Stem Cells in Inflammatory Disease
Recent studies have underscored a striking connection between tissue injury, repair and malignancy that may be of significant importance to the pathogenesis of systemic rheumatic diseases. At the center of this connection lies the stem cell, the effector of tissue repair and regeneration that can arise from the tissue itself or be recruited from immigrant precursors. Although satellite cells have been well defined as one source of muscle regeneration, much remains unknown about the role of immigrant stem-cell populations in this process. The injury-repair interface represents an important confluence for the forces that amplify and sustain chronic autoimmune processes, and is the theme underlying many of the reviews in this section. Although the association of rheumatic autoimmune diseases with a variety of malignancies is becoming increasingly clear, the mechanisms underlying this association remain largely obscure. Two hypotheses that attempt to clarify possible mechanistic links between chronic injury-repair and malignancy in the rheumatic diseases are discussed below.
Potent Antitumor Response Crossreacts With Regenerating Muscle and Causes Self-Sustaining Muscle Damage
Recent studies have demonstrated that high levels of myositis-specific autoantigens are expressed in cancer tissue as well as in myositis (but not normal) muscle. In myositis, autoantigen expression is enriched particularly in cells showing features of regeneration, suggesting that regenerating cells in the context of the chronic inflammatory environment in myositis muscle may play a role in shaping the myositis-specific immune response. In this model, there are several critical components needed to induce self-sustaining chronic inflammation in muscle tissue: (i) the lack of expression of myositis antigens in normal muscle; (ii) the induction of expression of such antigens in regenerating muscle cells; (iii) the shared antigen profile in various tumors; (iv) the initiation of an effective anticancer immune response targeting this shared antigen profile; and (v) muscle damage, which induces muscle regeneration and the subsequent expression of high autoantigen levels. This muscle damage may well be nonspecific, induced by exercise, drugs, virus infection and many other stimuli. Furthermore, muscle damage may occur at any time after initiation of an antitumor immune response - which itself may be silent.
A central component of this model is that the muscle-specific immune-mediated damage and resulting regeneration will continue even if the tumor is effectively removed by the immune response, and reflects a substrate cycle driven by expression of high levels of autoantigens in stem cells involved in repair. Pathways of activation of resident muscle stem cells, recruitment of immigrant stem cells to damaged tissues, and regulation of autoantigen expression are particularly relevant in this regard, and may be of therapeutic potential. While the ability of the immune system to recognize cancer cells is intuitively attractive, the shared antigenic fingerprints of nontransformed regenerating cells and cancers suggests that additional information about the rules governing the immune responses to regenerating and stem cells versus cancers is needed.
Chronic Inflammation and Tissue Damage Recruits Stem Cells, Which Accumulate Mutations and May Become Transformed
Although there is a clustering of diagnosis of malignancy around the time of initial diagnosis of myositis, this is not universally true. Some tumors are diagnosed after the rheumatic syndrome becomes well established. This is particularly true for scleroderma and Sjögren's syndrome-associated malignancies. Possible explanations of this observation include: (i) malignancy developing at later times is due to drug toxicity; (ii) the appearance of malignancy is unrelated to the rheumatic syndrome; (iii) tumor escape from the effective immune response; and (iv) increased stem-cell recruitment and mutation in the environment of chronic inflammation and repair. Defining which of these mechanisms are relevant to human myositis will be extremely challenging. Patient population studies on subtypes of rare phenotypes will be very difficult to pursue. Even with new molecular diagnostic techniques that can detect tumors at very early stages, defining silent tumors before they emerge is not yet feasible in large scale. Very little is known about stem-cell recruitment to the chronically inflamed microenvironment or on their behavior and changes at that site. A recent study by Houghton and colleagues using a mouse model demonstrates a very striking connection between chronic inflammation, hematopoietic stem-cell recruitment and mutation, and cancer formation in the inflamed target tissue. These authors showed that chronic Helicobacter pylori infection stimulates the recruitment of bone marrow derived stem cells (BMDC) into the gastric mucosa, which engraft permanently into the tissue stem-cell niche, assuming functions of the former. In the inflammatory microenvironment generated by H. pylori, the engrafted BMDCs accumulate mutations, and appear to be the cells that give rise to the gastric tumors arising in these animals. Understanding the role of hematopoietic stem cells in tissue repair in various target organs in the rheumatic diseases (including myositis) is a major priority.
Data from emerging studies provide a growing body of evidence that stem cells play critical roles at the injury-repair interface. While performing the function of regeneration so critical for life, they may also be inadvertent partners in pathology, through their ability to self-renew and express various autoantigens also expressed in tumors. These properties may provide the key ingredients for generating a feed-forward cycle of tissue damage so frequently observed in autoimmune rheumatic diseases. There is much to be discovered about the repair pathways in autoimmune tissue damage, and how these might be influenced therapeutically to turn down the amplitude of such feed-forward loops.
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