Roles of Mast Cells in Autoimmune Inflammation

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Autoimmune diseases comprise a group of diverse disorders (42). Although they differ in effector mechanisms and site of tissue damage, they are all characterized by immune reactivity to self-antigens. The ensuing inflammation leads to destruction of specific cells or tissues. Clonally expanded populations of self-reactive B or T lymphocytes may initiate some of the inflammatory events, but other immune cells also are essential for the full manifestation of disease. It is not surprising, given the potent proinflammatory capability of mast cells, that mast cells have been implicated in these processes. A wealth of correlative data is available that implicate mast cells in the inflammation that is associated with autoimmune disease. For example, multiple sclerosis is a CD4+ T-cell-mediated autoimmune disease characterized by inflammation in the central nervous system (CNS [43,44]). It is associated with an early breach of the blood-brain barrier, focal perivascular mononuclear cell infiltrates, gliosis, and demyelination of the CNS white matter (44-46). A major autoimmune response appears to occur against myelin proteins and/or myelin-producing cells of the CNS (i.e., oligodendrocytes), leading to demyelination, a hallmark of these diseases. More than100 yr ago, Neuman observed that mast cells were associated with CNS plaques in patients with multiple sclerosis (MS [47]). This finding has been confirmed in several subsequent studies. In both the murine model of MS, experimental allergic encephalomyelitis (EAE) and the human disease, it was shown that sites of inflammatory demyelination are also sites of mast cell accumulation in brain and spinal cord (48-50). In acute EAE, the percentage of degranulated mast cells increases with the clinical onset of disease symptoms (51). Tryptase, a mast cell-specific proteolytic enzyme, is elevated in the cerebrospinal fluid of patients with MS (52), and mast cell-derived proteases can degrade myelin in vitro (53,54). Myelin can directly stimulate mast cell degranulation as well (49,51,55). Differences in disease susceptibility may be influ enced by genetically determined mast cell numbers. Indeed, the classic EAE-susceptible murine strain, SJL/J, has increased numbers of mast cells compared to the resistant C3H strain (56). Mast cell-stabilizing drugs used to treat both human disease and experimental demyelinating diseases in rodents have met with some success (57-60). Finally, compelling data linking mast cells and MS were very recently obtained in microarray analyses of MS plaques. Transcripts encoding the histamine 1 receptor as well as mast cell-specific genes, including tryptase and FceRI, are increased significantly in plaques from patients with chronic MS compared with normal control patients (61).

Rheumatoid arthritis, a chronic inflammatory disease of the diarthrodial joints, appears to be exacerbated by mast cells. In collagen-induced arthritis, mast cells accumulate in the swollen paws of mice and are subject to degranulation as disease progresses (62). Mast cells also are implicated in a model of spontaneous disease observed in K/BxN mice (63). Like the human disease, the symptoms appear to be initiated by T cells, but B cells also are required. IgG antibodies to a ubiquitous cytoplasmic enzyme, glucose-6-phospate isomerase, are able to transfer disease in a strain-independent fashion (6469). These antibodies aggregate as immune complexes with the enzyme at the articular cavity. One of the first events is the degranulation of local mast cells in the joint. In humans, mast cells accumulate in the synovial tissue and fluids of affected joints (70).

Many other examples of the connection between mast cells and autoimmu-nity exist. Mast cell infiltrates are prevalent in the salivary glands of patients with Sjogren's syndrome, an inflammatory disorder of the tear ducts and salivary glands (71). Bullous pemphigoid, a blistering skin disease, is characterized by degranulated mast cells in the blisters and high concentrations of mast cell-derived chemoattractants in blister fluids (72-75). Mast cell involvement is also suspected in experimental vasculitis and thyroid eye disease (76,77). Because mast cells are located within the pancreatic ducts and implicated in other inflammatory conditions of the pancreas (78-82), there exists a likely role for mast cells in the islet cell destruction associated with type I diabetes. In vivo proof of a role for mast cells has been shown for EAE, serum-induced rheumatoid arthritis, and bullous pemphigoid using mast cell-deficient mice (63,83,84). Although this proof does not definitely prove mast cells alter the course of the human disease counterparts, the features of mast cells, including their widespread distribution, their ability to migrate during an immune response, and the nature of the mediators they produce, make it likely that they do make an important contribution.

It is likely that the details of mast cell activation and their mode of action are somewhat different in these various disease syndromes. Mast cells may be activated relatively late in the inflammatory process by the self-reactive antibodies

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Fig. 2. Mast cell exacerbates the inflammation associated with autoimmunity. (A) Mast cells activated by microbial pathogens, cytokines, neuropeptides, or stress may release mediators that could differentially mature/activate dendritic cells (DCs). This release may be particularly relevant in settings in which infection-associated autoimmunity is important. (B) In the lymph nodes, resident or newly recruited mast cells can become activated by cytokines, neuropeptides, or stress hormones to release IL-4, IL-12, histamine, and influence the polarization of T cells by directly affecting T cells. (C) Mast cells activated at sites of inflammation will secrete a number of chemotactic factors, including MIP1(3 and LTB4, that can selectively recruit lymphocytes and granulocytes. Histamine and serotonin increase vascular permeability. (D) Mast cells also are present at sites of inflammation and may directly damage tissue via release of proteases and TNF-a. (E) In contrast to proinflammatory roles, mast cells also may have a protective effect by suppressing inflammation through release of transforming growth factor (TGF)-(3 and IL-10.

Fig. 2. Mast cell exacerbates the inflammation associated with autoimmunity. (A) Mast cells activated by microbial pathogens, cytokines, neuropeptides, or stress may release mediators that could differentially mature/activate dendritic cells (DCs). This release may be particularly relevant in settings in which infection-associated autoimmunity is important. (B) In the lymph nodes, resident or newly recruited mast cells can become activated by cytokines, neuropeptides, or stress hormones to release IL-4, IL-12, histamine, and influence the polarization of T cells by directly affecting T cells. (C) Mast cells activated at sites of inflammation will secrete a number of chemotactic factors, including MIP1(3 and LTB4, that can selectively recruit lymphocytes and granulocytes. Histamine and serotonin increase vascular permeability. (D) Mast cells also are present at sites of inflammation and may directly damage tissue via release of proteases and TNF-a. (E) In contrast to proinflammatory roles, mast cells also may have a protective effect by suppressing inflammation through release of transforming growth factor (TGF)-(3 and IL-10.

observed in rheumatoid arthritis, MS, and systemic lupus erythematosus (SLE) or by complement or cytokines that are present locally. In MS, this can contribute to the activation of CNS antigen-presenting cells and direct destruction of the myelin sheath. Likewise, mast cell products may be directly involved in joint destruction in RA. Mast cell chemokines, particularly IL-8, that recruit neutrophils appear to be important in bullous pemphigus (84). As proposed for mast cells in allergic responses, these cells also may have influence during the inductive phase of disease. The influence of mast cells on dendritic cells at the site of antigen entry may regulate dendritic cell function or T-cell development directly (Fig. 2).

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