Mast cells (MCs) are key effectors of inflammation in tissues. In progressive kidney disease they constitute an essential feature of the observed interstitial infiltrate of inflammatory cells. Their presence was largely interpreted as being contributory to pathology. Recent experimental evidence, however, has highlighted that MCs participate in multiple features of chronic inflammatory responses in kidneys through diverse effects that besides promoting inflammation can also suppress aspects of these responses and exert beneficial actions. The appropriate and timely controlled secretion of a wide range of inflammatory products by these cells, besides inducing an initial inflammatory response, was shown to take part in subsequent anti-inflammatory mechanisms and repair activity that contribute to healing. MCs may also crucially participate in possible regenerative processes in the kidney. This chapter reviews the beneficial actions that MCs may have in kidneys. It is postulated that, when appropriately controlled, their prime action is to contribute to the restoration of tissue homeostasis.

Introduction

Chronic kidney disease (CKD) is a growing health problem worldwide as it leads to the development of renal failure with no treatment options except for replacement therapy . CKD can be caused by disorders that affect any of the kidney structures, including glomeruli, renal vessels and the tubulointerstitial compartment. They are either genetically inherited, e.g. autosomal dominant polycystic kidney disease, or acquired. The latter can arise in response to toxic, metabolic (diabetes), hemodynamic (hypertension), postischemic, infectious or autoimmune injury leading to damage of renal tissue. Independent of its origin, the initial injury launches an inflammatory cascade to oppose the injurious insult and initiate tissue repair with eventually limited fibrosis and epithelial regeneration. However, in case of chronic stimulation or defective regulation, the disease will enter into a progressive phase characterized by the development of extensive renal fibrosis with destruction of individual nephrons and blood vessels. Two-thirds of the nephrons will already have been destroyed before CKD is diagnosed, and from then on the damage progresses to end-stage renal failure regardless of the original cause of injury. The relentless decline in renal function can be slowed by therapies based on converting enzyme inhibitors or angiotensin II (Ang II) receptor type-1 antagonists but they are only partially effective . To date, replacement therapy by either dialysis or transplantation remains the only option for supportive therapy once the ultimate renal failure occurs. Therefore, strategies aiming to shift the balance towards repair and kidney regenerative processes are necessary in order to develop more effective and specific treatments for progressive renal failure and to halt the ever-increasing number of people requiring dialysis and transplantation. Importantly, researchers have now obtained a more subtle view of the inflammatory process, realizing that it represents a highly dynamic entity aiming to fight the injurious insult and to contribute to tissue repair and resolution of the inflammation. Therapeutic strategies must therefore be designed to reinforce these positive regulatory actions while suppressing defective inflammatory mechanisms.

An essential characteristic of progressive renal diseases is the presence of an interstitial infiltrate of leukocytes, which is thought to play a pivotal role in the inherent inflammatory process. Initially thought as being contributory to disease progression, recent data have made it clear that these infiltrating cells also have a variety of positive actions enabling the organism to reduce tissue injury and achieve regeneration. Besides macrophages and T cells, the infiltrate also includes mast cells (MCs), suggesting their functional implication. MCs are of hematopoietic origin. Their precursors, after a short passage in circulation, migrate into tissues where they complete their final maturation under the influence of stem cell factor (SCF) and a variety of other cytokines and growth factors [interleukin (IL)-3, IL-4, IL-9, nerve growth factor (NGF)] . They represent a heterogeneous population of cells that can be found in virtually every tissue of the human body, including the kidney . While initially studied for their role in allergies, research in the past two decades has revealed that MCs are highly versatile effector cells with multiple roles in innate and adaptive immunity as well as in the inflammatory processes . Although initially thought to contribute to the pathogenesis of renal diseases, several recent experimental evidences using MC-deficient mice favor a more subtle view. They indicated that MCs can also have beneficial roles in the reparation and tissue remodeling processes that accompany healing. This chapter will review the knowledge that has accumulated on the role of MCs in renal disease, with a particular emphasis on their roles in repair and regeneration.

Basic Biology of Mast Cells

Origin, Tissue Distribution and Heterogeneity of Mast Cells

MCs were originally described by the German immunologist Paul Ehrlich, who noticed in various connective tissues the presence of cells with metachromatic behavior, i.e. the property to change the color of the applied aniline dyes . He named them “Mastzellen”, meaning “well-fed”, cells owing to the presence of numerous cytoplasmic granules, which he thought to contain phagocytosed material or nutrients ( Fig. 6.1 ). Although many questions remain regarding their differentiation, MCs are of hematopoietic origin, arising from a CD34 ⁺ and CD117 ⁺ (c-kit) stem cell in the bone marrow . After a short passage in blood, committed MC progenitors migrate into tissues where they undergo the final stages of their differentiation under the influence of various cytokines and growth factors. The main survival and developmental factor is SCF, also known as kit-ligand. This is exemplified by the virtual absence of MCs in mice carrying natural mutations in either SCF (WCB6F ₁ – Kitl ^Sl / Kitl ^Sl−d mice) or its receptor c-kit (WBB6F1- Kit ^W /Kit ^W−v or C57BL/6- Kit ^W−sh /Kit ^W−sh mice) . However, a series of other cytokines and growth factors may additionally be important in influencing the phenotype and number of MCs, including IL-3, IL-4, IL-9, NGF and transforming growth factor-β ₁ (TGF-β ₁ ) . Murine bone marrow-derived mast cells (BMMCs) can be cultured in the presence of IL-3 alone, although addition of SCF allows a more mature phenotype to be obtained. By contrast, for growth of human primary MCs from CD34 ⁺ stem cells in cord or peripheral blood SCF is absolutely required. MCs are predominant in tissues facing the external environment such as the skin, the airways and the intestine, but can be found in virtually every vascularized tissue. While their numbers may be low in certain types of tissues, e.g. in the kidney, they can increase markedly under chronic inflammatory conditions.

Resting and stimulated mast cells (MCs). The top panel shows electron micrographs of a resting (left) and stimulated (right) rat peritoneal MC. Scale bar = 1μm. (Courtesy of G. Zabucchi and Maria Rosa Soranzo, University of Trieste, Italy.) Resting cells contain numerous cytoplasmic secretory granules that are filled with electron-dense material. Stimulated cells have undergone partial exocytosis of granular content by a process implying granule–granule and granule plasma membrane fusion. The bottom panel shows granulated and degranulated mouse connective tissue type MCs in kidney capsules stained with toluidine blue. Note that in degranulated cells, the expelled toluidine blue staining granular matrix can be seen in the tissue surrounding the MC. Inset shows higher magnification (100×) of one of the MCs. Please see color plate at the end of the book.

MCs are phylogenetically old cells, which apparently occur in all species containing vascularized tissues . They are round or elongated cells with a diameter ranging between 10 and 20 μm containing a single nucleus and numerous (up to 1000) secretory granules in their cytoplasm storing histamine (also serotonin in rodents), proteoglycans, cytokines and neutral serine proteases ( Fig. 6.1 ). MC populations are heterogeneous and can be divided into specific subpopulation of cells initially discovered by their differential staining properties with various histochemical dyes, which is mainly based on their differential content in proteoglycans . Thus, rodent MCs were classified into connective tissue type mast cells (CTMCs) and mucosal mast cells (MMCs). By contrast, human MCs were classified according to their protease content into tryptase-positive mast cells (MC _T ) and tryptase/chymase-positive mast cells (MC _TC ). However, even within these defined cell populations additional phenotypic differences may exist relating, for example, to protease content. Hence, in human kidney a third subpopulation of chymase-positive MCs has been described (see below) .

In addition to the phenotypical heterogeneity the two classes of MCs are further characterized by a functional heterogeneity that can be attributed to their differential mediator content and differential receptor expression. For example, murine MMCs lack tryptase-dependent biological functions. They also have biochemical differences, MMCs being low in histamine and high in activation-elicited cysteinyl leukotriene (LTC) production, while CTMCs have a high histamine content and generating the prostanoid prostaglandin D ₂ (PGD ₂ ) in marked preference to LTC. Furthermore, MMCs are also unable to respond to polybasic compounds and complement-activated mechanisms owing to the lack of expression of various G-protein activated receptors including, for example, C3a and C5a receptors for complement fragments. It is likely that additional phenotypic variations occur at the different anatomical sites where they reside, which may depend on the presence of local growth factors and cytokines.

Receptors Expressed by Mast Cells

MCs are sentinels that express a large variety of cell surface receptors allowing them to respond to different physiological or pathophysiological situations ( Fig. 6.2 ). Besides the well-studied high-affinity IgE receptor known for its involvement in allergies or adaptive immune responses, other immunoreceptors include Fc receptors (FcR) that bind to IgG subclasses conferring MCs responsiveness to stimulation with immune complexes in host defense, but also in autoimmunity. While mouse MCs express the activating FcγRIII, human MCs express both activating FcγRIIA and under certain conditions FcγRI, the latter being induced by low concentrations of interferon-γ (IFN-γ). Mouse MCs also express the FcγRIIB, while its expression in human MCs is not firmly established . FcγRIIB functions as a general inhibitor of cell activation when coaggregated with another activating immune receptor.

Examples of surface receptors expressed by mast cells. These can be further classified as receptors involved in specific or adaptive immunity as well as danger signals. hu: human; mo: mouse; FcR: Fc receptor; MHC: major histocompatibility complex; VIP: vasoactive intestinal peptide; CGRP: calcitonin gene-related peptide; ACTH: adrenocorticotropic hormone; SP: substance P; CXCR: CXC chemokine receptor; IL: interleukin; TGF: transforming growth factor; EP3/4R: Prostaglandin E receptor subtype 3 or 4; P2X7: purinergic ATP receptor; TLR: Toll-like receptor.

In addition, MCs express various receptors involved in innate immunity . These include several types of Toll-like receptors (TLRs), able to become activated upon interaction with pathogen-associated molecular products (PAMPs) present in bacteria [i.e. lipopolysaccharide (LPS), flagellin] and viruses (dsDNA, ssRNA and parasites). The initial reports focused on TLR2 and TLR4 but since then other functional TLRs have been discovered on MCs . Importantly, MCs also express a variety of receptors or danger-associated molecular products (DAMPs) including the purinergic ATP receptor (P2X7), prostanoid receptors (EP3/4) and TLRs; the latter respond, for example, to high mobility group box 1 protein (HMGB1), a protein released in the surroundings when cells are injured or become necrotic. Stimulation of TLRs can lead to the production of proinflammatory cytokines in the absence of degranulation . MCs have also been shown to express receptors for a number of cytokines, chemokines and growth factors. Many of them, including the chemokine receptor CCR1 or SCF, are known to upregulate the responsiveness to other stimuli . Furthermore, certain of them are able to upregulate the expression of receptors, such as FcγRI by IFN-γ, which can modulate the cellular responsiveness . Some of them, such as receptors for SCF, IL-9 or certain chemokines, may also be a means to attract MCs to a given anatomical site. Thus, it has been shown that IL-9 transgenic mice are particularly enriched in MCs in some tissues, including the kidney .

Furthermore, depending on the activating product MCs are able to selectively release a specific set of cytokines/chemokines, suggesting that they have the capability of fine tuning the effector response. Several forms of infection or tissue injury also lead to the activation of complement. MCs have long been known to express complement receptors such as CR3 (CD11b–CD18), CR4 (CD11c–CD18) or receptors recognizing complement split products such as C3aR and C5aR (CD88) . The expression of CR3 and CR4 is variable depending on the type of MC, but can also be upregulated upon activation. C3aR and C5aR are expressed only on certain types of MCs, in general CTMC, indicating functional heterogeneity depending on the anatomical site.

MCs express also a variety of receptors that are activated by polybasic compounds such as compound 48/80, mastoparan and polymers of basic amino acids or a number of related peptides. The responses can be inhibited by pertussis toxin, indicating that they involve G-protein-coupled receptors. As for C3aR and C5aR, CTMCs can be distinguished from MMCs by their property to respond to stimulation with compound 48/80. MCs also respond to stimulation with certain neuropeptides, including substance P (SP), calcitonin gene-related peptide (CGRP), somatotropin release inhibitory factor (SRIF), vasoactive intestinal peptide (VIP) and adrenocorticotropic hormone (ACTH) . This suggests that MCs could represent an important connection between the immune and the central nervous system.

Model Systems to Study Mast Cell Functions

A useful model system to study the in vivo function of MCs has been the availability of MC-deficient mice. Several MC-deficient rodents carrying natural mutations such as Kit ^W /Kit ^W−v , Kit ^W−41 /Kit ^W−41 and Kit ^W−f /Kit ^W−f mice, as well as Kit ^W−s /Kit ^W−s rats, have been used to investigate MC biology in vivo . The most often used model has been the WBB6F1- Kit ^W /Kit ^W−v mouse; however, C57BL/6- Kit ^W−sh /Kit ^W−sh mice are nowadays gaining in popularity. Although both types of model are profoundly deficient in MCs, and lack melanocytes and interstitial cells of Cajal, Kit ^W−sh /Kit ^W−sh mice have fewer abnormalities. In particular, in contrast to W/W ^v mice they are fertile and not anemic. Thus, they can easily be crossed with mice carrying other abnormalities. As both types of mice exhibit deficiencies not only in the MC compartment, lack of responsiveness in a given experimental model does not necessarily mean that MCs play a role. It is therefore necessary to selectively repair the MC deficiency by the adoptive transfer of genetically compatible in vitro derived BMMCs. They are obtained from bone marrow after culture in IL-3 or culture with a combination of IL-3 and SCF. Sometimes they are also generated from embryonic stem cells (ESCs). Such MC knockin mice can then be used to assess the extent of MC implication. While the effective restoration of responsiveness may allow reasonable conclusions to be drawn about the implication of MCs, partial or lack of restoration is more difficult to interpret . Notably, it has been found that following adoptive transfer of MCs the anatomical distribution and numbers as well as certain functional properties may not necessarily be completely identical to wild-type mice, which may complicate the interpretation of results . Another MC-deficient strain, WCB6F ₁ – Kitl ^Sl / Kitl ^Sl−d mice, carrying natural mutations in the ligands of c-kit (Kitl or SCF), has been used less because the absence of biologically active SCF does not enable reconstitution of MCs in these animals .

The reconstitution with MCs provides an additional advantage as they allow the reconstitution of mice with MCs deficient in a receptor or particular mediator that are derived from mutant mice or mutant ESCs. Thus, it has been shown in the EAE model of multiple sclerosis that MCs deficient in the activating FcγRIII are unable to restore disease susceptibility, suggesting the implication of pathological IgG immune complexes . Similarly, in the model of autoimmune arthritis induced by the application of arthritogenic antibodies, besides the role of activating FcγR, a crucial role for IL-1β released by MCs in the initiation of the response could be demonstrated .

Beneficial Role of Mast Cells in Inflammation

While there is no doubt that MCs are implicated in multiple chronic inflammatory diseases, many of these may be the result of the increasing inadequacy of the environment of our modern hygienic society. Indeed, the hygiene hypothesis postulates that owing to the altered challenge with common pathogens encountered during bacterial, viral and parasitic infection, the immune system becomes deviated, leading to inappropriate responsiveness towards otherwise inoffensive antigens such as environmental allergens or towards antigens of the own body, leading to allergy and autoimmune disease . This is supported by epidemiological data showing a tremendous increase in allergic disease in the past five decades. Besides allergies, certain autoimmune diseases such as type 1 diabetes and multiple sclerosis have also increased, probably also promoted by the absence of stimulation with environmental pathogens. Similarly, in renal diseases a constant increase in disease incidence has been observed during the past three decades. In particular, the number of patients developing CKD owing to diabetes and hypertension has risen sharply . A large part of the increase can be attributed to the change in lifestyle as well as to the aging of the population in Western countries. It is possible that inflammatory processes engendered by inappropriately reactive MCs and other inflammatory cells contribute to the severity and accelerated progression.

Indeed, for some of these diseases MCs have been incriminated as major actors of the inherent pathophysiological mechanisms, such as in allergies. Yet, research during the past two decades has also made clear the physiological functions of MCs and their mediators, in particular in host defense against pathogens, where they may have major roles in protection . They have also revealed a more subtle role of MCs in the inflammatory process that highlight their important function in tissue repair following injury.

Undoubtedly, the first reports of beneficial roles played by MCs were related to their capacity to function in innate and adaptive host defense mechanisms. Because IgE production is markedly upregulated during immune responses to infections with intestinal parasites, with MC numbers being considerably upregulated, this question was investigated in MC-deficient mice. The results clearly showed a more severe disease in the absence of MCs in a parasitic nematode infection model, with higher larval counts and lower worm expulsion in MC-deficient than in wild-type mice . Other parasitic infection models in the skin such as infestations with larval Haemophysalis longicornis ticks clearly showed an aggravating role when IgE or MCs were absent in experimental animal models . Besides parasitic infection, MCs play important roles against bacterial infections. In the mid-1990s MCs were shown to exert a powerful protective effect in host defense against sepsis . Using the model of bacterial sepsis induced by cecal ligation and puncture, mice-deficient in MCs were found to be highly susceptible to infection and died within a few days, while more than 60% of wild-type mice survived. Further analysis revealed that MC produced TNF, which is rapidly mobilized owing to its presence as a preformed mediator stored in cytoplasmic secretory granules, and is a major protective mediator as neutralizing antibodies abrogated the MC protective effect. However, TNF has also been incriminated in the pathogenesis of sepsis and septic shock. In particular, increasing concentrations and especially persistence of high concentrations of TNF during sepsis have been associated with non-survival. This shows that regulating the inflammatory response is a crucial issue. Given these opposing effects of TNF in the disease process, it is not surprising that strategies aiming to treat sepsis with neutralizing antibodies have essentially failed.

MCs are commonly thought to respond to the presence of toxic products or venoms such as snake or bee venom through the release of tissue-damaging molecules that can sometimes lead to the induction of anaphylactic shock. However, a recent study has made clear that by responding strongly they might also participate in detoxification. Indeed, MC-released proteases, in particular MC-CPA, were shown to cleave and neutralize the major toxins of snake or bee venoms, or otherwise diminish the toxins’ adverse effects . A similar finding also reports the neutralization of endogenously produced endothelin-1 by MC-CPA . These results clearly provide evidence for the physiological function of anaphylactic responses. They call for a rethinking of the associated pathology where systemic distribution of venom may cause anaphylactic shock only in susceptible individuals that are unable to control the systemic activation of MCs.

Several studies have indicated the important contribution of MCs in tissue repair and remodeling processes in response to injury. An important physiological role of MCs could be clearly demonstrated in an in vivo model of healing of skin wounds . Wound closure was significantly impaired in MC-deficient mice. Histomorphometric analyses of MC degranulation at the wound edges revealed distance-dependent MC activation, with MC degranulation being most prominent directly adjacent to the wound. As a consequence, recruitment of other inflammatory cells important for the repair process was promoted, with histamine being an important mediator, as inhibition with the selective histamine H ₁ -receptor antagonist resulted in significantly delayed skin wound closure.

MCs also participate in hair follicle cycling, a process requiring substantial architectural changes in the skin including proteolysis, angiogenesis and nerve supply rearrangements. Indeed, MC-deficient mice exhibit markedly reduced cycling efficiency . Along the same line, it was found that MCs participate in bone remodeling. MC-deficient mutants when subjected to an induced cycle of bone remodeling showed a delayed onset of the remodeling cycle, a decreased duration and extent of the active formation phase as well as diminished new bone matrix synthesis . This probably involves a paracrine mechanism, which influences osteoclast and osteoblast activity. Indeed, histamine was shown to influence the early rapid phase of osteoclast activation during bone remodeling .

Mast Cells as Regulators of Immune and Inflammatory Reactions

Immune cell infiltration is generally considered as being causally linked to disease progression and chronicity. Only recently has it become clear that immune cells can also participate in the resolution of inflammation, imposing a highly dynamic view of the inherent processes. For example, the capacity to shift macrophages from a proinflammatory M1 to an anti-inflammatory M2 phenotype, the production of anti-inflammatory cytokines or the activation of regulatory cells, i.e. regulatory T cells, may represent important responsive mechanisms of the organism to resolve injury . Likewise, MCs are able to produce and release a wide range of inflammatory compounds. In general, these are proinflammatory and constitute a necessary response to fight infections or eliminate injury-promoting products. They involve the recruitment, maturation and function of other immune effectors as shown in the model of bacterial sepsis , the upregulation of adhesion molecules, for example by secretion of TNF , the initiation of tissue responses such as bronchial smooth muscle contraction by LTC ₄ , the degradation of endogenous or exogenous toxins , and the activation of T-cell responses, for example by performing adjuvant functions . Yet, there is also an increasing awareness that MCs have also many immunomodulatory and even immunosuppressive functions. For example, it is known that by the secretion of Th2-promoting cytokines (IL-4, IL-13) they can promote the production of IgE, interact with T cells for antigen presentation and generally influence the migration, maturation or differentiation and function of other immune effectors by the secretion of numerous immunomodulatory cytokines and chemokines. The first evidence for immunosuppressive functions has come from studies of contact hypersensitivity responses to ultraviolet B (UVB) light in the skin, where it was shown that skin MCs mediate UVB light-induced suppression of contact hypersensitivity induced by a hapten, an effect that is mediated by histamine . More recently, MCs were also shown to suppress contact dermatitis induced by urashiol and chronic irradiation with UVB light and therefore contribute to the resolution of inflammation. It was further shown that IL-10 was importantly contributing to the immunosuppressive function, as reconstitution of MC-deficient mice with MCs from IL-10-deficient mice could not restore the immunosuppressive function, in contrast to the reconstitution with wild-type MCs. Furthermore, MCs were also shown to represent essential intermediates in promoting peripheral tolerance by regulatory T cells in a mouse skin allograft model. This was dependent on IL-9, a cytokine produced by Treg to recruit immunosuppressive MCs . It is not known how MCs contribute to immunosuppression in this model, but it could involve the mutual interaction between these cells to enhance their immunosuppressive functions .

Inflammation and Kidney Diseases: A Regenerative Perspective

Kidney diseases are initiated by an injury that can be at the level of either the glomerular, the renal vascular or the tubulointerstitial compartment. The immediate consequence is the initiation of a multistep process with a well-orchestrated succession of events that can be caricatured as four phases that may also happen at least in part in parallel: an inflammatory phase, an anti-inflammatory phase, a repair phase and a regeneration phase ( Fig. 6.3 ). The initial injury is followed by an inflammatory phase predominating in the targeted renal compartment. It is characterized by the release of inflammatory products resulting in increased vascular permeability through activation of endothelial cells followed by leukocyte infiltration including MCs. At the same time kidney-resident cells including mesangial cells, tubular cells and fibroblasts become activated. This inflammatory step is followed by an anti-inflammatory phase that is tightly associated with the initiation of a repair process and even regeneration in some cases. Together these events aim towards the healing of local tissue damage, involving a highly dynamic and complex process that includes, in addition to the infiltrative cells already present from the inflammatory phase, the proliferation of kidney-resident cells and even the putative colonization and differentiation of medullary multipotent stem cells in kidney-resident cells, apoptosis of infiltrative and damaged resident cells, extracellular matrix (ECM) expansion and tissue remodeling, as well as activation of profibrotic cells such as myofibroblasts for local scar formation, which is eventually limited by antifibrotic processes . Ideally, inflammation will resolve without scarring with restoration of tissue structure and function as has, for example, been observed after acute ischemic injury . Resolution of inflammation requires removal of the initiating stimulus, dissipation of mediators and the cessation of cell infiltration. It is accompanied by the clearance of inflammatory cells by migration and apoptosis and by activation of proteases to restore the ECM in its original form. As the inflammatory episode may have led to the loss of renal parenchyma and its replacement by extensive fibrosis, adaptive processes may follow through structural hypertrophy and eventually also regenerative mechanisms. For example, in human renal diseases treatment with Ang II receptor blockers or angiotensin-converting enzyme (ACE) inhibitors can slow down fibrosis development, probably as a result of the disease progression over years leading to irreversible destruction of renal parenchyma. However, it has become clear from animal studies that an early fibrotic process is reversible in several models of progressive renal disease using ACE inhibition or inhibition of Ang II receptors, clearly indicating the regenerative potential of kidneys . Furthermore, cell-tracing studies have demonstrated regeneration and transdifferentiation potential following injury, although the type of cell, intrarenal, hematopoietic lineage marrow cells (HLMCs), mesenchymal stem cells (MSCs) or macrophages, seems to be somewhat a matter of debate and also depends on the experimental model used . In postischemic kidneys, following reparation, almost normal renal histology and function is restored . In case the inflammation does not resolve owing to the persistence of the initiating insult or inadequate regulation, iterative cycles of repair take place, augmenting the risk of being incomplete, and thereby further increasing the risk of persistent injury with nephron and vessel loss and replacement by fibrotic tissue. Although the human kidney can sustain the destruction of a certain number of nephrons, end-stage renal disease will inevitably develop when more than two-thirds of the renal parenchyma is lost.

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