Clinical, immunologic and genetic profiles of DOCK8-deficient patients in Kuwait

doi:10.1016/j.clim.2012.03.002

Clinical Immunology

Volume 143, Issue 3, June 2012, Pages 266-272

https://doi.org/10.1016/j.clim.2012.03.002 Get rights and content

Abstract

Deficiency of dedicator of cytokinesis 8 (DOCK8) is a newly described combined primary immunodeficiency disease. It was found to account for 15% of combined immune deficiency cases in the National Primary Immunodeficiency Disorders Registry in Kuwait, a country with high prevalence of consanguinity. We present the clinical, immunologic and molecular characteristics of 9 Kuwaiti patients with DOCK8 deficiency and discuss differences that distinguish DOCK8 deficiency from atopic dermatitis. Clinical immunologists in areas with high incidence of consanguinity should have a high index of suspicion of DOCK8 deficiency in children with recalcitrant eczema, recurrent non-cutaneous infections and lymphopenia.

Highlights

► DOCK8-deficient patients have selective TH2 bias. ► DOCK8 deficiency is characterized by progressive lymphopenia. ► DOCK8 deficiency is characterized by poor T-lymphocyte stimulation to mitogens. ► Hypermelanosis of oral mucosa is a new finding in DOCK8-deficient patients.

Introduction

Deficiency of dedicator of cytokinesis 8 (DOCK8) is a newly described combined primary immunodeficiency disease (PID) characterized by susceptibility to viral infections, recurrent sinopulmonary infections, atopy, early onset malignancies and autoimmunity [1], [2], [3], [4]. Reported immunologic abnormalities include T-cell lymphopenia, defective T-cell proliferation, decreased IgM, elevated IgE, eosinophilia and a variable IgG antibody response [5]. The disease is caused by biallelic loss-of-function mutations in the DOCK8 gene, most of which lead to absent or trace amounts of expressed DOCK8 protein [6].

Autosomal recessive primary immunodeficiency diseases are more prevalent in Kuwait compared to other populations, because of a high rate of consanguinity [7]. The present study presents the clinical, immunologic and molecular characteristics of 9 Kuwaiti patients who presented with DOCK8 deficiency between the years 2004 and 2011.

Section snippets

Patients data

The patients data were retrieved from the Kuwait National Primary Immunodeficiency Disorders Registry (KNPIDR), which began recruiting patients in 2004. The project was approved by the Human Subjects Research and Ethics Committee of the Ministry of Health, Kuwait.

Mutation analysis of the DOCK8 gene

Genomic DNA was extracted from whole blood using QIAamp DNA Blood Kit (Qiagen, Valencia, CA). For some patients and family members, total RNA was prepared from blood using QIAamp RNA Blood Kit (Qiagen), and cDNA was synthesized as

Patient characteristics and clinical presentations

A total of 9 DOCK8-deficient patients (3 males and 6 females) from 4 families are presented in this report. They represent 3.73% of all patients with PID and 15% of the patients with combined T- and B-cell immunodeficiencies registered in the KNPIDR. All of the patients were born to consanguineous parents. The details of the clinical presentations are shown in Table 1. One patient (A49) was screened and diagnosed early in life because of family history of the disease. All of the patients

Discussion

Combined immunodeficiency due to DOCK8 deficiency is an autosomal recessive disease, which appears to be common in populations where the frequency of consanguineous marriages is high. In Kuwait, where the incidence of consanguinity is 54% [11], DOCK8 deficiency accounted for a significant proportion (15%) of patients who suffer from combined T- and B-cell immunodeficiencies.

The clinical phenotype in the present group of patients is consistent with that in the two initial reports of DOCK8

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgments

We are very grateful to the patients and their families for participation in this study. The project was supported by the Kuwait Foundation for Advancement of Sciences (2010-1302-05) and by a grant from the Dubai Harvard Foundation for Medical Research (RSG and LDN).

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Biliary tract–related liver disease due to cryptosporidium infection can be quite significant. However, significant liver disease not associated with cryptosporidium has also been reported.39,40 Malignancy is a key feature of DOCK 8 deficiency and tends to be particularly aggressive and arises at a younger age.37
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Sclerosing cholangitis secondary to chronic infection has also been reported in DOCK8-deficient patients [15]. Similar to what is seen in patients with CD40 ligand deficiency, hepatobiliary infection with Cryptosporidium can be particularly damaging and difficult to treat [12]. Other reported parasitic infections include Entamoeba histolytica and Giardia lamblia [6,15,42].
Dedicator of cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency that exemplifies the broad clinical features of primary immunodeficiencies (PIDs), extending beyond recurrent infections to include atopy, autoimmunity and cancer. It is caused by loss of function mutations in DOCK8, encoding a guanine nucleotide exchange factor highly expressed in lymphocytes that regulates the actin cytoskeleton. Additional roles of DOCK8 have also emerged, including regulating MyD88-dependent Toll-like receptor signaling and the activation of the transcription factor STAT3. DOCK8 deficiency impairs immune cell migration, function and survival, and it impacts both innate and adaptive immune responses. Clinically, DOCK8 deficiency is characterized by allergic inflammation as well as susceptibility towards infections, autoimmunity and malignancy. This review details the pathophysiology, clinical features and management of DOCK8 deficiency. It also surveys the recently discovered combined immunodeficiency due to DOCK2 deficiency, highlighting in the process the emerging spectrum of PIDs resulting from DOCK protein family abnormalities.
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The autosomal recessive hyper-IgE syndrome (HIES) caused by dedicator of cytokinesis 8 (DOCK8) deficiency shares clinical features with autosomal dominant HIES because of signal transducer and activator of transcription 3 (STAT3) mutations, including recurrent infections and mucocutaneous candidiasis, which are suggestive of T_H17 cell dysfunction. The mechanisms underlying this phenotypic overlap are unclear.
We sought to elucidate common mechanisms operating in the different forms of HIES.
We analyzed the differentiation of CD4⁺ T_H cell subsets in control and DOCK8-deficient subjects. We also examined the role of DOCK8 in regulating STAT3 activation in T cells. T_H cell differentiation was analyzed by ELISA, flow cytometry, and real-time PCR measurements of cytokines and T_H cell transcription factors. The interaction of DOCK8 and STAT3 signaling pathways was examined by using flow cytometry, immunofluorescence, coimmunoprecipitation, and gene expression analysis.
There was a profound block in the differentiation of DOCK8-deficient naive CD4⁺ T cells into T_H17 cells. A missense mutation that disrupts DOCK8 guanine nucleotide exchange factor (GEF) activity while sparing protein expression also impaired T_H17 cell differentiation. DOCK8 constitutively associated with STAT3 independent of GEF activity, whereas it regulated STAT3 phosphorylation in a GEF activity–dependent manner. DOCK8 also promoted STAT3 translocation to the nucleus and induction of STAT3-dependent gene expression.
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Clinical, immunologic and genetic profiles of DOCK8-deficient patients in Kuwait

Abstract

Highlights

Introduction

Section snippets

Patients data

Mutation analysis of the DOCK8 gene

Patient characteristics and clinical presentations

Discussion

Conflict of interest statement

Acknowledgments

J. Allergy Clin. Immunol.

Blood

Large deletions and pointmutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome

J. Allergy Clin. Immunol.

Combined immunodeficiency associated with DOCK8 mutations

N. Engl. J. Med.

DOCK8 deficiency

Ann. N. Y. Acad. Sci.

Clinical manifestations of hyper IgE syndromes

Dis. Markers

Dedicator of cytokinesis 8 (DOCK8) deficiency

Curr. Opin Allergy Clin. Immunol.

Genetic, clinical, and laboratory markers for DOCK8 immunodeficiency syndrome

Dis. Markers