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The effects of aging on T and B cell tolerance to AChR in myasthenia gravis
Author(s) -
Stacy Sue,
Williams Earlanda,
Krolick Keith A.,
Kraig Ellen
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.669.9
Subject(s) - myasthenia gravis , epitope , acetylcholine receptor , immunology , t cell , biology , antibody , transgene , immune tolerance , genetically modified mouse , antigen , endocrinology , microbiology and biotechnology , medicine , immune system , receptor , biochemistry , gene
Autoimmune myasthenia gravis (MG) is a T cell dependent, B cell mediated disease in which symptoms of muscle weakness often show a late age of onset. Thus, it has been suggested that tolerance to muscle acetylcholine receptor (AChR) may weaken with age. To address this, we developed a murine transgenic model in which the Torpedo californica AChRα chain (TAChRα) is expressed as a neoself antigen. This results in T cell tolerance, as evidenced by diminished proliferation to alpha chain epitopes. Surprisingly, this T cell tolerance to TAChR was maintained in old transgenic animals and could not be broken by multiple immunizations or by IL12. Moreover, “old” transgenic lymph node cells (LNCs) produced reduced levels of IL2, INFγ, and TNFα, relative to LNCs from nontransgenic mice; the same pattern was observed in young animals. To assess the effects of aging on autoantibody responses, the sera from old TAChR‐immunized mice were tested for reactivity to recombinant Torpedo or mouse AChRα chains. An age‐associated loss of reactivity was seen and there was no difference in the response to self (mouse) epitopes. Thus, mice were then immunized with recombinant TAChRα chain. This eliminated bystander help and revealed that the TAChR transgenic animals did exhibit B cell tolerance to TAChRα; reduced titers of induced TAChRα reactive antibodies were seen. In old mice, the immune responses were very low, but there was no detectable loss of tolerance. Thus, our data suggest that aging dysfunction alone is not sufficient to break B cell and T cell tolerance to AChR. Support: Myasthenia Gravis Foundation, Nathan Shock Aging Center, NIH R03 AG 14557 and San Antonio Area Foundation.