Combined Immunodeficiency Associated with<i>DOCK8</i>Mutations

Zhang, Qian; Davis, Jeremiah C.; Lamborn, Ian T.; Freeman, Alexandra F.; Jing, Huie; Favreau, Amanda J.; Matthews, Helen; Davis, Joie; Turner, Maria L.; Uzel, Gülbû; Holland, Steven M.; Su, Helen C.

doi:10.1056/nejmoa0905506

Cited by 674 publications

(792 citation statements)

References 37 publications

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“…The first is that a recent study of mice deficient in the NLR inflammasome adaptor ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain) identified a defect in DC antigen processing and movement but was subsequently found to be due to loss of another member of the DOCK family, DOCK2, and unrelated to loss of ASC (24,25). The second is that more than 35 different mutations located throughout the Dock8 gene in humans are associated with immunodeficiency (ClinVar database) (13). The reason for this potential genetic instability that leads to functional changes of Dock8 is unclear and might relate to the sheer size of the gene (>200 kb in total with a >7 kb coding region in both mouse and human).…”

Section: Nlrp10-deficient Mice Have Normal DC Migration When Dock8 Ismentioning

confidence: 99%

“…3E) (4, 9). Dock8 mutations in humans are responsible for a rare form of immunodeficiency, autosomal recessive hyper-IgE syndrome, which affects both T-cell and B-cell function (13,28,29). The effect of Dock8 mutation on human DC migration and the subsequent impact on adaptive immune responses, however, remain unanswered questions.…”

Section: C3h/hejmentioning

confidence: 99%

“…Furthermore, mice harboring inactivating mutations in Dock8 lack marginal zone B-cell development, long-term antibody production following immunization, and memory CD8 + T-cell responses to viral infections (11,12). In humans, inactivating mutations in Dock8 were recently identified as the primary genetic cause underlying autosomal recessive hyper-IgE syndrome (13). This syndrome presents with eczema, recurrent infections of the skin and respiratory tract, increased serum IgE, eosinophilia, recurrent fungal and viral infections, extensive food and environmental allergies, and, in certain patients, squamous cell dysplasia and carcinomas (14).…”

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confidence: 99%

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Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration

Krishnaswamy¹,

Singh²,

Gowthaman³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Dendritic cells (DCs) are the primary leukocytes responsible for priming T cells. To find and activate naïve T cells, DCs must migrate to lymph nodes, yet the cellular programs responsible for this key step remain unclear. DC migration to lymph nodes and the subsequent T-cell response are disrupted in a mouse we recently described lacking the NOD-like receptor NLRP10 (NLR family, pyrin domain containing 10); however, the mechanism by which this pattern recognition receptor governs DC migration remained unknown. Using a proteomic approach, we discovered that DCs from Nlrp10 knockout mice lack the guanine nucleotide exchange factor DOCK8 (dedicator of cytokinesis 8), which regulates cytoskeleton dynamics in multiple leukocyte populations; in humans, loss-of-function mutations in Dock8 result in severe immunodeficiency. Surprisingly, Nlrp10 knockout mice crossed to other backgrounds had normal DOCK8 expression. This suggested that the original Nlrp10 knockout strain harbored an unexpected mutation in Dock8, which was confirmed using whole-exome sequencing. Consistent with our original report, NLRP3 inflammasome activation remained unaltered in NLRP10-deficient DCs even after restoring DOCK8 function; however, these DCs recovered the ability to migrate. Isolated loss of DOCK8 via targeted deletion confirmed its absolute requirement for DC migration. Because mutations in Dock genes have been discovered in other mouse lines, we analyzed the diversity of Dock8 across different murine strains and found that C3H/HeJ mice also harbor a Dock8 mutation that partially impairs DC migration. We conclude that DOCK8 is an important regulator of DC migration during an immune response and is prone to mutations that disrupt its crucial function.D endritic cells (DCs) are crucial for the initiation of an adaptive immune response. Upon acquiring antigens in the periphery, DCs undergo a maturation process that includes antigen processing, cytokine production, and up-regulation of costimulatory molecules. A mature DC must then migrate from peripheral tissues to draining lymph nodes (LNs) to fulfill its role as an antigen-presenting cell that primes naïve T cells (1). Although the signals that induce this maturation process are now well-established (1), relatively little is understood about DC migration aside from the primary chemotactic cue provided by CCR7 that guides DCs to the LN (2, 3).We recently described a genetically modified NLRP10 (NLR family, pyrin domain containing 10) knockout strain in which this migration step was disrupted while leaving the remainder of the DC maturation program, including CCR7 expression, intact (4).NLRP10 is the only NOD-like receptor (NLR) without a leucine-rich repeat domain, the putative pathogen-associated molecular pattern (PAMP)-binding domain. It has been proposed to both positively and negatively regulate other NLRs, such as NOD1 and NLRP3, respectively (5, 6). Although we found that NLRP3 inflammasome activation was unaltered in the absence of NLRP10, we discovered that Nlrp10 −/− mice could ...

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Section: Nlrp10-deficient Mice Have Normal DC Migration When Dock8 Ismentioning

confidence: 99%

Section: C3h/hejmentioning

confidence: 99%

mentioning

confidence: 99%

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Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration

Krishnaswamy¹,

Singh²,

Gowthaman³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…1,2 The disorder has recently been characterized at the molecular level by Zhang et al, who described mutations in DOCK8, a member of a family of Rho-Rac GTP-exchange factors, in 11 patients from 8 families suffering from AR-HIES. Four of the presented patients had died at the age between 13 and 21 years, three of these patients had developed squamous cell carcinoma, most likely because of persistent human papillomavirus infections.…”

Section: Introductionmentioning

confidence: 99%

Curative treatment of autosomal-recessive hyper-IgE syndrome by hematopoietic cell transplantation

Gatz

Benninghoff

Schütz

et al. 2010

Bone Marrow Transplant

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Autosomal-recessive hyper-IgE syndrome (AR-HIES) is a combined immunodeficiency recently found to be associated with mutations of DOCK8. Clinically, this disorder is characterized beside recurrent bacterial complications, in particular by an unusual susceptibility to extensive cutaneous viral complications and by a high risk for squamous cell carcinoma. Here, we report on lasting control over the disorder in two patients by hematopoietic cell transplantation (HCT). Both patients were suffering from extensive long-lasting cutaneous viral complications, in particular from disfiguring molluscum contagiosum infections, when treated at the age of 10 and 17 years. Donors were matched unrelated, and conditioning was carried out with a combination of fludarabine, melphalan and BM-targeted radioimmunotherapy. Both patients developed stable, full donor cell chimerism, with the exception of persistent lowIgA serum levels and the exception of normal immune functions. Over the course of several months, cutaneous manifestations of viral disease resolved completely and both patients remain clinically well and free of infectious complications at 4 and 2 years, respectively, after transplantation. This represents the first report indicating HCT to be curative in patients with AR-HIES, which should be considered early before life-threatening complications develop, which include malignancies.

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“…Dedicator of cytokinesis 8 (DOCK8) deficiency has recently been identified as the most common cause of AR-HIES. 5,6 CASE REPORT Our patient was born to consanguineous parents in 2002. At the age of 8 months, she developed a herpetic lesion of the right upper eyelid, complicated by blepharitis, a palpebral abscess, and facial cellulitis.…”

mentioning

confidence: 99%

Ten-Year Follow-Up of a DOCK8-Deficient Child With Features of Systemic Lupus Erythematosus

Jouhadi¹,

Khadir²,

Ailal³

et al. 2014

Pediatrics

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Dedicator of cytokinesis 8 (DOCK8) deficiency is an innate error of adaptive immunity characterized by recurrent infections with viruses, bacteria, and fungi, typically high serum levels of immunoglobulin E, eosinophilia, and a progressive deterioration of T-and B-cell-mediated immunity. DOCK8 mutations are the second most common cause of hyper-immunoglobulin E syndromes (HIES). We report a case of DOCK8 deficiency associated with systemic lupus erythematosus (SLE). Association of SLE with HIES is very rare; to our knowledge, this is the sixth such case reported in the literature. A 10-year-old girl of consanguineous parents was followed in our clinic because of HIES since early childhood. She developed SLE with purpuric and necrotic skin lesions, diffuse arthritis, and glomerulonephritis. These autoimmune features were corroborated by the presence of antinuclear, anti-DNA, and antiphospholipid antibodies. The combination of HIES and autoimmunity makes treatment difficult, because the use of immunosuppressive drugs needed for SLE may worsen existing symptoms caused by the immunodeficiency. Our observation is the first case of association of SLE with HIES in the literature where the primary immune disease is genetically documented and labeled as DOCK8 deficiency.

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Combined Immunodeficiency Associated withDOCK8Mutations

Cited by 674 publications

References 37 publications

Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration

Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration

Curative treatment of autosomal-recessive hyper-IgE syndrome by hematopoietic cell transplantation

Ten-Year Follow-Up of a DOCK8-Deficient Child With Features of Systemic Lupus Erythematosus

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