Intranasal administration of abatacept enhances IL-35+ and IL-10+ producing Bregs in lung tissues of ovalbumin-sensitized asthmatic mice model

Alenazy, Maha Fahad; Sharif-Askari, Fatemeh Saheb; El-Wetidy, Mohammad S.; Sharif-Askari, Narjes Saheb; Hachim, Ibrahim Y.; Temsah, Mohamad-Hani; Saddik, Basema; Al-Kufaidy, Roua; Omair, Maha A.; Alshawakir, Yasser A.; Fathaddin, Amany Adulgadel; Hannawi, Suad; Hamid, Qutayba; Omair, Mohammed A.; Al‐Muhsen, Saleh; Halwani, Rabih

doi:10.1371/journal.pone.0271689

Cited by 5 publications

(5 citation statements)

References 36 publications

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“…Although patients with and without auto-Abs to type I IFNs did not show overt clinical differences in COVID-19, they differed in plasma IL-17 levels (Table 1 ). An in vivo study demonstrated an inverse association between lung tissue levels of IL-17 and LAG3 cTregs/uTregs 20 , which might explain the lower frequency of LAG3 cTregs/uTregs in the blood of these patients. However, further research is needed to fully understand the mechanistic link between LAG3 expression and IL-17 regulation.…”

Section: Discussionmentioning

confidence: 97%

Increased blood immune regulatory cells in severe COVID-19 with autoantibodies to type I interferons

Saheb Sharif-Askari,

Hafezi

et al. 2023

Sci Rep

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The hallmark of severe COVID-19 is an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. While regulatory T (Treg) and B (Breg) cells, as the main elements of immune homeostasis, contribute to the control of hyperinflammation during COVID-19 infection, we hypothesized change in their levels in relation to disease severity and the presence of autoantibodies (auto-Abs) to type I IFNs. Cytometric analysis of blood of 62 COVID-19 patients with different severities revealed an increased proportion of conventional (cTreg; CD25+FoxP3+) and unconventional (uTreg; CD25-FoxP3+) Tregs, as well as the LAG3+ immune suppressive form of cTreg/uTreg, in the blood of severe COVID-19 cases compared to the milder, non-hospitalized cases. The increase in blood levels of cTreg/uTreg, but not LAG3+ cTreg/uTreg subtypes, was even higher among patients with severe COVID-19 and auto-Abs to type I IFNs. Regarding Bregs, compared to the milder, non-hospitalized cases, the proportion of IL-35+ and IL-10+ Bregs was elevated in the blood of severe COVID-19 patients, and to a higher extent in those with auto-Abs to type I IFNs. Moreover, blood levels of cTreg, LAG3+ cTreg/uTreg, and IL-35+ and IL-10+ Breg subtypes were associated with lower blood levels of proinflammatory cytokines such as IL-6, IL-17, TNFα, and IL-1β. Interestingly, patients who were treated with either tocilizumab and/or a high dose of Vitamin D had higher blood levels of these regulatory cells and better control of the proinflammatory cytokines. These observations suggest that perturbations in the levels of immunomodulatory Tregs and Bregs occur in COVID-19, especially in the presence of auto-Abs to type I IFNs.

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Section: Discussionmentioning

confidence: 97%

Increased blood immune regulatory cells in severe COVID-19 with autoantibodies to type I interferons

Saheb Sharif-Askari,

Hafezi

et al. 2023

Sci Rep

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“…Abatacept, a fusion CTLA‐4 protein approved for rheumatoid and psoriatic arthritis, has been shown to influence the IL‐10 axis. Intranasal administration of abatacept in asthmatic mice showed increased IL‐10‐ and IL‐35‐producing Bregs and LAG3+ Tregs 94 . Administration of the protein Alt a 1, a major allergen found in fungi (specifically Alternaria alternata ), was shown to decrease asthmatic symptoms and increase Breg levels in a mouse model 95 .…”

Section: Developing Breg‐targeted Immunotherapiesmentioning

confidence: 98%

“…Intranasal administration of abatacept in asthmatic mice showed increased IL-10-and IL-35-producing Bregs and LAG3+ Tregs. 94 Administration of the protein Alt a 1, a major allergen found in fungi (specifically Alternaria alternata), was shown to decrease asthmatic symptoms and increase Breg levels in a mouse model. 95 Last, IL expression is known to be regulated by epigenetic shifts in histone acetylation/deacetylation.…”

Section: Aitmentioning

confidence: 99%

The dichotomy of regulatory B cells in cancer versus allergic disease

Dang,

Yu,

Galant‐Swafford

et al. 2023

Molecular Carcinogenesis

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Regulatory B cells (Bregs) are an immunosuppressive cell phenotype that affects the immune system by limiting the inflammatory cascade. Dysregulation of Bregs can interestingly play a dichotomous role in the pathophysiology of many diseases and is especially highlighted when examining cancer pathology compared to allergic disease. This study reviews the existing literature on Bregs and compares their role in allergic disease in contrast to cancer development. Upregulation of Bregs in cancer states has been associated with poor prognostic outcomes across various cancer types, and Breg proliferation was associated with chronic interferon signaling, activation of the BCR–BTK (B cell receptor‐Bruton's tyrosine kinase) pathway, and release of C–X–C motif ligand 13. In contrast, Breg dysfunction has been identified as a key mechanism in many allergic diseases, such as allergic asthma, allergic rhinitis, atopic dermatitis, and contact dermatitis. Development of Breg‐targeted immunotherapies is currently at the preclinical level, but strategies differentially focus on Breg depletion in cancer versus Breg stimulation in allergy. Our review highlights the divergent functions that Bregs play in cancer compared to allergy. We conclude that natural homeostasis hinges on a fine balance between the dichotomous role of Bregs—over or underactivation can result in a pathological state.

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“…Previously, we and others have confirmed the pathophysiology of allergic airway inflammation in the mouse model of asthma. [12,[28][29][30][31] However, the initial trigger in the development of AAI in an asthma mouse model, especially with respect to gut-lung axis, has not yet been studied. Therefore, to validate the development of AAI in pre-challenge and post-challenge conditions, we investigated the mRNA expression of Th2 cytokines in lung tissues.…”

Section: Translocation Of Type 2 Inflammation From Gut To Lung In Mou...mentioning

confidence: 99%

Allergic Airway Inflammation Emerges from Gut Inflammation and Leakage in Mouse Model of Asthma

Selvakumar,

Eladham,

Hafezi

et al. 2023

Advanced Biology

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Asthma is an allergic airway inflammatory disease characterized by type 2 immune responses. Growing evidence suggests an association between allergic airways and intestinal diseases. However, the primary site of disease origin and initial mechanisms involved in the development of allergic airway inflammation (AAI) is not yet understood. Therefore, the initial contributing organs and mechanisms involved in the development of AAI are investigated using a mouse model of asthma. This study, without a local allergen challenge into the lungs, demonstrates a significant increase in intestinal inflammation with signature type‐2 mediators including IL‐4, IL‐13, STAT6, eosinophils, and Th2 cells. In addition, gut leakage and mRNA expressions of gut leakage markers significantly increase in the intestine. Moreover, reduced mRNA expressions of tight junction proteins are observed in gut and interestingly, in lung tissues. Furthermore, in lung tissues, an increased pulmonary barrier permeability and IL‐4 and IL‐13 levels associated with significant increase of lipopolysaccharide‐binding protein (LBP‐gut leakage marker) and eosinophils are observed. However, with local allergen challenges into the lungs, these mechanisms are further enhanced in both gut and lungs. In conclusion, the primary gut originated inflammatory responses translocates into the lungs to orchestrate AAI in a mouse model of asthma.

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Intranasal administration of abatacept enhances IL-35+ and IL-10+ producing Bregs in lung tissues of ovalbumin-sensitized asthmatic mice model

Cited by 5 publications

References 36 publications

Increased blood immune regulatory cells in severe COVID-19 with autoantibodies to type I interferons

Increased blood immune regulatory cells in severe COVID-19 with autoantibodies to type I interferons

The dichotomy of regulatory B cells in cancer versus allergic disease

Allergic Airway Inflammation Emerges from Gut Inflammation and Leakage in Mouse Model of Asthma

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