Clinical and Laboratory Findings in Iranian Patients with Leukocyte Adhesion Deficiency (Study of 15 Cases)

Movahedi, Masoud; Entezari, Neda; Pourpak, Zahra; Mamishi, Setareh; Chavoshzadeh, Zahra; Gharagozlou, Mohammad; Mir-Saeeid-Ghazi, Bahram; Fazlollahi, Mohammad Reza; Zandieh, Fariborz; Bemanian, Mohammad Hasan; Farhoudi, Aboulhasan; Aghamohammadi, Asghar

doi:10.1007/s10875-007-9129-4

Cited by 6 publications

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“…Although the yeast form can bind to gut mucosal membranes with further colonization (20,49), it is thought that the filamentous morphology provides some advantage during interaction with the mammalian immune system as a part of fungal anti-host defense, and the ability of C. albicans to rapidly and reversibly switch between yeast and filamentous morphologies is crucial to its pathogenicity (16,55,65,82). In recent years, Candida infections ranked as the fourth most common cause of bloodstream infections and are the leading cause of life-threatening nosocomial fungal infections (1,87).…”

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confidence: 99%

“…16% of patients; Candida esophagitis has also been frequently reported (6,7). In three more-recent reports, a total of 27 cases of LAD-1 patients were described, all of which had infections of different etiologies: C. albicans infections in 13 patients (48%), 17 patients (63%) dead from infections, and in 6 cases (22% of all LAD-1 patients or 46% of all cases of mortality) the cause of death was fungal septicemia (44,65,71). In most cases, the degree of severity of these symptoms may be correlated with the level of ␤ 2 expression on the patients' leukocytes.…”

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confidence: 99%

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Regulation of Innate Immune Response toCandida albicansInfections by α_Mβ₂-Pra1p Interaction

2011

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Candida albicans is a common opportunistic fungal pathogen and is the leading cause of invasive fungal diseases in immunocompromised individuals. The induction of cell-mediated immunity to C. albicans is one of the main tasks of cells of the innate immune system, and in vitro evidence suggests that integrin ␣ M ␤ 2 (CR3, Mac-1, and CD11b/CD18) is the principal leukocyte receptor involved in recognition of the fungus. Using ␣ M ␤ 2 -KO mice and mutated strains of C. albicans in two models of murine candidiasis, we demonstrate that neutrophils derived from mice deficient in ␣ M ␤ 2 have a reduced ability to kill C. albicans and that the deficient mice themselves exhibit increased susceptibility to fungal infection. Disruption of the PRA1 gene of C. albicans, the primary ligand for ␣ M ␤ 2 , protects the fungus against leukocyte killing in vitro and in vivo, impedes the innate immune response to the infection, and increases fungal virulence and organ invasion in vivo. Thus, recognition of pH-regulated antigen 1 protein (Pra1p) by ␣ M ␤ 2 plays a pivotal role in determining fungal virulence and host response and protection against C. albicans infection.

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confidence: 99%

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confidence: 99%

Regulation of Innate Immune Response toCandida albicansInfections by α_Mβ₂-Pra1p Interaction

2011

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“…Patients with the severe form of the disease tend to succumb early in life to overwhelming infection, whereas, those with a moderate form of the disease often survive through it to adulthood (12). Oral candidiasis is also a frequently observed symptom and must be treated aggressively (13).…”

Section: Discussionmentioning

confidence: 99%

Leukocyte adhesion deficiency type I - a focus on oral disease in a young child

Yashodadevi

Rakesh²,

Devaraju³

et al. 2011

Med Oral

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This paper presents a case of the moderate form of Leukocyte adhesion deficiency type 1 (LAD-1) in a 4 year-old boy. LAD-1 is a rare, inherited immunodeficiency that affects 1 in 1 million people yearly. Affected patients are susceptible to recurrent bacterial and fungal infections, impaired pus formation and delayed wound healing. In the oral clinical finding, more important is a generalized prepuberal periodontitis that can affect the primary and permanent dentitions. For this reason cooperation between dentists and pediatricians is essential in these patients. Evaluating immune system in these patients included peripheral blood leukocyte counts, measurement of serum immunoglobulin levels, assessment of complement level and function, flow cytometric analysis of lymphocyte subsets, and tests of phagocytic function (nitrobluetetrazolium test (NBT)). In families with known molecular defect, an earlier prenatal diagnosis is possible by chorionic villi biopsy. The most important focus should be to control infections. Treatment includes systemic antibiotics and in many cases bone marrow transplantation.

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“…14,20 Classical symptoms of LAD-I patients and CD18-deficient mice include neutrophilia and defects in neutrophil trafficking, 15,19 while splenomegaly is observed in CD18-deficient mice 17,21 and occasionally in LAD-I humans. 22 Transgenic lines exhibited mild neutrophilia, splenomegaly, and a marked reduction in neutrophil trafficking with the extent of each correlating with the level of CD18 silencing. We anticipate that the robust nature of gene knockdown and the high degree of cell specificity will allow our RNAi-transgenic approach to gain wide acceptance as a reverse genetics tool in the study of neutrophil function.…”

Section: Introductionmentioning

confidence: 99%

Neutrophil-selective CD18 silencing using RNA interference in vivo

Culleré

Lauterbach

Tsuboi

et al. 2008

Blood

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Tissue-specific silencing of genes may be used for genetic engineering in mice and has possible therapeutic applications in humans. Current strategies in mice rely on Cre/loxP technology requiring the generation of multiple transgenic lines and breeding strategies. Here, we describe the selective silencing of CD18, a leukocyte-specific integrin in neutrophils using a micro RNA (miRNA) strategy that requires the generation of one transgenic line. CD18-specific miRNA hairpin driven by the myeloid specific human MRP8 promoter resulted in the generation of transgenic lines with 75% to 95% reduction in CD18 protein levels in neutrophils and monocytes. Minimal decreases in T cells and a partial diminution in macrophages were observed. Neutrophil CD18 silencing resulted in neutrophilia, splenomegaly, and significant defects in neutrophil trafficking with the degree of alterations correlating with the extent of CD18 silencing. Thus, our data demonstrate the utility of using miRNA approaches to silence genes in neutrophils, which are terminally differentiated cells with a short half-life that largely precludes their genetic manipulation in vitro. Furthermore, the mouse models provide a valuable tool to examine the contribution of CD18 on neutrophils to leukocyte adhesion deficiency type I (LAD-I), a complex inherited disorder in which reduced or absent CD18 expression in multiple leukocyte subsets leads to impaired innate and adaptive immune responses. IntroductionHomologous recombination combined with the Cre/loxP system has been used to achieve conditional or tissue-specific targeting of gene expression in mice. This approach requires the generation of homologous targeted embryonic stem cells, and multiple transgenic lines and breeding strategies. 1 Recent advances in RNA interference (RNAi) have provided an attractive alternative to silencing genes in vivo that is more rapid and also has possible therapeutic applications. RNAi is a posttranscriptional genesilencing mechanism that is induced by double-stranded RNA. Introduction of chemically synthesized small interfering RNAs (siRNAs) and/or transfections of DNA-based vector systems driving the expression of short hairpin RNAs (shRNAs) by RNA pol III promoters (U6 and H1) have been used as powerful tools to examine the function of specific genes. Endogenous micro RNAs (miRNA) are small single-stranded RNAs that regulate genes required for a wide range of cellular functions. miRNAs are produced by the processing of primary transcripts (pri-mRNA) by the RNAse III type enzyme Drosha into pre-miRNAs (approximately 70 nucleotide stem-loop RNAs), which are exported to the cytoplasm and further cleaved by the cytoplasmic RNase III Dicer into miRNA-containing RNA duplexes. In the case of near-perfect complementarity to the targets, the outcome is endonucleolytic cleavage of the target mRNA, 2-5 while binding to partially complementary sites, predominantly in the 3ЈUTR, causes mRNA degradation or repression of translation. [6][7][8] The expression of artificial miRNAs by RNA P...

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Clinical and Laboratory Findings in Iranian Patients with Leukocyte Adhesion Deficiency (Study of 15 Cases)

Cited by 6 publications

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Regulation of Innate Immune Response toCandida albicansInfections by α_Mβ₂-Pra1p Interaction

Regulation of Innate Immune Response toCandida albicansInfections by α_Mβ₂-Pra1p Interaction

Leukocyte adhesion deficiency type I - a focus on oral disease in a young child

Neutrophil-selective CD18 silencing using RNA interference in vivo

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Clinical and Laboratory Findings in Iranian Patients with Leukocyte Adhesion Deficiency (Study of 15 Cases)

Cited by 6 publications

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Regulation of Innate Immune Response toCandida albicansInfections by αMβ2-Pra1p Interaction

Regulation of Innate Immune Response toCandida albicansInfections by αMβ2-Pra1p Interaction

Leukocyte adhesion deficiency type I - a focus on oral disease in a young child

Neutrophil-selective CD18 silencing using RNA interference in vivo

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Regulation of Innate Immune Response toCandida albicansInfections by α_Mβ₂-Pra1p Interaction

Regulation of Innate Immune Response toCandida albicansInfections by α_Mβ₂-Pra1p Interaction