Pertussis toxin-induced inhibition of Wnt/β-catenin signaling in dendritic cells promotes an autoimmune response in experimental autoimmune uveitis

Zhang, Zhihui; Li, Yongtao; Chen, Nu; Li, Huan; Chen, Shuang; Cui, Xuexue; Shao, Hui; Wei, Lai; Ma, Jian-Xing; Zhang, Song; Li, Xiaorong; Zhang, Xiaomin

doi:10.1186/s12974-023-02707-y

Cited by 3 publications

(1 citation statement)

References 81 publications

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“…Although the etiology and pathogenesis of VKH disease remain unclear, it has been reported to be related to genetic and immunological factors. [ 18 ] Previous genetic studies have found several genes associated with VKH disease, including IL23R‐C1orf141, ADO‐ZNF365‐EGR2, IL17F, CTLA4, and MIF. [ 19 , 20 , 21 , 22 ] Human leukocyte antigens (HLAs), such as HLA‐DRB1 * 0405, DRB1 * 0401, and HLA‐B * 51, are strongly associated with VKH disease or Behcet's disease in various ethnic populations.…”

Section: Introductionmentioning

confidence: 99%

OR11H1 Missense Variant Confers the Susceptibility to Vogt‒Koyanagi‒Harada Disease by Mediating Gadd45g Expression

Li,

Wang,

Wang

et al. 2024

Advanced Science

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Vogt‒Koyanagi‒Harada (VKH) disease is a severe autoimmune disease. Herein, whole‐exome sequencing (WES) study are performed on 2,573 controls and 229 VKH patients with follow‐up next‐generation sequencing (NGS) in a collection of 2,380 controls and 2,278 VKH patients. A rare c.188T>C (p Val63Ala) variant in the olfactory receptor 11H1 (OR11H1) gene is found to be significantly associated with VKH disease (rs71235604, Pcombined = 7.83 × 10−30, odds ratio = 3.12). Functional study showes that OR11H1‐A63 significantly increased inflammatory factors production and exacerbated barrier function damage. Further studies using RNA‐sequencing find that OR11H1‐A63 markedly increased growth arrest and DNA‐damage‐inducible gamma (GADD45G) expression. Moreover, OR11H1‐A63 activates the MAPK and NF‐κB pathways, and accelerates inflammatory cascades. In addition, inhibiting GADD45G alleviates inflammatory factor secretion, likely due to the regulatory effect of GADD45G on the MAPK and NF‐κB pathways. Collectively, this study suggests that the OR11H1‐A63 missense mutation may increase susceptibility to VKH disease in a GADD45G‐dependent manner.

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Section: Introductionmentioning

confidence: 99%

OR11H1 Missense Variant Confers the Susceptibility to Vogt‒Koyanagi‒Harada Disease by Mediating Gadd45g Expression

Li,

Wang,

Wang

et al. 2024

Advanced Science

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Research Progress on the Role of Wnt Signaling Pathway in Autoimmune Diseases

徐

2023

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Intranasal sensitization model of alopecia areata using pertussis toxin as adjuvant

Liu,

Freeborn,

Okeugo

et al. 2024

Front. Immunol.

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BackgroundNasopharyngeal Bordetella pertussis (BP) colonization is common, with about 5% of individuals having PCR evidence of subclinical BP infection on nasal swab, even in countries with high vaccination rates. BP secretes pertussis toxin (PTx). PTx is an adjuvant commonly used to induce autoimmunity in multiple animal models of human disease. Colocalization of PTx and myelin from myelinated nerves in the nasopharynx may lead to host sensitization to myelin with subsequent autoimmune pathology.MethodsC57BL/6J female adult mice were given varied doses and schedules of intranasal PTx, MOG35-55 antigen, or controls to test whether intranasal administration of PTx and myelin oligodendrocyte peptide (MOG35-55) could induce experimental autoimmune encephalomyelitis (EAE) in mice. While we observed systemic cell-mediated immunity against MOG35-55, we did not observe EAE. Unexpectedly, many mice developed alopecia. We systematically investigated this finding.ResultsPatchy alopecia developed in 36.4% of mice with the optimized protocol. Pathology consistent with alopecia areata was confirmed histologically by documenting concomitant reduced anagen phase and increased telogen phase hair follicles (HFs) in biopsies from patches of hair loss in mice with alopecia. We also found reduced CD200 staining and increased CD3+T cells surrounding the HFs of mice with alopecia compared to the mice without alopecia, indicating HF Immune Privilege (HFIP) collapse. Systemic immune responses were also found, with increased proportions of activated T cells and B cells, as well as MHCII+ dendritic cells in peripheral blood and/or splenocytes. Finally, in mice initially exposed to intranasal MOG35-55 and PTx in combination, but not to either agent alone, splenocytes were shown to proliferate after in vitro stimulation by MOG35-55. Consistent with prior investigations, PTx exhibited a dose-response effect on immune cell induction and phenotype, with the lowest PTx dose failing to induce autoimmunity, the highest PTx dose suppressing autoimmunity, and intermediate doses optimizing autoimmunity.ConclusionsWe propose that this is the first report of an autoimmune disease in an animal model triggered by colocalization of intranasal PTx and autoantigen. This model parallels a natural exposure and potential intranasal sensitization-to-pathology paradigm and supports the plausibility that nasopharyngeal subclinical BP colonization is a cause of alopecia areata.

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Pertussis toxin-induced inhibition of Wnt/β-catenin signaling in dendritic cells promotes an autoimmune response in experimental autoimmune uveitis

Cited by 3 publications

References 81 publications

OR11H1 Missense Variant Confers the Susceptibility to Vogt‒Koyanagi‒Harada Disease by Mediating Gadd45g Expression

OR11H1 Missense Variant Confers the Susceptibility to Vogt‒Koyanagi‒Harada Disease by Mediating Gadd45g Expression

Research Progress on the Role of Wnt Signaling Pathway in Autoimmune Diseases

Intranasal sensitization model of alopecia areata using pertussis toxin as adjuvant

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