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)

WHIM (warts, hypogammaglobulinemia, infections, and myelokatexis) syndrome is a rare immunodeficiency syndrome linked to heterozygous mutations of the chemokine receptor CXCR4 resulting in truncations of its cytoplasmic tail. Leukocytes from patients with WHIM syndrome display impaired CXCR4 internalization and enhanced chemotaxis in response to its unique ligand SDF-1/CXCL12, which likely contribute to the clinical manifestations. Here, we investigated the biochemical mechanisms underlying CXCR4 deficiency in WHIM syndrome. We report that after ligand activation, WHIM-associated mutant CXCR4 receptors lacking the carboxy-terminal 19 residues internalize and activate Erk 1/2 slower than wild-type (WT) receptors, while utilizing the same trafficking endocytic pathway. Recruitment of beta-Arrestin 2, but not beta-Arrestin 1, to the active WHIM-mutant receptor is delayed compared to the WT CXCR4 receptor. In addition, while both kinases Grk3 and Grk6 bind to WT CXCR4 and are critical to its trafficking to the lysosomes, Grk6 fails to associate with the WHIM-mutant receptor whereas Grk3 associates normally. Since beta-Arrestins and Grks play critical roles in phosphorylation and internalization of agonist-activated G protein-coupled receptors, these results provide a molecular basis for CXCR4 dysfunction in WHIM syndrome.
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PMID:Impaired recruitment of Grk6 and beta-Arrestin 2 causes delayed internalization and desensitization of a WHIM syndrome-associated CXCR4 mutant receptor. 1995 69

Disseminated Mycobacterium avium complex (MAC) infection is a rare but severe disease mostly seen in patients with AIDS. It has been previously described in patients suffering from other kinds of immunodeficiency (e.g. primary immunodeficiency diseases in children or hairy cell leukaemia). We report two cases of disseminated MAC disease in young women with extended granulomatosis that revealed a new form of severe immunodeficiency syndrome. Both clinical observations initially appeared to be very similar to WHIM syndrome (Warts, Hypogammaglobulinemia, Infection, Myelokathexis), a rare immunodeficiency disease correlated with CXC chemokine receptor 4 (CXCR4) mutation leading to an impaired internalization of the receptor upon its ligand CXCL12. We investigated the CXCR4 status of the lymphocytes in both patients and found a severe defect in CXCL12-promoted internalization but no mutation of its gene. Moreover, myelokathexis was not noted in bone marrow biopsies and therefore a diagnosis of WHIM syndrome could not be assessed. This immunodeficiency syndrome associated with CXCR4 dysfunction was responsible for severe MAC infection in our patients, with a fatal outcome in one case. It may be possible that these patients would have benefited from early antimycobacterial infection or azythromycin prophylaxis.
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PMID:Two cases of disseminated Mycobacterium avium infection associated with a new immunodeficiency syndrome related to CXCR4 dysfunctions. 2014 20

Heterozygous truncating mutations in CXCR4 have been identified as a cause of WHIM syndrome (warts, hypogammaglobulinemia, immunodeficiency and myelokathexis). The receptor truncations have been proposed to lead to altered lymphocyte trafficking. The purpose of the described studies was to characterize the B-cell repertoire in WHIM subjects. We confirmed profound B-cell lymphopenia and demonstrated oligoclonality of the circulating B-cell pool by HCDR3 spectratyping. The response to immunization was studied in one subject utilizing a bacteriophage PhiX174 immunization protocol. Spectratyping showed oligoclonality at baseline with normalization of the HCDR3 length distribution by 5 months after immunization with PhiX174 with eventual return to the baseline state. Isotype switching from phage specific neutralizing antibody of the IgM class to IgG was markedly reduced. Overall, these data suggest that impaired CXCR4 signaling in WHIM syndrome results in defective B-cell function and abnormal isotype switching, possibly through effects on germinal center trafficking of lymphocytes.
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PMID:Oligoclonality, impaired class switch and B-cell memory responses in WHIM syndrome. 2022 38

CXCR4 is a G protein-coupled chemokine receptor that has been implicated in the pathogenesis of primary immunodeficiency disorders and cancer. Autosomal dominant gain-of-function truncations of CXCR4 are associated with warts, hypo-gammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a primary immunodeficiency disorder characterized by neutropenia and recurrent infections. Recent progress has implicated CXCR4-SDF1 (stromal cell-derived factor 1) signaling in regulating neutrophil homeostasis, but the precise role of CXCR4-SDF1 interactions in regulating neutrophil motility in vivo is not known. Here, we use the optical transparency of zebrafish to visualize neutrophil trafficking in vivo in a zebrafish model of WHIM syndrome. We demonstrate that expression of WHIM mutations in zebrafish neutrophils induces neutrophil retention in hematopoietic tissue, impairing neutrophil motility and wound recruitment. The neutrophil retention signal induced by WHIM truncation mutations is SDF1 dependent, because depletion of SDF1 with the use of morpholino oligonucleotides restores neutrophil chemotaxis to wounds. Moreover, localized activation of a genetically encoded, photoactivatable Rac guanosine triphosphatase is sufficient to direct migration of neutrophils that express the WHIM mutation. The findings suggest that this transgenic zebrafish model of WHIM syndrome may provide a valuable tool to screen for agents that modify CXCR4-SDF1 retention signals.
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PMID:Live imaging of neutrophil motility in a zebrafish model of WHIM syndrome. 2094 86

Four reports have been published on an association between acute myeloid leukaemia (AML) and primary lymphedema, with or without congenital deafness. We report seven new cases, including one extended family, confirming this entity as a genetic syndrome. The lymphedema typically presents in one or both lower limbs, before the hematological abnormalities, with onset between infancy and puberty and frequently affecting the genitalia. The AML is often preceded by pancytopenia or myelodysplasia with a high incidence of monosomy 7 in the bone marrow (five propositi and two relatives). Associated anomalies included hypotelorism, epicanthic folds, long tapering fingers and/or neck webbing (four patients), recurrent cellulitis in the affected limb (four patients), generalized warts (two patients), and congenital, high frequency sensorineural deafness (one patient). Children with lower limb and genital lymphedema should be screened for hematological abnormalities and immunodeficiency.
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PMID:Emberger syndrome-primary lymphedema with myelodysplasia: report of seven new cases. 2080 46

WHIM syndrome is a dominantly inherited primary immunodeficiency disorder representing the first identified example of human disease caused by mutations in the gene encoding for the chemokine receptor CXCR4. Pathogenesis is mediated by CXCR4 hyperfunction, leading to increased responsiveness to its unique ligand CXCL12 (also known as SDF-1). The altered CXCR4/CXCL12 interaction likely impairs cellular homeostasis and trafficking, resulting in immunological dysfunctions. The acronym WHIM resumes the main features of the syndrome: Warts, Hypogammaglobulinemia, Infections and Myelokathexis, which is abnormal retention of mature neutrophils in the bone marrow. WHIM patients suffer from recurrent bacterial infections since childhood and manifest a specific susceptibility to HPV infections. Hematological findings include neutropenia, lymphopenia and hypogammaglobulinemia. Because of the rarity of the disease and the heterogeneity in clinical presentation, diagnosis is often delayed. In the majority of patients, the phenotype is incomplete at the onset and WHIM syndrome is not suspected. Early identification may improve clinical and therapeutic management. Symptomatic treatments include G-CSF, substitutive immunoglobulins and antibiotic prophylaxis. A new therapeutic strategy might include the potent inhibitor of CXCR4 function plerixafor (Mozobil), as an agent specifically targeting the molecular defect in order to attenuate the phenotypic manifestations of the syndrome.
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PMID:Clinical and genetic features of Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) syndrome. 2150 20

Primary immunodeficiencies (PIDs) are commonly characterized by an increased susceptibility to specific infections and, in certain instances, a higher than usual incidence of malignancies. Although improved diagnosis and early treatment of PIDs have reduced early morbidity and mortality from infection, the development of cancer remains a significant cause of premature death. The emergence of cancer in patients with PIDs often results from impairments in the immune response that lead to weakened surveillance against oncogenic viruses, premalignant or malignant cells, or both. Here we review the clinical and biologic features of several PIDs associated with enhanced susceptibility to viral infections and cancer, including X-linked lymphoproliferative disease; IL-2-inducible T-cell kinase deficiency; epidermodysplasia verruciformis; warts, hypogammaglobulinemia, infections, and myelokathexis syndrome; autosomal recessive hyper-IgE syndrome; X-linked agammaglobulinemia; and common variable immunodeficiency. It is of importance that we gain in-depth insights into the fundamental molecular nature of these unique PIDs to better understand the pathogenesis of virus-associated malignancies and to develop innovative therapeutic strategies.
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PMID:Primary immunodeficiency diseases associated with increased susceptibility to viral infections and malignancies. 2151 36

Generalized verrucosis has been described in the past as synonymous with epidermodysplasia verruciformis. It has been shown, however, that epidermodysplasia verruciformis and other genetic or immunodeficiency diseases are just a subset of diffuse infections with human papillomavirus termed "generalized verrucosis." This article defines generalized verrucosis and distinct diseases associated with generalized warts. The indications for histopathologic testing, human papillomavirus typing, and other laboratory analyses and potential treatment options are discussed.
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PMID:Generalized verrucosis: a review of the associated diseases, evaluation, and treatments. 2306 95

Molluscum contagiosum virus (MCV) is a poxvirus that causes localized papules in healthy persons. We evaluated a woman with severe immunodeficiency and disseminated MCV. During treatment with CMX-001, an antiviral with activity against other poxviruses, MCV DNA was detected in 20% of plasma samples. When the patient was not receiving CMX-001, MCV DNA was detected in 50% of samples. We also noted improvement in warts on her fingers during CMX-001 therapy. Although MCV is caused by direct inoculation of virus into skin in healthy persons, in a severely immunocompromised person MCV DNA was present in blood and may spread by viremia.
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PMID:Detection of molluscum contagiosum virus (MCV) DNA in the plasma of an immunocompromised patient and possible reduction of MCV DNA with CMX-001. 2226 88

We describe a novel clinical phenotype associating T- and B-cell lymphopenia, intermittent neutropenia, and atrial septal defects in 3 members of a consanguineous kindred. Their clinical histories included recurrent bacterial infections, viral infections, mucocutaneous candidiasis, cutaneous warts, and skin abscesses. Homozygosity mapping and candidate gene sequencing revealed a homozygous premature termination mutation in the gene STK4 (serine threonine kinase 4, formerly having the symbol MST1). STK4 is the human ortholog of Drosophila Hippo, the central constituent of a highly conserved pathway controlling cell growth and apoptosis. STK4-deficient lymphocytes and neutrophils exhibit enhanced loss of mitochondrial membrane potential and increased susceptibility to apoptosis. STK4 deficiency is a novel human primary immunodeficiency syndrome.
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PMID:The phenotype of human STK4 deficiency. 2250 47


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