The development of autoimmunity to tissue transglutaminase (TGase 2) is a striking feature of coeliac disease, an enteropathy that develops in genetically susceptible individuals upon exposure to dietary gluten. IgA anti-TGase 2 autoantibodies are present in at least 98% of coeliac patients on a gluten-containing diet and provide a valuable tool for the diagnosis of the disorder. During disease development, the formation of TGase 2-gliadin complexes through TGase 2 activity appears to be central for B-cell epitope spreading from gliadin to TGase 2. However, the potential role of an immune response against TGase 2 in the pathogenesis of coeliac disease and for the development of the intestinal lesion remains unclear. Recently, an inhibitory effect of anti-TGase 2 autoantibodies from coeliac patients on TGase 2 activity in vitro has been described. Here, we report that a cellular and humoral response against TGase 2 can be induced in TGase 2 (-/-) and wildtype mice on a C57BL/6 background by s.c. immunization with human recombinant or guinea pig TGase 2 in complete Freund's adjuvant. Immunized wildtype, but not TGase 2 (-/-) mice develop periductal lymphocytic infiltrates in lacrimal glands. Although no intestinal lesions were found, this observation lends support to the concept that the development of autoimmunity against TGase 2 is a pathological event that might ultimately lead to organ damage.