Anti-TNF Therapy Induces CD4+ T-Cell Production of IL-22 and Promotes Epithelial Repairs in Patients With Crohn’s Disease

Fang, Leilei; Pang, Zhi; Shu, Weigang; Wu, Wei; Sun, Mingming; Cong, Yingzi; Liu, Zhanju

doi:10.1093/ibd/izy126

Cited by 42 publications

(45 citation statements)

References 38 publications

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“…Similar to the beneficial role of Tregs in mucosal immunity, the Th22 subset of CD4+ T-cells has been shown to promote homeostasis. In this regard, IL-22 produced by these cells induces the expression of tight junction proteins (i.e., claudin 1 and ZO-1) in epithelial cells, thus increasing the integrity of the mucosal epithelial barrier and protecting it from inflammation (54). Accordingly, it has been shown that the administration of anti-TNF-α therapy (infliximab) in CD patients, which ameliorates gut inflammation, upregulates IL-22 production contributing to intestinal epithelial barrier repair (54).…”

Section: T-cell Driven Inflammation Plays a Fundamental Role In The Pmentioning

confidence: 99%

“…In this regard, IL-22 produced by these cells induces the expression of tight junction proteins (i.e., claudin 1 and ZO-1) in epithelial cells, thus increasing the integrity of the mucosal epithelial barrier and protecting it from inflammation (54). Accordingly, it has been shown that the administration of anti-TNF-α therapy (infliximab) in CD patients, which ameliorates gut inflammation, upregulates IL-22 production contributing to intestinal epithelial barrier repair (54). Regarding the antigens recognised by the adaptive immune system in IBD, several autoantigens and microbiota-derived antigens have been described in both CD and UC (55, 56).…”

Section: T-cell Driven Inflammation Plays a Fundamental Role In The Pmentioning

confidence: 99%

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T-Cell-Driven Inflammation as a Mediator of the Gut-Brain Axis Involved in Parkinson's Disease

2019

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Parkinson's disease (PD) is a neurodegenerative disorder affecting mainly the dopaminergic neurons of the nigrostriatal pathway, a neuronal circuit involved in the control of movements, thereby the main manifestations correspond to motor impairments. The major molecular hallmark of this disease corresponds to the presence of pathological protein inclusions called Lewy bodies in the midbrain of patients, which have been extensively associated with neurotoxic effects. Importantly, different research groups have demonstrated that CD4 + T-cells infiltrate into the substantia nigra of PD patients and animal models. Moreover, several studies have consistently demonstrated that T-cell deficiency results in a strong attenuation of dopaminergic neurodegeneration in animal models of PD, thus indicating a key role of adaptive immunity in the neurodegenerative process. Recent evidence has shown that CD4 + T-cell response involved in PD patients is directed to oxidised forms of α-synuclein, one of the main constituents of Lewy bodies. On the other hand, most PD patients present a number of non-motor manifestations. Among non-motor manifestations, gastrointestinal dysfunctions result especially important as potential early biomarkers of PD, since they are ubiquitously found among confirmed patients and occur much earlier than motor symptoms. These gastrointestinal dysfunctions include constipation and inflammation of the gut mucosa and the most distinctive pathologic features associated are the loss of neurons of the enteric nervous system and the generation of Lewy bodies in the gut. Moreover, emerging evidence has recently shown a pivotal role of gut microbiota in triggering the development of PD in genetically predisposed individuals. Of note, PD has been positively correlated with inflammatory bowel diseases, a group of disorders involving a T-cell driven inflammation of gut mucosa, which is strongly dependent in the composition of gut microbiota. Here we raised the hypothesis that T-cell driven inflammation, which mediates dopaminergic neurodegeneration in PD, is triggered in the gut mucosa. Accordingly, we discuss how structural components of commensal bacteria or how different mediators produced by gut-microbiota, including short-chain fatty acids and dopamine, may affect the behaviour of T-cells, triggering the development of T-cell responses against Lewy bodies, initially confined to the gut mucosa but later extended to the brain.

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Section: T-cell Driven Inflammation Plays a Fundamental Role In The Pmentioning

confidence: 99%

Section: T-cell Driven Inflammation Plays a Fundamental Role In The Pmentioning

confidence: 99%

T-Cell-Driven Inflammation as a Mediator of the Gut-Brain Axis Involved in Parkinson's Disease

2019

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“…Based on murine colitis models it is anticipated that high levels of IL22BP promote inflammation by inference of IL-22 mediated mucosal healing [212]. In agreement, upon response to anti-TNF-α therapy intestinal CD4 + T-cells isolated from IBD patients exhibit reduced amounts of IL-22BP expression but still express IL-22 [212], and may even up-regulate IL-22 production [215].…”

Section: Does the Il-22-il-22bp Pathway Contribute To Disease Pathology?mentioning

confidence: 93%

Dissecting the Heterogeneity in T-Cell Mediated Inflammation in IBD

Tindemans

Joosse

Samsom

2020

Cells

101

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Infiltration of the lamina propria by inflammatory CD4+ T-cell populations is a key characteristic of chronic intestinal inflammation. Memory-phenotype CD4+ T-cell frequencies are increased in inflamed intestinal tissue of IBD patients compared to tissue of healthy controls and are associated with disease flares and a more complicated disease course. Therefore, a tightly controlled balance between regulatory and inflammatory CD4+ T-cell populations is crucial to prevent uncontrolled CD4+ T-cell responses and subsequent intestinal tissue damage. While at steady state, T-cells display mainly a regulatory phenotype, increased in Th1, Th2, Th9, Th17, and Th17.1 responses, and reduced Treg and Tr1 responses have all been suggested to play a role in IBD pathophysiology. However, it is highly unlikely that all these responses are altered in each individual patient. With the rapidly expanding plethora of therapeutic options to inhibit inflammatory T-cell responses and stimulate regulatory T-cell responses, a crucial need is emerging for a robust set of immunological assays to predict and monitor therapeutic success at an individual level. Consequently, it is crucial to differentiate dominant inflammatory and regulatory CD4+ T helper responses in patients and relate these to disease course and therapy response. In this review, we provide an overview of how intestinal CD4+ T-cell responses arise, discuss the main phenotypes of CD4+ T helper responses, and review how they are implicated in IBD.

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“…129 Homozygous deletion of IL-17A reduced enthesitis severity, while neutralization of IL-22 reduced enthesitis but exacerbated ileitis, 147 perhaps due to the well-accepted ability of IL-22 to reenforce mucosal barrier integrity. 190,191 It is remarkable that this SKG model and TNF transgenic models exhibit both experimental terminal ileitis and enthesitis in the same model systems in two different strains with two major cytokines that are therapeutic targets in SpA-and enthesitis-related disease.…”

Section: Skg Modelmentioning

confidence: 98%

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

Bridgewood

Sharif

Sherlock

et al. 2020

Immunological Reviews

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The inflammatory disorders collectively termed the seronegative spondyloarthropathies (SpA) include ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, the arthritis associated with inflammatory bowel disease including Crohn's disease and ulcerative colitis, the arthritis related to anterior uveitis, and finally, somewhat controversially Behcet's disease. All of these diseases are associated with SNPs in the IL‐23R or the interleukin‐23 (IL‐23) cytokine itself and related downstream signaling JAK pathway genes and the interleukin‐17 (IL‐17) pathway. In rheumatoid arthritis, the target of the immune response is the synovium but the SpA disorders target the tendon, ligament, and joint capsule skeletal anchorage points that are termed entheses. The discovery that IL‐23R–expressing cells were ensconced in healthy murine enthesis, and other extraskeletal anchorage points including the aortic root and the ciliary body of the eye and that systemic overexpression of IL‐23 resulted in a severe experimental SpA, confirmed a fundamentally different immunobiology to rheumatoid arthritis. Recently, IL‐23R–expressing myeloid cells and various innate and adaptive T cells that produce IL‐17 family cytokines have also been described in the human enthesis. Blockade of IL‐23 pathway with either anti‐p40 or anti‐p19 subunits has resulted in some spectacular therapeutic successes in psoriasis and PsA including improvement in enthesitis in the peripheral skeleton but has failed to demonstrate efficacy in AS that is largely a spinal polyenthesitis. Herein, we discuss the known biology of IL‐23 at the human enthesis and highlight the remarkable emerging story of this unique skeletal tissue.

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Anti-TNF Therapy Induces CD4+ T-Cell Production of IL-22 and Promotes Epithelial Repairs in Patients With Crohn’s Disease

Abstract: Our results uncover a novel mechanism whereby anti-TNF therapy upregulates IL-22 production in CD patients through promoting Th22 cell differentiation and contributes to intestinal epithelial barrier repairs.

Cited by 42 publications

References 38 publications

T-Cell-Driven Inflammation as a Mediator of the Gut-Brain Axis Involved in Parkinson's Disease

T-Cell-Driven Inflammation as a Mediator of the Gut-Brain Axis Involved in Parkinson's Disease

Dissecting the Heterogeneity in T-Cell Mediated Inflammation in IBD

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

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