title: Effector mechanisms of the autoimmune syndrome in the murine model of autoimmune polyglandular syndrome type 1.
abstract: Mutations in the Aire gene result in a clinical phenomenon known as Autoimmune Polyglandular Syndrome (APS) Type I, which classically manifests as a triad of adrenal insufficiency, hypoparathyroidism, and chronic mucocutaneous infections. In addition to this triad, a number of other autoimmune diseases have been observed in APS1 patients including Sjögren's syndrome, vitiligo, alopecia, uveitis, and others. Aire-deficient mice, the animal model for APS1, have highlighted the role of the thymus in the disease process and demonstrated a failure in central tolerance in aire-deficient mice. However, autoantibodies have been observed against multiple organs in both mice and humans, making it unclear what the specific role of B and T cells are in the pathogenesis of disease. Using the aire-deficient mouse as a preclinical model for APS1, we have investigated the relative contribution of specific lymphocyte populations, with the goal of identifying the cell populations which may be targeted for rational therapeutic design. In this study, we show that T cells are indispensable to the breakdown of self-tolerance, in contrast to B cells which play a more limited role in autoimmunity. Th1 polarized CD4(+) T cells, in particular, are major contributors to the autoimmune response. With this knowledge, we go on to use therapies targeted at T cells to investigate their ability to modulate disease in vivo. Depletion of CD4(+) T cells using a neutralizing Ab ameliorated the disease process. Thus, therapies targeted specifically at the CD4(+) T cell subset may help control autoimmune disease in patients with APS1.
authors.affiliation: Diabetes Center, University of California, San Francisco, CA 94143, USA.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Devoss
authors.forename: Anthony K
authors.initials: AK
authors.lastname: Shum
authors.forename: Kellsey P A
authors.initials: KP
authors.lastname: Johannes
authors.forename: Wen
authors.initials: W
authors.lastname: Lu
authors.forename: Anna K
authors.initials: AK
authors.lastname: Krawisz
authors.forename: Peter
authors.initials: P
authors.lastname: Wang
authors.forename: Ting
authors.initials: T
authors.lastname: Yang
authors.forename: Norbert P
authors.initials: NP
authors.lastname: Leclair
authors.forename: Cecilia
authors.initials: C
authors.lastname: Austin
authors.forename: Erich C
authors.initials: EC
authors.lastname: Strauss
authors.forename: Mark S
authors.initials: MS
authors.lastname: Anderson