RNA and protein expression of the murine autoimmune regulator gene (Aire) in normal, RelB‐deficient and in NOD mouse

Mutations in the putative transcription factor autoimmune regulator (AIRE) gene are responsible for autoimmune polyendocrinopathy‐candidiosis‐ectodermal dystrophy (APECED; OMIM#240300), a monogenic recessively inherited disease characterized by destructive autoimmune diseases of the endocrine organs, chronic candidiosis of mucous membranes and ectodermal dystrophies. In this study the expression of murine homolog for AIRE protein, Aire, was detected in a fraction of thymic medullary epithelial cells. Subcellularly, in thymus the protein appears as concentrated into nuclear dot‐like structures, whereas in transfected cells the protein is also bound along a cytosolic fibrillar network. By RT‐PCR Aire mRNA was detected in thymus, lymph node, spleen and testis although the second round PCR amplified Aire specific band from most mouse tissues analyzed. Furthermore, the Aire mRNA was detected in dendritic cell (DC) populations isolated from thymus and spleen, representing both myeloid‐ and lymphoid‐related lineages of DC. We also demonstrate that the Aire protein is absent in the thymus of RelB‐deficient mouse and in NOD thymus most of the Aire positive cells showed an abnormal morphology. These results suggest that the Aire protein is associated with the normal development and / or action of a subset of thymic medullary stromal cells involved in tolerance induction.

[1]  Li Wu,et al.  CD4 and CD8 Expression by Dendritic Cell Subtypes in Mouse Thymus and Spleen1 , 2000, The Journal of Immunology.

[2]  S. Antonarakis,et al.  Autoimmune regulator is expressed in the cells regulating immune tolerance in thymus medulla. , 1999, Biochemical and biophysical research communications.

[3]  S. Antonarakis,et al.  Isolation and characterization of the mouse Aire gene. , 1999, Biochemical and biophysical research communications.

[4]  J. She,et al.  Cloning ofAire,the Mouse Homologue of the Autoimmune Regulator (AIRE) Gene Responsible for Autoimmune Polyglandular Syndrome Type 1 (APS1) , 1999 .

[5]  H. Lehrach,et al.  The mouse Aire gene: comparative genomic sequencing, gene organization, and expression. , 1999, Genome research.

[6]  L. Peltonen,et al.  Localization of the APECED protein in distinct nuclear structures. , 1999, Human molecular genetics.

[7]  H. Lehrach,et al.  AIRE encodes a nuclear protein co-localizing with cytoskeletal filaments: altered sub-cellular distribution of mutants lacking the PHD zinc fingers. , 1999, Human molecular genetics.

[8]  A. D'amico,et al.  RelB Is Essential for the Development of Myeloid-Related CD8α− Dendritic Cells but Not of Lymphoid-Related CD8α+ Dendritic Cells , 1998 .

[9]  S. Antonarakis,et al.  Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins. , 1998, Molecular endocrinology.

[10]  T. Gibson,et al.  The APECED polyglandular autoimmune syndrome protein, AIRE-1, contains the SAND domain and is probably a transcription factor. , 1998, Trends in biochemical sciences.

[11]  L. Peltonen,et al.  An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains , 1997, Nature Genetics.

[12]  K. Shortman,et al.  Dendritic cell subtypes in mouse lymphoid organs: cross-correlation of surface markers, changes with incubation, and differences among thymus, spleen, and lymph nodes. , 1997, Journal of immunology.

[13]  M. Aurrand-Lions,et al.  Thymocytes and RelB‐dependent medullary epithelial cells provide growth‐promoting and organization signals, respectively, to thymic medullary stromal cells , 1997, European journal of immunology.

[14]  A. Coutinho,et al.  Abnormal T cell selection on nod thymic epithelium is sufficient to induce autoimmune manifestations in C57BL/6 athymic nude mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[15]  A. Kelso,et al.  A subclass of dendritic cells regulates the response of naive CD8 T cells by limiting their IL-2 production. , 1996, Journal of immunology.

[16]  L. Glimcher,et al.  Unopposed positive selection and autoreactivity in mice expressing class II MHC only on thymic cortex , 1996, Nature.

[17]  K. Shortman,et al.  Thymic dendritic cell precursors: relationship to the T lymphocyte lineage and phenotype of the dendritic cell progeny , 1996, The Journal of experimental medicine.

[18]  P. Schur,et al.  Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease. , 1996, The Journal of clinical investigation.

[19]  F. Watrin,et al.  Deletion of the mouse T-cell receptor beta gene enhancer blocks alphabeta T-cell development. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[20]  K. Shortman,et al.  A subclass of dendritic cells kills CD4 T cells via Fas/Fas-ligand- induced apoptosis , 1996, The Journal of experimental medicine.

[21]  J. Miller,et al.  Deletion of high-avidity T cells by thymic epithelium. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[22]  A. Coutinho,et al.  Lymphocytes selected in allogeneic thymic epithelium mediate dominant tolerance toward tissue grafts of the thymic epithelium haplotype. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Warren Strober,et al.  Dominant interfering fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome , 1995, Cell.

[24]  D. Lo,et al.  Expression of relB is required for the development of thymic medulla and dendritic cells , 1995, Nature.

[25]  F. Weih,et al.  Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-κB/Rel family , 1995, Cell.

[26]  T. Mandel,et al.  Induction of Insulitis in Athymic (Nude) Mice: The Effect of NOD Thymus and Pancreas Transplantation , 1995, Diabetes.

[27]  G. Anderson,et al.  Thymic epithelial cells provide unique signals for positive selection of CD4+CD8+ thymocytes in vitro , 1994, The Journal of experimental medicine.

[28]  J. Sprent,et al.  B7 expression on thymic medullary epithelium correlates with epithelium-mediated deletion of V beta 5+ thymocytes. , 1994, Journal of immunology.

[29]  R. Flavell,et al.  Clonal deletion of V beta 5+ T cells by transgenic I-E restricted to thymic medullary epithelium. , 1993, Journal of immunology.

[30]  P. Linsley,et al.  Medullary thymic epithelium expresses a ligand for CTLA4 in situ and in vitro. , 1993, Journal of immunology.

[31]  A. Coutinho,et al.  The Role of Thymic Epithelium in the Establishment of Transplantation Tolerance , 1993, Immunological reviews.

[32]  T. Wilson,et al.  Thymic microenvironmental abnormalities and thymic selection in NZB.H-2bm12 mice. , 1993, Journal of immunology.

[33]  G. Schönrich,et al.  Anergy induced by thymic medullary epithelium , 1992, European journal of immunology.

[34]  B. Nabarra,et al.  Thymus reticulum of autoimmune mice. 3. Ultrastructural study of NOD (non-obese diabetic) mouse thymus. , 1991, International journal of experimental pathology.

[35]  T. Wilson,et al.  The phenotypic heterogeneity of mouse thymic stromal cells. , 1990, Immunology.

[36]  H. Kolb,et al.  Mouse models of insulin dependent diabetes: low-dose streptozocin-induced diabetes and nonobese diabetic (NOD) mice. , 1987, Diabetes/metabolism reviews.

[37]  P. Ahonen.  Autoimmune polyendocrinopathy – candidosis – ectodermal dystrophy (APECED): autosomal recessive inheritance , 1985, Clinical genetics.

[38]  S. Anderson,et al.  Epithelial heterogeneity in the murine thymus: fucose-specific lectins bind medullary epithelial cells. , 1985, Journal of immunology.

[39]  Qiaoyi Chen,et al.  Mutation analyses of North American APS‐1 patients , 1999, Human mutation.

[40]  A. J. Lopez,et al.  Alternative splicing of pre-mRNA: developmental consequences and mechanisms of regulation. , 1998, Annual review of genetics.

[41]  Shinsei Minoshima,et al.  Positional cloning of the APECED gene , 1997, Nature Genetics.

[42]  L. Peltonen,et al.  An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome 21 , 1994, Nature Genetics.