Local transgenic expression of GM-CSF initiates autoimmune gastritis in transgenic mice

Mark Biondo, Zeyad Nasa, Aiden Marshall, Ban Hock Toh and Frank Alderuccio

Department of Pathology and Immunology, Monash University Medical School, Melbourne, Victoria, 3181

Mechanisms leading to the breakdown of immunological tolerance and initiation of autoimmunity are poorly understood. Experimental autoimmune gastritis (EAG) is a paradigm of organ-specific autoimmunity arising from a pathogenic autoimmune response to the gastric H/K ATPase. Many characterised models of EAG require an induced state of lymphopenia which limit their usefulness in understanding how autoimmunity arises in animals with intact immune systems. We generated transgenic mice expressing GM-CSF in the stomach to test whether local production of a pro-inflammatory cytokine was sufficient to break tolerance and initiate autoimmunity. Without further manipulation, transgenic mice develop spontaneous gastritis with circulating antibodies to the gastric H/K ATPase. T cells from transgenic mice proliferate in response to the gastric H/K ATPase and gastritis can be transferred to nu/nu mice by CD4 T cells. Autoimmunity is not a consequence of alteration of lymphocyte populations or perturbation of the CD4+CD25+ regulatory population. We propose that in PC-GM-CSF tg mice, local tolerance mechanisms within the stomach's draining lymph

GM-CSF expressed in the stomach can induce autoimmune gastritis in a transgenic mouse model

Frank Alderuccio, Mark Biondo and Ban Hock Toh

Department of Pathology and Immunology, Monash University Medical School, Melbourne, Victoria, 3181

Experimental Autoimmune gastritis is characterised by autoantibodies directed to the gastric H/K ATPase and destruction of parietal and zymogenic cells within the gastric mucosa by mononuclear infiltrating cells. Experimental autoimmune gastritis can be reproduced in BALB/c CrSlc mice by methods that induce lymphopenia such as neonatal thymectomy. These procedures often involve manipulation of the immune system and are thought to alter the balance of effector and regulatory T cells in favour of the former population. While these models have their usefulness, they cannot be used to address how an autoimmune response may arise in hosts with an intact immune system.

GM-CSF (granulocyte macrophage colony stimulating factor) is a pro-inflammatory cytokine implicated in the stimulation and differentiation of antigen presenting cells such as macrophages and dendritic cells, which are critical for the initiation of immune responses. GM-CSF, along with other cytokines has been identified in the gastric lesions of mice following neonatal thymectomy. In the present study, we have produced transgenic mice (PC-GMCSF-tg) expressing GM-CSF in parietal cells of the stomach. Without further manipulation such as thymectomy, PC-GMCSF-tg mice develop features of autoimmune gastritis including H/K ATPase specific autoantibodies and mononuclear cell infiltrate with cellular destruction within the gastric mucosa. T cells from PC-GMCSF-tg mice proliferate in vitro following stimulation with gastric membranes with proliferation restricted to cells from the paragastric lymph node and not those from the spleen, mesenteric or inguinal lymph nodes. Adoptive transfer of lymphocytes from these transgenic mice to nu/nu recipients results in gastritis in the recipients. These studies indicate that a local inflammatory response in the stomach, mimicked here by transgenic GM-CSF expression, is sufficient to break tolerance and induce autoimmunity in a susceptible mouse strain.