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

• Published in: The Journal of immunology (1950) Vol. 166; no. 3; pp. 2090 - 2099
• Main Authors: Biondo, Mark, Nasa, Zeyad, Marshall, Aiden, Hock Toh, Ban, Alderuccio, Frank
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.02.2001
• Subjects: Adoptive Transfer; Animals; Autoantibodies - biosynthesis; Autoimmune Diseases - enzymology; Autoimmune Diseases - genetics; Autoimmune Diseases - immunology; Autoimmune Diseases - pathology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; CD4-Positive T-Lymphocytes - transplantation; Cell Membrane - immunology; Crosses, Genetic; Dendritic Cells - immunology; Dendritic Cells - pathology; Experimental autoimmune gastritis; Gastritis - enzymology; Gastritis - genetics; Gastritis - immunology; Gastritis - pathology; Gene Expression Regulation - immunology; Granulocyte-Macrophage Colony-Stimulating Factor - biosynthesis; Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Granulocyte-Macrophage Colony-Stimulating Factor - physiology; H(+)-K(+)-Exchanging ATPase - immunology; Lymphocyte Activation - genetics; Lymphocyte Count; Lymphocyte Subsets - cytology; Lymphocyte Subsets - immunology; Macrophages - immunology; Macrophages - pathology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Mice, Transgenic; Parietal Cells, Gastric - immunology; Parietal Cells, Gastric - metabolism; Parietal Cells, Gastric - pathology; Receptors, Interleukin-2 - biosynthesis; Swine; T-Lymphocyte Subsets - cytology; Transgenes - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.166.3.2090

Mechanisms leading to breakdown of immunological tolerance and initiation of autoimmunity are poorly understood. Experimental autoimmune gastritis is a paradigm of organ-specific autoimmunity arising from a pathogenic autoimmune response to gastric H/K ATPase. The gastritis is accompanied by autoantibodies to the gastric H/K ATPase. The best characterized model of experimental autoimmune gastritis requires neonatal thymectomy. This procedure disrupts the immune repertoire, limiting its usefulness in understanding how autoimmunity arises in animals with intact immune systems. Here we tested whether local production of GM-CSF, a pro-inflammatory cytokine, is sufficient to break tolerance and initiate autoimmunity. We generated transgenic mice expressing GM-CSF in the stomach. These transgenic mice spontaneously developed gastritis with an incidence of about 80% after six backcrosses to gastritis-susceptible BALBc/CrSlc mice. The gastritis is accompanied by mucosal hypertrophy, enlargement of draining lymph nodes and autoantibodies to gastric H/K ATPase. An infiltrate of dendritic cells and macrophages preceded CD4 T cells into the gastric mucosa. T cells from draining lymph nodes specifically proliferated to the gastric H/K ATPase. CD4 but not CD8 T cells transferred gastritis to nude mouse recipients. CD4(+) CD25(+) T cells from the spleen retained anergic suppressive properties that were reversed by IL-2. We conclude that local expression of GM-CSF is sufficient to break tolerance and initiate autoimmunity mediated by CD4 T cells. This new mouse model should be useful for studies of organ-specific autoimmunity.