The Interactions Between Autoinflammation and Type 2 Immunity: From Mechanistic Studies to Epidemiologic Associations

Sylvester, McKella; Son, Aran; Schwartz, Daniella M.

doi:10.3389/fimmu.2022.818039

Cited by 9 publications

(4 citation statements)

References 213 publications

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“…This is clearly the case for IgG4-RD, where allergic and atopic symptoms are common (62,63). Also, the frequencies of allergic rhinitis, allergic conjunctivitis, atopic dermatitis, and asthma are increased in SLE, suggesting a relationship between autoimmunity and TH2 immunity in a subset of SLE patients (64,65). This subset of patients may benefit from IKAROS depletion.…”

Section: Discussionmentioning

confidence: 99%

IKZF1 and UBR4 gene variants drive autoimmunity and Th2 polarization in IgG4-related disease

Liu,

Zheng,

Sturmlechner

et al. 2024

Journal of Clinical Investigation

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IgG4-related disease (IgG4-RD) is a systemic immune-mediated fibroinflammatory disease whose pathomechanisms remain poorly understood. Here, we identified gene variants in familial IgG4-RD and determined their functional consequences. All 3 affected members of the family shared variants of the transcription factor IKAROS, encoded by IKZF1 , and the E3 ubiquitin ligase UBR4. The IKAROS variant increased binding to the FYN promoter, resulting in higher transcription of FYN in T cells. The UBR4 variant prevented the lysosomal degradation of the phosphatase CD45. In the presence of elevated FYN, CD45 functioned as a positive regulatory loop, lowering the threshold for T cell activation. Consequently, T cells from the affected family members were hyperresponsive to stimulation. When transduced with a low-avidity, autoreactive T cell receptor, their T cells responded to the autoantigenic peptide. In parallel, high expression of FYN in T cells biased their differentiation toward Th2 polarization by stabilizing the transcription factor JunB. This bias was consistent with the frequent atopic manifestations in patients with IgG4-RD, including the affected family members in the present study. Building on the functional consequences of these 2 variants, we propose a disease model that is not only instructive for IgG4-RD but also for atopic diseases and autoimmune diseases associated with an IKZF1 risk haplotype.

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Section: Discussionmentioning

confidence: 99%

IKZF1 and UBR4 gene variants drive autoimmunity and Th2 polarization in IgG4-related disease

Liu,

Zheng,

Sturmlechner

et al. 2024

Journal of Clinical Investigation

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“…Treg cell deficiency has been documented in pSS patients [ 80 ], with peripheral blood levels significantly lower than those of healthy controls, suggesting that Treg cell deficiency may be involved in salivary gland destruction [ 81 ]. Type 2 immune response which Th2 cells involved in has a regulatory relationship with autoinflammation [ 82 ]. Th2 cells have been found to promote renal inflammation in patients with systemic lupus erythematosus [ 83 ], and to play a part in the process of pSS by participating in costimulation and assisting B cell activation, with the cytokines they produce dominating the early stages of pSS [ 84 ].…”

Section: Discussionmentioning

confidence: 99%

Identification and verification of inflammatory biomarkers for primary Sjögren’s syndrome

Liu,

Wang,

Wang

et al. 2024

Clin Rheumatol

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Introduction Primary Sjögren’s syndrome (pSS) is an autoimmune disease characterized by inflammatory infiltration, and dysfunction of the salivary and lacrimal glands. This research aimed to explore the disease pathogenesis and improve the diagnosis and treatment of pSS by mining inflammation-associated biomarkers. Methods Five pSS-related datasets were retrieved from the Gene Expression Omnibus (GEO) database. Inflammation-associated biomarkers were determined by the least absolute shrinkage and selection operator (LASSO) and support vector machines recursive feature elimination (SVM-RFE). Single sample gene set enrichment analysis (ssGSEA) was implemented to profile the infiltration levels of immune cells. Real-time quantitative PCR (RT-qPCR) verified the expression of biomarkers in clinical samples. Results Four genes (LY6E, EIF2AK2, IL15, and CXCL10) were screened as inflammation-associated biomarkers in pSS, the predictive performance of which were determined among three pSS-related datasets (AUC > 0.7). Functional enrichment results suggested that the biomarkers were involved in immune and inflammation-related pathways. Immune infiltration analysis revealed that biomarkers were notably connected with type 2 T helper cells, regulatory T cells which were significantly expressed between pSS and control. TESTOSTERONE and CYCLOSPORINE were predicted to take effect by targeting CXCL10 and IL15 in pSS, respectively. Conclusion Four inflammation-associated biomarkers (LY6E, EIF2AK2, IL15, and CXCL10) were explored, and the underlying regulatory mechanisms and targeted drugs associated with these biomarkers were preliminarily investigated according to a series of bioinformatics methods based on the online datasets of pSS, which provided a reference for understanding the pathogenesis of pSS. Key Points• Inflammation-associated biomarkers (LY6E, EIF2AK2, IL15, and CXCL10) were firstly identified in Sjögren’s syndrome based on LASSO and SVM-RFE analyses.• CXCL10, EIF2AK2 and LY6E were prominently positively correlated with immature B cells, while IL15 were significantly negatively correlated with memory B cells in Sjögren’s syndrome.• LY6E, EIF2AK2, IL15, and CXCL10 were significantly more highly expressed in clinical Sjögren’s syndrome samples compared to healthy control samples, which was consistent with the analysis results of the GEO database. •LY6E, EIF2AK2, IL15, and CXCL10 might be used as the biomarkers for the treatment and diagnosis of Sjögren’s syndrome.

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“…However, growing evidence suggests that, in some contexts, autoin ammatory pathways and cytokines may enhance type 2 immune responses. Conversely, type 2 immune cells and cytokines may regulate autoin ammatory responses in complex and context-dependent manners 34 .…”

Section: Discussionmentioning

confidence: 99%

Allergy and autoinflammation drive persistent systemic inflammatory response in Meniere Disease

Frejo,

Cara,

Flook

et al. 2024

Preprint

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Meniere disease (MD) is an inner ear disorder associated with genetic and environmental factors. Several triggers may induce an inflammatory response that may persist over time, leading to a chronic inflammatory process. This study aims to determine if the inflammatory state observed in some MD patients is mediated by allergy or autoinflammation. A 2-year longitudinal study including 72 patients was designed to track levels of cytokines and chemokines in plasma samples. We used discriminant and trajectory analyses to define functional clusters. Furthermore, THP-1 cells were treated with MD patients’ plasma and NaCl to study their capacity to polarize to M1 or M2 macrophages, and qPCR was used to study the upstream events leading to cytokine release. We identified 4 groups of patients according to their cytokine levels. First, an autoimmune group with high TNF-α levels (19%). An allergic phenotype (24%) with elevated IgE and the capacity to polarize macrophages into M2. The third with an autoinflammatory phenotype had increased IL-1β (14%) activated through CASP1 and NLRP3. The last group had low levels of cytokines (42%). Most individuals remained in the same group according to their cytokine levels over time; interestingly, 36% of patients with an allergic profile also showed high levels of IL-1β. We characterized 2 immunophenotypes according to cytokines and IgE levels. The first may drive an allergic reaction led by IgE and classical allergy-related cytokines. A second group of patients seems to be mediated by the production of IL-1β and the inflammasome pathway.

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The Interactions Between Autoinflammation and Type 2 Immunity: From Mechanistic Studies to Epidemiologic Associations

Cited by 9 publications

References 213 publications

IKZF1 and UBR4 gene variants drive autoimmunity and Th2 polarization in IgG4-related disease

IKZF1 and UBR4 gene variants drive autoimmunity and Th2 polarization in IgG4-related disease

Identification and verification of inflammatory biomarkers for primary Sjögren’s syndrome

Allergy and autoinflammation drive persistent systemic inflammatory response in Meniere Disease

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