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Mast Cells are Important Modifiers of Autoimmune Disease: With so Much Evidence, Why is There Still Controversy?

Brown MA, Hatfield JK - Front Immunol (2012)

Bottom Line: Similar to their role as first responders in infection settings, mast cells likely orchestrate early recruitment of immune cells, including neutrophils, to the sites of autoimmune destruction.This co-localization promotes cellular crosstalk and activation and results in the amplification of the local inflammatory response thereby promoting and sustaining tissue damage.However, these potent immune cells are undoubtedly major contributors to autoimmunity and should be considered as important targets for therapeutic disease intervention.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine Chicago, IL, USA.

ABSTRACT
There is abundant evidence that mast cells are active participants in events that mediate tissue damage in autoimmune disease. Disease-associated increases in mast cell numbers accompanied by mast cell degranulation and elaboration of numerous mast cell mediators at sites of inflammation are commonly observed in many human autoimmune diseases including multiple sclerosis, rheumatoid arthritis, and bullous pemphigoid. In animal models, treatment with mast cell stabilizing drugs or mast cell ablation can result in diminished disease. A variety of receptors including those engaged by antibody, complement, pathogens, and intrinsic danger signals are implicated in mast cell activation in disease. Similar to their role as first responders in infection settings, mast cells likely orchestrate early recruitment of immune cells, including neutrophils, to the sites of autoimmune destruction. This co-localization promotes cellular crosstalk and activation and results in the amplification of the local inflammatory response thereby promoting and sustaining tissue damage. Despite the evidence, there is still a debate regarding the relative role of mast cells in these processes. However, by definition, mast cells can only act as accessory cells to the self-reactive T and/or antibody driven autoimmune responses. Thus, when evaluating mast cell involvement using existing and somewhat imperfect animal models of disease, their importance is sometimes obscured. However, these potent immune cells are undoubtedly major contributors to autoimmunity and should be considered as important targets for therapeutic disease intervention.

No MeSH data available.


Related in: MedlinePlus

Mast cells amplify autoimmune responses through multiple mechanisms. (1) Naïve autoreactive B and T cells are activated in the secondary lymphoid organs via antigen presentation by APCs. (2) B and T cells undergo differentiation and proliferation leading to a large pool of autoreactive effector cells. Plasma cells secrete self-reactive IgG and/or IgE antibodies. (3) T cells and antibody direct the immune response to the target tissue by entering the bloodstream and trafficking to sites of relevant autoantigen expression. (4) Mast cells are activated early in disease either through TLR/NLR engagement or T cell-mast cell crosstalk via cell–cell contact or soluble mediators. FcR and C3aR/C5aR engagement on mast cells may also play a role. The possibility of activation through cross-talk with other cell types has not been verified. (5) T cells are reactivated through antigen encounter within the target tissue or through cross-talk with mast cells and other resident immune cells. (6) The subsequent release of mediators by mast cells and T cells results in increased vascular permeability and in the recruitment of other inflammatory cells, including neutrophils. (7) The resulting increasing cascade of mediators released by the cells that have co-localized at target tissue sites contribute to amplified inflammation that can directly or indirectly sustain tissue damage.
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Figure 1: Mast cells amplify autoimmune responses through multiple mechanisms. (1) Naïve autoreactive B and T cells are activated in the secondary lymphoid organs via antigen presentation by APCs. (2) B and T cells undergo differentiation and proliferation leading to a large pool of autoreactive effector cells. Plasma cells secrete self-reactive IgG and/or IgE antibodies. (3) T cells and antibody direct the immune response to the target tissue by entering the bloodstream and trafficking to sites of relevant autoantigen expression. (4) Mast cells are activated early in disease either through TLR/NLR engagement or T cell-mast cell crosstalk via cell–cell contact or soluble mediators. FcR and C3aR/C5aR engagement on mast cells may also play a role. The possibility of activation through cross-talk with other cell types has not been verified. (5) T cells are reactivated through antigen encounter within the target tissue or through cross-talk with mast cells and other resident immune cells. (6) The subsequent release of mediators by mast cells and T cells results in increased vascular permeability and in the recruitment of other inflammatory cells, including neutrophils. (7) The resulting increasing cascade of mediators released by the cells that have co-localized at target tissue sites contribute to amplified inflammation that can directly or indirectly sustain tissue damage.

Mentions: There is a complex interplay of susceptibility factors that must coalesce in an individual in order for autoimmune disease to develop. Genetics, hormonal influences and environment play important roles and some of these factors have been identified (for review see Kivity et al., 2009; Rubtsov et al., 2010; Rai and Wakeland, 2011; Pennell et al., 2012). However, many of the specific determinants that initiate an autoimmune response and allow it to be sustained and cause pathology are still enigmatic. By definition, the “directors” of autoimmune responses are cells of the adaptive immune system. Thus, an early event in the development of autoimmunity is the activation and expansion of T and/or antibody-producing B cells bearing self molecule-reactive receptors. Naïve autoreactive T or B cells first encounter antigen in secondary lymphoid organs where they undergo differentiation and acquire their effector function. These primed CD4+ T helper cells, CD8+ T cytolytic cells or secreted antibody molecules enter the blood stream and migrate to sites of inflamed tissues expressing relevant autoantigens (Figure 1). T cells, through the elaboration of cytotoxic mediators, and antibodies, through complement fixation or their ability to activate resident accessory cells such as macrophages and mast cells via Fc receptor engagement, can play direct roles in tissue destruction at these sites (Lohr et al., 2005).


Mast Cells are Important Modifiers of Autoimmune Disease: With so Much Evidence, Why is There Still Controversy?

Brown MA, Hatfield JK - Front Immunol (2012)

Mast cells amplify autoimmune responses through multiple mechanisms. (1) Naïve autoreactive B and T cells are activated in the secondary lymphoid organs via antigen presentation by APCs. (2) B and T cells undergo differentiation and proliferation leading to a large pool of autoreactive effector cells. Plasma cells secrete self-reactive IgG and/or IgE antibodies. (3) T cells and antibody direct the immune response to the target tissue by entering the bloodstream and trafficking to sites of relevant autoantigen expression. (4) Mast cells are activated early in disease either through TLR/NLR engagement or T cell-mast cell crosstalk via cell–cell contact or soluble mediators. FcR and C3aR/C5aR engagement on mast cells may also play a role. The possibility of activation through cross-talk with other cell types has not been verified. (5) T cells are reactivated through antigen encounter within the target tissue or through cross-talk with mast cells and other resident immune cells. (6) The subsequent release of mediators by mast cells and T cells results in increased vascular permeability and in the recruitment of other inflammatory cells, including neutrophils. (7) The resulting increasing cascade of mediators released by the cells that have co-localized at target tissue sites contribute to amplified inflammation that can directly or indirectly sustain tissue damage.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3369183&req=5

Figure 1: Mast cells amplify autoimmune responses through multiple mechanisms. (1) Naïve autoreactive B and T cells are activated in the secondary lymphoid organs via antigen presentation by APCs. (2) B and T cells undergo differentiation and proliferation leading to a large pool of autoreactive effector cells. Plasma cells secrete self-reactive IgG and/or IgE antibodies. (3) T cells and antibody direct the immune response to the target tissue by entering the bloodstream and trafficking to sites of relevant autoantigen expression. (4) Mast cells are activated early in disease either through TLR/NLR engagement or T cell-mast cell crosstalk via cell–cell contact or soluble mediators. FcR and C3aR/C5aR engagement on mast cells may also play a role. The possibility of activation through cross-talk with other cell types has not been verified. (5) T cells are reactivated through antigen encounter within the target tissue or through cross-talk with mast cells and other resident immune cells. (6) The subsequent release of mediators by mast cells and T cells results in increased vascular permeability and in the recruitment of other inflammatory cells, including neutrophils. (7) The resulting increasing cascade of mediators released by the cells that have co-localized at target tissue sites contribute to amplified inflammation that can directly or indirectly sustain tissue damage.
Mentions: There is a complex interplay of susceptibility factors that must coalesce in an individual in order for autoimmune disease to develop. Genetics, hormonal influences and environment play important roles and some of these factors have been identified (for review see Kivity et al., 2009; Rubtsov et al., 2010; Rai and Wakeland, 2011; Pennell et al., 2012). However, many of the specific determinants that initiate an autoimmune response and allow it to be sustained and cause pathology are still enigmatic. By definition, the “directors” of autoimmune responses are cells of the adaptive immune system. Thus, an early event in the development of autoimmunity is the activation and expansion of T and/or antibody-producing B cells bearing self molecule-reactive receptors. Naïve autoreactive T or B cells first encounter antigen in secondary lymphoid organs where they undergo differentiation and acquire their effector function. These primed CD4+ T helper cells, CD8+ T cytolytic cells or secreted antibody molecules enter the blood stream and migrate to sites of inflamed tissues expressing relevant autoantigens (Figure 1). T cells, through the elaboration of cytotoxic mediators, and antibodies, through complement fixation or their ability to activate resident accessory cells such as macrophages and mast cells via Fc receptor engagement, can play direct roles in tissue destruction at these sites (Lohr et al., 2005).

Bottom Line: Similar to their role as first responders in infection settings, mast cells likely orchestrate early recruitment of immune cells, including neutrophils, to the sites of autoimmune destruction.This co-localization promotes cellular crosstalk and activation and results in the amplification of the local inflammatory response thereby promoting and sustaining tissue damage.However, these potent immune cells are undoubtedly major contributors to autoimmunity and should be considered as important targets for therapeutic disease intervention.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine Chicago, IL, USA.

ABSTRACT
There is abundant evidence that mast cells are active participants in events that mediate tissue damage in autoimmune disease. Disease-associated increases in mast cell numbers accompanied by mast cell degranulation and elaboration of numerous mast cell mediators at sites of inflammation are commonly observed in many human autoimmune diseases including multiple sclerosis, rheumatoid arthritis, and bullous pemphigoid. In animal models, treatment with mast cell stabilizing drugs or mast cell ablation can result in diminished disease. A variety of receptors including those engaged by antibody, complement, pathogens, and intrinsic danger signals are implicated in mast cell activation in disease. Similar to their role as first responders in infection settings, mast cells likely orchestrate early recruitment of immune cells, including neutrophils, to the sites of autoimmune destruction. This co-localization promotes cellular crosstalk and activation and results in the amplification of the local inflammatory response thereby promoting and sustaining tissue damage. Despite the evidence, there is still a debate regarding the relative role of mast cells in these processes. However, by definition, mast cells can only act as accessory cells to the self-reactive T and/or antibody driven autoimmune responses. Thus, when evaluating mast cell involvement using existing and somewhat imperfect animal models of disease, their importance is sometimes obscured. However, these potent immune cells are undoubtedly major contributors to autoimmunity and should be considered as important targets for therapeutic disease intervention.

No MeSH data available.


Related in: MedlinePlus