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Genetic dissection of lymphopenia from autoimmunity by introgression of mutated Ian5 gene onto the F344 rat. J Autoimmun 2003 Dec;21(4):315-24

Date

11/20/2003

Pubmed ID

14624755

Pubmed Central ID

PMC7126882

DOI

10.1016/s0896-8411(03)00138-0

Scopus ID

2-s2.0-0242659141 (requires institutional sign-in at Scopus site)   32 Citations

Abstract

Peripheral T cell lymphopenia (lyp) in the BioBreeding (BB) rat is linked to a frameshift mutation in Ian5, a member of the Immune Associated Nucleotide (Ian) gene family on rat chromosome 4. This lymphopenia leads to type 1 (insulin-dependent) diabetes mellitus (T1DM) at rates up to 100% when combined with the BB rat MHC RT1 u/u genotype. In order, to better study the lymphopenia phenotype without possible confounding effects of diabetes or other autoimmune disease, we generated congenic F344.lyp rats by introgression of lyp on diabetes-resistant MHC RT1 lv1/lv1 F344 rats. Analysis of thymic CD4 and CD8 T lymphocytes revealed no difference in the percentage of CD4(-)CD8(+)and CD4(+)CD8(-)subsets in lyp/lyp compared to +/+ F344 rats. The same subsets was however dramatically reduced in blood (P=0.005), spleen (P=0.019) and mesenteric lymph nodes (MLN) (P<0.0001). Compared to F344 +/+ rats double positive CD4(+)CD8(+)T cells were increased only in lyp/lyp spleen (P=0.034) while double negative CD4(-)CD8(-)were increased in thymus (P=0.033), spleen (P=0.012), MLN (P<0.0001), and peripheral blood (P<0.0001). There were no signs of inflammatory lesions in organs and tissues in F344.lyp/lyp rats examined at 120 days of age or older. We thus conclude that the lymphopenia phenotype was reconstituted by introgression of lyp on to F344 rats without subsequent development of organ-specific autoimmunity. The congenic F344.lyp rat should prove useful to dissect the mechanisms by which the Ian5 frameshift mutation affects T cell selection, differentiation and maturation without organ-specific autoimmunity.

Author List

Moralejo DH, Park HA, Speros SJ, MacMurray AJ, Kwitek AE, Jacob HJ, Lander ES, Lernmark A

Author

Anne E. Kwitek PhD Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Animals, Congenic
Autoimmunity
Breeding
Flow Cytometry
Genome
Leukocyte Count
Lymphoid Tissue
Lymphopenia
Mutation
Physical Chromosome Mapping
Rats
Rats, Inbred F344
T-Lymphocyte Subsets
T-Lymphocytes