Immunogenetics

, Volume 60, Issue 2, pp 105–114

Evolutionarily conserved and divergent regions of the Autoimmune Regulator (Aire) gene: a comparative analysis

  • Mark Saltis
  • Michael F. Criscitiello
  • Yuko Ohta
  • Matthew Keefe
  • Nikolaus S. Trede
  • Ryo Goitsuka
  • Martin F. Flajnik
Original Paper

DOI: 10.1007/s00251-007-0268-9

Cite this article as:
Saltis, M., Criscitiello, M.F., Ohta, Y. et al. Immunogenetics (2008) 60: 105. doi:10.1007/s00251-007-0268-9

Abstract

During T cell differentiation, medullary thymic epithelial cells (MTEC) expose developing T cells to tissue-specific antigens. MTEC expression of such self-antigens requires the transcription factor autoimmune regulator (Aire). In mammals, defects in aire result in multi-tissue, T cell-mediated autoimmunity. Because the T cell receptor repertoire is randomly generated and extremely diverse in all jawed vertebrates, it is likely that an aire-dependent T cell tolerance mechanism also exists in nonmammalian vertebrates. We have isolated aire genes from animals in all gnathostome classes except the cartilaginous fish by a combination of molecular techniques and scanning of expressed sequence tags and genomic databases. The deduced amino acid sequences of Aire were compared among mouse, human, opossum, chicken, Xenopus, zebrafish, and pufferfish. The first of two plant homeodomains (PHD) in human Aire and regions associated with nuclear and cytoplasmic localization are evolutionarily conserved, while other domains are either absent or divergent in one or more vertebrate classes. Furthermore, the second zinc-binding domain previously named Aire PHD2 appears to have greater sequence similarity with Ring finger domains than to PHD domains. Point mutations in defective human aire genes are generally found in the most evolutionarily conserved regions of the protein. These findings reveal a very rapid evolution of certain regions of aire during vertebrate evolution and support the existence of an aire-dependent mechanism of T cell tolerance dating back at least to the emergence of bony fish.

Keywords

Comparative immunology Autoimmunity Transcription factors Autoimmune regulator 

Supplementary material

251_2007_268_MOESM1_ESM.pdf (129 kb)
Supplemental Fig. 1cDNA sequence of X. tropicalis (X.t.) aire. The overhead line denotes overlap of one or more EST sequences. Primers underlined. Bold letters denote the probe region used in Northern blotting and cDNA library screening. Amino acid sequence of a partial X. laevis (X.l.) sequence aligned to the X. tropicalis sequence (PDF 132 kb)
251_2007_268_MOESM2_ESM.pdf (136 kb)
Supplemental Fig. 2Chicken genomic fragment amplified by PCR. The bold sequence corresponds to exons derived from PCR amplification of cDNA. Primers used for PCR amplification are underlined. Major splice junctions are denoted by black triangles. Minor splice junctions are denoted by gray triangles. A turkey genomic fragment is aligned for a portion of the chicken sequence. The sequence in the gray box is consistent with an identified microsatellite identified in the turkey suggesting an area of genomic instability (PDF 139 kb)
251_2007_268_MOESM3_ESM.pdf (114 kb)
Supplemental Fig. 3Zebrafish alignment to other teleost fishes. Aire from two species of pufferfish were reconstructed based on alignment to zebrafish Aire. Sequences were subsequently aligned using Clustal W followed by manual adjustment (PDF 116 kb)
251_2007_268_MOESM4_ESM.pdf (237 kb)
Supplemental Fig. 4Pairwise sequence identity comparison of the putative Aire amino acid sequences aligned by exon. For reference, the equivalent human domain is listed above each alignment. Bioedit (Hall 1999) was used to create sequence identity matrices (PDF 242 kb)

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Mark Saltis
    • 1
  • Michael F. Criscitiello
    • 1
  • Yuko Ohta
    • 1
  • Matthew Keefe
    • 3
  • Nikolaus S. Trede
    • 2
  • Ryo Goitsuka
    • 4
  • Martin F. Flajnik
    • 1
  1. 1.Department of Microbiology and ImmunologyUniversity of Maryland, BaltimoreBaltimoreUSA
  2. 2.Division of Pediatrics, The Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUSA
  3. 3.Division of Molecular BiologyUniversity of UtahSalt Lake CityUSA
  4. 4.Research Institute for Biological SciencesTokyo University of ScienceNodaJapan

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