<i><scp>RAG</scp></i> gene defects at the verge of immunodeficiency and immune dysregulation

Villa, Anna; Notarangelo, Luigi D.

doi:10.1111/imr.12713

Cited by 52 publications

(55 citation statements)

References 153 publications

(364 reference statements)

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“…Infants born with serious, but incomplete, defects in T‐cell development (leaky severe combined immune deficiency) classically show eosinophilia and erythroderma. These signs of a type 2 immune response might be confused with AD 242,243 . Affected infants often fail to thrive, suffer from thrush and other opportunistic infections, diarrhea, or bronchiolitis.…”

Section: Lessons From Primary Immune Deficiencies Linked To Type 2 Immentioning

confidence: 99%

Type 2 immunity in the skin and lungs

Akdiş

Arkwright

Brüggen

et al. 2020

Allergy

381

357

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There has been extensive progress in understanding the cellular and molecular mechanisms of inflammation and immune regulation in allergic diseases of the skin and lungs during the last few years. Asthma and atopic dermatitis (AD) are typical diseases of type 2 immune responses. interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin are essential cytokines of epithelial cells that are activated by allergens, pollutants, viruses, bacteria, and toxins that derive type 2 responses. Th2 cells and innate lymphoid cells (ILC) produce and secrete type 2 cytokines such as IL-4, IL-5, IL-9, and IL-13. IL-4 and IL-13 activate B cells to class-switch to IgE and also play a role in T-cell and eosinophil migration to allergic inflammatory tissues. IL-13 contributes to maturation, activation, nitric oxide production and differentiation of epithelia, production of mucus as well as smooth muscle contraction, and extracellular matrix generation. IL-4 and IL-13 open tight junction barrier and cause barrier leakiness in the skin and lungs. IL-5 acts on activation, recruitment, and survival of eosinophils. IL-9 contributes to general allergic phenotype by enhancing all of the aspects, such as IgE and eosinophilia. Type 2 ILC contribute to inflammation in AD and asthma by enhancing the activity of Th2 cells, eosinophils, and their cytokines. Currently, five biologics are licensed to suppress type 2 inflammation via IgE, IL-5 and | 1583 AKDIS et Al. 1 | INTRODUC TI ON Allergic diseases cause significant morbidity and mortality with almost one billion cases, accounting for a significant portion of overall healthcare costs. The dysregulated immune response, chronic inflammation, and remodeling in the affected tissues define a dynamic and heterogeneous spectrum of anaphylaxis, food allergy, asthma, allergic rhinitis, chronic rhinosinusitis with nasal polyposis (CRSwNP), and atopic dermatitis (AD). Two main subtypes of immune responses driving asthma and AD have been defined, namely type 2-high and type 2-low. 1-4 Precision medicine and biomarker discovery is important for the management of asthma and AD in the context of a better selection of good responders to treatment, prediction of outcomes, and design of disease-modifying strategies. Progress has been made in profiling the type 2 immune response-driven diseases. In contrast, the non-type 2 immune response in asthma and AD is insufficiently understood. The majority of patients with AD, CRS and asthma involve, or result from, an overexpression of type 2 inflammatory pathways (Figure 1). 5-7 A specific type 2 set of cytokines are produced during the induction and maintenance of allergic immune response with the contribution of epithelial cells, dendritic cells (DC), T cells, innate lymphoid cells (ILC), eosinophils, mast cells (MC), and basophils. Activation of Th2 and ILC2 pathways is at the core of type 2 inflammation. Th2 cytokines include interleukin (IL)-4, IL-5, IL-9, IL-13, and IL-31, and main type 2 cytokines of ILC2 are IL-5, IL-9, and IL-13. 8,9 IL-4 induces Th2 cell di...

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Section: Lessons From Primary Immune Deficiencies Linked To Type 2 Immentioning

confidence: 99%

Type 2 immunity in the skin and lungs

Akdiş

Arkwright

Brüggen

et al. 2020

Allergy

381

357

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“…RAG1 or RAG2 hypomorphic mutations are responsible for Omenn syndrome, which is an autosomal recessive disease of neonates characterized by erythroderma, chronic diarrhea, hepatosplenogaly, and lymphadenopathy [105,106]. Elevated numbers of Th2 cells, an overproduction of IL-4 and IL-5, and elevated serum IgE as well as eosinophilia were found in some of these patients.…”

Section: Th2 Related Diseasesmentioning

confidence: 99%

CD4 T Helper Cell Subsets and Related Human Immunological Disorders

Zhu

2020

IJMS

224

138

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The immune system plays a critical role in protecting hosts from the invasion of organisms. CD4 T cells, as a key component of the immune system, are central in orchestrating adaptive immune responses. After decades of investigation, five major CD4 T helper cell (Th) subsets have been identified: Th1, Th2, Th17, Treg (T regulatory), and Tfh (follicular T helper) cells. Th1 cells, defined by the expression of lineage cytokine interferon (IFN)-γ and the master transcription factor T-bet, participate in type 1 immune responses to intracellular pathogens such as mycobacterial species and viruses; Th2 cells, defined by the expression of lineage cytokines interleukin (IL)-4/IL-5/IL-13 and the master transcription factor GAΤA3, participate in type 2 immune responses to larger extracellular pathogens such as helminths; Th17 cells, defined by the expression of lineage cytokines IL-17/IL-22 and the master transcription factor RORγt, participate in type 3 immune responses to extracellular pathogens including some bacteria and fungi; Tfh cells, by producing IL-21 and expressing Bcl6, help B cells produce corresponding antibodies; whereas Foxp3-expressing Treg cells, unlike Th1/Th2/Th17/Tfh exerting their effector functions, regulate immune responses to maintain immune cell homeostasis and prevent immunopathology. Interestingly, innate lymphoid cells (ILCs) have been found to mimic the functions of three major effector CD4 T helper subsets (Th1, Th2, and Th17) and thus can also be divided into three major subsets: ILC1s, ILC2s, and ILC3s. In this review, we will discuss the differentiation and functions of each CD4 T helper cell subset in the context of ILCs and human diseases associated with the dysregulation of these lymphocyte subsets particularly caused by monogenic mutations.

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“…We also sequenced the TCRb repertoires of Treg and CD4 1 Tconv cells from mice with hypomorphic mutations in Rag2 (R229Q) or Rag1 (R972Q, F971L, and R972W). 8 The 3 missense Rag1 mutations support different capacities to accomplish V(D)J recombination and T-and B-cell development (R972Q > F971L > R972W), and T-cell infiltrates were detected in target organs of the most severe R972W model (see Fig E2 in this article's Online Repository at www.jacionline. org).…”

Section: To the Editormentioning

confidence: 99%