Sjögren’s syndrome (SS) has been described as “an autoimmune disease of the exocrine glands, which particularly involves the salivary and lacrimal glands. The secretory tissues in the affected glands are progressively destroyed and replaced by a lymphoreticular cell infiltrate. This process may occur as an isolated phenomenon, in which case it is termed primary Sjögren’s syndrome, or in conjunction with a connective tissue or collagen disease, in which case it is referred to as secondary Sjögren’s syndrome”(1). Implicit within this description is the concept that the characteristic salivary gland hypofunction of SS is the direct consequence of immune-mediated destruction of the secretory acinar tissue. The assumption that lack of glandular function is the direct consequence of tissue loss has become so ingrained that it has directed SS research for more than 60 years.

More recently, our understanding of the pathology underlying the glandular hypofunction associated with SS has undergone a dramatic change. Two key observations have led to this change: 1) many patients with SS have within their salivary glands large amounts of acinar tissue that is unable to function in vivo, as demonstrated by the lack of salivary flow (2–4), and 2) data from work on salivary acinar cells isolated from patients with SS demonstrates that the remaining tissue is functional in vitro (5, 6), but with a reduced sensitivity to threshold levels of muscarinic stimulation (5). In