An autoimmune disease with multiple molecular targets abrogated by the transgenic expression of a single autoantigen in the thymus.

Abstract

Many autoimmune diseases are characterized by autoantibody reactivities to multiple cellular antigens. Autoantigens are commonly defined as targets of the autoimmune B cell response, but the role, if any, of these autoantigens in T cell-mediated autoimmune diseases is generally unknown. Murine experimental autoimmune gastritis is a CD4+ T cell-mediated organ-specific autoimmune disease induced by neonatal thymectomy of BALB/c mice. The murine disease is similar to human autoimmune gastritis and pernicious anemia, and is characterized by parietal and chief cell loss, submucosal mononuclear cell infiltrates, and autoantibodies to the alpha and beta subunits of the gastric H/K ATPase. However, the specificity of T cells that cause the disease is not known. To examine the role of the H/K ATPase in this T cell-mediated disease, transgenic mice were generated that express the beta subunit of the H/K ATPase under the control of the major histocompatibility complex class II I-Ek alpha promoter. We show that transgenic expression of the gastric H/K ATPase beta subunit specifically prevents the onset of autoimmune gastritis after neonatal thymectomy. In addition, thymocyte transfer experiments suggest that tolerance of pathogenic autoreactive T cells is induced within the thymus of the transgenic mice. We conclude that the beta subunit of the gastric H/K ATPase is a major T cell target in autoimmune gastritis and that thymic expression of a single autoantigen can abrogate an autoimmune response to multiple autoantigens.

Local Transgenic Expression of Granulocyte Macrophage-Colony Stimulating Factor Initiates Autoimmunity

“…Anti-parietal cell autoantibodies were detected by indirect immunofluorescence on frozen or paraffin-embedded sections of normal mouse stomach (13). Gastric H/K ATPase ␣-and ␤-subunit reactivity was detected by immunofluorescence reactivity with Sf9 cells infected with baculovirus encoding rat ATPase ␣-or ␤-subunit.…”

“…Transgene expression of GM-CSF mRNA was detected by RT-PCR essentially as previously described (13). Total RNA was isolated from lung, spleen, heart, liver, and stomach using the Ultraspec II RNA isolation kit (Biotecx Laboratories, Houston, TX).…”

“…Circulating anti-H/K ATPase autoantibodies were assayed by ELISA on 96-well plates coated with purified pig H/K ATPase as previously described (13). Anti-parietal cell autoantibodies were detected by indirect immunofluorescence on frozen or paraffin-embedded sections of normal mouse stomach (13).…”

“…Transgenic (tg) mice expressing the gastric H/K ATPase ␤-subunit in the thymus are resistant to the development of gastric autoimmunity. These studies suggest that an immune response to the H/K ATPase ␤-subunit is necessary for disease induction (12,13) although T cell responses have been shown to both the ␣-and ␤-subunits of the H/K ATPase (14 -16).…”

Non‐Th2 Regulatory T‐Cell Control of Th1 Autoimmunity

“…This finding has however been denied by Tung [84] who did not see any difference in the protection afforded by spleen cells from males, females or ovariectomized females. The fact that the transgenic expression of the b subunit of the H 1 K 1 ATPase, the target gastric antigen in the post-thymectomy gastritis prevents the onset of gastritis, without altering other manifestations of autoimmunity is also suggestive of the specificity of autoreactive regulatory T cells [85].…”