis in Mouse Models of Menopause and Dry Skin

2021 ◽  
Author(s):  
Nao Ichimasu ◽  
Yue Chen ◽  
Keisuke Kobayashi ◽  
So Suzuki ◽  
Sakiko Chikazawa ◽  
...  
Keyword(s):  
Mouse Models ◽  
Dry Skin ◽  
Type 2 Cytokines

Inflammation of the Ileal Anal Pouch: Do Biologics Really Change the Trajectory?

2019 ◽  
Vol 26 (7) ◽  
pp. 1087-1088
Author(s):  
Amy L Lightner
Keyword(s):  
Ulcerative Colitis ◽  
Ileal Pouch ◽  
Mucosal Healing ◽  
Pouch Failure ◽  
Inflammatory Conditions

Inflammatory conditions of the ileal pouch are relatively common after ileal pouch anal anastomoses. Although biologics can induce mucosal healing and may have decreased rates of colectomy for medically refractory ulcerative colitis in recent years, they have not decreased rates of pouch failure due to inflammatory conditions of the pouch.

scholarly journals The autophagy gene Atg16l1 differentially regulates Treg and TH2 cells to control intestinal inflammation

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Agnieszka M Kabat ◽  
Oliver J Harrison ◽  
Thomas Riffelmacher ◽  
Amin E Moghaddam ◽  
Claire F Pearson ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Treg Cells ◽  
Th2 Cells ◽  
Metabolic Adaptation ◽  
Cell Responses ◽  
Th2 Cell ◽  
Autophagy Gene ◽  
Th Cell ◽  
Inflammatory Bowel

A polymorphism in the autophagy gene Atg16l1 is associated with susceptibility to inflammatory bowel disease (IBD); however, it remains unclear how autophagy contributes to intestinal immune homeostasis. Here, we demonstrate that autophagy is essential for maintenance of balanced CD4+ T cell responses in the intestine. Selective deletion of Atg16l1 in T cells in mice resulted in spontaneous intestinal inflammation that was characterized by aberrant type 2 responses to dietary and microbiota antigens, and by a loss of Foxp3+ Treg cells. Specific ablation of Atg16l1 in Foxp3+ Treg cells in mice demonstrated that autophagy directly promotes their survival and metabolic adaptation in the intestine. Moreover, we also identify an unexpected role for autophagy in directly limiting mucosal TH2 cell expansion. These findings provide new insights into the reciprocal control of distinct intestinal TH cell responses by autophagy, with important implications for understanding and treatment of chronic inflammatory disorders.

scholarly journals Pulmonary type-2 innate lymphoid cells in paediatric severe asthma: phenotype and response to steroids

2019 ◽  
Vol 54 (2) ◽  
pp. 1801809 ◽  
Author(s):  
Prasad Nagakumar ◽  
Franz Puttur ◽  
Lisa G. Gregory ◽  
Laura Denney ◽  
Louise Fleming ◽  
...  
Keyword(s):  
Symptom Control ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Th2 Cells ◽  
Poor Control ◽  
Inhaled Steroids ◽  
Elevated Type

Children with severe therapy-resistant asthma (STRA) have poor control despite maximal treatment, while those with difficult asthma (DA) have poor control from failure to implement basic management, including adherence to therapy. Although recognised as clinically distinct, the airway molecular phenotype, including the role of innate lymphoid cells (ILCs) and their response to steroids in DA and STRA is unknown.Immunophenotyping of sputum and blood ILCs and T-cells from STRA, DA and non-asthmatic controls was undertaken. Leukocytes were analysed longitudinally pre- and post-intramuscular triamcinolone in children with STRA. Cultured ILCs were evaluated to assess steroid responsiveness in vitro.Airway eosinophils, type 2 T-helper (Th2) cells and ILC2s were significantly higher in STRA patients compared to DA and disease controls, while IL-17+ lymphoid cells were similar. ILC2s and Th2 cells were significantly reduced in vivo following intramuscular triamcinolone and in vitro with steroids. Furthermore, asthma attacks and symptoms reduced after systemic steroids despite persistence of steroid-resistant IL-17+ cells and eosinophils.Paediatric STRA and DA have distinct airway molecular phenotypes with STRA characterised by elevated type-2 cells. Systemic corticosteroids, but not maintenance inhaled steroids resulted in improved symptom control and exacerbations concomitant with a reduction in functional ILC2s despite persistently elevated IL-17+ lymphoid cells.

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