Mast Cells Are Important Modifiers of Autoimmune Disease

REVIEW ARTICLE published: 07 June 2012 doi: 10.3389/ﬁmmu.2012.00147 Mast cells are important modiﬁers of autoimmune disease: with so much evidence, why is there still controversy?

Melissa A. Brown* and Julianne K. Hatﬁeld

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

Edited by: There is abundant evidence that mast cells are active participants in events that medi- Toshiaki Kawakami, La Jolla Institute ate tissue damage in autoimmune disease. Disease-associated increases in mast cell for Allergy and Immunology, USA numbers accompanied by mast cell degranulation and elaboration of numerous mast cell Reviewed by: Miriam Wittmann, University of mediators at sites of inflammation are commonly observed in many human autoimmune Leeds, UK diseases including multiple sclerosis, rheumatoid arthritis, and bullous pemphigoid. In ani- John Ryan, Virginia Commonwealth mal models, treatment with mast cell stabilizing drugs or mast cell ablation can result University, USA in diminished disease. A variety of receptors including those engaged by antibody, com- *Correspondence: plement, pathogens, and intrinsic danger signals are implicated in mast cell activation in Melissa A. Brown, Department of Microbiology and Immunology, disease. Similar to their role as first responders in infection settings, mast cells likely orches- Northwestern University Feinberg trate early recruitment of immune cells, including neutrophils, to the sites of autoimmune School of Medicine, 303 E. Chicago destruction.This co-localization promotes cellular crosstalk and activation and results in the Avenue, Tarry 6-701, Chicago, IL amplification of the local inflammatory response thereby promoting and sustaining tissue 60611, USA. e-mail: m-brown12@ damage. Despite the evidence, there is still a debate regarding the relative role of mast cells northwestern.edu in these processes. However, by definition, mast cells can only act as accessory cells to the self-reactiveT 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 undoubt- edly major contributors to autoimmunity and should be considered as important targets for therapeutic disease intervention.

Keywords: mast cells, autoimmunity, neutrophils, MC-T cell crosstalk, mast cell deﬁcient mice

INTRODUCTION roles and some of these factors have been identified (for review Autoimmune and allergic diseases share fundamentally important see Kivity et al., 2009; Rubtsov et al., 2010; Rai and Wakeland, features in that both are the result of “hypersensitive” immune 2011; Pennell et al., 2012). However, many of the specific deter- responses directed toward inherently harmless antigens. It is this minants that initiate an autoimmune response and allow it to overzealous response that causes the pathology. In fact, as late as be sustained and cause pathology are still enigmatic. By defin- the 1960s many disease models that we now know are autoimmune ition, the “directors” of autoimmune responses are cells of the were labeled as“experimental allergic”neuritis, encephalomyelitis, adaptive immune system. Thus, an early event in the develop- orchitis, uveitis, and glomerulonephritis, reflecting this concept ment of autoimmunity is the activation and expansion of T and/or (Mackay and Anderson, 2010). But this nomenclature has been antibody-producing B cells bearing self molecule-reactive recep- largely abandoned and the myriad of common mechanisms that tors. Naïve autoreactive T or B cells first encounter antigen in link allergy and autoimmunity are sometimes forgotten. Mast cells, secondary lymphoid organs where they undergo differentiation clearly implicated in both immediate- and delayed-type allergic and acquire their effector function. These primed CD4+ Thelper responses, may underlie the relationship between various types of cells, CD8+ T cytolytic cells or secreted antibody molecules enter hypersensitive diseases, yet their role in autoimmunity is still often the blood stream and migrate to sites of inflamed tissues expressing questioned. Here we review the data that implicates mast cells in a relevant autoantigens (Figure 1). T cells, through the elaboration variety of autoimmune diseases and address some of the possible of cytotoxic mediators, and antibodies, through complement fix- reasons for the controversy. We also discuss how many of the same ation or their ability to activate resident accessory cells such as mast cell mediated mechanisms that confer protection in infection macrophages and mast cells via Fc receptor engagement, can play settings or mediate allergic responses are pathologic in the face of direct roles in tissue destruction at these sites (Lohr et al., 2005). a T- or B-cell directed response to a self antigen. While the adaptive immune response initiates autoimmune inflammation, innate immune cells are critical for sustaining the AUTOIMMUNITY: DIRECTED BY THE ADAPTIVE IMMUNE response that leads to pathology (reviewed in Bach et al.,2004; Ten- SYSTEM BUT SUSTAINED BY INNATE IMMUNE CELLS ner, 2004; Marshak-Rothstein and Ohashi, 2007; Pisetsky, 2008; There is a complex interplay of susceptibility factors that must coa- Chervonsky, 2009; Maciejewska Rodrigues et al., 2009). However, lesce in an individual in order for autoimmune disease to develop. because autoimmunity is dependent on self-reactive T and/or B Genetics, hormonal influences and environment play important cells, innate immune cells can only play a modifying role at best.

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

It is this secondary, albeit critical, role of innate cells that often association with blood vessels and nerves (reviewed in Rao and makes it difficult to definitively determine their relative contri- Brown,2008). Depending on the mode of activation,mast cells can bution because of the overlaps in immune cell function. The release unique arrays of immune modulating molecules that exist reliance on inherently imperfect animal models of human disease preformed in granules within minutes. Activation also induces to define the interplay between adaptive and innate immune cells the new synthesis of cell surface associated and soluble immune exacerbates this problem. The spontaneous or actively induced mediators that can exert prolonged effects on a response (Galli development of disease in animals is rarely physiologic and is often et al., 2005; Metz et al., 2007). Although cross-linking of the high associated with an overly robust autoreactive B or T cell response, affinity IgE receptor (FcεRI) is the best studied mode of mast cell one that does not recapitulate the gradual inflammatory processes stimulation, the last few years have been transformative in terms that characterize the development of most chronic human autoim- of identifying a range of other mast cell activating receptors that mune illnesses. Thus, the contribution of modulatory cells can be act in this capacity leading to either protective or pathologic out- masked, especially if they exert their critical effects early in dis- comes. Indeed, there are few infection or disease states in which ease. Such limitations have sometimes led to inconsistent results these potent immunomodulatory cells have not been directly or and controversy in the field about which cells make substantial indirectly implicated (Rao and Brown, 2008) and thus it follows contributions to disease pathogenesis. The challenge in convinc- that mast cells are most certainly modifiers of autoimmune disease ingly implicating such accessory cells is perhaps best illustrated by as well. the studies of mast cells in autoimmunity. Despite a wealth of sup- portive evidence, the contribution of mast cells to autoimmunity, MAST CELLS AS MODIFIERS OF AUTOIMMUNITY I: particularly to rheumatoid arthritis (RA) and multiple sclerosis CORRELATIVE EVIDENCE (MS), is still debated. The idea that mast cells are involved in the initiation and sustaining events of autoimmunity is not based on conventional wisdom, MAST CELLS: POTENT IMMUNOMODULATORY CELLS but rather on substantial data from studies of both human disease Mast cells are c-kithi,FcεRI+ granular cells of the innate immune and animal models (Benoist and Mathis, 2002; Lee et al., 2002; system that reside in most tissues, but do not circulate in a mature Gregory and Brown, 2006; Rao and Brown, 2008; Sayed et al., form in the blood. They are most prevalent at sites that inter- 2008; Walker et al., 2011). Here we focus primarily on studies face with the external environment and are often found in close of RA, bullous pemphigoid (BP), type I diabetes and multiple

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sclerosis (MS), where the evidence for a mast cell contribution is studies in a model of spontaneous diabetes in NOD mice. Treat- particularly convincing. ment of NOD mice with anti-FcεRI antibodies, which activate In RA the primary targets of the autoantibody-directed mast cells and basophils to produce IL-4, delays diabetes (Hubner immune response are the synovial joints (Lee and Weinblatt, et al., 2011). It is postulated that in this model system IL-4 is exert- 2001; Lee et al., 2002). Although mast cells are normal residents ing anti-inflammatory effects by skewing CD4+ T helper cells to within the synovium, their numbers are increased in human dis- a Th2 dominated response. ease and this is associated with the local production of several Multiple sclerosis is a CD4+ T cell-dependent disease in which mast cell-derived mediators (reviewed in Nigrovic and Lee, 2007). myelinated nerves in the relatively immunologically sequestered Tryptase, a preformed mast cell-specific protease, is thought to CNS are targeted for destruction leading to variable neurologic initiate the inflammatory response by complexing with heparin dysfunction (Sospedra and Martin, 2005; Hauser and Oksenberg, to induce the release of neutrophil chemotactic factors such as 2006). Mast cells are observed in plaques of patients assessed TNF, IL-1β, and IL-17, as well as IL-33 by synovial fibroblasts post-mortem as are transcripts encoding tryptase, histamine, (Shin et al., 2009; Hueber et al., 2010). IL-33, in turn, acts directly and FcεRI, identified by microarray analyses (Lock et al., 2002). on mast cells to initiate the expression of additional inflammatory Tryptase and histamine are also detected in the cerebral spinal cytokines and chemokines (Xu et al., 2008, 2010; Verri et al., 2010). fluid of some patients (Tuomisto et al., 1983; Rozniecki et al., Tryptase can also directly activate synovial fibroblasts through its 1995). In experimental autoimmune encephalomyelitis (EAE), a interaction with the protease-activated receptor 2 (PAR2) enhanc- mouse model of MS induced by immunization with myelin pep- ing their ability to express proteases that degrade cartilage and tides in CFA, treatment of mice with proxicromil an inhibitor bone (Palmer et al., 2007; Sawamukai et al., 2010). In human RA, a of mast cell degranulation, cyproheptadine, a serotonin receptor 6- to 25-fold expansion of mast cells has been observed in affected antagonist or reserpine, which depletes mast cell granules, inhibits joints when compared to numbers in normal joints (Nigrovic and disease (Dietsch and Hinrichs, 1989; Dimitriadou et al., 2000). Lee, 2007). Mast cell numbers also increase more than threefold in multiple animal models of RA (Aloe et al., 1993; Kakizoe et al., MAST CELLS AS MODIFIERS OF AUTOIMMUNITY II: 1999; Shin et al., 2006) and it has been postulated that they are CONFOUNDING EVIDENCE FROM IN VIVO STUDIES OF MAST essential for the joint-specific vascular leak phenomenon involving CELL DEFICIENT MICE both histamine and serotonin (Binstadt et al., 2006). In collagen- Although compelling, measures of increased mast cell numbers, induced arthritis, increased mast cell numbers and the associated mast cell activation profiles, or efficacy of mast cell-inhibitory neutrophil influx to the joints as well as exacerbated clinical sever- drugs are not proof of mast cell involvement. The most definitive ity are reduced by treatment with the mast cell stabilizer, sodium studies implicating mast cells have relied on the use of mast cell nedocromil (Pimentel et al., 2011). deficient mice, most commonly those with mutations in Kit, the Bullous pemphigoid is a skin blistering disease that can be gene encoding c-kit, the stem cell factor (SCF) receptor (W/Wv, induced in mice by injection of an antibody (anti-BP180) directed W−sh mice) or in Kitlg, the gene encoding the c-kit ligand, SCF to hemidesmosomes, structures involved in cell–cell adherence (Sl/Sld mice). The differentiation and long term survival of mast (Kasperkiewicz and Zillikens, 2007). Early events in this model cells is dependent on sustained high level SCF/c-kit signaling and of disease include massive degranulation of skin mast cells that mice with W/Wv,W−sh/W−sh, or Sl/Sld mutations that compro- precede the characteristic neutrophil influx and blister formation. mise this signaling exhibit defects in mast cell development (Galli Cromolyn sodium, another mast cell stabilizing drug, blocks these and Kitamura, 1987; Grimbaldeston et al., 2005). These mice events (Chen et al., 2001; Navi et al., 2007). In human disease, are imperfect models because they also bear other hematologic degranulated mast cells are prominent in lesions where histamine, and non-hematologic defects including neutropenia, anemia, pig- tryptase, and several mast cell-associated chemokines are detected ment production defects, reduced intestinal mobility and sterility in blister fluid (Baba et al., 1976; Dvorak et al., 1982; Katayama (W/Wv), or time-dependent loss of mast cells, cardiac abnormal- et al., 1984; D’Auria et al., 2000). ities, and neutrophilia (W−sh/W−sh; Galli and Kitamura, 1987; In Type I diabetes, CD8+ T cells are thought to play a pre- Grimbaldeston et al., 2005; Nigrovic et al., 2008). Sl/Sld mice also dominant role in the destruction of the insulin-producing islet develop lymphocytic leukemia at a high rate and have shortened cells of the pancreas although CD4+ T cells and antibodies are life spans (Galli and Kitamura, 1987). Systemic or local reconsti- also implicated. The resulting loss of blood glucose regulation tution of Kit mutant mice with bone marrow derived mast cells can lead to retinopathy, neuropathy, cardiovascular disease, and (BMMC) selectively restores most mast cell populations, although nephropathy (Bluestone et al., 2010). Gene expression profiling not always to wild type levels,but does not correct other mutant Kit of the pancreatic lymph nodes in the spontaneous BB rat model related abnormalities. If a wild type phenotype is re-established in revealed activated mast cell transcripts that correlate with dis- Kit mutant mice by selective repopulation of tissue mast cells, it is ease and treatment with cromolyn sodium, results in a significant generally accepted that mast cells are implicated. delay in disease onset (Geoffrey et al., 2006). Inhibitors of tyro- Several recent reports have described the generation of unique sine kinase can also inhibit and reverse spontaneous disease in the strains of mast cell deficient mice that do not appear to have NOD mouse model of Type I diabetes, however, specific inhibitors the accompanying profound hematologic defects of Kit mutant of c-kit, a tyrosine kinase-associated receptor required for mast mice, although their characterization is still incomplete (Dudeck cell development, have marginal effects on limiting disease pro- et al., 2011; Feyerabend et al., 2011; Lilla et al., 2011; Otsuka et al., gression (Louvet et al., 2008). Paradoxically, a protective role for 2011). These mice provide the promise that a more unequivo- mast cells in this disease has been proposed based on results of cal assessment of mast cell contributions in vivo can be achieved. www.frontiersin.org June 2012 | Volume 3 | Article 147 | 3 Brown and Hatfield Mast cells and autoimmunity

Of particular interest to this discussion of autoimmune disease were specifically deposited in the joint of wild type mice within are the Cpa3Cre/+ mice. Carboxypeptidase 3 (Cpa3) is a mast cell minutes after transfer, while deposition was delayed and reduced specific protease expressed early in development and Cpa3Cre/+ in W/Wv animals (Wipke et al., 2002, 2004). In antigen-induced mice contain a transgene encoding cre-recombinase under the arthritis, a chronic arthritis model induced by the direct injection control of the carboxypeptidase 3 (Cpa3) promoter (Feyerabend of methylated bovine serum albumen into the joint, there is little et al., 2011). It is presumed that the high level expression of Cre- difference in early disease severity in wild type and Kit W/Wv mice, recombinase in mast cell precursors that express Cpa3 is toxic, but mast cell deficient mice develop significantly reduced cartilage causing genomic instability and the ultimate demise of this cell damage over time, a phenotype reversed by BMMC reconstitution lineage at an early stage in development. With the exception of (van den Broek et al., 1988). However, in the collagen-induced a small diminution in basophil numbers, no other cell lineages arthritis model, there are no clinical disease differences leading the appear to be affected. Below, we review the controversial evidence authors to suggest that either this model is mast cell-independent that supports and refutes a role for mast cells in autoimmunity or that mast cells have a minor role (Pitman et al., 2011). using mast cell deficient mice. In the BP model, WBB6 Kit W/Wv mice exhibit reduced neutrophil accumulation in the skin and diminished skin blistering EVIDENCE FOR MAST CELL INFLUENCE IN AUTOIMMUNITY USING upon transfer of serum autoantibodies compared to wild type KIT W/WV MICE mice, whereas a wild type-like disease with associated neutrophil Results in Kit W/Wv mice have provided the most consistent sup- influx is restored upon mast cell reconstitution (Chen et al., 2002). portive evidence for mast cell involvement in autoimmunity. Of Notably,administration of IL-8,a neutrophil chemoattractant,can note, in most autoimmune disease models examined using these overcome the mast cell-deficiency (Chen et al., 2001). mice, including RA, BP, and EAE, the mast cell-dependent neu- Evidence of mast cell involvement in EAE pathogenesis using trophil recruitment discussed above is an important pathogenic Kit W/Wv mice has been less consistent. EAE is induced by immu- event, one that is absent in Kit W/Wv mice (D’Auria et al., 2000; nization of mice with myelin peptide in CFA (Mix et al., 2010). Chen et al., 2006; Kasperkiewicz and Zillikens, 2007; Monach et al., Original studies of WBB6 Kit W/Wv mice and their wild type 2010; Sayed et al., 2010; Kaplan, 2011; Walker et al., 2011; Warde, littermates in a chronic model of MS induced by myelin oligo- W/Wv 2011). Despite the inherent neutropenia of Kit mice, restora- dendrocyte glycoprotein35–55 peptide (MOG)35–55 immunization tion of mast cells results in normal disease-related neutrophil revealed that the absence of mast cells does not abolish disease, but influx to inflamed tissues indicating that the few neutrophils there is significantly reduced severity (Secor et al., 2000). This sus- present in these mice are mobilized in a mast cell-dependent ceptibility is restored to wild type levels by BMMC reconstitution, manner. The relationship of mast cells and neutrophils was first a procedure that does not correct the c-kit-related anemia in these defined in infection settings where mast cells,acting as first respon- mice. Mast cells that normally reside in the meninges are essen- ders, release multiple mediators including histamine, PAF, TNF, tial for this fulminant disease and act to regulate BBB integrity CXCL2, and IL-8 within minutes of activation and initiate the and inflammatory cell entry into the CNS (Sayed et al., 2010). influx of neutrophils (Zhang et al., 1992; Malaviya et al., 1996a; Neutrophils are among the first cells to enter the CNS in EAE and Biedermann et al., 2000). As in infection, in autoimmune disease, their requirement for disease pathogenesis was confirmed by stud- neutrophils likely promote disease-associated changes in vascu- ies of mice lacking the chemokine receptor, CXCR2, expressed on lar permeability, but also contribute directly to self-tissue damage neutrophils. CXCR2−/− mice cannot mobilize neutrophils from through the release of proteases, reactive oxygen intermediates, the bone marrow in response to inflammatory signals and fail to and chemoattractants that regulate the influx of other inflamma- develop EAE (Carlson et al.,2008). Mast cells and mast cell-derived tory cells, contributing to a cascade of damaging events (reviewed TNF are required for neutrophil influx into the CNS (Sayed et al., in Kumar and Sharma, 2010; Mantovani et al., 2011). 2010). Despite the convincing data in mouse models, neutrophil Mast cell dependence has been demonstrated in models of RA involvement in MS is still controversial. Neutrophils are short- (K/BxN serum transfer-induced and antigen-induced RA) using lived cells and likely exert effects during the initiation of disease (WB xC57BL/6)F1 (WBB6) Kit W/Wv mice where, as in human or in flares associated with relapsing-remitting disease. These cells RA, neutrophils are the dominant lineage in synovial effusions are not detected in post-mortem assessment of the meninges or (Nigrovic and Lee, 2007). K/BxN mice exhibit an early and spon- CNS as expected, leading many to dismiss them as participants in taneous onset of RA-like symptoms due to the presence of glucose- MS pathogenesis. 6-phosphate reactive autoantibodies and transfer of K/BxN serum Severe PLP131–159-induced disease in SJL mice is also mast into wild type but not WBB6 Kit W/Wv mice, induces disease (Corr cell-dependent. This model is considered by some to be more rele- and Crain, 2002; Lee et al., 2002). Disease susceptibility is restored vant because it mimics the most commonly presenting relapsing- to Kit mutant mice by BMMC reconstitution. Mast cell reconsti- remitting form of human disease, one observed in at least 85% of tution with IL-1β−/− BMMCs fails to restore disease susceptibility patients. SJL Kit W/Wv mice exhibit a significantly reduced disease in the K/BxN serum transfer model, indicating that disease patho- course that corresponds to decreased infiltration of inflammatory genesis is mediated by mast cell-derived IL-1β (Nigrovic et al., cells to the CNS and mast cell reconstitution restores wild type 2007). Mast cells also directly modulate access of arthritogenic disease susceptibility (Sayed et al., 2011). While there has been antibodies to the joint in the hyperacute phase of K/BxN serum independent corroboration that mast cells are important in dis- transfer arthritis, a feature likely directly or indirectly related to the ease by other groups using Kit W/Wv mice (Stelekati et al., 2009; effects of mast cells on vascular permeability. Labeled antibodies Piconese et al., 2011), other studies report no disease differences

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(Bennett et al., 2009). The basis of this disparity is still not clear, POTENTIAL MECHANISMS OF MAST CELL ACTIVATION IN but there are several potential explanations including age-related AUTOIMMUNE DISEASE differences in susceptibility, the use of distinct disease induction There are a multitude of receptors expressed on mast cells protocols that result in overwhelming T cell responses and unique that are candidates for involvement in autoimmune modulation housing- or diet-related gut microbiota that alter the general (Figure 2). As discussed below, many of these receptors and their immune responsiveness of the mice. ligands have been implicated in autoimmune disease, but whether they are acting to activate mast cells in the context of disease is still STUDIES USING KIT W−SH/W−SH MICE FAIL TO REVEAL A MAST CELL in question. INFLUENCE IN RA AND EAE − − C57BL/6 Kit W sh/W sh mice were originally touted as better sub- PATHOGEN- AND DANGER-ASSOCIATED MOLECULAR PATTERN jects for in vivo studies of mast cell-dependent events because they MOLECULES IN INFECTION-ASSOCIATED AUTOIMMUNITY: are on a pure C57BL/6 background and are fertile (Grimbalde- OVERCOMING TOLERANCE ston et al., 2005). However, contradicting the results of studies It is well established that the activation and expansion of self- in Kit W/Wv mice, there is no decrease in EAE or RA disease reactive T and B cells can occur only under defined conditions: severity in Kit W−sh/W−sh suggesting mast cells are not impor- either the normal mechanisms of negative selection fail to delete tant (Zhou et al., 2007; Piconese et al., 2011). These results may particular self-reactive clones during development, there is a fail- be explained by the fact that unlike neutropenic Kit W/Wv mice, ure of normal peripheral mechanisms that maintain tolerance to Kit W−sh/W−sh mice have a baseline pro-inflammatory phenotype self, the normal sequestration of antigens that prevent lympho- that includes neutrophilia, splenomegaly, and increased mast cell cyte access to self antigens is breached or infection with certain precursors in the spleen. Thus, their pre-existing inflammatory pathogens elicits an adaptive immune response that cross-reacts state, particularly the neutrophilia, likely obviates the need for with self antigens, a phenomenon termed molecular mimicry the mast cell-dependent neutrophil recruitment that affects early (Nurieva et al., 2011; Pillai et al., 2011). disease-promoting events. Although not definitively established in humans, the development of several autoimmune diseases has been linked to exposure STUDIES USING Cpa3 CRE+/− MICE FAIL TO IMPLICATE MAST CELLS IN to infectious agents (Kivity et al., 2009). For example, prior EBV RA AND EAE infections are postulated to increase the predisposition to Systemic ArecentstudybyFeyerabend et al. (2011) using the newly lupus erythematosus (SLE), RA, MS, Sjogren’s syndrome, and pol- described Cpa3cre+/− mice also fails to corroborate a role for mast yarteritis nodosa (Barzilai et al.,2007),while autoimmune diabetes cells in EAE and RA. Cpa3cre+/− mice are refractory to induction susceptibility is associated with enterovirus infections (Richardson of anaphylaxis and fail to exhibit the normal protective expansion et al., 2009). Bacterial infections including H. pylori are implicated of intestinal mast cells associated with N. Brasiliensis infection in susceptibility to autoimmune gastritis and Sjorgrens syndrome supporting the validity of using these mice in models in which (Annibale et al., 2001; D’Elios et al., 2004). In addition to elicit- IgE-activated mast cells are the major effector cells. Yet Cpa3cre/+ ing a cross-reactive pathogen-specific adaptive immune response, mice are susceptible to RA induction by transfer of K/BxN serum, infectious agents can engage a class of pathogen- and danger- in contrast to Kit W/Wv mice. In addition, no diminution of EAE associated receptors on both adaptive and innate immune cells, disease severity was observed in either Cpa3cre/+ or Kit W/Wv mice including mast cells. These receptors, including Toll-like receptors when compared to their wild type littermate controls. Two con- (TLRs) and Nacht-LRRs (NLRs), are expressed either within the clusions were made based on these results: (1) mast cells are plasma membrane or in endosomal compartments and recognize dispensable in both models of RA and MS (EAE) and, (2) other conserved components of bacteria, viruses, and protozoa (such c-kit-regulated events influence the susceptibility of mice to RA. as lipopolysaccharide, LPS), double stranded RNA, flagellin, and A corollary to these conclusions is that mast cells are only relevant non-methylated CpG DNA, collectively termed pathogen asso- in IgE-dependent allergic disease (Katz and Austen, 2011). ciated molecular patterns (PAMPs; reviewed in Kawai and Akira, Yet these conclusions may be premature for a number of rea- 2011).Activation of immune cells through TLRs and NLRs induces sons. For example, mast cells express a myriad of other activating the expression of multiple inflammatory mediators that can ulti- receptors that have been documented to play important physio- mately result in local tissue damage causing the release of nor- logic roles in many inflammatory responses outside allergy (Rao mally sequestered tissue antigen. Subsequent recognition of these and Brown, 2008; Sayed et al., 2008). In addition, as discussed antigens by T or B cells will induce activation and initiate autoim- earlier mast cells are not the major effector cells in T and/or B cell- munity. Alternatively, infection-induced activation of accessory dependent autoimmune responses as they are in IgE-dependent immune cells, including mast cells, macrophages, and neutrophils, responses, thus they are relegated to accessory roles. The strong can boost inflammation and transform a relatively modest autore- disease induction conditions used in the EAE experiments in this active response into one that causes detectable pathology. study (corroborated by high morbidity in all groups Feyerabend Toll-like receptors/NLRs are also highly effective at sensing and et al., 2011) make it likely that a vigorous T cell response masks responding to tissue injury, such as that induced in autoimmu- the mast cell contribution. There is abundant evidence support- nity (Zhang et al., 2010; Kufer and Sansonetti, 2011). Just as ing mast cell contributions to autoimmune inflammation and it is pathogens are detected by virtue of “Stranger” signals, damaged important to delineate the underlying reasons for this conflicting cells release “Danger” signals, designated as alarmins or Damage data. Associated Molecular Patterns (DAMPs) that are also sensed by

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FIGURE 2 | Mast cell activation and response in autoimmunity. (A) Mast cross-talk with many cells of the innate and adaptive immune system. cells express a variety of activating receptors that may play a role in modifying Demonstrated effects of mast cells include elicitation of dendritic cell (DC) autoimmune disease. These include IgG receptors FcγR1, FcγRIIB, and and neutrophil (PMN) maturation and recruitment. Mast cells interact directly FcγRIII; the high afﬁnity IgE receptor, FcεR1; complement receptors C3R and with B cells to affect activation, proliferation and differentiation. Mast cells can C5aR; TLRs and NLRs that sense pathogen and intrinsic danger signals; as affect the development of CD4+ T helper cells, can act as antigen presenting well as LTβR and ICAM-1 which can engage with LTβR-ligand and LFA-1, cells and express mediators and cell surface molecules that co-stimulate and respectively, on T cells. (B) Mast cells, through expression of cell surface activate T cells. Mast cells can also inhibit or support T regulatory cell function, interaction molecules or mast cell-derived mediators, engage in critical depending on the setting.

TLRs and NLRs (reviewed in Bianchi, 2007; Piccinini and Mid- when engaged can trigger the expression of a number of activa- wood, 2010; Marek and Kagan, 2012). In mammals, TLR3, TLR7, tion molecules, including CD40 and ICAM-1, on salivary gland and TLR9 detect microbial nucleic acids, as well as those released epithelial cells (Spachidou et al., 2007). TLR2 ligation specifi- from necrotic cells. For example, damaged cells release heat shock cally activates Th17 cytokine production in the peripheral blood proteins such as Hsp60,Hsp70,and alpha-β crystalline that are rec- mononuclear cells of Sjogren’s syndrome patients (Kwok et al., ognized by TLR2 and TLR4 as well as endogenous cellular products 2012). Based on studies in MS models where TLR2, 4, 7, and such as uric acid crystals and aggregated peptides that activate 9 have been implicated in exacerbated disease (Marta et al., NLRs. ATP release from damaged cells acts through purinergic 2009) and TLR3 is protective (Touil et al., 2006), the targeting of receptor-regulated channels to cause cytosolic ion fluxes that are these molecules for therapy has been proposed (Gambuzza et al., detected by NLRs. The resulting signals generated through such 2011). cell injury can activate immune cells, contributing to the persis- With the exception of TLR5, there is evidence that most other tence of the inflammatory response and promoting more tissue TLRs are expressed on mast cells and are functional (Marshall destruction. et al., 2003a,b; Marshall, 2004). For example, activation of mature There is emerging evidence that TLRs/NLRs are important mast cells through TLR2 results in their production of several receptors in autoimmune diseases (Fischer and Ehlers, 2008; pro-inflammatory cytokines critical in autoimmunity including Mills, 2011). Activation through TLR2, 3, 4, and 9 is associ- IL-17, IFNγ, TNF, and IL-1β (Mrabet-Dahbi et al., 2009). Mast ated with disease in animal models of RA (Ronaghy et al., cells also express the NLR, NLRP3, and activation of this intracel- 2002; Abdollahi-Roodsaz et al., 2008; Hoffmann et al., 2011; Goh lular receptor activates the inflammasome,a multiprotein complex and Midwood, 2012) and TLR4 engagement can overcome the that regulates the processing and secretion of the IL-1 family of requirement for IL-1β in the serum transfer model of this dis- cytokines including IL-1β and IL-18 through the activation of cas- ease (Choe et al., 2003). Similarly, TLR1, 2, 3, and 7 signals pase 1 (Nakamura et al., 2009). Mast cells clearly are capable of mediate islet inflammation in rat and mouse models of type I responding to PAMP and DAMP signals and it will be critical diabetes (Lien and Zipris, 2009). TLR1, 2, 3, and 4 are expressed to determine whether this is an important mode of activation in in the salivary glands of patients with Sjogren’s syndrome and autoimmune disease.

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FcεRI AND FcγR ACTIVATION OF MAST CELLS: COMMON Complement MECHANISMS LINKING AUTOIMMUNITY AND ALLERGY The complement system, named for its ability to complement The connection between IgE- and IgG-mediated mast cell the action of antibodies and phagocytes in an immune response, responses and autoimmunity is still a tenuous one and is just consists of several proteins synthesized by the liver that exist as beginning to gain some traction (Valenta et al., 2009). As dis- inactive pro-proteins. Under inflammatory conditions, a prote- cussed earlier, allergy and autoimmunity are both considered olytic cascade is initiated that results in the cleavage and generation hypersensitive diseases that result from inappropriate responses of active components, some of which act as direct chemoattrac- to innocuous antigens. However, it is notable that self-reactive tants or bind to specific G protein-coupled receptors on cells IgG and IgE antibodies are commonly detected in both aller- and stimulate their activation (reviewed in Ricklin et al., 2010). gic and autoimmune diseases including atopic dermatitis, RA, Complement activation is triggered by the direct binding of com- systemic lupus erythematosis,Hashimoto’s thyroiditis,Graves’dis- plement proteins to microbial surfaces (alternative pathway) or via ease, BP and MS, and their animal models (Permin and Wiik, 1978; complement binding to complement-fixing antibody isotypes that Bartholomew et al., 1991; Valenta et al., 1991; Cooper et al., 1993; have been cross-linked by antigen (classical pathway). A mannose Ghohestani et al., 1998; Pedotti et al., 2001; Metcalfe et al., 2002; binding lectin-induced pathway also exists (lectin pathway) and Concha et al., 2004; Smith et al., 2005; Fairley et al., 2007). In these processes of complement fixation, chemoattraction, and cell atopy, these autoreactive antibodies are primarily detected in those activation are essential for protection from infection. individuals with severe and chronic diseases such as atopic der- Mast cells have an intimate relationship with complement in matitis, but not in patients with mild respiratory allergies (Valenta that they can activate complement components, but they also et al., 1991). Many of the self antigens that react with IgE are express surface receptors that directly bind the breakdown prod- homologs of environmental antigens, including the actin bind- ucts of this proteolytic cascade. It has been speculated that mast ing protein, profilin, serum albumin, collagen and desmoplakin, cell degranulation induces release of chemoattractants (e.g.,LTβ4), and responses to these are thought to result from cross-reactivity vasoactive amines (e.g., histamine), and proteases (e.g., tryptase; (Patterson et al., 1986; Bartholomew et al., 1991; Valenta et al., (Dawicki and Marshall,2007). C3 and C5 complement proteins are 1991; Cooper et al., 1993; Spitzauer et al., 1994; Ghohestani recruited through the permeable local vasculature to sites of mast et al., 1998). Alternatively there is speculation that inflammation cell residence and are cleaved through the action of mast cell pro- associated with IgE-dependent mast cell responses to environ- teases to C3a and C5a (Schwartz et al., 1983; Fukuoka et al., 2008). mental allergens induces tissue damage and in a Th2 dominated These byproducts can activate mast cells through the engagement immune environment these self antigens, no longer sequestered of complement receptors expressed on mast cells, C3aR and C5aR, from the immune system, elicit an IgE response (Valenta et al., leading to further chemokine/cytokine production and release 2009). (Wyatt et al., 1979; Biesecker et al., 1981; Falk et al., 1983). Mast cells also express multiple IgG Fc receptors. Important Not unexpectedly, the best evidence of complement activation participants in protective immune responses to pathogens, IgG in autoimmunity comes from studies of antibody-mediated dis- receptor cross-linking elicits mast cell activation in allergy and eases such as RA, BP, and SLE. Mice depleted of complement are also plays critical roles in autoimmunity. In fact, IgG autoan- refractory to collagen-induced arthritis (Backlund et al., 2002). tibodies are hallmarks of many autoimmune diseases and have Antibodies specific for double stranded DNA form immune com- been detected in BP, RA, SLE, and MS (reviewed in Sayed et al., plexes and their deposition in the glomeruli of patients with 2008). IgG-specific Fc receptors include both the activating forms, SLE activates complement, generating C3a and C5a (Wyatt et al., FcγRI and FcγRIII, as well as the inhibitory FcγRIIB. FcγRIIB 1979; Biesecker et al., 1981; Falk et al., 1983). Although com- engagement down regulates both FcγRIII- and FcεRI-induced plement activation normally promotes immune complex clear- mast cell mediator release (Miyajima et al., 1997) and the loss ance, the deposition of complement activation products also of this inhibitory receptor renders mice susceptible to induced contributes to inflammation and local tissue injury (Rothfield autoimmune arthritis and spontaneous SLE and leads to exacer- and Stollar, 1967; Couser, 1985; Couser et al., 1985; Perkinson bated EAE (Abdul-Majid et al., 2002; Lock et al., 2002; Pedotti et al., 1985; Mackworth-Young et al., 1986). In BP,COL17-specific et al., 2003; Robbie-Ryan et al., 2003). Kit W/Wv mice reconstituted autoantibodies target human type XVII collagen (Robson et al., with either FcRγ−/− mast cells (which lack functional FcγRIII, 2003). Access of these antibodies to the basement membrane elicits FcεRI, and FcγRI) or with mast cells lacking only FcγRIII exhibit an inflammatory cascade that includes complement activation, a reduced and delayed EAE disease course, suggesting that acti- infiltration of neutrophils and eosinophils, and degranulation of vation of mast cells through these receptors modulates disease dermal mast cells (Oikarinen et al., 1983; Stahle-Backdahl et al., (Robbie-Ryan et al.,2003). Mast cell-derived IL-1β,which is neces- 1994; Chen et al., 2001; Robson et al., 2003; Liu et al., 2008). In sary for disease in the K/BxN model, is produced after stimulation a mouse model of BP induced by administration of anti-hCOL17 through autoantibody engagement of FcγRIII (Nigrovic et al., antibody, altering the capacity of the antibody to fix comple- 2007). ment abrogates its disease-causing ability (Li et al., 2010). In SLE, Clearly such findings, particularly the presence of self-reactive complement activation deposition of complement at sites of tis- IgE antibodies in both allergy and autoimmunity, blur the distinc- sue damage is often observed, however, deficiencies in the early tion between these classes of disease and suggest that allergy and components of the complement cascade are strongly associated autoimmunity share similar antibody-dependent mechanisms to with disease. In animal models of disease, the lack of C1q or C4 activate mast cells and elicit tissue damage in disease. results in loss of apoptotic cell clearance, increasing the supply of

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autoantigens that are targets of the immune response and promot- There is an abundance of evidence that mast cells affect the ing a predisposition to SLE-like disease (Cook and Botto, 2006). In activation state and functionality of T cells. Included among the EAE, complement acts in concert with autoantibody to promote many tissue sites where mast cells reside are the secondary lym- demyelination (Urich et al., 2006). However, while C3, but not C5, phoid organs and a number of studies have demonstrated that is required for disease, the deletion of both C3aR and C5aR has their numbers increase in the lymph nodes and spleen in response no effect on disease severity, perhaps illustrating another instance to some inflammatory signals (Tanzola et al., 2003; Kashiwakura where immune redundancy or strong induction of disease in this et al., 2004; Sayed et al., 2010). At these sites of T cell priming as experimental setting obscures the role for these molecules (Reiman well as other tissue sites where T cells are reactivated, bystander et al., 2002; Boos et al., 2004; Morgan et al., 2004; Ramos et al., mast cells can potentially influence the differentiation phenotype 2009). of T cells through their ability to express a myriad of T cell polariz- There is only limited data demonstrating a direct link between ing cytokines including IL-4 and histamine (Mekori and Metcalfe, complement-activated mast cells and autoimmune disease. For 1999). Mast cell-derived TNF, in concert with OX40L, enhances example, in the K/BxN model, C5aR expression on mast cells T cell activation and proliferation and also contributes to the is necessary for neutrophil recruitment and subsequent disease polarization of Th2 cells in a model of airway hyperreactivity development (Nigrovic et al., 2010). The development of BP (Nakae et al., 2006, 2007a,b). Mast cells express MHC Class I and in mice requires the expression of C5aR on mast cells, which inducible MHC Class II molecules and thus have the potential to is required for their degranulation (Heimbach et al., 2011). In act as antigen presenting cells (APCs) and there are several reports EAE, the data are equivocal. Targeted deletion of receptors for that substantiate mast cell APC function both in vitro and in vivo C3a and C5a does not protect mice from disease, yet deletion of (Frandji et al., 1993, 1995; Fox et al., 1994; Malaviya et al., 1996b; C3 convertase regulator complement receptor 1-related protein y Kambayashi et al., 2008, 2009). However, if mast cells serve in this (Crry) exacerbates disease (Reiman et al., 2002; Ramos et al., 2009; capacity, it is likely that they are more relevant in recall responses Ramaglia et al., 2012). There is also evidence that C5 may actually and not in the priming of naïve T cells. Given the emerging appre- promote remyelination and prevent gliosis in the CNS (Weerth ciation of superantigens in allergic pathogenesis,particularly those et al., 2003). derived from Staphylococcus (Barnes, 2011), it is tempting to spec- ulate that mast cells “present” superantigens to T cells and initiate Immune cell crosstalk their activation. The ability of mast cells to present staphylococ- The concept that cell–cell interactions result in cross-activation cal enterotoxin B to CD8+ T cells supports this idea (Frandji has now become a prevailing paradigm in immunology. There are et al., 1996). Through the expression of co-stimulatory molecules many examples of mast cell interactions with T cells,DCs,and neu- such as CD80, CD86, CD40, CD40L, GITR, and 4-1BB as well as trophils, although the consequences of most of these interactions the inhibitory molecules PD-L1, PD-L2, and Fas, mast cells can have not yet been ascribed to autoimmune disease pathogenesis. alter T cell effector function (Nakae et al., 2005, 2007c; Lu et al., Mast cell activation is likely to be an early and initiating event 2006; Stelekati et al., 2007, 2009; Piconese et al., 2009; Hershko and that triggers cell co-localization and facilitates such interactions, Rivera, 2010). given that many mast cell mediators released early in a response A newer concept is that T cells can activate and alter mast cell act to recruit cells to sites of inflammation. As alluded to above, function. Many of the studies to support this idea have been per- mast cell derived TNF, CXCL2, and LTβ4, for example, recruit formed in vitro using membranes isolated from activated T cells neutrophils to inflamed tissues (Ramos et al., 1991, 1994; Zhang and mechanisms that underlie T cell mediated mast cell activa- et al., 1992, 1995; Mercer-Jones et al., 1999; Biedermann et al., tion have not been extensively explored. However, activated T 2000; Wang and Thorlacius, 2005; Nakamura et al., 2009). Sim- cells induce human mast cells to release MMP-9, an event that ilarly, mast dependent neutrophil recruitment to affected tissues is blocked by inhibiting TNF (Baram et al., 2001). Human mast has been demonstrated in animal models of autoimmunity includ- cells also produce the neutrophil chemoattract IL-8 upon interac- ing the synovium in RA, the skin in BP, and the meninges in EAE tion with activated, but not resting, T cells (Salamon et al., 2005). (Chen et al., 2001, 2002; Sayed et al., 2010; Pimentel et al., 2011). Oncostatin M, a multifunctional cytokine of the IL-6 family, is A subset of these same mediators, particularly TNF and LTβ4 also released by human mast cells after interaction with activated T recruit DCs and T cells while IL-16, lymphotactin (MIP-1α), and cells, but not after cross-linking through the IgE receptor (Sala- MIP-1β are chemotactic for CD4+ and CD8+ T cells (reviewed mon et al., 2008). Two receptor-ligand interactions have been in Mekori and Metcalfe, 1999). In a model of cutaneous contact implicated in T cell-driven mast cell activation. Upon engagement hypersensitivity, mast cell activation is essential for DC migration of the lymphotoxin-β receptor (LTβR), expressed on mast cells, to the skin and histamine and PGE2, both produced by mast cells, with its ligand, expressed on activated T cells, mast cells release induce the expression of Th2-recruiting cytokines by DCs (McIl- pro-inflammatory cytokines including IL-4,IL-6,TNF,MIP-2,and roy et al.,2006). Mast cells also affect DC function in a skin allograft RANTES (Stopfer et al., 2004). Interaction of LFA-1, expressed on model where mast cell derived GM-CSF sustains the DC popula- activated T cells, and ICAM-1, expressed on mast cells, induces tion that is required for tolerance at the graft site (de Vries et al., MC degranulation (Inamura et al., 1998). 2011). Here we will focus on mast cell interactions with effector T Mast cells have a paradoxical relationship with T regulatory cells and regulatory T cells, as these are arguably the best-described (Treg) cells. Most studies that have investigated mast cell-T regu- interactions and also the mostly likely to play a significant role in latory cell crosstalk were done using a skin allograft model. In this autoimmunity. model Treg cell-derived IL-9 recruits and activates mast cells to the

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site of the allograft and mast cell presence within the graft is neces- often strikingly similar to their roles in infection and allergic sary for long term allograft survival (Lu et al., 2006). Treg cells can disease suggesting that we may gain more mechanistic insight also inhibit mast cell degranulation via OX40/OX40L interaction by concentrating on these commonalities. However, in each and thus help to maintain tolerance, as shown in both allograft individual disease there is likely to be variability in the response of transplant and allergic disease models (Gri et al., 2008; Piconese mast cells based on the tissue site(s) they are derived from, their et al., 2009). In contrast, in in vitro studies, mast cell-derived mode of activation and the interacting cells that are in play. In histamine can block Treg cell mediated suppression through H1 addition, it is probable that as in mice, human mast cells exhibit receptors (Forward et al., 2009). unique and genetically determined responses to activation that may contribute to the severity of or susceptibility to a particular FUTURE QUESTIONS autoimmune disease. Thus, the challenge in ultimately targeting Despite the advances in our understanding of these enigmatic cells, these cells in therapy will be to understand how they contribute to there is still much to be learned about how mast cells impact initiating disease and to promoting chronicity and what dictates autoimmunity. Mast cell actions in autoimmune responses are the quality and magnitude of a particular mast cell response.

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Zhou, J. S., Xing, W., Friend, D. S., conducted in the absence of any com- Citation: Brown MA and Hatfield JK Copyright © 2012 Brown and Hat- Austen, K. F., and Katz, H. R. (2007). mercial or financial relationships that (2012) Mast cells are important mod- field. This is an open-access article dis- Mast cell deficiency in Kit(W-sh) could be construed as a potential con- ifiers of autoimmune disease: with tributed under the terms of the Cre- mice does not impair antibody- flict of interest. so much evidence, why is there still ative Commons Attribution Non Com- mediated arthritis. J. Exp. Med. 204, controversy? Front. Immun. 3:147. doi: mercial License, which permits non- 2797–2802. 10.3389/fimmu.2012.00147 commercial use, distribution, and repro- Received: 20 March 2012; accepted: 19 This article was submitted to Frontiers in duction in other forums, provided Conflict of Interest Statement: The May 2012; published online: 07 June Inflammation, a specialty of Frontiers in the original authors and source are authors declare that the research was 2012. Immunology. credited.

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