The assessment of genetically determined predispositions to clinical diseases is a themecentral to the vision of a personalized health care. Rare deleterious germline mutationshave been found to cause up to 150 different primary immunodeficiencies. In mostinstances, there is predisposition to multiple infectious diseases. However, it is nowbecoming apparent that rare mutations in some genes can result in more subtle/narrowclinical phenotypes. This study aims at establishing an ex-vivo genome-widetranscriptome assay to measure leukocyte responses to host- and pathogen-derivedimmune activators in such patients. Specifically, we are first proposing to characterizeblood leukocyte responsiveness in control subjects.
This aim will use whole genomeexpression microarrays to assess responsiveness in whole blood of 12 healthy subjectsexposed to Toll-like and Interleukin 1 receptor family ligands. Secondly, we will identifyspecific alterations in patterns of blood leukocyte responsiveness in the blood of patientswith known inborn errors of TLR immunity.
This aim will assess responsiveness of 18subjects with increased susceptibility to invasive pneumococcal disease attributed to adefect in function of two key signaling molecules: IRAK4 and MYD88. Altogether thisproject will serve as a foundation for the development of novel tools to screen for andcharacterize primary immune deficiencies.
Constitutes a basis for the development of novel genome-wide transcriptome profiling strategy for the detection and identification of primary immunodeficiencies. This assay may be used for determining susceptibility to recurrent, life threatening infections.
| Alsina, Laia; Israelsson, Elisabeth; Altman, Matthew C et al. (2014) A narrow repertoire of transcriptional modules responsive to pyogenic bacteria is impaired in patients carrying loss-of-function mutations in MYD88 or IRAK4. Nat Immunol 15:1134-42 |
| Boisson, Bertrand; Laplantine, Emmanuel; Prando, Carolina et al. (2012) Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat Immunol 13:1178-86 |
| Guo, Yiqi; Audry, Magali; Ciancanelli, Michael et al. (2011) Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity. J Exp Med 208:2083-98 |
