Abstract
IntroductionSjögren syndrome (SjS) is a systemic autoimmune disease in which an immunological attack primarily against the salivary and lacrimal glands results in the loss of acinar cell tissue and function, leading to stomatitis sicca and keratoconjunctivitis sicca. In recent years, two genetic regions, one on chromosome 1 (designated autoimmune exocrinopathy 2 or Aec2) and the second on chromosome 3 (designated autoimmune exocrinopathy 1 or Aec1) derived from nonobese diabetic (NOD) mice, have been shown to be necessary and sufficient to replicate SjS-like disease in nonsusceptible C57BL/6 mice.MethodsStarting with the SjS-susceptible C57BL/6-derived mouse, referred to as C57BL/6.NOD-Aec1Aec2, we generated a large set of recombinant inbred (RI) lines containing portions of Aec2 as a means of identifying more precisely the genetic elements of chromosome 1 responsible for disease development.ResultsDisease profiling of these RI lines has revealed that the SjS susceptibility genes of Aec2 lie within a region located at approximately 79 ± 5 cM distal to the centromere, as defined by microsatellite markers. This chromosomal region contains several sets of genes known to correlate with various immunopathological features of SjS as well as disease susceptibility genes for both type 1 diabetes and systemic lupus erythematosus in mice. One gene in particular, tumor necrosis factor (ligand) superfamily member 4 (or Ox40 ligand), encoding a product whose biological functions correlate with both physiological homeostasis and immune regulations, could be a potential candidate SjS susceptibility gene.ConclusionsThese new RI lines represent the first step not only in fine mapping SjS susceptibility loci but also in identifying potential candidate SjS susceptibility genes. Identification of possible candidate genes permits construction of models describing underlying molecular pathogenic mechanisms in this model of SjS and establishes a basis for construction of specific gene knockout mice.
Highlights
Sjögren syndrome (SjS) is a systemic autoimmune disease in which an immunological attack primarily against the salivary and lacrimal glands results in the loss of acinar cell tissue and function, leading to stomatitis sicca and keratoconjunctivitis sicca
In phase 2, believed to result from the glandular cell injury of phase 1, small numbers of macrophages and dendritic cells are attracted to the exocrine gland where these sentinel cells recruit T and B lymphocytes that form lymphocytic foci (LF), some of which histologically appear as germinal centers
In phase 3, the onset of clinical disease as defined by salivary and lacrimal gland secretory dysfunction occurs, possibly resulting first from the production of autoantibodies that interfere with the neural-acinar cell signaling pathways and from progressive loss of acinar cell mass hastened by the action of effector T cells
Summary
Sjögren syndrome (SjS) is a systemic autoimmune disease in which an immunological attack primarily against the salivary and lacrimal glands results in the loss of acinar cell tissue and function, leading to stomatitis sicca and keratoconjunctivitis sicca. Sjögren syndrome (SjS) is a chronic, systemic, human autoimmune disease in which an immunological attack initially against the salivary and lacrimal glands results, respectively, in dry mouth (stomatitis sicca) and dry eye (keratoconjunctivitis sicca) disease(s) [1,2,3]. In phase 1, a number of aberrant physiological and biochemical activities, thought to result from a genetically based retarded salivary gland organogenesis and increased acinar cell apoptosis, occur prior to and independent of detectable autoimmunity. In phase 3, the onset of clinical disease as defined by salivary and lacrimal gland secretory dysfunction occurs, possibly resulting first from the production of autoantibodies that interfere with the neural-acinar cell signaling pathways and from progressive loss of acinar cell mass hastened by the action of effector T cells
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