Imbalance in T-Helper 17 Cells and Targeted Therapy in an Infant with SAM-like Syndrome

Hernández‐Martín, Ángela; Kennedy-Batalla, Rebeca; Villarroya, Elvira Cañedo; Bernaldo‐de‐Quirós, Esther; Carazo-Gallego, Begoña; Vera, Ángel Jacinto Traver; Torrelo, Antonio; Noguera‐Morel, Lucero; González-Sarmiento, Rogelio; Bolling, Marieke C.; Martínez‐Bonet, Marta; Pion, Marjorie; Correa‐Rocha, Rafael

doi:10.1056/nejmc1908531

Cited by 30 publications

(20 citation statements)

References 5 publications

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“…Analysis of immune subsets by flow cytometry. The frequency and absolute counts of different T-cell subsets were analysed in peripheral blood from patients using a combination of specific antibodies as previously described 47,48 . Briefly, we determined by flow cytometry (Gallios Cytometer, Beckman Coulter, France) the frequency and absolute counts of CD4+ T cells and CD8+ T cells, including markers for the following subsets: activated (HLA-DR+) and effector memory (CD45RA− CD27−).…”

Section: Methodsmentioning

confidence: 99%

Basiliximab impairs regulatory T cell (TREG) function and could affect the short-term graft acceptance in children with heart transplantation

López‐Abente

Martínez‐Bonet

Bernaldo‐de‐Quirós

et al. 2021

Sci Rep

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CD25, the alpha chain of the IL-2 receptor, is expressed on activated effector T cells that mediate immune graft damage. Induction immunosuppression is commonly used in solid organ transplantation and can include antibodies blocking CD25. However, regulatory T cells (Tregs) also rely on CD25 for their proliferation, survival, and regulatory function. Therefore, CD25-blockade may compromise Treg protective role against rejection. We analysed in vitro the effect of basiliximab (BXM) on the viability, phenotype, proliferation and cytokine production of Treg cells. We also evaluated in vivo the effect of BXM on Treg in thymectomized heart transplant children receiving BXM in comparison to patients not receiving induction therapy. Our results show that BXM reduces Treg counts and function in vitro by affecting their proliferation, Foxp3 expression, and IL-10 secretion capacity. In pediatric heart-transplant patients, we observed decreased Treg counts and a diminished Treg/Teff ratio in BXM-treated patients up to 6-month after treatment, recovering baseline values at the end of the 12-month follow up period. These results reveal that the use of BXM could produce detrimental effects on Tregs, and support the evidence suggesting that BXM induction could impair the protective role of Tregs in the period of highest incidence of acute graft rejection.

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Section: Methodsmentioning

confidence: 99%

Basiliximab impairs regulatory T cell (TREG) function and could affect the short-term graft acceptance in children with heart transplantation

López‐Abente

Martínez‐Bonet

Bernaldo‐de‐Quirós

et al. 2021

Sci Rep

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“…This work may explain recent reports that three patients with SAM or SAM-like syndrome responded well to the IL-23 inhibitor ustekinumab or secukinumab, supporting the efficacy of targeting the Th17 response in these disorders (46,47). Future work that continues to analyze shared and distinct features of Dsg1 deficiency and common skin disorders could provide an opportunity to develop more targeted therapeutic approaches for both rare and common inflammatory disorders.…”

Section: Discussionmentioning

confidence: 55%

Th17-skewed inflammation due to genetic deficiency of a cadherin stress sensor

Godsel

Roth-Carter

Koetsier

et al. 2020

Preprint

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Desmoglein 1 (Dsg1) is a cadherin restricted to stratified tissues of terrestrial vertebrates, which serve as essential physical and immune barriers. Dsg1s importance in epidermal integrity is underscored by genetic, autoimmune and bacterial toxin-mediated disorders interfering with Dsg1 function. Dsg1 loss-of-function mutations in humans result not only in skin lesions, but also multiple allergies, and isolated patient keratinocytes exhibit increased pro-allergic cytokine expression. However, the mechanism by which genetic deficiency of Dsg1 causes chronic inflammation is unknown. To determine the systemic response to Dsg1 loss, we deleted the three tandem Dsg1 genes in mice using CRISPR/Cas9. Whole transcriptome analysis of E18.5 Dsg1-/- skin showed changes consistent with the observed aberrant differentiation and barrier impairment. Comparing epidermal transcriptomes from E18.5 Dsg1-deficient mice and humans with Dsg1 mutations revealed a shared psoriatic-like IL-17-skewed inflammatory signature and less so a pro-allergic IL-4/13 signature. Although the impaired intercellular adhesion observed in Dsg1-/- mice resembles that resulting from autoimmune anti-Dsg1 pemphigus foliaceus antibodies, transcriptomic analysis of pemphigus skin lesions lacks a prominent IL-17 signature. Thus, beyond impairing the physical barrier, chronic loss of Dsg1 function through gene mutation results in a psoriatic-like inflammatory signature before birth, possibly predisposing to skin inflammation.

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“…In this case report, subcutaneous therapy with 75 mg of secukinumab was given once a week, for 4 weeks, followed by a monthly maintenance dose until 18 months of age. The treatment resulted in clinical improvement of the skin, adequate weight, and height gain, and a significant enhancement of life quality 2 (Figure 1).…”

Section: Figurementioning

confidence: 99%

“…In addition, Hernández‐Martín's work 2 demonstrates the importance of looking beyond the well‐established Th2 mechanisms when addressing severe dermatitis. The relatively underappreciated Th17 axis has emerged as a relevant therapeutic target for patients with skin barrier disorders.…”

Section: Figurementioning

confidence: 99%

“…Initially, the treatment of eczematous disorders focused on the Th2 response without considering the key contribution of Th17 cells. However, recent work by Hernández‐Martín et al 2 reports the successful treatment of a 9‐month‐old patient with severe dermatitis, allergies, and metabolic wasting (SAM)‐like syndrome via targeting the Th17 pathway.…”

Section: Figurementioning

confidence: 99%

See 1 more Smart Citation

Biologics as a therapeutic approach for a Th17‐mediated severe dermatitis in skin barrier disorders

Riggioni

Alvaro‐Lozano

Alsina

2020

Allergy

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Imbalance in T-Helper 17 Cells and Targeted Therapy in an Infant with SAM-like Syndrome

Cited by 30 publications

References 5 publications

Basiliximab impairs regulatory T cell (TREG) function and could affect the short-term graft acceptance in children with heart transplantation

Basiliximab impairs regulatory T cell (TREG) function and could affect the short-term graft acceptance in children with heart transplantation

Th17-skewed inflammation due to genetic deficiency of a cadherin stress sensor

Biologics as a therapeutic approach for a Th17‐mediated severe dermatitis in skin barrier disorders

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