Sjogrens syndrome as failed local immunohomeostasis: prospects for cell-based therapy.
Sjogrens syndrome has been estimated to affect between 0.2% and 2% or more of the population. It is an autoimmune disease with the hallmark histopathology of focal, periductal, and perivascular CD4(+) cell infiltration of the lacrimal and salivary glands. The immunohistopathology is typically associated with severe lacrimal and salivary dysfunctions, which contribute to debilitating ocular surface and oral symptoms. The quality of life of patients with Sjogrens syndrome often is degraded further by serious, multisystemic manifestations, and they are subject to a forty-fold increased risk of developing B cell lymphomas. In normal lacrimal glands, secretory epithelial cells, autoimmune effector lymphocytes, and regulatory lymphocytes can be seen as collaborating to maintain a local immunohomeostasis. The epithelium contributes by secreting immunomodulatory paracrine factors and also by continuously exposing autoantigens, which thereby become available for uptake by professional antigen presenting cells (APCs). Local or systemic perturbations may initiate autoimmune pathophysiology by impairing the replacement of normally-turning-over regulatory cells, by altering epithelial production of immunomodulatory paracrine factors, by inducing intact epithelial cells to begin secreting previously cryptic epitopes (epitopes that previously were not available to bind to major histocompatibility complex (MHC) molecules and so could not be recognized by T cell antigen receptors), and by inducing epithelial cells to begin expressing MHC Class II molecules and presenting formerly cryptic epitopes directly to CD4(+) cells. This process has been modeled ex vivo with mixed cell reactions comprised of isolated epithelial cells and autologous lymphocytes. This development has occurred as studies of anterior chamber-associated immune deviation (ACAID) and other immunoregulatory phenomena have elucidated the origins and functions of several different kinds of regulatory lymphocytes and shown that regulatory lymphocytes can be generated ex vivo. It now is possible to envision strategies for exploiting each possible mode of epithelial autoantigen exposure to produce therapeutic regulatory cells that might be capable of re-establishing normal immunohomeostasis. Consideration of the hypothetical therapies identifies a number of basic questions that warrant investigation.
Mircheff
Austin K
AK
Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA. amircheff@usc.edu