Mast cells in inflammatory arthritis

Mast cells are present in limited numbers in normal human synovium, but in rheumatoid arthritis and other inflammatory joint diseases this population can expand to constitute 5% or more of all synovial cells. Recent investigations in a murine model have demonstrated that mast cells can have a critical role in the generation of inflammation within the joint. This finding highlights the results of more than 20 years of research indicating that mast cells are frequent participants in non-allergic immune responses as well as in allergy. Equipped with a diversity of surface receptors and effector capabilities, mast cells are sentinels of the immune system, detecting and delivering a first response to invading bacteria and other insults. Accumulating within inflamed tissues, mast cells produce cytokines and other mediators that may contribute vitally to ongoing inflammation. Here we review some of the non-allergic functions of mast cells and focus on the potential role of these cells in murine and human inflammatory arthritis.     

A strain of Lactobacillus casei inhibits the effector phase of immune inflammation

Some nonpathogenic bacteria were found to have protective effects in mouse models of allergic and autoimmune diseases. These "probiotics" are thought to interact with dendritic cells during Ag presentation, at the initiation of adaptive immune responses. Many other myeloid cells are the effector cells of immune responses. They are responsible for inflammation that accounts for symptoms in allergic and autoimmune diseases. We investigated in this study whether probiotics might affect allergic and autoimmune inflammation by acting at the effector phase of adaptive immune responses. The effects of one strain of Lactobacillus casei were investigated in vivo on IgE-induced passive systemic anaphylaxis and IgG-induced passive arthritis, two murine models of acute allergic and autoimmune inflammation, respectively, which bypass the induction phase of immune responses, in vitro on IgE- and IgG-induced mouse mast cell activation and ex vivo on IgE-dependent human basophil activation. L. casei protected from anaphylaxis and arthritis, and inhibited mouse mast cell and human basophil activation. Inhibition required contact between mast cells and bacteria, was reversible, and selectively affected the Lyn/Syk/linker for activation of T cells pathway induced on engagement of IgE receptors, leading to decreased MAPK activation, Ca(2+) mobilization, degranulation, and cytokine secretion. Also, adoptive anaphylaxis induced on Ag challenge in mice injected with IgE-sensitized mast cells was abrogated in mice injected with IgE-sensitized mast cells exposed to bacteria. These results demonstrate that probiotics can influence the effector phase of adaptive immunity in allergic and autoimmune diseases. They might, therefore, prevent inflammation in patients who have already synthesized specific IgE or autoantibodies.     

The two faces of mast cells in food allergy and allergic asthma: The possible concept of Yin Yang

The purpose of this review is to discuss the role of mast cells in allergic inflammation. We have focused on inflammation associated with allergic asthma and food allergy. Mast cells are ‘first line of defense’ innate/adaptive immune cells and are widely distributed in tissues in surfaces exposed to the environment. Especially in allergic settings mast cells are extensively studied, as they can be activated to release a wide range of mediators by allergen-IgE specific triggers. In addition, in allergic inflammation mast cells can also be activated non-allergic triggers. Recent studies revealed that mast cells, besides the classical role of pro-inflammatory effector cell, have also emerged as modulators of allergic sensitization and down-regulators of allergic inflammation. Therefore, mast cells can be regarded as ‘Ying Yan’ modulators in allergic responses in intestinal tract and airways. This article is part of a Special Issue entitled: Mast Cells in Inflammation.     

New insights into the role of mast cells in autoimmunity: Evidence for a common mechanism of action?

Mast cells are classically considered innate immune cells that act as first responders in many microbial infections and have long been appreciated as potent contributors to allergic reactions. However, recent advances in the realm of autoimmunity have made it clear that these cells are also involved in the pathogenic responses that exacerbate disease. In the murine models of multiple sclerosis, rheumatoid arthritis and bullous pemphigoid, both the pathogenic role of mast cells and some of their mechanisms of action are shared. Similar to their role in infection and a subset of allergic responses, mast cells are required for the efficient recruitment of neutrophils to sites of inflammation. Although this mast cell-dependent neutrophil response is protective in infection settings, it is postulated that neutrophils promote local vascular permeability and facilitate the entry of inflammatory cells that enhance tissue destruction at target sites. However, there is still much to learn. There is little information regarding mechanisms of mast cell activation in disease. Nor is it known how many mast cell-derived mediators are relevant and whether interactions with other cells are implicated in these diseases including T cells, B cells and astrocytes. Here we review the current state of knowledge about mast cells in autoimmune disease. We also discuss findings regarding newly discovered mast cell actions and factors that modulate mast cell function. We speculate that much of this new information will ultimately contribute to a greater understanding of the full range of mast cell actions in autoimmunity. This article is part of a Special Issue entitled: Mast cells in inflammation.     

TSG-6 protein, a negative regulator of inflammatory arthritis, forms a ternary complex with murine mast cell tryptases and heparin

TSG-6 (TNF-α-stimulated gene/protein 6), a hyaluronan (HA)-binding protein, has been implicated in the negative regulation of inflammatory tissue destruction. However, little is known about the tissue/cell-specific expression of TSG-6 in inflammatory processes, due to the lack of appropriate reagents for the detection of this protein in vivo. Here, we report on the development of a highly sensitive detection system and its use in cartilage proteoglycan (aggrecan)-induced arthritis, an autoimmune murine model of rheumatoid arthritis. We found significant correlation between serum concentrations of TSG-6 and arthritis severity throughout the disease process, making TSG-6 a better biomarker of inflammation than any of the other arthritis-related cytokines measured in this study. TSG-6 was present in arthritic joint tissue extracts together with the heavy chains of inter-α-inhibitor (IαI). Whereas TSG-6 was broadly detectable in arthritic synovial tissue, the highest level of TSG-6 was co-localized with tryptases in the heparin-containing secretory granules of mast cells. In vitro, TSG-6 formed complexes with the tryptases murine mast cell protease-6 and -7 via either heparin or HA. In vivo TSG-6-tryptase association could also be detected in arthritic joint extracts by co-immunoprecipitation. TSG-6 has been reported to suppress inflammatory tissue destruction by enhancing the serine protease-inhibitory activity of IαI against plasmin. TSG-6 achieves this by transferring heavy chains from IαI to HA, thus liberating the active bikunin subunit of IαI. Because bikunin is also present in mast cell granules, we propose that TSG-6 can promote inhibition of tryptase activity via a mechanism similar to inhibition of plasmin.     

Effector T cells in rheumatoid arthritis: lessons from animal models

The development of an immune response to self antigens drives naive T cells to differentiate into subsets of CD8(+) and CD4(+) effector cells including T(H)1, T(H)2, cells and the more recently described T(H)17, and regulatory T cells (T(reg)). Rheumatoid arthritis is an autoimmune disease that engages an uncontrolled influx of inflammatory cells to the joints, eventually leading to joint damage. The role that effector T cells play in the local or systemic maintenance of, or protection against, inflammation and subsequent joint damage is now becoming better understoodthrough the use of animal models. In this review, we will explore the different animal models of RA, and their contribution to elucidating the role that effector T cells play in the regulation, induction, and maintenance of inflammatory joint disease. This understanding will aid in the design of more effective therapeutic strategies for rheumatoid arthritis and other autoimmune disorders.     

Mast cells and inflammation

Mast cells are well known for their role in allergic and anaphylactic reactions, as well as their involvement in acquired and innate immunity. Increasing evidence now implicates mast cells in inflammatory diseases where they are activated by non-allergic triggers, such as neuropeptides and cytokines, often exerting synergistic effects as in the case of IL-33 and neurotensin. Mast cells can also release pro-inflammatory mediators selectively without degranulation. In particular, IL-1 induces selective release of IL-6, while corticotropin-releasing hormone secreted under stress induces the release of vascular endothelial growth factor. Many inflammatory diseases involve mast cells in cross-talk with T cells, such as atopic dermatitis, psoriasis and multiple sclerosis, which all worsen by stress. How mast cell differential responses are regulated is still unresolved. Preliminary evidence suggests that mitochondrial function and dynamics control mast cell degranulation, but not selective release. Recent findings also indicate that mast cells have immunomodulatory properties. Understanding selective release of mediators could explain how mast cells participate in numerous diverse biologic processes, and how they exert both immunostimulatory and immunosuppressive actions. Unraveling selective mast cell secretion could also help develop unique mast cell inhibitors with novel therapeutic applications. This article is part of a Special Issue entitled: Mast cells in inflammation.     

Mast cells and inflammation

Mast cells are well known for their role in allergic and anaphylactic reactions, as well as their involvement in acquired and innate immunity. Increasing evidence now implicates mast cells in inflammatory diseases where they are activated by non-allergic triggers, such as neuropeptides and cytokines, often exerting synergistic effects as in the case of IL-33 and neurotensin. Mast cells can also release pro-inflammatory mediators selectively without degranulation. In particular, IL-1 induces selective release of IL-6, while corticotropin-releasing hormone secreted under stress induces the release of vascular endothelial growth factor. Many inflammatory diseases involve mast cells in cross-talk with T cells, such as atopic dermatitis, psoriasis and multiple sclerosis, which all worsen by stress. How mast cell differential responses are regulated is still unresolved. Preliminary evidence suggests that mitochondrial function and dynamics control mast cell degranulation, but not selective release. Recent findings also indicate that mast cells have immunomodulatory properties. Understanding selective release of mediators could explain how mast cells participate in numerous diverse biologic processes, and how they exert both immunostimulatory and immunosuppressive actions. Unraveling selective mast cell secretion could also help develop unique mast cell inhibitors with novel therapeutic applications. This article is part of a Special Issue entitled: Mast cells in inflammation.     

The multitasking mast cell: positive and negative roles in the progression of autoimmunity

Among the potential outcomes of an aberrantly functioning immune system are allergic disease and autoimmunity. Although it has been assumed that the underlying mechanisms mediating these conditions are completely different, recent evidence shows that mast cells provide a common link. Mast cells reside in most tissues, are particularly prevalent at sites of Ag entry, and act as sentinel cells of the immune system. They express many inflammatory mediators that affect both innate and adaptive cellular function. They contribute to pathologic allergic inflammation but also serve an important protective role in bacterial and parasite infections. Given the proinflammatory nature of autoimmune responses, it is not surprising that studies using murine models of autoimmunity clearly implicate mast cells in the initiation and/or progression of autoimmune disease. In this review, we discuss the defined and hypothesized mechanisms of mast cell influence on autoimmune diseases, including their surprising and newly discovered role as anti-inflammatory cells.     

Staging the initiation of autoantibody-induced arthritis: a critical role for immune complexes

In the K/BxN mouse model of arthritis, autoantibodies against glucose-6-phosphate isomerase cause joint-specific inflammation and destruction. We have shown using micro-positron emission tomography that these glucose-6-phosphate isomerase-specific autoantibodies rapidly localize to distal joints of mice. In this study we used micro-positron emission tomography to delineate the stages involved in the development of arthritis. Localization of Abs to the joints depended upon mast cells, neutrophils, and FcRs, but not on C5. Surprisingly, anti-type II collagen Abs alone did not accumulate in the distal joints, but could be induced to do so by coinjection of irrelevant preformed immune complexes. Control Abs localized to the joint in a similar manner. Thus, immune complexes are essential initiators of arthritis by sequential activation of neutrophils and mast cells to allow Abs access to the joints, where they must bind a target Ag to initiate inflammation. Our findings support a four-stage model for the development of arthritis and identify checkpoints where the disease is reversible.     

肥大细胞在肿瘤发生发展中的作用

肥大细胞是人体主要免疫细胞之一,因其作为导致过敏反应发生的最直接效应细胞而著称.肥大细胞最主要的结构特征为其胞内含有大量嗜碱性颗粒,该颗粒内又富含种类众多的生物活性物质,包括组胺、血管内皮生长因子(vascular endothelial growth factor,VEGF)、成纤维细胞生长因子(fibroblast...     

IL-17/Th17 targeting: on the road to prevent chronic destructive arthritis?

Interleukin-17A (IL-17A) contributes to the pathogenesis of arthritis. Data from experimental arthritis indicate IL-17 receptor signaling as a critical pathway in turning an acute synovitis into a chronic destructive arthritis. The identification of six IL-17 family members (IL-17A-F) may extend the role of this novel cytokine family in the pathogenesis of chronic destructive joint inflammation. Whether the successful anti-IL-17A cytokine therapy in murine arthritis can be effectively translated to human arthritis need to be tested in clinical trials in humans. Interestingly, IL-17A and IL-17F are secreted by the novel T helper subset named Th17. This novel pathogenic T cell population induces autoimmune inflammation in mice and is far more efficient at inducing Th1-mediated autoimmune inflammation in mice than classical Th1 cells (IFN-gamma). In addition to IL-17A and IL-17F, Th17 cells are characterized by expression of IL-6, TNF, GM-CSF, IL-21, IL-22 and IL-26. Th17 cells have been established as a separate lineage of T helper cells in mice distinct from conventional Th1 and Th2 cells. Whether this also applies to human Th17 and whether RA is a Th1 or a Th17 mediated disease is still not clear. This review summarizes the findings about the role of IL-17 in arthritis and discusses the impact of the discovery of the novel Th17 cells for arthritis. Further studies are needed to unravel the role of Th17 cells and the interplay of IL-17 and other Th17 cytokines in the pathogenesis of arthritis and whether regulating Th17 cell activity will have additional value compared to neutralizing IL-17A activity alone. This might help to reach the ultimate goal not only to treat RA patients but to prevent the development of this crippling disease.     

Exosomes derived from IL-10-treated dendritic cells can suppress inflammation and collagen-induced arthritis

We have demonstrated previously that local, adenoviral-mediated gene transfer of viral IL-10 to a single joint of rabbits and mice with experimental arthritis can suppress disease in both the treated and untreated contralateral joints. This contralateral effect is mediated in part by APCs able to traffic from the treated joint to lymph nodes as well as to untreated joints. Moreover, injection of dendritic cells (DC) genetically modified to express IL-4 or Fas ligand was able to reverse established murine arthritis. To examine the ability of exosomes derived from immunosuppressive DCs to reduce inflammation and autoimmunity, murine models of delayed-type hypersensitivity and collagen-induced arthritis were used. In this study, we demonstrate that periarticular administration of exosomes purified from either bone marrow-derived DCs transduced ex vivo with an adenovirus expressing viral IL-10 or bone marrow-derived DCs treated with recombinant murine IL-10 were able to suppress delayed-type hypersensitivity responses within injected and untreated contralateral joints. In addition, the systemic injection of IL-10-treated DC-derived exosomes was able suppress the onset of murine collagen-induced arthritis as well as reduce severity of established arthritis. Taken together, these data suggest that immature DCs are able to secrete exosomes that are involved in the suppression of inflammatory and autoimmune responses. Thus DC-derived exosomes may represent a novel, cell-free therapy for the treatment of autoimmune diseases.     

Effects of Mild and Moderate Monoclonal Antibody Dose on Inflammation,Bone Loss,and Activation of the Central Nervous System in a Female Collagen Antibody-induced Arthritis Mouse Model

Induction of severe inflammatory arthritis in the collagen antibody-induced arthritis (CAIA) murine model causes extensive joint damage and pain-like behavior compromising analysis. While mild models are less severe, their reduced, variable penetrance makes assessment of treatment efficacy difficult. This study aimed to compare macroscopic and microscopic changes in the paws, along with central nervous system activation between a mild and moderate CAIA model. Balb/c mice (n=18) were allocated to control, mild, and moderate CAIA groups. Paw inflammation, bone volume (BV), and paw volume (PV) were assessed. Histologically, the front paws were assessed for joint inflammation, cartilage damage, and pre/osteoclast-like cells and the lumbar spinal cord and the periaqueductal gray (PAG) region of the brain for glial reactivity. A moderate CAIA dose induced (1) significantly greater local paw inflammation, inflammatory cell infiltration, and PV; (2) significantly more osteoclast-like cells on the bone surface and within the surrounding soft tissue; and (3) significantly greater glial reactivity within the PAG compared with the mild CAIA model. These findings support the use of a moderate CAIA model (higher dose of monoclonal antibodies with low-dose lipopolysaccharide) to induce more consistent histopathological features, without excessive joint destruction.     

The contribution of the nervous system to inflammation and inflammatory disease

Recent studies have identified a major contribution of the nervous system to inflammation and to inflammatory disease. In particular, substances released from the peripheral terminals of small diameter primary afferent fibers and from sympathetic postganglionic nerve (SPGN) terminals have been implicated in several of the major components of acute inflammation (e.g., vasodilatation and plasma extravasation) as well as in the regulation of tissue injury in an inflammatory disease model, experimental arthritis in the rat. Although the release of peptides from primary afferent terminals has received the most attention, our studies have established an important contribution of mast cells and the SPGN terminals to acute inflammation. We describe studies which indicate that plasma extravasation provoked by activation of small diameter primary afferents in the knee joint of the rat involves a cascade of events in which the mast cell and then the sympathetic terminal are sequentially activated. Our studies indicate that release of prostaglandins, but neither norepinephrine nor neuropeptide Y, from the SPGN terminal contributes to increased plasma extravasation. Although activation of the SPGN terminal (via the mast cell) or more directly, via injection of bradykinin, increased plasma extravasation, surgical or pharmacological sympathectomy decreased the severity of experimental arthritis. In related studies we demonstrated that adrenal medullary-derived epinephrine can exacerbate arthritis through a beta-receptor-mediated regulation of the release of an as yet unidentified substance(s) from the SPGN terminal. Our results raise important questions as to whether acute inflammation contributes to tissue repair or to further injury in the setting of disease.     

Mast cells reside in myometrium and cervix, but are dispensable in mice for successful pregnancy and labor

Parturition is associated with myometrial and cervical inflammation. The causes and consequences of this inflammatory response are not clear. Mast cells (MCs) are important inducers of allergic and non-allergic inflammation, and their secreted products can induce myometrial contractions. Thus, mast cell activation has been hypothesized to have a role in initiating labor and/or driving labor-associated inflammation. We report that small numbers of MCs expressing chymase and tryptase are present in the myometrium and cervix of pregnant women. Labor did not lead to any change in mast cell abundance in these tissues, but was associated with reduced expression of the mast-cell regulator FcεR1A, indicative of a change in mast cell properties. This coincided with contraction-dependent myocyte production of interleukin-10 (IL-10), a known suppressor of FcεR1A expression. MCs were also found in the uterine horn and cervical region of pregnant C57BL/6 mice, increasing in number in the cervix, but not the myometrium, with labor. As expected, these cells were absent from mast-cell-deficient Kit(W-sh) mice. Nonetheless, pregnant Kit(W-sh) mice showed no defects in the timing of labor induction or in the upregulation of leukocyte markers during labor. Thus, MCs are present in the uterus and cervix of humans and mice, and our mouse studies suggest that they do not have a vital role in the induction of labor, or in the promotion of labor-associated inflammation.     

Mesenchymal stem cells in arthritis: role of bone marrow microenvironment

Based on their capacity to suppress immune responses, multipotent mesenchymal stromal cells (MSCs) are intensively studied for regenerative medicine. Moreover, MSCs are potent immunomodulatory cells that occur through the secretion of soluble mediators including nitric oxide, transforming growth factor beta, and HLAG5. The MSCs, however, are also able to express inflammatory mediators such as prostaglandin E₂ or IL-6. MSCs in the bone marrow are in close contact with T cells and B cells, and they regulate immunological memory by organizing defined numbers of dedicated survival niches for plasma cells and memory T cells in the bone marrow. The role of MSCs in arthritis remains controversial - in some studies, murine allogeneic MSCs are able to decrease arthritis; in other studies, MSCs worsen the local inflammation. A recent paper in Arthritis Research and Therapy shows that bone marrow MSCs have decreased osteoblastic potential in rheumatoid arthritis, which may be related to chronic inflammation or to loss of expression of IL-1 receptor agonist. That article raises the importance of the bone marrow microenvironment for MSC biology.     

The inhibitory receptor IRp60 (CD300a) is expressed and functional on human mast cells

Mast cell-mediated responses are likely to be regulated by the cross talk between activatory and inhibitory signals. We have screened human cord blood mast cells for recently characterized inhibitory receptors expressed on NK cells. We found that IRp60, an Ig superfamily member, is expressed on human mast cells. On NK cells, IRp60 cross-linking leads to the inhibition of cytotoxic activity vs target cells in vitro. IRp60 is constitutively expressed on mast cells but is down-regulated in vitro by the eosinophil proteins major basic protein and eosinophil-derived neurotoxin. An immune complex-mediated cross-linking of IRp60 led to inhibition of IgE-induced degranulation and stem cell factor-mediated survival via a mechanism involving tyrosine phosphorylation, phosphatase recruitment, and termination of cellular calcium influx. To evaluate the role of IRp60 in regulation of allergic responses in vivo, a murine model of allergic peritonitis was used in which the murine homolog of IRp60, LMIR1, was neutralized in BALB/c mice by mAbs. This neutralization led to a significantly augmented release of inflammatory mediators and eosinophilic infiltration. These data demonstrate a novel pathway for the regulation of human mast cell function and allergic responses, indicating IRp60 as a candidate target for future treatment of allergic and mast cell-associated diseases.