dock8 deficiency
Recently Published Documents


TOTAL DOCUMENTS

92
(FIVE YEARS 38)

H-INDEX

19
(FIVE YEARS 4)

2021 ◽  
Vol 2 ◽  
Author(s):  
Minnie Jacob ◽  
Afshan Masood ◽  
Zakiya Shinwari ◽  
Mai Abdel Jabbar ◽  
Hamoud Al-Mousa ◽  
...  

Dedicator of cytokinesis 8 deficiency is an autosomal recessive primary immune deficiency disease belonging to the group of hyperimmunoglobulinemia E syndrome (HIES). The clinical phenotype of dedicator of cytokinesis 8 (DOCK8) deficiency, characterized by allergic manifestations, increased infections, and increased IgE levels, overlaps with the clinical presentation of atopic dermatitis (AD). Despite the identification of metabolomics and cytokine biomarkers, distinguishing between the two conditions remains clinically challenging. The present study used a label-free untargeted proteomics approach using liquid-chromatography mass spectrometry with network pathway analysis to identify the differentially regulated serum proteins and the associated metabolic pathways altered between the groups. Serum samples from DOCK8 (n = 10), AD (n = 9) patients and healthy control (Ctrl) groups (n = 5) were analyzed. Based on the proteomics profile, the PLS-DA score plot between the three groups showed a clear group separation and sample clustering (R2 = 0.957, Q2 = 0.732). Significantly differentially abundant proteins (p < 0.05, FC cut off 2) were identified between DOCK8-deficient and AD groups relative to Ctrl (n = 105, and n = 109) and between DOCK8-deficient and AD groups (n = 85). Venn diagram analysis revealed a differential regulation of 24 distinct proteins from among the 85 between DOCK8-deficient and AD groups, including claspin, haptoglobin-related protein, immunoglobulins, complement proteins, fibulin, and others. Receiver-operating characteristic curve (ROC) analysis identified claspin and haptoglobin-related protein, as potential biomarkers with the highest sensitivity and specificity (AUC = 1), capable of distinguishing between patients with DOCK8 deficiency and AD. Network pathway analysis between DOCK8-deficiency and AD groups revealed that the identified proteins centered around the dysregulation of ERK1/2 signaling pathway. Herein, proteomic profiling of DOCK8-deficiency and AD groups was carried out to determine alterations in the proteomic profiles and identify a panel of the potential proteomics biomarker with possible diagnostic applications. Distinguishing between DOCK8-deficiency and AD will help in the early initiation of treatment and preventing complications.


2021 ◽  
Vol 12 ◽  
Author(s):  
Jinqiu Jiang ◽  
Tao Qin ◽  
Liang Zhang ◽  
Qiao Liu ◽  
Jiabin Wu ◽  
...  

Mutations in human DOCK8 cause a combined immunodeficiency syndrome characterized by allergic diseases such as asthma and food allergy. However, the underlying mechanism is unclear. Regulatory B (Breg) cells that produce IL-10 exert potent immunosuppressive functions in patients with allergic and autoimmune disorders. DOCK8-deficient B cells show diminished responses to TLR9 signaling, suggesting a possible defect in IL-10-producing Breg cells in those with DOCK8 deficiency, which may contribute to allergies. Here, we isolated peripheral blood mononuclear cells from DOCK8-deficient patients and generated a Dock8 KO mouse model to study the effect of DOCK8 deficiency on Breg cells. DOCK8-deficient patients and Dock8 KO mice harbored quantitative and qualitative defects in IL-10-producing Breg cells; these defects were caused by abnormal Dock8-/- CD4+ T cells. We found that recombinant murine (rm)IL-21 restored the function of Bregs both in vitro and in Dock8 KO mice, leading to reduced inflammatory cell infiltration of the lungs in a murine asthma model. Overall, the results provide new insight into the potential design of Breg-based or IL-21-based therapeutic strategies for allergic diseases, including asthma associated with DOCK8 deficiency.


2021 ◽  
Vol 127 (5) ◽  
pp. S104-S105
Author(s):  
B. Trogen ◽  
B. Martinez-Flores ◽  
A. Nowak-Wegrzyn ◽  
A. Schneider

Author(s):  
Leila Shakerian ◽  
Maryam Nourizadeh ◽  
Mohsen Badalzadeh ◽  
Mohammad Reza Fazlollahi ◽  
Raheleh Shokouhi Shoormasti ◽  
...  

T-cell receptor excision circles (TREC)/Kappa-deleting recombination excision circles (KREC) assay has been recently recognized for detecting patients with primary (T- and/or B-cell) immunodeficiency (PID). We aimed to investigate the alterations of these biomarkers in some combined immunodeficiency patients compared to the healthy controls in different age groups. TREC and KREC were assessed in a total of 82 PID patients, most of them with exact genetic diagnosis (3 months to 42 years); using quantitative real-time-polymerase chain reaction (PCR). Patients had a final diagnosis of common variable immunodeficiency (n=23), ataxia-telangiectasia (AT) (n=17), hyper-IgE syndrome (HIES) (7 with DOCK8 deficiency, 4 with signal transducer and activator of transcription 3 (STAT3) deficiency, and 8 children with unknown genetic defects), Wiskott-Aldrich syndrome (WAS) (n=20), purine nucleoside phosphorylase (PNP)deficiency(n=1), dedicator of cytokinesis2 (DOCK2) deficiency (n=1), recombinase activating gene1 (RAG1) deficiency (n=1). Very low to zero amounts of TREC and/or KREC were detected in 14 out of 23 cases of common variable immunodeficiency (CVID), 14 out of 17 cases of AT, 8 out of 20 cases of WAS, 6 out of 7 cases of DOCK8-deficiency patients, 4 out of 8 cases of HIES with unknown genetic defects and all patients with defects in DOCK2, PNP, and RAG1. STAT3-deficient patients were normal for both biomarkers. All patients showed a significant difference in both markers compared to age-matched healthy controls. Our findings highlight that apart from severe types of T/B cell defects, this assay can also be used for early diagnosis the patients with late-onset of disease and even PIDs without a positive family history.


Author(s):  
Elif Tugce Aydin Goker ◽  
Deniz Cagdas Ayvaz ◽  
Inci Bajin ◽  
Musa Kukul ◽  
Elif Soyak Aytekin ◽  
...  

Castleman disease is a rare, heterogeneous disorder that driven by proinflammatory responses. Human herpes virus-8 has a major role in pathogenesis of multicentric Castleman disease. There is also a subgroup of cases, human herpes virus-8 negative, idiopathic multicentric Castleman disease. The role of primary immunodeficiencies in idiopathic Castleman disease are poorly described. DOCK8 deficiency is a combined primary immunodeficiency. It has a broad clinic spectrum including atopy, autoimmunity and cancer. We present a 10-year-old, DOCK8 deficient patient. He had giant lobular capillary hemangiomas on his neck, iliac and gluteal regions and multiple lymphadenopathies. Abdominal lymph node pathology revealed hyaline vascular type Castleman disease and human herpes virus-8 staining was negative. His lesions were shown to be infected with orf virus. Our case is the first case to relate idiopathic multicentric Castleman disease and DOCK8 deficiency; also, very unusual presentation of orf virus infection in humans.


2021 ◽  
Vol 9 ◽  
Author(s):  
Edna Venegas-Montoya ◽  
Aidé Tamara Staines-Boone ◽  
Luz María Sánchez-Sánchez ◽  
Jorge Alberto García-Campos ◽  
Rubén Antonio Córdova-Gurrola ◽  
...  

Autosomal recessive (AR) DOCK8 deficiency is a well-known actinopathy, a combined primary immune deficiency with impaired actin polymerization that results in altered cell mobility and immune synapse. DOCK8-deficient patients present early in life with eczema, viral cutaneous infections, chronic mucocutaneous candidiasis, bacterial pneumonia, and abscesses, together with eosinophilia, thrombocytosis, lymphopenia, and variable dysgammaglobulinemia that usually includes Hyper-IgE. In fact, before its genetic etiology was known, patients were described as having a form of Hyper-IgE syndrome, a name now deprecated in favor of genetic defects. We describe a school-age male patient with a clinical picture suggestive of DOCK8 deficiency, except for high serum IgE or a family history: early onset, failure to thrive, eczema, warts, condyloma, bronchiolitis, pneumonia, recurrent otitis media, bronchiectasis, candidiasis, leukocytosis, eosinophilia, high IgA, low IgG, and low CD4+ T cells. We were able to confirm the diagnosis through protein expression and whole-exome sequencing. We review the clinical, laboratory, and genetic features of 200 DOCK8-deficient patients; at least 4 other patients have had no elevated IgE, and about 40% do not have Hyper-IgE (above 1,000 IU/mL). Despite this, the constellation of signs, symptoms, and findings allow the suspicion of DOCK8 deficiency and other actinopathies.


Author(s):  
Johannes Raedler ◽  
Thomas Magg ◽  
Meino Rohlfs ◽  
Christoph Klein ◽  
Tanja Vallée ◽  
...  

AbstractBi-allelic variants in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency, characterized by recurrent sinopulmonary and skin infections, food allergies, eczema, eosinophilia, and elevated IgE. Long-term outcome is poor given susceptibility to infections, malignancy, and vascular complications. Allogeneic hematopoietic stem cell transplantation is currently the only curative treatment option and has shown promising outcome. The impact of mixed chimerism on long-term outcome is unclear. We reasoned that reversal of disease phenotype would depend on cell lineage-specific chimerism. DOCK8 variants were confirmed by Sanger and/or exome sequencing and immunoblot and/or intracellular flow cytometry. Donor chimerism was analyzed by XY-fluorescence in situ hybridization or quantitative short tandem repeat PCR. Outcome was assessed by laboratory tests, lymphocyte subsets, intracellular DOCK8 protein flow cytometry, T-cell proliferation analysis, and multiparameter immunoblot allergy screening. We report on nine patients, four of whom with mixed chimerism, with a median follow-up of 78 months after transplantation. Overall, we report successful transplantation with improvement of susceptibility to infections and allergies, and resolution of eczema in all patients. Immunological outcome in patients with mixed chimerism suggests a selective advantage for wild-type donor T-cells but lower donor B-cell chimerism possibly results in a tendency to hypogammaglobulinemia. No increased infectious and allergic complications were associated with mixed chimerism. Aware of the relatively small cohort size, we could not demonstrate a consistent detrimental effect of mixed chimerism on clinical outcomes. We nevertheless advocate aiming for complete donor chimerism in treating DOCK8 deficiency, but recommend reduced toxicity conditioning.


2021 ◽  
Vol 559 ◽  
pp. 135-140
Author(s):  
Keisuke Matsubara ◽  
Kazufumi Kunimura ◽  
Nana Yamane ◽  
Ryosuke Aihara ◽  
Tetsuya Sakurai ◽  
...  

Sign in / Sign up

Export Citation Format

Share Document