11 research outputs found
Innate immunity genes as determinants of resistance/susceptibility to human disease : studies in leukemia patients
La leucémie lymphoblastique aiguë des cellules Pré-B (B-ALL) reste le type de cancer le
plus souvent diagnostiqué chez les enfants. Des études ont montré que des déterminants
génétiques jouent un rÎle important dans la susceptibilité/résistance au développement de
ce cancer. Ă cet Ă©gard, les gĂšnes Killer-cell Immunoglobulin-like Receptor (KIR) sont
d'une importance particuliĂšre. Ces gĂšnes sont fortement polymorphiques et codent pour
des rĂ©cepteurs qui contrĂŽlent lâactivitĂ© fonctionnelle des cellules Natural Killer (NK).
Notre hypothĂšse est que les gĂšnes activateurs des KIR sâassocient avec la rĂ©sistance innĂ©e
pour développer la B-ALL. Afin d'évaluer cette hypothÚse, nous avons entrepris une
étude de cas-contrÎles chez des enfants canadiens-français dans laquelle nous avons
utilisĂ© l'ADN gĂ©nomique de 100 patients atteints de B-ALL ainsi que lâADN de 245
individus sains. La présence ou l'absence de chaque gÚne KIR a été détectée par PCR en
utilisant des amorces de séquences spécifiques. Nous avons trouvé que la présence des
gÚnes KIR activateurs est significativement diminuée chez les enfants leucémiques par
rapport aux témoins. En outre, le nombre de ces gÚnes a aussi montré une association
significative linĂ©aire avec la rĂ©sistance au dĂ©veloppement dâune B-ALL. Cela suggĂšre des
effets additifs de ces gÚnes permettant de conférer une protection contre ce cancer. Ces
rĂ©sultats pourraient ĂȘtre utiles afin de dĂ©celer de façon prĂ©coce les enfants ayant un risque
de développer cette leucémie. Enfin, des stratégies thérapeutiques basées sur les
rĂ©cepteurs KIR pourraient ĂȘtre envisagĂ©es et s'avĂ©rer utiles concernant le traitement de ce
cancer chez les enfants.Investigating genetic determinants that play a role in conferring susceptibility/resistance
to the development of acute B cell leukemia (B-ALL) in children is highly desirable. We
hypothesized that activating Killer-cell Immunoglobulin-like Receptor (KIR) genes,
which are implicated in NK cell activation, may represent one of these determinants. To
test this hypothesis, we conducted a case-control study in French-Canadian children in
which we used genomic DNA from 100 B-ALL patients and 245 healthy controls. The
presence or absence of each KIR gene was detected by PCR using sequence-specific
primers. We found that the frequencies of these genes are significantly reduced in B-ALL
cases when compared with their healthy counterparts. Furthermore, we found that these
genes had an additive effect in reducing risk for developing the cancer. The results may
be useful in early identification of children at risk for developing this cancer. Moreover,
KIR-based therapies may prove to be useful in treating this cancer
Chimerism in Children With Primary Immunodeficiencies is Influenced by Number of Activating Killer Cell Immunoglobulin-Like Receptor Genes in the Donor and/or Killer Cell Immunoglobulin-Like Receptor Ligand Mismatch
KIR and KIR ligand polymorphism: a new area for clinical applications?
Killer immunoglobulin-like receptors (KIRs) play an essential role in the regulation of natural killer (NK) activity, allowing NK cells to sense and respond to human leukocyte antigen (HLA) class I downregulation, an important hallmark for viral infections and tumor transformation. KIR and HLA genes are located on different chromosomes and KIR/HLA class I interaction represents an example of genetic epistasis in which the presence of receptor/ligand pairs is necessary for the induction of functional activity, while the presence of one in the absence of the other is not sufficient to influence NK cell function. Due to the high degree of HLA class I and KIR gene variability, KIR/KIR-ligand (KIR-L) interactions are extraordinarily diverse. KIR polymorphism arises from both haplotypic and allelic variations and was shaped by natural selection. KIR variability affects NK cell education influencing the KIR repertoire, KIR expression, the strength of KIR/KIR-L interactions and the capability to deliver signals. Moreover, it may influence NK cell function during infections, autoimmune diseases, pregnancy and allogeneic transplantation. This review summarizes the genetic and functional features of KIR/KIR-L interactions and gives an overview of their potential relevance in clinical studies
The role of KIR genes and their cognate HLA class I ligands in childhood acute lymphoblastic leukemia
The Childhood Leukemia International Consortium
Background: Acute leukemia is the most common cancer in children under 15 years of age; 80% are acute lymphoblastic leukemia (ALL) and 17% are acute myeloid leukemia (AML). Childhood leukemia shows further diversity based on cytogenetic and molecular characteristics, which may relate to distinct etiologies. Case-control studies conducted worldwide, particularly of ALL, have collected a wealth of data on potential risk factors and in some studies, biospecimens. There is growing evidence for the role of infectious/immunologic factors, fetal growth, and several environmental factors in the etiology of childhood ALL. The risk of childhood leukemia, like other complex diseases, is likely to be influenced both by independent and interactive effects of genes and environmental exposures. While some studies have analyzed the role of genetic variants, few have been sufficiently powered to investigate gene-environment interactions. Objectives: The Childhood Leukemia International Consortium (CLIC) was established in 2007 to promote investigations of rarer exposures, gene-environment interactions and subtype-specific associations through the pooling of data from independent studies. Methods: By September 2012, CLIC included 22 studies (recruitment period: 1962-present) from 12 countries, totaling approximately 31. 000 cases and 50. 000 controls. Of these, 19 case-control studies have collected detailed epidemiologic data, and DNA samples have been collected from children and child-parent trios in 15 and 13 of these studies, respectively. Two registry-based studies and one study comprising hospital records routinely obtained at birth and/or diagnosis have limited interview data or biospecimens. Conclusions: CLIC provides a unique opportunity to fill gaps in knowledge about the role of environmental and genetic risk factors, critical windows of exposure, the effects of gene-environment interactions and associations among specific leukemia subtypes in different ethnic groups. © 2013 Elsevier Ltd