Macabre TH2 skewing in DOCK8 deficiency

Janssen, Erin; Wilkie, Hazel

doi:10.1016/j.jaci.2021.02.025

Cited by 6 publications

(7 citation statements)

References 11 publications

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“…10,11 Las células natural killer (NK) están disminuidas en 25 % de los pacientes con Def-DOCK8, además presentan citotoxicidad defectuosa debido a la disminución en la formación de la sinapsis inmune y a la producción alterada de IFN-γ. 12 Los niveles de IgM en suero suelen ser bajos, pero muchos pacientes tienen niveles elevados de IgG y una característica primordial es la elevación de IgE, aunque se han reportado pacientes con variantes patogénicas que mantienen niveles normales de IgE. 13 Se ha descrito también disminución de la respuesta a antígenos polisacáridos.…”

Section: Deficiencia De Dock8unclassified

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Inmunodeficiencia combinada debida a deficiencia de DOCK8. Lo que sabemos hasta ahora

Liquidano‐Perez

Maza-Ramos

Yamazaki‐Nakashimada

et al. 2023

RAM

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La inmunodeficiencia combinada (IDC) por deficiencia de DOCK8 es un error innato de la inmunidad, caracterizado por alteración en linfocitos T y B; el espectro de manifestaciones incluye alergia, autoinmunidad, inflamación, predisposición a cáncer e infecciones recurrentes. La deficiencia de DOCK8 se puede distinguir de otras IDC o dentro del espectro de síndromes de hiper-IgE porque presenta una profunda susceptibilidad a las infecciones virales de la piel, con cánceres de piel asociados y alergias alimentarias graves. El locus subtelomérico 9p24.3, donde se ubica DOCK8, incluye numerosos elementos repetitivos de secuencia que predisponen a la generación de grandes deleciones de la línea germinal, así como a la reparación del ADN somático, mediada por recombinación. La producción residual de la proteína DOCK8 contribuye al fenotipo variable de la enfermedad. Las infecciones virales graves de la piel y la vasculopatía asociada a virus de la varicela Zóster (VVZ) reflejan una función importante de la proteína DOCK8, que normalmente se requiere para mantener la integridad de los linfocitos a medida que las células migran a través de tejidos. La pérdida de DOCK8 provoca deficiencias inmunitarias a través de otros mecanismos, incluido un defecto de supervivencia celular. Existen alteraciones en la respuesta de las células dendríticas, lo que explica la susceptibilidad a infección por virus, así como en los linfocitos T reguladores que podrían ayudar a explicar la autoinmunidad en los pacientes. El trasplante de células hematopoyéticas pluripotenciales es por el momento el único tratamiento curativo, mejora el eccema, la alergia y la susceptibilidad a infecciones.

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Section: Deficiencia De Dock8unclassified

“…El defecto es intrínseco a los propios linfocitos T. El aumento de IL-4 promueve el cambio de clase de isotipo de IgE en los linfocitos B. En los pacientes, el aumento de IL-5 también contribuye al aumento de eosinófilos, que a su vez incrementa respuestas alérgicas iniciadas por los mastocitos 12.…”

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Inmunodeficiencia combinada debida a deficiencia de DOCK8. Lo que sabemos hasta ahora

Liquidano‐Perez

Maza-Ramos

Yamazaki‐Nakashimada

et al. 2023

RAM

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“…DOCK8 DEFICIENCY DOCK8 is a protein involved in cytoskeletal arrangements important for cell adhesion, migration, and structure. 23 After T-cell receptor engagement, the guanine nucleotide exchange factor activity of this allows for CDC42 activation in order to remodel actin and stabilize the immune system, playing a major factor in the motility of immune cells. 23 Mutated DOCK8 leads to profound T-cell dysfunction and causes a defect in lymphocyte migration to the skin with resultant cutaneous infection.…”

Section: Wiskott-aldrich Syndromementioning

confidence: 99%

“…23 After T-cell receptor engagement, the guanine nucleotide exchange factor activity of this allows for CDC42 activation in order to remodel actin and stabilize the immune system, playing a major factor in the motility of immune cells. 23 Mutated DOCK8 leads to profound T-cell dysfunction and causes a defect in lymphocyte migration to the skin with resultant cutaneous infection. 24 While many of the cuta-neous manifestations present similarly to those seen in Job's Syndrome, one may consider DOCK8 deficiency if associated atopic features such as allergies and asthma are present.…”

Section: Wiskott-aldrich Syndromementioning

confidence: 99%

When to Worry It’s More than Atopic Dermatitis

Dodson

Foschi

Lio

2023

Journal of Dermatology for Physician Assistants

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The purpose of this article is to review the diagnosis of atopic dermatitis along with various disease mimickers. Traditionally, atopic dermatitis is a clinical diagnosis with distinctive history, morphology, and distribution of pruritic eczematous lesions aiding in determining the condition and treatment. However, multiple other conditions may mimic atopic dermatitis, requiring further workup. We review diagnostic mimickers of atopic dermatitis and divide them into four major categories: immunodeficiencies, malignancies, nutritional deficiencies, and systemic disease. In addition, we organize a workup to be considered if there is a high suspicion for something other than atopic dermatitis. Although there are multiple other conditions that can mimic atopic dermatitis, there are gaps in not only considering them, but also in recognizing when to proceed with further workup and what to include.

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“…In the absence of DOCK8, the capacity of Tregs to suppress the proliferation of T cells is absent causing autoimmunity ( Shi et al, 2018 ; Du et al, 2021 ). This may be attributed to an impaired function of the role of DOCK8 in IL-2 signalling ( Randall et al, 2011 ; Shi et al, 2018 ), impaired Treg migration ( Randall et al, 2021 ), and defective thymocyte differentiation to Treg ( Janssen et al, 2021 ). Susceptibility towards atopic diseases may in addition be caused by the bias towards Th2 ( Engelhardt et al, 2015 ), lack of peripheral B cell tolerance, and increases in autoantibody production ( Du et al, 2021 ).…”

Section: The Role Of Dock8mentioning

confidence: 99%

CRISPR/Cas-Based Gene Editing Strategies for DOCK8 Immunodeficiency Syndrome

et al. 2022

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Defects in the DOCK8 gene causes combined immunodeficiency termed DOCK8 immunodeficiency syndrome (DIDS). DIDS previously belonged to the disease category of autosomal recessive hyper IgE syndrome (AR-HIES) but is now classified as a combined immunodeficiency (CID). This genetic disorder induces early onset of susceptibility to severe recurrent viral and bacterial infections, atopic diseases and malignancy resulting in high morbidity and mortality. This pathological state arises from impairment of actin polymerization and cytoskeletal rearrangement, which induces improper immune cell migration-, survival-, and effector functions. Owing to the severity of the disease, early allogenic hematopoietic stem cell transplantation is recommended even though it is associated with risk of unintended adverse effects, the need for compatible donors, and high expenses. So far, no alternative therapies have been developed, but the monogenic recessive nature of the disease suggests that gene therapy may be applied. The advent of the CRISPR/Cas gene editing system heralds a new era of possibilities in precision gene therapy, and positive results from clinical trials have already suggested that the tool may provide definitive cures for several genetic disorders. Here, we discuss the potential application of different CRISPR/Cas-mediated genetic therapies to correct the DOCK8 gene. Our findings encourage the pursuit of CRISPR/Cas-based gene editing approaches, which may constitute more precise, affordable, and low-risk definitive treatment options for DOCK8 deficiency.

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Macabre TH2 skewing in DOCK8 deficiency

Cited by 6 publications

References 11 publications

Inmunodeficiencia combinada debida a deficiencia de DOCK8. Lo que sabemos hasta ahora

Inmunodeficiencia combinada debida a deficiencia de DOCK8. Lo que sabemos hasta ahora

When to Worry It’s More than Atopic Dermatitis

CRISPR/Cas-Based Gene Editing Strategies for DOCK8 Immunodeficiency Syndrome

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