title: Cellular mosaicism for X-linked polymorphisms and IRAK1 expression presents a distinct phenotype and improves survival following sepsis.
abstract: ChrX cellular mosaicism for X-linked genetic polymorphisms in females versus the single ChrX representation in males denotes a genetic difference, which may contribute to gender bias in the inflammatory response. This hypothesis was tested in female F1 offspring of consomic mice (BL6J-ChrX(A/J)/NaJ) that were homokaryotic or mosaic for the active BL6 and AJ ChrXs or for IRAK1 deficiency linked to the BL6 ChrX. Sepsis was initiated by CLP. IRAK1-deficient and IRAK1-mosaic mice showed similar protection from sepsis-induced mortality and reduced IL-6 and IL-10 release compared with WT. BM cellularity and blood B cell counts were increased in naive IRAK1-mosaic mice compared with WT-mosaic or IRAK1-deficient animals. Sepsis-induced BM cell depletion was greater in IRAK1-mosaic mice compared with WT-mosaic or IRAK1-deficient subjects, whereas splenic B and T cell depletion was less in IRAK1-mosaic and IRAK1-deficient than WT-mosaic mice. Skewing toward AJ or BL6-ChrX-expressing cells was assessed by testing allele-specific expression of strain-variant Xkrx and BTK genes. In naive IRAK1-mosaic mice, BM and blood cells with the active BL6-ChrX, were greater than cells expressing the AJ-ChrX (cell ratio 2.5 in IRAK1-mosaic; 1.5 in WT-mosaic mice). Sepsis decreased cell ratios more in IRAK1-mosaic than in WT-mosaic mice. The study reveals functional variability in cellular mosaicism for IRAK1 expression and natural X-linked polymorphisms during sepsis. Mosaicism for IRAK1 expression is accompanied by skewing toward deficient immune cell populations, producing a phenotype that is preconditioned for improved sepsis outcome similar to that observed in IRAK1 deficiency.
authors.affiliation: 1.Rutgers New Jersey Medical School, 185 South Orange Ave., MSB G-578, Newark, NJ 07103, USA. spolaric@njms.rutgers.edu.
authors.forename: Rachna
authors.initials: R
authors.lastname: Chandra
authors.forename: Stephanie
authors.initials: S
authors.lastname: Federici
authors.forename: Zoltán H
authors.initials: ZH
authors.lastname: Németh
authors.forename: Balázs
authors.initials: B
authors.lastname: Csóka
authors.forename: James A
authors.initials: JA
authors.lastname: Thomas
authors.forename: Robert
authors.initials: R
authors.lastname: Donnelly
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Spolarics
mesh_terms: D000818:Animals; D002469:Cell Separation; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D050172:Genes, X-Linked / Q000235:genetics*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009030:Mosaicism; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000235:genetics* / Q000276:immunology / Q000473:pathology
chemical_list: D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse
keywords: B cells; X-chromosome; gender; inflammation; sex chromosomes; skewing