Cellular stress and innate inflammation in organ-specific autoimmunity: lessons learned from vitiligo

Abstract

For decades, research in autoimmunity has focused primarily on immune contributions to disease. Yet recent studies report elevated levels of reactive oxygen species and abnormal activation of the unfolded protein response in cells targeted by autoimmunity, implicating cellular stress originating from the target tissue as a contributing factor. A better understanding of this contribution may help to answer important lingering questions in organ-specific autoimmunity, as to what factors initiate disease and what directs its tissue specificity. Vitiligo, an autoimmune disease of the skin, has been the focus of translational research for over 30 years, and both melanocyte stress and immune mechanisms have been thought to be mutually exclusive explanations for pathogenesis. Chemical-induced vitiligo is a unique clinical presentation that reflects the importance of environmental influences on autoimmunity, provides insight into a new paradigm linking cell stress to the immune response, and serves as a template for other autoimmune diseases. In this review, I will discuss the evidence for cell stress contributions to a number of autoimmune diseases, the questions that remain, and how vitiligo, an underappreciated example of organ-specific autoimmunity, helps to answer them.

Keywords: cellular stress; innate immunity; organ-specific autoimmunity; vitiligo.

Figure 1

Patchy depigmentation of the skin is characteristic of vitiligo.

Figure 2. Initiation of autoimmunity through the stress-immune interface

Secretory cells produce large amounts of protein, which requires energy and releases ROS as a byproduct. ROS may originate in mitochondria and damage mitochondrial DNA and membranes. The risk of protein misfolding correlates with increased protein production and the presence of intracellular ROS. Protein misfolding activates the UPR, which may initiate autophagy and stimulate the production and secretion of exosomes or other proinflammatory molecules. Exosomes contain cell-specific antigens and DAMPs, which are absorbed by nearby dendritic cells and mature them into efficient stimulators of autoreactive T cells, resulting in T cell priming and ultimate induction of cell-specific autoimmunity. Chemical exposures and genetic factors modulate these pathways, and thus influence the predisposition to develop autoimmune diseases.