New concepts for the development of autoimmune exocrinopathy derived from studies with the NOD mouse model

The non-obese diabetic (NOD) mouse is now recognized as an appropriate mode l to study autoimmune exocrinopathy prevalent in human Sjogren's syndrome p atients. With increasing age, NOD mice undergo histopathological changes si milar to human Sjogren's syndrome patients, but more importantly, exhibit t he same clinical manifestation of declining exocrine tissue secretory funct ion. Studies with the immunodeficient NOD-acid mouse have provided evidence for the temporal loss in the expression of several major salivary proteins and a decreased presence of acinar cells in salivary tissues. The diminish ed presence of acinar cells is accompanied by an increase in the enzymes as sociated with apoptosis in the absence of T- and B-lymphocytes. Despite the se alterations, NOD-scid mice, unlike NOD mice, do not lose secretory funct ion. Recent analyses of a second congenic NOD strain, the NOD.Igmnull, whic h lacks B-lymphocytes, indicate the histological presence of a T-cell infil trate of the exocrine glands, increased caspace activity and induction of t he biochemical alterations in protein expression observed in NOD and NOD-sc id mice. NOD.Igmnull mice also do not lose secretory function, but can be m anipulated to generate a reduced secretory response following the infusion of IgG fractions from autoimmune NOD mice or Sjogren's syndrome patients. T hese observations, in the absence of components of the adaptive arm of the immune system, have given rise to the concept that autoimmune exocrinopathy develops in two phases. The initial phase is lymphocyte independent and oc curs as a consequence of an innate error in exocrine tissue homeostasis or differentiated function. The subsequent tissue specific immunological attac k, generated in part by B-cell autoantibodies, is responsible for the loss of secretory function. Our preliminary observations in both NOD mice and Sj ogren's syndrome patients is that antibody directed against the cell surfac e muscarinic/cholinergic receptors appears to play an important part in the onset of clinical disease.