The New Perspective Mast Cells in Gastrointestinal Disease

The New Perspective Mast Cells in Gastrointestinal Disease

Widodo Judarwanto. Children Allergy Online Clinic, Jakarta Indonesia

The function of mast cells in allergic inflammatory reactions is well documented in the literature. Mast cells also play an important role in the regulation of gastrointestinal visceral sensitivity and vascular permeability. Several studies have noted an increased number of mast cells in the mucosa of patients with gastrointestinal diseases such as irritable bowel syndrome, mastocytic enterocolitis, and systemic mastocytosis. The role of mast cells in the symptomatology of these and other diseases has only recently been fully appreciated and could provide avenues for new therapeutic opportunities. Mast cells are metachromatic cells found widely throughout the body. In gastrointestinal tract they reside particularly in mucosa having close contact with external environment. Their certain role in health and disease remains unclear. Mast cells seem to be involved in lots of allergenic and non-allergenic inflammatory events taking place throughout the gastrointestinal tract including IgE-dependent hypersensitivity reaction, gastritis with or without Helicobacter pylori infection, Crohn’s disease, ulcerative colitis, irritable bowel syndrome.

The gastrointestinal tract is a rich source of mast cells with an enormous surface area that permits a high degree of interaction between the mast cell and the intestinal contents. The active metabolic products of the mast cell influence gastrointestinal secretion, absorption, and motility through paracrine effects of local mast cell activation and also cause systemic effects through the release of cellular products into the bloodstream. Recent advances in our knowledge of the immune system and the recognition that the gastrointestinal immune function might be partially mediated through gastrointestinal mucosal mast cells has opened mast cell research to the field of gastroenterology. Local gastrointestinal proliferation of mast cells in response to recognized or obscure stimuli can alter gastrointestinal function and induce systemic symptoms. Symptoms can arise from the increased number of mast cells, overproduction of specific mast cell mediators, and hyperactivity of the enteric nervous system that induces mast cell activation. The diseases mentioned represent a small proportion of areas where mast cell function might play an important role in the response to disease and generation of symptoms.

The morphology and functions of gastrointestinal mast cells (MCs) under physiological and pathological conditions were described. Special attention was paid to the MCs origin, differentiation and morphological and biochemical aspects of their degranulation. Mast cells are important component of normal architecture of the gastrointestinal tract. Many substances released from MCs during degranulation are biologically active and mediate numerous processes: blood flow regulation, epithelial and endothelial permeability, mucosal secretion, gastrointestinal tract motility, immunological events related to the antigens of various origin, angiogenesis, cancer development. Thus MC is often considered as an important agent in pathogenesis of many gastrointestinal diseases. The gastrointestinal diseases which was described in this paper are following: bacterial and parasitic infections, peptic ulcer, ulcerative colitis, Leśniowski-Crohn’s disease, inflammatory polyps, intestinal graft-versus-host reaction, neoplastic tumors, mastocytosis, intestinal ischemia.

The role of the mast cell in clinical gastrointestinal disease with special reference to systemic mastocytosis.

The gastrointestinal tract is a rich source of mast cells with an enormous surface area that permits a high degree of interaction between the mast cell and intestinal luminal contents. The active metabolic products of the mast cell influence gastrointestinal secretion, absorption, and motility through paracrine effects of local mast cell degranulation and also cause systemic effects through the release of cellular products into the blood stream. Systemic mastocytosis influences physiologic function through the systemic effects of mast cell products released from focal (e.g., bone marrow) or wide spread increases in mast cell number. Local gastrointestinal proliferation of mast cells in response to recognized (e.g., gluten in celiac sprue) or obscure stimuli can alter gastrointestinal function and induce systemic symptoms. Celiac sprue, inflammatory bowel disease, and non-ulcer dyspepsia are three examples of gastrointestinal diseases in which mast cells can be implicated in the pathophysiology of the symptoms

Functional gastrointestinal disorders (FGIDs) are common and currently defined by a symptom-based classification with no discernable pathology. In functional dyspepsia (FD), the duodenum is now implicated as a key area where symptoms originate.This is attributed to immune activation with increasing evidence indicating a role for duodenal eosinophilia. In irritable bowel syndrome (IBS), mastocytosis has been documented throughout the small and large intestine. Eosinophils and mast cells are an important link between innate and adaptive immunity, and are important in allergic type TH2 inflammation. Eosinophils may give rise to symptoms due to release of preformed cytokine proteins, which trigger neural excitation, muscle spasm, and pain. The close relationship of mast cells to nerves in IBS may similarly give rise to symptoms. Genetic studies also support of the role of innate immunity in FGIDs. The data supporting a prime role for eosinophils and mast cells in subsets of FD and IBS has become credible, and these data should be used to implement advances in diagnosis and therapeutic trials.

Cross-talk between the immune- and nervous-system is considered an important biological process in health and disease. Because mast cells are often strategically placed between nerves and surrounding (immune)-cells they may function as important intermediate cells. The current knowledge on bidirectional interaction between mast cells and nerves and its possible relevance in (inflammation-induced) increased nociception. Mast cell mediators involved in sensitization of TRP channels, thereby contributing to nociception, as well as neuron-released neuropeptides and their effects on mast cell activation.

Mast cells have an important immunoregulatory function, particularly at the mucosal border between the body and the environment. Due to the gastrointestinal tract’s large interface with the environment, mast-cell overproduction or overactivation can lead to gastrointestinal disorders. These cells have been found to play an increasingly important role in the pathophysiology of gastrointestinal diseases. This changing paradigm may lead to new therapeutic opportunities for several chronic digestive conditions.

Mast cells may play a common but, heretofore, underappreciated role in gastrointestinal diseases and thus recommend that patients with chronic unexplained diarrhea undergo colo-noscopic biopsies with special mast-cell stains.

Mast cells may be regarded as prototypes of innate immune cells that can be controlled by neuronal mediators. Their activation has been implicated in many types of neuro-inflammatory responses, and related disturbances of gut motility, via direct or indirect mechanisms that involve several mechanisms relevant to disease pathogenesis such as changes in epithelial barrier function or activation of adaptive or innate immune responses. The evidence for the involvement of mast cells in the inflammation of the bowel wall caused by bowel manipulation that leads to motility disturbances such as postoperative gastroparesis and ileus. Also in IBD there is substantial evidence for the involvement of mast cells and a mast cell-mediated neuroimmune interaction showing an increased number and an increased degranulation of mast cells. The potential of mast cell inhibition as a bona fide drug target to relief postoperative ileus. Further research on mast cell-related therapy either by stabilizing the mast cells or by blocking specific mast cell mediators as adjunctive therapy in IBD is encouraged, bearing in mind that several drugs currently used in the treatment of IBD possess properties affecting mast cell activities.

Interactions between intestinal mast cells, enteric neurons and visceral afferents which are part of the gut brain axis. The relevance of the mast cell-nerve axis in the human intestine. Similarities and important differences in the organization of the mast cell-nerve axis between human and rodents are discussed. Functionally important human mast cell mediators with neural actions in the human ENS are histamine (H1-4 receptors), proteases (PAR1 receptors), several cytokines and chemokines and probably also serotonin (5-HT(3) receptors). On the other hand, mediator release from human intestinal mast cells is modulated by neuropeptides released from enteric and visceral afferent nerves

Immunology of Mast Cells
Mast cells express surface receptors for fragment crystallizable portions of immunoglobulin (Ig)E and certain classes of IgG that enable the binding of antibodies to the cell surface. The introduction of an antigen causes a mast-cell granulated release of numerous inflammatory mediators such as histamine and serotonin. Several enzymes are also released, including cytokines and proteases, which are crucial to allergic reactions and anaphylactic-type responses. Once a genetically susceptible individual is sensitized to a given allergen and an IgE antibody forms, subsequent exposure to this allergen induces the manifestation of atopic disease. This reaction may be attenuated by the use of medications that inhibit the release of mast-cell mediators, called mast-cell stabilizers, or the actions of mediators such as antihistamines.

As mast cells have an important function in innate immunity, they are able to respond to bacterial and parasitic infections via secretion of their mediators and thus achieve optimal induction of inflammatory and adaptive immune responses. Recent evidence has found that mast cells may play a role in the last-phase response and chronic remodeling of mucosal tissue, as histamine and tryptase have been shown to stimulate fibroblast growth in vitro and in vivo.

Mast cells can be found throughout normal connective tissue, often next to blood vessels or nerves or beneath epithelial surfaces, where these cells are exposed to the environment via the respiratory and gastrointestinal tracts. For example, mast cells located next to venules could influence the entry of foreign substances due to their fast response. Histamine and lipid mediators also affect vascular permeability, enabling a local influx of plasma proteins such as complement and immunoglobu-lins. Within these different anatomical sites, mast cells can vary widely in terms of their ability to respond to stimuli, responsiveness, and mediator content.

The mast cell and mast cell disease.

Mast cell disease or mastocytosis is a heterogeneous group of clinical disorders characterized by the proliferation and accumulation of mast cells in a variety of tissues, most often the skin. The signs and symptoms of mast cell disease are varied, dependent on the localization of mast cells in different organs and the local and systemic effects of mediators released from these cells. Although mast cell disease is most commonly identified in the skin, involvement of the skeletal, hematopoietic, gastrointestinal, cardiopulmonary, and central nervous systems may be seen. Clinical management of mastocytosis depends most heavily on knowledge of the diverse effects of mast cell mediators on various tissues and organs, the stimuli that can cause their release, and the different methods available for blocking the effects of these mediators.

Mastocytosis represents a spectrum of clinical disorders that results from an aberrant proliferation of tissue mast cells. This disease process may be confined to the skin (cutaneous mastocytosis) or may involve multiple organs (systemic mastocytosis). Parameters that are useful in differentiating cutaneous from systemic disorders include patient age, symptom complex, and clinical signs. A wide range of clinical symptoms may be encountered in patients with mastocytosis which result from the release of pharmacologically potent mast cell mediators. Distinct cutaneous patterns resulting from skin mast cell infiltrates can be helpful in identifying patients with systemic involvement. The diagnosis of mastocytosis is confirmed by demonstrating increased tissue mast cells in involved organs. The overall prognosis for patients with proliferative mast cell disease is relatively good, although a small percentage are at risk for developing a fatal neoplastic disorder (malignant mastocytosis). Treatment of mastocytosis is directed at both inhibiting mast cell degranulation and blocking the potential systemic effects of released secretory products. Future therapeutic advances depend upon an improved understanding of the basic mechanisms involved in mast cell mediator release and the forces that govern mast cell growth and development.

Gastrointestinal Physiology and Mast-Cell Function
The number of mast cells at a given site can vary, depending upon the location and immunologic status of the host. Mast cells comprise 2–5% of mononuclear cells in the lamina propria of the normal gastrointestinal tract, representing an average of cells per high-power field in the duodenum and colon.5,6 Previous studies have documented an increased number of mast cells in gastrointestinal mucosa tissue samples from patients with gastrointestinal diseases such as irritable bowel syndrome.

Mast cells are preferentially located next to nerve terminals in the lamina propria, where they are activated by secreted neuropeptides such as substance P. When stimulated by substance P, these mast cells release inflam-matory mediators, such as serotonin and proteases, as well as proinflammatory cytokines. Other mediators are important for the function and regulation of the gastrointestinal tract. For example, the release of histamine and prostaglandin D2 is important for chloride and water secretion as well as control of intestinal motility.

Due to their location, mast cells may play a role in visceral sensitivity. Reaction from motor neurons secondary to degranulation can result in hypersecretion and power propulsion, causing diarrhea and abdominal pain. Mediators released by mast-cell degranulation also sensitize silent nocireceptors in the large intestine. This mechanism has been demonstrated in animal models in which degranulation of mast cells resulted in a reduced threshold for pain, with rectal distension that could be prevented by treatment with mast-cell stabilizing drugs.10 Receptors for mast-cell mediators are also found on vagal and spinal sensory afferent neurons, which could likewise contribute to abdominal pain. Mast cells are also affected by both acute and chronic stress. Anatomic connections between mast cells and enteric nerve fibers have been demonstrated in human gastrointestinal mucosa and are known to increase with inflammation.

The mast cell–enteric nerve association provides a physiologic means for bidirectional communication between the central nervous system and intestinal tract through which stress may influence gastrointestinal function. As stress has been shown to induce mast-cell activation, mediators released secondary to an external stressor may affect motility, visceral sensitivity, and gut barrier function.

Evaluation Clinical and laboratory

Histologic evaluation, determination of enzyme activity, and allergy testing may aid in the investigation of conditions with a suspected mast-cell etiology. Endoscopic biopsies of the stomach, small bowel, and colon can help to determine whether the number of mast cells in the mucosa has increased. Except for urticaria pigmentosa (fixed reddish brown maculopapular lesions) and cutaneous mastocytosis, mast-cell biopsy findings are difficult to identify via standard hematoxylin and eosin staining, and in many cases, specific pathologic features such as crypt distortion, mucin depletion, cryptitis, abscesses, granulomas, thickened collagen bands, shortened villi, or excessive eosinophils/lympocytes

The excess of mast cells can be evaluated via immunohistochemical analysis for CD117, mast-cell tryptase, or Giemsa staining. Many patients with mast cell–induced gastrointestinal disease may be missed if these stains are not used.

As the role of mast cells in the pathology of gastrointestinal disease is still evolving, no specific criteria currently exist for diagnosis. One study suggested a cutoff of mast cells per high-power field within the lamina propria, as this value is. standard deviations above the normal value found in the general population; however, other studies have not supported this cutoff. Criteria for the diagnosis of systemic mastocytosis specify a value of mast-cell aggregates in an extracutaneous organ, as mast cells are often found in confluent sheets and aggregates of over 100 cells per high-power field. Other studies have suggested that the number of appreciated cells can be affected by the fixing or staining technique. Mast cells in the lamina propria, other gastrointestinal findings in systemic mastocytosis include eosinophil infiltrates and architectural changes such as the broadening and flattening of villi in the small bowel and changes in crypt size, shape, and space in the colon.

The presence of serum tryptase levels persistently over 20 ng/mL may also aid in the diagnosis of mast-cell disease. This value is a minor criterion for diagnosis of systemic mastocytosis due to the usual increase in tryptase levels in systemic disease; however, this enzyme may not be as elevated in focal gastrointestinal conditions such as irritable bowel syndrome. Jejunal aspirates have been evaluated for increased levels of tryptase in patients with various numbers of mucosal mast cells, but no correlation has been found between the number of mucosal mast cells and the levels of luminal tryptase detected.

Allergy assessment with skin prick tests or radio-allergosorbent tests (RASTs) followed by an exclusion diet based upon these results is warranted for suspected IgE-mediated gastrointestinal symptoms. These tests can often be misleading due to their significant number of false-positive and false-negative results. In a study of symptomatic patients with endoscopically proven mucosal changes to certain food allergens, only 46% of patients had positive skin tests and only 50% had positive RASTs.

Mast Cells in Gastrointestinal Disease

Gastrointestinal Food Allergy

Mast cells are important in food allergies. Sensitivity to glycoproteins in food is caused by a series of interactions among T cells, B cells, antigen-presenting cells, and mast cells. Infection or inflammatory processes in the gastrointestinal tract can lead to increased intestinal permeability, which causes antigens to bypass the normal route of presentation to columnar intestinal epithelial cells and allows for allergic sensitization as antigens reach IgE antibodies bound to mast cells. These reactions lead to symptoms such as shock, rash, angioedema, pruritus, vomiting, and diarrhea. Endoscopic observation has revealed local vasodilatation, edema, mucus secretion, and petechial hemorrhage. One such study evaluated patients with food allergies 30 minutes after placing a known allergen on gastric mucosa. These patients had a significant number of hyperemic and edematous patches of thick gray mucus and scattered petechiae at this site. An IgE-mediated mechanism was suggested for this reaction. Studies have demonstrated the presence of food-specific IgE antibodies and an increased number of intestinal mast cells compared to normal controls prior to the challenge; following the food challenge, a decreased number of stainable mast cells and a decreased amount of tissue histamine were observed.

Diarrhea-Predominant Irritable Bowel Syndrome

The prevalence of irritable bowel syndrome in the adult population ranges from 3% to 20%.bAlthough the prevalence of this condition is rising, its etiology remains unclear. Diagnosis of irritable bowel syndrome depends upon the presence of altered bowel habits and abdominal pain as well as the exclusion of other conditions. Treatment is predominately based upon symptom control. Studies such as the one conducted by Jakate and associates highlight the possibility that a subset of patients with diarrhea-predominant irritable bowel syndrome may have increased numbers of mast cells. This finding could theoretically transform the paradigm of diarrhea-predominant irritable bowel syndrome.

Increased numbers of mast cells have been found in the cecum, terminal ileum, and jejunum of patients with irritable bowel syndrome in several studies.
However, other studies have demonstrated normal numbers of mast cells in irritable bowel syndrome patients; Hahn and Hornick evaluated the concentration of mast cells in patients with irritable bowel syndrome and did not find a significant increase in terminal ileal and colonic biopsies. If the number of mast cells is increased, the effect of mast-cell mediators on the gastrointestinal tract could explain the symptomatology of diarrhea-predominant irritable bowel syndrome. Animal studies have shown that increased numbers of intestinal mast cells are associated with intestinal hypermotility caused by food allergies.

Mast-cell mediators released after degranulation can also sensitize nociceptors in the intestine. Mast-cell trypt-ase and histamine can activate enteric nerves, resulting in neuronal hyperexcitability. The sensitization of noci-ceptors due to mast-cell degranulation could play a role in abdominal pain among patients with irritable bowel syndrome. Psychological factors appear to play a role in increased colonic mast-cell concentration. Human studies have shown increased mast-cell colonic concentration in irritable bowel syndrome patients with high depression and fatigue scores. This finding suggests that mast cell– inducing psychological factors may play a causal role in symptoms of irritable bowel syndrome.

Although not accepted by all gastroenterologists, the term mastocytic enterocolitis was coined by Jakate and coworkers to describe an increase in mucosal mast cells in patients with chronic diarrhea. The researchers assessed mucosal mast cells in patients with chronic functional diarrhea and normal-appearing biopsies via hematoxylin and eosin stains. Biopsy samples were obtained from the colon, duodenum, or both. Samples were compared to control patients who underwent biopsies to evaluate gastro-duodenal complaints not involving diarrhea. In addition, specimens were compared to biopsies from patients with specific gastrointestinal conditions causing diarrhea (eg, collagenous colitis, Crohn’s colitis, celiac disease). All biopsies were stained for mast-cell tryptase by immuno-histochemical analysis. The mean standard deviation of the concentration of mast cells per high-power field in the control patients, compared in the study group and in the group with spe-cific diarrheal conditions. Increased numbers of mast cells were found in 33 of the 47 patients with chronic functional diarrhea (70%). Symptoms were controlled in 22 of the 33 patients treated with antihistamine H1 blockers.6 Similarly, a case report of a young woman with bloody diarrhea who had increased numbers of mucosal mast cells in colonic biopsies was cited in the allergy literature. Her symptoms improved with oral cromolyn and balsalazide therapy, though she was later lost to follow-up.

Both this case study and the study by Jakate and colleagues indicate that the predominant symptoms were diarrhea and abdominal pain. In the study conducted by Jakate and associates, 21 of the 47 patients (45%) experienced abdominal pain.
Although the exact cause of increased numbers of mast cells in chronic diarrhea is unknown, it is thought to be a response to immunologic stimuli causing a brain-gut interaction. Jakate and colleagues measured serum tryptase levels in 3 patients and found no elevation, which implied localized mucosal mast-cell infiltration rather than systemic mastocytosis. The diagnosis of mastocytic enterocolitis was not made with routine hematoxylin and eosin or Toluidine blue staining. Immunostaining for mast-cell tryptase revealed intracytoplasmic brown stains highly specific for mast cells.

All patients with unexplained diarrhea, abdominal pain, normal endoscopies, and unremarkable biopsies via hematoxylin and eosin stains may benefit from further evaluation for mastocytic enterocolitis. Additional evaluation will be required to confirm mastocytic enterocolitis as a true entity separate from diarrhea-predominant irritable bowel syndrome.

Accumulation of mast cells and macrophages in focal active gastritis of patients with Crohn’s disease.

Recent studies have shown that focal active gastritis seems to be the typical gastric pathology in Crohn’s disease. Furusu H reported that to compare the incidence of focal active gastritis, Helicobacter pylori infection and distribution of gastric mast cells and macrophages in patients with Crohn’s disease, ulcerative colitis and H. pylori gastritis without inflammatory bowel disease. Patients with histologically confirmed Crohn’s disease or ulcerative colitis  and control patients without inflammatory bowel disease were included in this study. Biopsy specimens were obtained from the antrum and corpus of each patient, and stained with hematoxylin and eosin and immunostained using antibodies to tryptase (AA1) and CD68. The number of mast cells and macrophages located in the lamina propria was determined.

Focal active gastritis was detected in 54% of H. pylori-negative patients with Crohn’s disease, but it was not found in patients with ulcerative colitis nor in the control group. The density of mast cells and macrophages in the lamina propria of H. pylori-positive patients was significantly higher than in H. pylori-negative patients in all groups. In the Crohn’s disease group, the number of mast cells and macrophages  in the lamina propria of H. pylori-negative patients with focal active gastritis was halfway between that in H. pylori-positive and H. pylori-negative patients. In focal active gastritis, mast cells accumulated at the border of focal active gastritis, whereas macrophages accumulated in the center of such lesions.

The diagnosis of focal active gastritis, using immunostain for mast cells and macrophages, is the histological hallmark of gastric Crohn’s disease. Macrophages might be associated with the formation of focal active gastritis in patients with Crohn’s disease.

Different distribution of mast cells and macrophages in colonic mucosa of collagenous colitis and inflammatory bowel disease.

Chronic inflammatory cells in colonic mucosa is a histopathologic feature in patients with collagenous colitis and inflammatory bowel disease. The aim of this study was to compare the distribution of mast cells and macrophages in the colonic mucosa of patients with collagenous colitis, Crohn’s disease, and ulcerative colitis.

Patients with histologically confirmed collagenous colitis, Crohn’s disease or ulcerative colitis and normal control patients were included in this study. Biopsy specimens were obtained from the sigmoid colon of each patient, and immunostained using antibodies to tryptase (AA1) and CD68. The number of mast cells and macrophages located in upper and lower part of the lamina propria was determined.

The number of mast cells in the upper part of lamina propria in patients with collagenous colitis, Crohn’s disease and ulcerative colitis, was higher than normal controls. The number of mast cells in the lower part of lamina propria in patients with Crohn’s disease  and ulcerative colitis  was higher than collagenous colitis and normal controls. The number of macrophages in the lower part of lamina propria in patients with Crohn’s disease and ulcerative colitis  was higher than in collagenous colitis and normal controls, although there were no significant differences in the number of macrophages present in the upper part of the lamina propria among the four groups.

The presence of a different distribution of mast cells and macrophages in collagenous colitis and inflammatory bowel disease, and these suggest that because mucosal mast cells have been implicated in the development of Th2 response collagenous colitis is more of a Th2 type reaction rather than Th1.

Systemic Mastocytosis

Mastocytosis is caused by the proliferation of mast cells in various extracutaneous organs. The most commonly involved sites are the liver, spleen, bone marrow, and gastrointestinal tract. Most cases of mastocytosis are associated with a C-KIT mutation and up to 93% involve codon 816 (C-KIT D816V).

Symptoms result from the infiltrated organ and mastcell mediator release and can affect the respiratory, digestive, neuropsychiatric, and hematologic systems. Urticaria pigmentosa is commonly seen in mastocytosis. Mast-cell infiltration can result in organ dysfunction in aggressive systemic mastocytosis (ASM). Gastrointestinal symptoms are present in 60–80% of cases. The most frequent digestive symptoms are abdominal pain and diarrhea. Due to increased histamine production in systemic mastocytosis, symptoms can also include esophagitis, gastric ulcer disease, and intestinal malabsorption.

Mast cells and nerves tickle in the tummy: implications for inflammatory bowel disease and irritable bowel syndrome.

Mast cells are well known as versatile cells capable of releasing and producing a variety of inflammatory mediators upon activation and are often found in close proximity of neurons. In addition, inflammation leads to local activation of neurons resulting in the release neuropeptides, which also play an important immune modulatory role by stimulation of immune cells. In intestinal disorders like inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), the number of mast cells is known to be much higher than in the normal intestine. Moreover, both these disorders are also reported to be associated with alterations in neuropeptide content and in neural innervation.

Mutual association between mast cells and enteric nerves has been demonstrated to be increased in pathophysiological conditions and contribute to spreading and amplification of the response in IBD and IBS. The focus lies on studies appointed to the direct interaction between mast cells and nerves in IBD, IBS, and animal models for these disorders so far.

Mucosal immunology of tolerance and allergy in the gastrointestinal tract.

The mucosal immune system typically exists in a state of active tolerance to food antigens and commensal bacteria. Tolerance to food proteins is induced in part by dendritic cells residing in the intestinal mucosa and implemented by regulatory T cells. Food allergy occurs when immune tolerance is disrupted and a sensitizing immune response characterized by food-specific IgE production occurs instead. Experimental food allergy in mice requires use of adjuvant or exploitation of alternate routes of sensitization to induce allergic sensitization, and can aid in understanding the mechanisms of sensitization to food allergens and the pathophysiology of gastrointestinal manifestations of food allergy.

Diagnosis

Diagnosis of mastocytosis is based upon criteria developed by the World Health Organization. In order to fulfill this criteria, 1 major and 1 minor criterion, or 3 minor criteria, must be met. An example of a major criterion is the presence of more than mast cells per high-power field in an extracutaneous organ. Examples of minor criteria are spindle-shaped cells comprising over 25% of mast-cell infiltrates, detection of the C-KIT D816V mutation, expression of CD2 and CD25 on CD117 mast cells, and a serum tryptase level higher than 20 ng/mL.
Management of systemic mastocytosis includes avoidance of triggers (eg, alcohol, nonsteroidal antiinflammatory drugs) and control of symptoms related to mast-cell mediator release. Cytoreductive therapy is reserved for patients with ASM.

Immunoreactivity for CD25 in gastrointestinal mucosal mast cells is specific for systemic mastocytosis.

Systemic mastocytosis (SM) is characterized by the accumulation of neoplastic mast cells in bone marrow and other organs. Gastrointestinal (GI) symptoms are common in both SM and cutaneous mastocytosis [urticaria pigmentosa (UP)], and are usually caused by the release of histamine and other inflammatory mediators. Occasionally, neoplastic mast cells may also directly infiltrate the GI tract. Previous studies have suggested that enumeration of the mast cells in GI biopsies may help establish the diagnosis of SM. However, mast cells have been reported to be increased in various inflammatory diseases, and mast cell density has not been systematically evaluated in other GI disorders. Recently, expression of CD25 by mast cells in bone marrow has been shown to be specific for SM. The quantitate and compare mast cells in mucosal biopsies from patients with SM involving the GI tract, UP with GI symptoms, and a control group of diverse inflammatory disorders, and to determine whether immunostaining for CD25 can be used to distinguish neoplastic from reactive mast cells in GI biopsies. Seventeen GI biopsies from 6 patients with SM; 17 GI biopsies from 5 patients with UP; and 157 control cases including 10 each normal stomach, duodenum, terminal ileum, and colon, Helicobacter pylori gastritis, bile reflux gastropathy, peptic duodenitis, celiac disease, Crohn disease, ulcerative colitis, lymphocytic colitis, and collagenous colitis, 20 biopsies from 16 patients with irritable bowel syndrome, 8 biopsies from 5 patients with parasitic infections, and 9 biopsies from 7 patients with eosinophilic gastroenteritis were immunostained for mast cell tryptase, c-kit (CD117), and CD25. Mucosal mast cells were quantitated, and the presence or absence of CD25 expression on mast cells was determined. In SM patients, mast cells in the small intestine and colon numbered >100/high-power field (HPF) in nearly all cases.

This was significantly higher than in GI biopsies from UP patients and all inflammatory diseases. Mast cell density in other disorders ranged from a mean of 12/HPF in H. pylori gastritis to 47/HPF in parasitic infections. Interestingly, all SM biopsies (and none of the other cases) contained aggregates or confluent sheets of mast cells. In addition, mast cells in all SM cases were positive for CD25, whereas GI mucosal mast cells in UP and all other control cases were negative. In conclusion, quantitation of mast cells can be helpful to diagnose SM in GI mucosal biopsies, although mast cells are also markedly increased in parasitic infections. Aggregates or sheets of mast cells are only seen in SM. Immunoreactivity for CD25 in GI mucosal mast cells is specific for SM and can be used to confirm the diagnosis.

Treatment

Treatments are aimed at stabilizing mast cells and controlling mediator release to prevent symptoms. Therapies to prevent mast-cell infiltration (such as fludarabine and interferon) have been used in ASM. Newer treatments with tyrosine kinase inhibitors have also been discussed to target the C-KIT mutation associated with ASM.

  • Antihistamines H2 antihistamines are targeted to decrease hypersecretion of gastric acid and can be helpful for treating the gastrointestinal symptoms of diarrhea and abdominal cramping. Ranitidine 150 mg orally every 12 hours or famotidine 10 mg orally every 12 hours can be used. H1 antihistamines can control flushing and pruritis.26 Patients evaluated in the study by Jakate and coworkers showed significant symptom improvement with H1 and H2 antihistamines.
  • Cromolyn An inhibitor of mast-cell degradation, cro-molyn can be used at a dose of 100–200 mg orally 4 times per day. Small studies have shown improvement in gastrointestinal symptoms with cromolyn therapy. In a large multicenter trial evaluating diarrhea-predominant irritable bowel syndrome patients, oral cromolyn was compared to elimination diet. Symptom improvement was seen in 67% of patients treated with oral cromolynsodium (1,500 mg/day) for 1 month compared to 60% of patients treated with elimination diet.
  • Antileukotriene Drugs Although antileukotriene drugs such as montelukast may cause abdominal pain, they have shown improvements in pruritus and flushing.
  • Budesonide If the aforementioned, targeted therapies fail, 9 mg daily of oral budesonide can be used as an alternative treatment.16
    Exclusion Diet As food allergies have been proposed in the pathogenesis of irritable bowel syndrome, patients with mast-cell infiltration may benefit from allergy testing and exclusion diets.21 The role of non-IgE delayed type 4 reaction is unclear in gastrointestinal food allergies. Diagnosing specific gastrointestinal food allergies is difficult, as IgE immediate type 1 reaction is rare. Methods such as skin prick tests and RASTs for IgE suggest that sensitization to certain allergens may develop. However, a positive test implies a food allergy without a clinical reaction.
  • A 2-week diet excluding certain foods should be adequate to assess response. Gradual reintroduction of foods accompanied by the development of symptoms suggests the presence of trigger foods. A meta-analysis reviewing 7 studies of elimination diets in patients with irritable bowel syndrome suggested that milk, wheat, eggs, and foods high in salicylates or amines consistently exacerbated symptoms.
  • Desensitization injections have been evaluated as a possible treatment, but inadequate evidence exists in IgE-medicated reactions to support their effectiveness.

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