Basophils and mast cells in renal injury - Kidney International

review

http://www.kidney-international.org & 2009 International Society of Nephrology

Basophils and mast cells in renal injury Matthias Mack1 and Alexander R. Rosenkranz2 1

Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany and 2Department of Internal Medicine, Nephrology and Hypertension, Innsbruck Medical University, Innsbruck, Austria

Until recently, basophils and mast cells were considered mainly effector cells with an innate immune response linked to allergy and parasite infection. Only in the past few years they were recognized as important regulators of adaptive immunity. The development of new methods and reagents has enabled detection and functional analysis of these rare cells in patients and murine disease models. Basophils are normally present in the peripheral blood, spleen, and bone marrow, but migrate into lymph nodes and tissues during inflammation. They are rapidly activated by cytokines (e.g., interleukin (IL)-3) and intact antigens that cross-link surface-bound immunoglobulins. Activated basophils change the phenotype of T cells toward Th2 and markedly support humoral memory responses. Mast cells also migrate into lymph nodes and interact with dendritic cells, T cells, and B cells. In this review, we describe how mast cells and basophils affect immune responses and discuss implications for renal diseases and transplant rejection. Kidney International (2009) 76, 1142–1147; doi:10.1038/ki.2009.320; published online 19 August 2009 KEYWORDS: basophils; glomerulonephritis; kidney; mast cells; T cells; transplant rejection

Based on similarities in lineage development, activation as well as release of mediators, basophils and mast cells (MCs) have long been considered to be closely related to each other. This view has been challenged by recent results in animal models that use advanced methods to study both cell types in vivo.1–3 Basophils and MCs derive from the granulocyte–monocyte progenitor in the bone marrow under the influence of the transcription factors GATA-2 and CEBP/a. Cytokines like IL-3 modulate the expansion and maturation of both cell types.4,5 Basophils are thought to leave the bone marrow as mature cells (characterized by expression of FceRI, CD49b and the high affinity IL-3 receptor CD123) and are found under basal conditions at low frequencies in the peripheral blood, spleen, liver and bone marrow.1 During immune responses and certain types of inflammation, basophils enter lymph nodes and peripheral tissues.3,6 MCs complete their maturation in peripheral tissues like the skin, intestine and peritoneal cavity. Mature MCs (characterized by expression of FceRI and c-Kit) are detectable in these tissues but not in the peripheral blood, spleen, lymph nodes or bone marrow. Although MCs are believed to have a long half-life, the halflife of basophils is only a few days based on in vivo measurements in mice. IDENTIFYING BASOPHILS

Correspondence: Matthias Mack, University Hospital Regensburg, Department of Internal Medicine II, Franz-Josef-Strauss Allee 11 93042 Regensburg, Germany. E-mail: [email protected] or Alexander Rosenkranz, Universita¨tsklinik fu¨r Innere Medizin IV, Anichstrasse 35, A-6020 Innsbruck, Austria. E-mail: [email protected] Received 27 May 2009; revised 7 July 2009; accepted 14 July 2009; published online 19 August 2009 1142

Human basophils can be easily detected by flow cytometry using surface IgE or the high affinity IL-3 receptor CD123 as marker.7 If CD123 is used, basophils need to be distinguished from eosinophils and plasmacytoid dendritic cells expressing similar amounts of CD123. Activation of basophils can also be determined by flow cytometry using upregulation of the surface markers CD63 and CD203c, an in vitro assay frequently used to measure reactivity of basophils to allergens in sensitized patients.7 Basophils can be identified in humans with antibodies directed against intracellular antigens by immunohistochemistry.8,9 Previous efforts to identify basophils by Giemsa staining or surface expression of IgE are thought to be less specific. Murine basophils can be clearly identified by flow cytometry using surface staining of IgE or FceRI together with expression of CD49b, a marker also expressed by NK cells and other leukocytes.1 If staining with antibodies against IgE or FceRI cannot be performed (for example, for isolation of non-activated basophils), high expression of CD49b, low expression of the pan leukocyte marker CD45 and absence of Kidney International (2009) 76, 1142–1147

M Mack and AR Rosenkranz: Basophils and mast cells in renal injury

GR-1 can be used to identify basophils in the peripheral blood and spleen.1,10 Immunohistochemical detection of murine basophils can be achieved with antibodies against FceRI provided that the presence of MCs is excluded. ACTIVATION OF BASOPHILS

Activated basophils have been shown to release cytokines (IL-4, IL-6, IL-13, TSLP), histamine, leukotrienes and the phospholipid platelet-activating factor. A large variety of stimuli have been described to activate or contribute to activation of basophils in vitro. These include cross linkage of surface Fc receptors for IgG and IgE as well as cytokines (for example, IL-1, IL-3, IL-5, IL-18, IL-33), growth factors (for example, GM–CSF, nerve growth factor, stem cell factor), chemokines (for example, CCL2, CCL11, CCL24, CCL13, CCL5, CXCL8, CXCL-1-3, CXCL-12), complement factors (C3a, C5a), toll-like receptor 2 and others. In addition, several molecules downregulate activation of basophils (for example, organic cation transporter 3, leukocyte immunoglobulin receptor 3 and FcgRIIb). For most of these factors, it is not known which role they have in vivo. Cross-linkage of surface immunoglobulins and IL-3 are the most important activators of basophils, and their role in vivo has been shown.4,5,11 Basophils express the low affinity FcgRIII, that binds IgG containing immune complexes, and the high affinity FceRI that binds monomeric IgE. Both immunoglobulin receptors contain the signal-transducing Fc receptor common g-chain (FcRg). The FcRg chain contains one intracellular ITAM motif (immuno tyrosine activation motif) that is phosphorylated by lyn kinase (a src family kinase member) and recruits syk (spleen tyrosine kinase, a ZAP-70 family member) that then mediates further signal transduction. Of interest, the IL-3 receptor was recently shown to contain the signal-transducing FcRg chain and to be responsible for at least some of the effects of IL-3 on basophils (for example, release of IL-4).12 FceRI receptors not occupied by IgE are internalized and degraded unless IL-3 is present, providing an additional link between both receptors. The high affinity IgE receptor and antigen-specific IgE are required for stable and prolonged binding of antigens on the surface of basophils.1,10 Following immunization with an antigen, only antigen-specific B cells and basophils can bind significant amounts of intact antigen on their cell surface. Even several months after primary immunization, sufficient antigen-specific IgE molecules lead to antigen binding on basophils. In contrast to stable binding of intact antigen, activation of basophils can also occur by IgG molecules in the absence of IgE molecules or FceRI.1 Rechallenging mice with antigens results in an immediate release of IL-4 and IL-6 in the spleen and bone marrow, which is almost completely dependent on the presence of basophils. In FcRg-deficient mice, no cytokine release was detectable after antigen rechallenge, whereas diminished cytokine release was found in FceRI-deficient mice.1 It has also been shown that anaphylactic responses can be induced in mice deficient for IgE and FceRI, but are absent in FcRg chain-deficient mice, Kidney International (2009) 76, 1142–1147

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suggesting that IgG has an important role in anaphylaxis. Of interest, basophils but not MCs are required for active and passive anaphylaxis in mice.11 IL-3 is mainly produced by activated CD4 þ T cells,6 but was recently shown to be secreted by basophils after IgEdependent activation. IL-3 is a strong activator of basophils that releases a wide spectrum of mediators from human and murine basophils. IL-3 also markedly prolongs the survival of basophils in culture by inducing anti-apoptotic pathways6 and induces basophilia in vivo by facilitating the differentiation of granulocyte–monocyte progenitors to basophil lineage-restricted progenitors.5,6 Although IL-3 is not essential for the generation of basophils and MCs, under physiologic conditions it is required for expansion of these cells after infection with parasites.4 ROLE OF BASOPHILS IN IMMUNITY AND POTENTIAL ROLE IN KIDNEY DISEASES

Apart from their role in anaphylaxis, hypersensitivity and parasite infection, basophils have recently been shown to be important for Th2 differentiation,3 humoral immune responses and immunological memory.1 Almost 20 years ago, basophils were found to release IL-4 after stimulation in murine or human bone marrow cells and splenocytes with cross linkage of Fc-receptors or with IL-3. Only recently the importance of basophils for production of IL-4 in models of parasite infection or immunization has been recognized using transgenic IL-4 reporter mice or newly developed methods to deplete basophils in vivo. Additional factors like TSLP and IL-6 were found to be released from basophils.1,3 Basophils express low levels of MHC-II and can either directly present antigens to CD4 þ T cells 13 or influence the cytokine milieu of T cells interacting with other antigen-presenting cells (for example, dendritic cells), thus inducing a Th2 response. The immediate activation of basophils during a memory immune response and their importance for Th2 differentiation, B-cell proliferation, plasma cell differentiation and immunoglobulin production after rechallenge with antigens may also have implications for the development of renal diseases.1 A memory-type immune response predominates in transplantation and many types of autoimmune diseases, where alloantigens/autoantigens are continuously present. These antigens, together with the specific antibodies, activate basophils, which may boost ongoing humoral immune responses and further enhance production of immunoglobulins (Figure 1). Immune complexes deposited in various structures of the kidney and autoantibodies (for example, anti-neutrophil cytoplasmic antibody (ANCA), anti-DNA, anti-GBM) have a prominent role in many types of kidney diseases. In addition, donor-specific antibodies are detectable in 5% of patients after kidney transplantation and associated with an unfavorable outcome. In a study performed in patients after kidney transplantation, basophils from 6 of 23 recipients showed microscopic signs of degranulation after contact with donor lymphocytes.14 In addition, basophils detected by Giemsa staining were present in the majority of 1143

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Antigens

Cytokines Activation IL-3

IgG IgE

IL-4, IL-6, TSLP Cell contact

IL-4, IL-6 Cell contact

Basophils IL-4, IL-21

TH cells

B cells CD40L

Ability for B-cell help IL-4, IL-5, IL-13, IL-10

Proliferation Plasma cell development Ig production

Renal damage

Figure 1 | Roles of basophils in immune regulation. Basophils present in the spleen and recruited to draining lymph nodes during immune responses are activated by cytokines, for example, IL-3 produced from CD4 þ T helper cells, and by intact antigens that cross-link surface-bound immunoglobulins (IgG and IgE). Activated basophils express unidentified membrane-bound molecules and release soluble factors (for example, IL-4, IL-6, TSLP) that affect T- and B-cell function. CD4 þ T cells differentiate into Th2 cells that gain the ability for B cell help and produce IL-4, IL-5, IL-10, IL-13, IL-21, and CD40L. Thereby basophils crucially support B-cell proliferation, differentiation into plasma cells, and immunoglobulin production. Immunoglobulins may be deposited in the kidney and drive auto- and alloimmunity in the case of autoantibodies or donor-specific antibodies. Immunoglobulins further enhance the reactivity of basophils to antigens. Cytokines released directly from basophils or from CD4 þ T cells exposed to basophils may also affect renal diseases (for example, by inducing fibrosis). IgG, immunoglobin G; IL, interleukin.

renal biopsies showing acute transplant rejection and accounted for 61% of the infiltrating granulocytes but only 1.9% of total infiltrating cells. No basophils were present in biopsies without rejection.15 Although these studies suggest that basophils may have a role in transplant rejection, additional investigations using new, more reliable methods to detect basophils and measure their activation in certain kidney diseases are needed. Basophils should be analyzed in minimal-change disease and focal segmental glomerulosclerosis, wherein T cells and allergy/atopy are thought to have a major role, and Th2 skewed cytokine profiles were found in affected patients. Basophils, as inducers of Th2 immune responses and an important source of IL-4, could initiate the disease and have a role in maintaining a Th2-immune response. They should also be examined in diseases driven by immunoglobulins directed against defined structures in the kidney (for example, anti-GBM nephritis), deposited in the glomeruli (for example, membranous nephropathy, lupus nephritis) or driven by systemic vasculitis (for example, ANCA-associated vasculitis). In these conditions, basophils may contribute to generating and maintaining high levels of specific immunoglobulins and thus cause disease progression. We would 1144

propose that basophils capture antibodies (for example, directed against neutrophils, ANCA) on their surface. After encounters with neutrophils or fragments from neutrophils, their specific immunoglobulins are cross linked by the autoantigens. Subsequently, basophils become activated, interact with T cells, and boost cellular and humoral immune responses directed against autoantigens. MAST CELLS—ORIGIN AND TISSUE DISTRIBUTION

In contrast to all other blood cells, which differentiate in the bone marrow and enter the circulation as mature cells, MCs never mature in the circulating blood. Mast cell precursors, identified by the markers CD34 þ CD13 þ c-kit þ FceRI, migrate from the bone marrow to different tissues, where they complete their differentiation and ultimately reside.16 Based on their granule content and therefore different staining patterns using chloroacetate esterase staining or toluidine blue, different subsets of MCs can be differentiated. In rodents, we distinguished between connective tissue MCs and mucosal MCs. Connective tissue MCs are mainly detected in the skin and peritoneal cavity, and their granule content consists of proteoglycan heparin, and large amounts of histamine and carboxypeptidase A. The mucosal MCs are found mainly in the mucosal layer of the gut and lungs; their granules contain chondroitin sulfate and, to a much lesser extent, histamine and carboxypeptidase A.17 In humans, two analogous subsets can be differentiated based on their granule content: one population only expresses the protease tryptase, whereas the other one contains tryptase and chymase. The latter is predominantly found within the connective tissue, mostly located at mucosal sites.17 A dynamic spectrum of MC subsets could exist, which adapt their phenotype and function according to the tissue microenvironment, including inflammation and infection. THE ROLE OF MAST CELLS AS IMMUNOMODULATORS

Although many studies show that the lack of MCs or of a specific MC product decrease the pathology associated with immune response,18 negative immunomodulatory functions have been described in vivo. Importantly, the positive immunoregulatory functions of MCs can either enhance host defense or promote autoimmune disease. MCs are crucial for host survival in a model of bacterial infection like the cecal ligation and puncture model leading to peritonitis,19 or in parasitic infections.18 In experimental autoimmune encephalomyelitis, MCs increase disease severity without being present in the central nervous system20 as shown by the production of IL-4 in the lymph nodes, which propagate the development of encephalitogenic Th1 cells.21 Negative anti-inflammatory immunomodulatory functions in vivo describe a central role for MC-derived IL-10. MC-derived IL-10 markedly limits the magnitude, and promotes the resolution of innate responses to chronic low-dose ultraviolet B irradiation.22 MC-derived IL-10 was shown to limit many aspects of these responses, including the numbers of granulocytes, macrophages, and T cells at the Kidney International (2009) 76, 1142–1147

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reaction sites, as well as local tissue swelling and ulceration.22 Although the mechanisms by which MC-derived IL-10 limit tissue changes in this model remains to be fully defined, MCs and IL-10 might influence these responses through a complex combination of direct and indirect effector and immunoregulatory functions.18 Immunomodulatory functions of MCs also include direct interaction with immune competent cells like dendritic cells (DCs), as well as T and B cells: Dendritic cells

MCs are often located near DCs in peripheral tissues and are especially important in the secondary lymphoid organs. They produce mediators like histamine, TNFa or IL-1, which could significantly influence the migration and maturation of DCs and exert their effects on T cells through DCs.20 Few studies have evaluated the effect of MCs on DCs, like the proteoglycan-induced migration of skin-derived Langerhans DCs or a model of contact hypersensitivity, which showed migration of DCs to the lymph nodes. This action leads to lymph node hypertrophy, which is dependent on the presence of MCs in the lymph nodes.23 T cells

In inflammatory conditions, MCs can migrate to secondary lymphoid organs bringing them next to naive T cells. On the other hand, MCs can recruit T cells to the sites of inflammatory reaction by secretion of various cytokines, thereby inducing adhesion molecules like ICAM-1 and VCAM-1 on endothelial cells.18,20 Recently, a study by Lu et al. showed an important interaction between MCs and a subpopulation of T cells, namely the CD4 þ CD25 þ Foxp3 þ regulatory T cells (Treg) in a model of skin allograft rejection. Treg-derived IL-9, an MC growth factor, was responsible for the recruitment of MCs to the skin allograft. Owing to blockade of IL-9, MCs were not able to migrate to the allograft, or MCs were completely absent in MC-deficient mice and the allograft was rejected.24

THE ROLE OF MAST CELLS IN RENAL INFLAMMATION

In the autologous phase of an accelerated nephrotoxic glomerulonephritis (GN) model, MCs protect the kidney from inflammatory response.26 We conclude that MCs may act as regulatory cells in the renal draining lymph nodes and provide a shift towards a Th2-response. This has been recently confirmed, and shown by remodeling and repair mechanisms mediated by MCs.27 Interestingly, in a study of a non-accelerated model of anti-GBM GN, the absence of MCs was found to be protective.28 Our experimental anti-GBM model is as follows (Figure 2): immature DCs are attracted to the kidney, bind to planted antigen and then travel to the regional renal lymph nodes. Here, DCs present the antigen to effector T cells, which differentiate and expand, followed by migration to the target organ, namely the kidney. We further speculate that Treg provides cytokines like the MC growth factor IL-9 to attract and promote the expansion of MCs, which directly effect DCs via histamine or provide conditions for the anti-inflammatory effect of Treg. Importantly, downregulation of the renal inflammatory response takes place in the ‘headquarters’ – the regional lymph nodes, where the ‘fate of the kidney’ is decided. When translating this model from experimental nephrology into human renal disease in many of the immune diseases affecting the kidney, that is, systemic lupus erythematosus, the antigen is presented outside of the kidney and the renal lymph node is not likely

Kidney Pro-inflammatory chemokines Cytokines Immature DC

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Initiation phase Immature DCs take up the antigen

Ag presentation to effector T-cells Treg MC

B cells

Although in vivo studies are lacking, some evidence shows the interaction between MCs and B cells. In a model of skin ultraviolet-irradiation, MCs primarily migrate to the B cell areas of draining lymph nodes.23 In vitro, it has been shown that MCs influence B-cell development and isotype class switching through expression of cytokines such as IL-4, IL-5, IL-6, and IL-13 and surface molecules such as CD40L.18 In addition, MCs have been shown to process and present antigen to T cells via MHC Class I and II molecules leading to T-cell activation.25 Regardless, the in vivo relevance of possible antigen presentation capacity is still unclear. Of note, MC migration from the skin to the draining lymph nodes upon ultraviolet irradiation represents a key step in the induction of immune suppression 23 and a critical mechanism for transmitting immunoregulatory signals from the periphery to the immune system.

Differentiation and migration to the lymph nodes

Effector T cell

Clonal expansion and differentiation of effector T cells

Effector phase Lymph node

Figure 2 | The hypothesized role of mast cells in the pathogenesis of the autologous phase of accelerated nephrotoxic glomerulonephritis. Immature dendritic cells (DC) are attracted via chemokines and cytokines to the kidney, where they take up the planted antigen. DC differentiate and migrate to the regional draining lymph nodes and present the antigen to effector T cells. In turn, effector T cells find their way to the interstitium of the kidney, where they propagate renal inflammation. Mast cells (MC), as well as regulatory T cells (Treg) in the regional lymph nodes, have the capacity to modulate the immune response. MC are assumed to be attracted by Treg to the lymph nodes. Whether MC act via a direct effect on the DC or by providing a specific milieu for the anti-inflammatory response initiated by Treg remains to be elucidated. 1145

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Table 1 | Human glomerulonephritis and significant tubulointerstitial mast cell infiltration. Data have been taken from the largest biopsy study investigating MC infiltration in human glomerulonephritis29 Human glomerulonephritis Minimal-change glomerulonephritis Membranous glomerulonephritis Focal segmental glomerulonephritis Membranoproliferative glomerulonephritis IgA nephritis Lupus nephritis ANCA-associated vasculitis

Significant mast cell infiltration No Borderline Yes Yes Yes Yes Yes

REFERENCES 1.

2.

3.

4.

5.

ANCA, anti-neutrophil cytoplasmic antibody.

6.

the major determinant of responses. On the other hand, diseases like Goodpasture syndrome, wherein the antigen is presented in the kidney, may be regulated by the interaction of immune competent cells in renal draining lymph nodes. To date, few reports have investigated the possible role of MCs in human GN. One such descriptive study showed a significant correlation between the influx of MCs and serum creatinine concentration (Table 1).29 MCs have gained attention as a critical factor in the development of tissue fibrosis in renal disorders such as chronic GN, IgA nephritis, rapidly progressive GN and renal transplantation.28,30 Based on observational data, MCs have been suggested to contribute to renal deterioration in glomerular diseases by inducing interstitial fibrosis; however, this proposal is not supported by experimental data. Therefore, the exact role of MCs in the progression of kidney disease and fibrosis remains unclear, although possible scenarios have been recently reviewed.28 Data on the role of basophils and MCs in human renal inflammation are scarce because of the fact that improved techniques for the detection and functional analyses have only recently become available. Based on observational and experimental evidence from human and animal studies, basophils and MCs could have a prominent role in renal inflammation. Therefore, future efforts to further examine the role of these populations in renal diseases should be conducted using improved techniques to detect those cells. Furthermore, the focus of future studies should be shifted away from the kidney towards studying secondary lymphoid organs, where the ‘fate of the kidney’ appears to be decided.

7.

8.

9.

10. 11.

12.

13.

14. 15. 16.

17.

18.

19.

20.

21.

22.

DISCLOSURE

The authors declared no competing interests.

23.

ACKNOWLEDGMENTS

We apologize to all of our colleagues whose work could not be cited because of space limitations. We acknowledge Kathrin Eller for preparation of figures and critical review of this paper. This work was supported by the Deutsche Forschungsgemeinschaft (MM) and Austrian Science Foundation Grant P 21402-B13 (ARR). 1146

24. 25.

Denzel A, Maus UA, Rodriguez Gomez M et al. Basophils enhance immunological memory responses. Nat Immunol 2008; 9: 733–742. Obata K, Mukai K, Tsujimura Y et al. Basophils are essential initiators of a novel type of chronic allergic inflammation. Blood 2007; 110: 913–920. Sokol CL, Barton GM, Farr AG et al. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat Immunol 2008; 9: 310–318. Lantz CS, Boesiger J, Song CH et al. Role for interleukin-3 in mast-cell and basophil development and in immunity to parasites. Nature 1998; 392: 90–93. Ohmori K, Luo Y, Jia Y et al. IL-3 induces basophil expansion in vivo by directing granulocyte-monocyte progenitors to differentiate into basophil lineage-restricted progenitors in the bone marrow and by increasing the number of basophil/mast cell progenitors in the spleen. J Immunol 2009; 182: 2835–2841. Bruhl H, Cihak J, Niedermeier M et al. Important role of interleukin-3 in the early phase of collagen-induced arthritis. Arthritis Rheum 2009; 60: 1352–1361. Boumiza R, Monneret G, Forissier MF et al. Marked improvement of the basophil activation test by detecting CD203c instead of CD63. Clin Exp Allergy 2003; 33: 259–265. Kepley CL, Craig SS, Schwartz LB. Identification and partial characterization of a unique marker for human basophils. J Immunol 1995; 154: 6548–6555. Plager DA, Weiss EA, Kephart GM et al. Identification of basophils by a mAb directed against pro-major basic protein 1. J Allergy Clin Immunol 2006; 117: 626–634. Mack M, Schneider MA, Moll C et al. Identification of antigen-capturing cells as basophils. J Immunol 2005; 174: 735–741. Tsujimura Y, Obata K, Mukai K et al. Basophils play a pivotal role in immunoglobulin-G-mediated but not immunoglobulin-E-mediated systemic anaphylaxis. Immunity 2008; 28: 581–589. Hida S, Yamasaki S, Sakamoto Y et al. Fc receptor gamma-chain, a constitutive component of the IL-3 receptor, is required for IL-3-induced IL-4 production in basophils. Nat Immunol 2009; 10: 214–222. Sokol CL, Chu NQ, Yu S et al. Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response. Nat Immunol 2009; 10: 713–720. Egido J, Crespo M, Sanchez MG et al. In-vitro basophil degranulation in drug-suspected acute renal failure. Lancet 1977; 2: 712–713. Colvin RB, Dvorak HF. Basophils and mast cells in renal allograft rejection. Lancet 1974; 1: 212–214. Chen CC, Grimbaldeston MA, Tsai M et al. Identification of mast cell progenitors in adult mice. Proc Natl Acad Sci USA 2005; 102: 11408–11413. Rao KN, Brown MA. Mast cells: multifaceted immune cells with diverse roles in health and disease. Ann N Y Acad Sci 2008; 1143: 83–104. Galli SJ, Grimbaldeston M, Tsai M. Immunomodulatory mast cells: negative, as well as positive, regulators of immunity. Nat Rev Immunol 2008; 8: 478–486. Rosenkranz AR, Coxon A, Maurer M et al. Impaired mast cell development and innate immunity in Mac-1 (CD11b/CD18, CR3)-deficient mice. J Immunol 1998; 161: 6463–6467. Sayed BA, Christy A, Quirion MR et al. The master switch: the role of mast cells in autoimmunity and tolerance. Annu Rev Immunol 2008; 26: 705–739. Gregory GD, Raju SS, Winandy S et al. Mast cell IL-4 expression is regulated by Ikaros and influences encephalitogenic Th1 responses in EAE. J Clin Invest 2006; 116: 1327–1336. Grimbaldeston MA, Nakae S, Kalesnikoff J et al. Mast cell-derived interleukin 10 limits skin pathology in contact dermatitis and chronic irradiation with ultraviolet B. Nat Immunol 2007; 8: 1095–1104. Byrne SN, Limon-Flores AY, Ullrich SE. Mast cell migration from the skin to the draining lymph nodes upon ultraviolet irradiation represents a key step in the induction of immune suppression. J Immunol 2008; 180: 4648–4655. Lu LF, Lind EF, Gondek DC et al. Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 2006; 442: 997–1002. Frandji P, Tkaczyk C, Oskeritzian C et al. Exogenous and endogenous antigens are differentially presented by mast cells to CD4+ T lymphocytes. Eur J Immunol 1996; 26: 2517–2528. Kidney International (2009) 76, 1142–1147

review


26.

27.

Hochegger K, Siebenhaar F, Vielhauer V et al. Role of mast cells in experimental anti-glomerular basement membrane glomerulonephritis. Eur J Immunol 2005; 35: 3074–3082. Kanamaru Y, Scandiuzzi L, Essig M et al. Mast cell-mediated remodeling and fibrinolytic activity protect against fatal glomerulonephritis. J Immunol 2006; 176: 5607–5615.

Kidney International (2009) 76, 1142–1147

28. 29. 30.

Holdsworth SR, Summers SA. Role of mast cells in progressive renal diseases. J Am Soc Nephrol 2008; 19: 2254–2261. Hiromura K, Kurosawa M, Yano S et al. Tubulointerstitial mast cell infiltration in glomerulonephritis. Am J Kidney Dis 1998; 32: 593–599. Mengel M, Reeve J, Bunnag S et al. Molecular correlates of scarring in kidney transplants: the emergence of mast cell transcripts. Am J Transplant 2009; 9: 169–178.

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