Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hyper-IgE syndromes (HIES; originally named Job's syndrome) are a collection of primary immunodeficiency syndromes resulting in elevated serum IgE levels and typified by recurrent staphylococcal skin abscesses, eczema and pulmonary infections. The disorder has autosomal dominant and recessive forms. Autosomal dominant HIES has been shown to be mainly due to STAT3 mutations and additionally results in connective tissue, skeletal, vascular and dental abnormalities. Autosomal recessive HIES has been shown to be mainly due to mutations in DOCK8; these patients are more prone to viral skin infections instead. This review article discusses the common clinical features of the syndrome, the genetic mutations responsible and the pathogenesis of the disease, as well as treatments currently used.
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PMID:An update on the hyper-IgE syndromes. 2321 May 25

Recently, patients with mutations in DOCK8 have been reported to have a combined immunodeficiency characterized by cutaneous viral infections and allergies. NK cells represent a first-line defense against viral infections, suggesting that DOCK8 might participate in NK cell function. In this study, we demonstrate that DOCK8-suppressed human NK cells showed defects in natural cytotoxicity as well as specific activating receptor-mediated NK cytotoxicity. Additionally, compared with control NK cells, NK cells depleted of DOCK8 showed defective conjugate formation, along with decreased polarization of LFA-1, F-actin, and cytolytic granules toward the cytotoxic synapse. Using a proteomic approach, we found that DOCK8 exists in a macromolecular complex with the Wiskott-Aldrich syndrome protein, an actin nucleation-promoting factor activated by CDC42, as well as talin, which is required for integrin-mediated adhesion. Taken together, our results demonstrate an important role for DOCK8 in NK cell effector function and provide important new mechanistic insight into how DOCK8 regulates F-actin and integrin-mediated adhesion in immune cells.
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PMID:Dedicator of cytokinesis 8 interacts with talin and Wiskott-Aldrich syndrome protein to regulate NK cell cytotoxicity. 2345 9

Mutations in the DOCK8 gene define the most common form of autosomal-recessive Hyper-IgE-syndrome (AR-HIES/OMIM#243700). In a patient with extensive molluscum contagiosum lesions, a homozygous DOCK8 gene deletion was demonstrated. In-vivo 18-FDG uptake showed multiple non-enlarged lymph nodes without uptake in the spleen. Lymph node biopsies for subsequent immunohistochemistry showed clear differences with the mouse model of DOCK8 deficiency in which these mice show no GCs. Unexpectedly, the patient's lymph nodes demonstrated lymphocyte polyclonality, follicular hyperplasia and an unusual IgE(+) plasma cell expansion. In contrast, the proliferative capacity of circulating B-cells was almost absent with little in-vitro Ig production or plasmablast formation. Also the T-cell proliferation indicated a partial defect. Hematopoietic stem cell transplantation (HSCT) was performed resulting in the disappearance of the molluscum contagiosum lesions. In sum, DOCK8 deficiency results in defective antibody responses and undirected plasma cell expansion in the lymph nodes, as part of a combined immunodeficiency cured by HSCT.
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PMID:Aberrant humoral immune reactivity in DOCK8 deficiency with follicular hyperplasia and nodal plasmacytosis. 2389 36

DOCK proteins constitute a family of evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho family of GTPases. Although DOCK family proteins do not contain the Dbl homology domain typically found in GEFs, they mediate the GTP-GDP exchange reaction through DHR-2 domain. Accumulating evidence indicates that the DOCK proteins act as major GEFs in varied biological settings. For example, DOCK2, which is predominantly expressed in hematopoietic cells, regulates migration and activation of leukocytes through Rac activation. On the other hand, it was recently reported that mutations of DOCK8, another member of the DOCK family proteins, cause a combined immunodeficiency syndrome in humans. This article reviews the structure, functions and signaling of DOCK2 and DOCK8, especially focusing on their roles in immune responses.
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PMID:Immune regulatory functions of DOCK family proteins in health and disease. 2391 89

Molluscum contagiosum virus is an important human skin pathogen: it can cause disfigurement and suffering in children, in adults it is less common and often sexually transmitted. Extensive and persistent skin infection with the virus can indicate underlying immunodeficiency. Traditional ablative therapies have not been compared directly with newer immune-modulating and specific antiviral therapies. Advances in research raise the prospect of new approaches to treatment informed by the biology of the virus; in human skin, the infection is localised in the epidermal layers, where it induces a typical, complex hyperproliferative lesion with an abundance of virus particles but a conspicuous absence of immune effectors. Functional studies of the viral genome have revealed effects on cellular pathways involved in the cell cycle, innate immunity, inflammation, and cell death. Extensive lesions caused by molluscum contagiosum can occur in patients with DOCK8 deficiency-a genetic disorder affecting migration of dendritic and specialised T cells in skin. Sudden disappearance of lesions is the consequence of a vigorous immune response in healthy people. Further study of the unique features of infection with molluscum contagiosum virus could give fundamental insight into the nature of skin immunity.
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PMID:Molluscum contagiosum virus infection. 2475 95

During recent years a number of primary immunodeficiencies resulting from impaired function of JAK-STAT molecules have been described. One of these is the Hyper-IgE syndrome (HIES) characterized by elevated IgE levels, eczema, recurrent staphylococcal skin and pulmonary infections and pleiotropic somatic manifestations. In 2007 the genetic basis of HIES was revealed by identification of dominant negative STAT3 mutations in HIES patients. Subsequently impaired function of Tyk2 and DOCK8 have been implicated in milder forms of HIES. Since STAT3 acts as a central transcription factor downstream of multiple cytokine and growth factor receptors and thus regulates antimicrobial responses and cell survival, impaired STAT3 function results in immunodeficiency and in some cases tumorigenesis. However, as the immunological and molecular basis of HIES is being unraveled, important biological and immunological insight into JAK-STAT signaling is emerging that may have implications for our understanding of the pathogenesis and clinical management of patients with HIES.
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PMID:STAT3 and the Hyper-IgE syndrome: Clinical presentation, genetic origin, pathogenesis, novel findings and remaining uncertainties. 2405 7

DOCK8 deficiency is a primary immunodeficiency characterized by recurrent sinopulmonary infections, dermatitis with cutaneous infections, elevated serum IgE levels, eosinophilia, and a high incidence of food allergy. Given the seriousness of DOCK8 deficiency, it is important to recognize it early and initiate appropriate therapy. Diagnosis relies on examining DOCK8 protein expression and sequencing of the 48 exons in the DOCK8 gene, but these assays are not always readily available. A major problem facing clinicians is that DOCK8 deficiency shares many clinical and laboratory features with severe atopic dermatitis. Here, we have identified biomarkers routinely measured by flow cytometry on whole blood in clinical immunology laboratories that may be used in distinguishing DOCK8 deficiency from severe atopic dermatitis. The use of these biomarkers may help the clinician identify those patients who are most likely to have DOCK8 mutations and would benefit from further specialized diagnostic testing.
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PMID:Flow cytometry biomarkers distinguish DOCK8 deficiency from severe atopic dermatitis. 2444 Jun 47

Different primary immunodeficiencies present increased levels of IgE and cutaneous infections of viral etiology. We report a case of a 2 y, 8 m old boy with combined immunodeficiency, dermatitis and disseminated molluscum contagiosum. The patient presented high titers of IgE, eosinophilia and pronounced TCD8 lymphopenia. Impaired proliferation assays and abnormal antibody response to vaccination were found. Normal results of ZAP-70 protein, NK function, and HLA I levels, to test quantitatives and functional defects of cytotoxic cells, lead us to suspect a mutation in DOCK8 gene. Positive result in molecular study together with clinical and immunology features in the patient confirmed the diagnosis of this new immunodeficiency, being to the authors' knowledge the first case recorded in a paediatric hospital in our country.
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PMID:[Combined immunodeficiency with cutaneous manifestations associated with DOCK8 mutation]. 2495 14

DOCK8 mutations result in an inherited combined immunodeficiency characterized by increased susceptibility to skin and other infections. We show that when DOCK8-deficient T and NK cells migrate through confined spaces, they develop cell shape and nuclear deformation abnormalities that do not impair chemotaxis but contribute to a distinct form of catastrophic cell death we term cytothripsis. Such defects arise during lymphocyte migration in collagen-dense tissues when DOCK8, through CDC42 and p21-activated kinase (PAK), is unavailable to coordinate cytoskeletal structures. Cytothripsis of DOCK8-deficient cells prevents the generation of long-lived skin-resident memory CD8 T cells, which in turn impairs control of herpesvirus skin infections. Our results establish that DOCK8-regulated shape integrity of lymphocytes prevents cytothripsis and promotes antiviral immunity in the skin.
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PMID:DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity. 2551 80

We present a 17-year old girl with DOCK-8 deficiency, severe untreated oral HSV-1 infection and associated aggressive periodontitis. DOCK-8 deficiency is a primary immunodeficiency, caused by biallelicloss-of-function mutations in the DOCK8 gene, often leading to severe viral and fungal mucocutaneous infections. Nevertheless, to date DOCK8 has not been associated with severe periodontitis and inflammatory bone loss around teeth. Understanding whether DOCK8 deficiency or severe HSV-1 infection underlies susceptibility to periodontitis is central to this case and may provide insights into susceptibility factors for periodontitis in the general population. Our clinical and microbiological data suggest that severe HSV-1 infection is the driver of periodontal inflammation in this case.
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PMID:A 17-year old patient with DOCK8 deficiency, severe oral HSV-1 and aggressive periodontitis - a case of virally induced periodontitis? 2560 Jun 4


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