Cytokine‐regulated Th17 plasticity in human health and diseases

Cerboni, Silvia; Gehrmann, Ulf; Preite, Silvia; Mitra, Suman

doi:10.1111/imm.13280

Cited by 72 publications

(67 citation statements)

References 165 publications

(325 reference statements)

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“…These are substrates for the serine kinases DYRK1A and HIPK2, which cause IDD, ASD, and abnormal feeding behavior when mutated 122–124 . DYRK1A also has important effects on innate immunity by regulating the balance between Th17 and T regulatory (Treg) cells, T cell subsets involved in the development of autoimmune diseases and inflammation 125–129 . Interestingly, Th17 mediates the effects of Streptococcus on neuroinflammation in a mouse model of PANDAS by causing a breach in the BBB, with subsequent brain infiltration of Th17 lymphocytes 125, 130–132 .…”

Section: Discussionmentioning

confidence: 99%

“…DYRK1A also has important effects on innate immunity by regulating the balance between Th17 and T regulatory (Treg) cells, T cell subsets involved in the development of autoimmune diseases and inflammation 125–129 . Interestingly, Th17 mediates the effects of Streptococcus on neuroinflammation in a mouse model of PANDAS by causing a breach in the BBB, with subsequent brain infiltration of Th17 lymphocytes 125, 130–132 . HIPK2 regulates PPM1D protein levels by inducing its degradation in DNA-damaged cells, triggering activation of the DNA repair pathway 133 .…”

Section: Discussionmentioning

confidence: 99%

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Identification of ultra-rare genetic variants in Pediatric Acute Onset Neuropsychiatric Syndrome (PANS) by exome and whole genome sequencing

Trifiletti¹,

Manusama

et al. 2021

Preprint

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Pediatric acute onset neuropsychiatric syndrome (PANS) is viewed as an autoimmune/autoinflammatory condition characterized by the abrupt onset of severe neurological and psychiatric symptoms, in particular obsessive-compulsive disorder (OCD), tics, anxiety, mood swings, irritability, and restricted eating, often triggered by infections. However, direct evidence of autoimmunity, infections, or a proinflammatory state is often lacking, and there is no unifying pathogenic pathway. This could be due to underlying genetic heterogeneity, which could lead to the development of PANS through different cellular and molecular pathways. Unfortunately, little is known about the genetic basis of PANS. Consequently, we carried out whole exome sequencing (WES) on a U.S. cohort of 386 cases who met diagnostic criteria for PANS, including 133 family triads, and whole genome sequencing (WGS) on ten cases from the European Union, who were selected for WGS because of severe PANS symptoms. We focused on identifying potentially deleterious genetic variants that were either de novo or ultra-rare with a minor allele frequency (MAF) < 0.001. Candidate mutations were found in 11 genes: PPM1D, SGCE, PLCG2, NLRC4, CACNA1B, SHANK3, CHK2, GRIN2A, RAG1, GABRG2, and SYNGAP1 in a total of 20 cases, which included two sets of siblings, and two or more unrelated subjects with ultra-rare variants in SGCE, NLRC4, RAG1, and SHANK3. The PANS candidate genes we identified separate into two broad functional categories. One group regulates peripheral innate and adaptive immune responses (e.g., PPM1D, CHK2, NLRC4, RAG1, PLCG2), some of which also influence microglia function. Another is expressed primarily at neuronal synapses or directly modulates synaptic function (SHANK3, SYNGAP1, GRIN2A, GABRG2, CACNA1B, SGCE). These neuronal PANS candidate genes are often mutated in autism spectrum disorder, developmental disorders, and myoclonus-dystonia. In fact, eight out of 20 cases in this study developed PANS superimposed on a preexisting neurodevelopmental disorder. There is, however, clinical overlap between these two groups and some crossover expression (e.g., some neuronal genes are expressed in immune cells and vice versa) that diminishes the neuronal/immune dichotomy. Genes in both categories are also highly expressed in the enteric nervous system, and in the choroid plexus and brain vasculature, suggesting they might contribute to a breach in the blood-CSF barrier and blood-brain barrier (BBB) that would permit the entry of autoantibodies, inflammatory cytokines, chemokines, prostaglandins, and autoantibodies into the brain. Thus, PANS is a genetically heterogeneous condition that can occur as a stand-alone neuropsychiatric condition or co-morbid with neurodevelopmental disorders, with candidate genes functioning at several levels of the neuroinflammatory axis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of ultra-rare genetic variants in Pediatric Acute Onset Neuropsychiatric Syndrome (PANS) by exome and whole genome sequencing

Trifiletti¹,

Manusama

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Th17 cells are an important T cell subpopulation linked with asthma and airway inflammation. These cells are known to secrete, among others, IL-17 [142]. In a study by Al-Harbi et al [119], the authors demonstrated an increase in the total number of Th17 cells and reduced expression of IL-17A and IL-23 after SFN-dependent Nrf2 activation in a mouse model of mixed granulocyte airway inflammation.…”

Section: T Lymphocytesmentioning

confidence: 97%

Nrf2—A Molecular Target for Sepsis Patients in Critical Care

et al. 2020

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The transcription factor NF-E2 p45-related factor 2 (Nrf2) is an established master regulator of the anti-oxidative and detoxifying cellular response. Thus, a role in inflammatory diseases associated with the generation of large amounts of reactive oxygen species (ROS) seems obvious. In line with this, data obtained in cell culture experiments and preclinical settings have shown that Nrf2 is important in regulating target genes that are necessary to ensure cellular redox balance. Additionally, Nrf2 is involved in the induction of phase II drug metabolizing enzymes, which are important both in degrading and converting drugs into active forms, and into putative carcinogens. Therefore, Nrf2 has also been implicated in tumorigenesis. This must be kept in mind when new therapy approaches are planned for the treatment of sepsis. Therefore, this review highlights the function of Nrf2 in sepsis with a special focus on the translation of rodent-based results into sepsis patients in the intensive care unit (ICU).

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“…Th17.1 cells show stronger pro-inflammatory properties, supported by higher proliferation ability in response to T cell receptor (TCR) signals, higher GM-CSF, CCL20 and IL-22 production ( 178 , 179 ). A latest study, tracking the plasticity of Th17 cells in periodontitis model, suggested that the transformation of classical Th17 cells to ex-Th17 cells occurs during the conversion from acute inflammation to chronic inflammation ( 180 ).…”

Section: Regulators Of Th17 Cells Differentiationmentioning

confidence: 99%

Th17 Cells in Periodontitis and Its Regulation by A20

et al. 2021

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Periodontitis is a prevalent chronic disease that results in loss of periodontal ligament and bone resorption. Triggered by pathogens and prolonged inflammation, periodontitis is modulated by the immune system, especially pro-inflammatory cells, such as T helper (Th) 17 cells. Originated from CD4+ Th cells, Th17 cells play a central role for they drive and regulate periodontal inflammation. Cytokines secreted by Th17 cells are also major players in the pathogenesis of periodontitis. Given the importance of Th17 cells, modulators of Th17 cells are of great clinical potential and worth of discussion. This review aims to provide an overview of the current understanding of the effect of Th17 cells on periodontitis, as well as a brief discussion of current and potential therapies targeting Th17 cells. Lastly, we highlight this article by summarizing the causal relationship between A20 (encoded by TNFAIP3), an anti-inflammatory molecule, and Th17 cell differentiation.

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Cytokine‐regulated Th17 plasticity in human health and diseases

Abstract: Orchestra of cytokines regulates phenotypic and functional plasticity of non‐pathogenic and pathogenic Th17 cells in human health and diseases.

Cited by 72 publications

References 165 publications

Identification of ultra-rare genetic variants in Pediatric Acute Onset Neuropsychiatric Syndrome (PANS) by exome and whole genome sequencing

Identification of ultra-rare genetic variants in Pediatric Acute Onset Neuropsychiatric Syndrome (PANS) by exome and whole genome sequencing

Nrf2—A Molecular Target for Sepsis Patients in Critical Care

Th17 Cells in Periodontitis and Its Regulation by A20

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