Immunophysiology of the Gut

Gelb

Preface

This book is the result of an effort by the organizing committee, with the support of Bristol–Myers Squibb/Mead Johnson, to bring together an internationally known group of mucosal immunologists, intestinal physiologists, and enteric neurophysiologists for a symposium entitled Immunophysiology of the Gut. This book, representing the collective research efforts of many individuals, attempts to integrate the mucosal immune system and intestinal physiology. In the past 15 years, the factors controlling mucosal immune responses have been defined more precisely. From these studies, it became apparent that various cytokines released from lymphoid tissues were involved in these complex immunologic responses. Cytokines were also found to have direct effects on intestinal epithelial cell function. Thus, cytokines not only regulate the maturation and function of immunologic cells, they also can influence intestinal mucus secretion, fluid and electrolyte absorption, and intestinal smooth muscle contractility. Presumably this comprehensive response to antigenic stimuli is nature’s way of protecting the intestinal epithelial surface from microorganisms, bacterial toxins, and foreign antigens.

An appreciation of these immune/physiologic interactions developed as intestinal physiologists and neurophysiologists began to identify a modulating role of intestinal hormones and neurotransmitters on mucosal immune responses. These secreted factors not only affect epithelial function and smooth muscle contraction, but also participate in the recruitment, maturation, and activation of lymphoid elements. This interrelationship between intestinal physiology and mucosal immunology became officially recognized and termed immunophysiology of the gut by Professor Gilbert Castro at the University of Texas in Houston. Since Dr. Castro’s initial review (G. A. Castro, 1982, Am. J. Physiol. 243, G321—G329), many new interactions between the enteric nervous system and the mucosal immune system have been noted. In addition, it is now apparent that nutrition can also play a role in neuroimmunophysiology of the gut. Micronutrients can affect intestinal bacterial colonization, act as foreign antigens, and stimulate enteric hormone release. Also, nutritional status can play an important role in intestinal immune and epithelial cell function and in the pathophysiology of gut inflammation.

In order to underscore the importance of this area of research, experts from the disciplines of mucosal immunology, intestinal physiology, and enteric neurophysiology were brought together to provide a review of their areas of expertise as well as their current research. Consequently, this monograph represents the first comprehensive and systematic coverage of the immunophysiology of the gut. The editors hope that this book will serve as a major information resource for this exciting and rapidly expanding field.

W. Allan Walker, Paul R. Harmatz and Barry K. Wershil

Part I

Immunophysiology of the Gut

Outline

Chapter 1: Introduction to Immunophysiology of the Gut

Chapter 2: Immunological Regulation of Epithelial Function

Chapter 3: Mesenchymal-Epithelial Interactions: The Subepithelial Fibroblastic Sheath as a Paracrine Modulator of Inflammation-Induced Intestinal Secretion

Chapter 4: Immune Regulation of Intestinal Arachidonic Acid Metabolism: Effects on Intestinal Water and Electrolyte Transport

Chapter 5: Gastrointestinal Anaphylaxis: Effect on Gastric and Intestinal Function

Chapter 6: Acute and Chronic Control of Colonic Chloride Secretion by Mast Cell Mediators

Introduction to Immunophysiology of the Gut

W. Allan Walker,     Mucosal Immunology Laboratory, Combined Program in Pediatric Gastroenterology and Nutrition, Children’s Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

As mentioned in the preface of this book, an important new area of research in mucosal immunology has developed over the last two decades that provides evidence that mucosal immune responses modulate gastrointestinal epithelial functions and provide a collective host defense against microorganisms and antigens crossing the intestinal epithelium from the luminal cavity. Gilbert Castro, the author of the first chapter in this section, was the first investigator to coin the term immunophysiology of the gut. His original work in this area involved the interaction of parasites infesting the intestine with increased numbers of mucosal mast cells that occur as a result of infection (Harai et al., 1987). He postulated that mediators released from these activated mast cells contributed to the epithelial changes associated with parasitic infestation (fluid secretion, mucus release, and increased peristalsis). Since this observation was made, others made by investigators such as Bloch and Walker (Walker et al., 1975; Lake et al., 1979), Bienenstock (Stead et al., 1989), Gall (Perdue and Gall, 1986; Scott et al., 1988), and Barrett (Wasserman et al., 1988) have further demonstrated an association between immunologic responses and intestinal function such as mucus secretion, myenteric plexus stimulus (enhanced peristalsis), and fluid and electrolyte secretion. In addition, a much clearer understanding of mucosal immune responses at the intestinal surface has evolved. For example, lymphoid cells (T cells and B cells) have been characterized and their specific function determined. The distribution of such cells within the lamina propria and intraepithelial spaces has been determined and the presumed function of these cells in the mucosal immune response demonstrated (Kagnoff, 1989), and factors affecting the migration of lymphoid and inflammatory cells to the gut have been identified. Furthermore, the roles of lymphokines in these processes are now better understood (Strober and James, 1987). In addition, a better understanding of antigen uptake across the specialized follicular intestinal epithelium (microfold cell) and of antigen processing by lymphoid cells within Peyer’s patches has explained the specific secretory immunoglobulin A (IgA) response by plasma cells in the lamina propria of the small and large intestine to luminal antigens. These advances in our understanding of mucosal immune responses at the cellular and molecular level have been matched by major advances in intestinal epithelial cell biology and a better understanding of mechanisms of intestinal secretion and fluid absorption (Sullivan and Field, 1991). We also have a better appreciation for the enterocyte’s interaction with external stimuli mediated by membrane receptors and signal transduction interactions (Brown, 1991). With the simultaneous expansion of our knowledge of gut immunology and epithelial cell biology came the realization that these two processes are intimately connected and each may have a reciprocal effect on the other. This section of the monograph is devoted to an in-depth analysis of exactly how that interrelationship between intestinal immunologic/inflammatory processes and epithelial cell function works. The individual chapters further refine our knowledge of immunophysiology of the gut (Powell, 1991).

In the first chapter, entitled Immunological Regulation of Epithelial Function, Professor Castro brings his background in parasitology to consider a general approach to the subject, which supports the notion that this phenomenon is an interdisciplinary and integrative process. He develops general concepts that demonstrates, unambiguously, that the immune system regulates epithelial function in the gut. The collective evidence for this theme is considered in order to develop generalities and concepts that contribute to our understanding of homeostasis and of disease processes as well as to consider potential applications of [this] new found knowledge. He considers the approaches that have been taken to arrive at these conclusions, including (1) determining the functional effect of inflammatory mediators on gastrointestinal (GI) tissues and (2) determining, in a multiple-step procedure, the effect of antigen applied to immune-sensitized GI tissues on physiologic and pathophysiologic responses that are evoked. These results provide evidence that soluble mediators of activated and stimulated mast cells can affect enterocyte fluid secretion and can also augment neuroendocrine effects on epithelial cell function. Mast cell mediator release can occur with parasitic infestation of the gut or with intestinal anaphylaxis caused by oral exposure of allergen to a presensitized gut. These models have helped define the role of type I, and to some extent types II–IV, hypersensitivity reactions in causing epithelial cell responses.

In the second chapter, entitled Mesenchymal–Epithelial Interactions: The Subepithelial Fibroblastic Sheath as a Paracrine Modulator of Inflammation-Induced Intestinal Secretion, Professor Don W. Powell, an intestinal epithelial cell biologist, with Dr. Helen M. Berschneider, examines the role of prostaglandins (a product of inflammation) on the subepithelial fibroblastic sheath–enterocyte interaction. His approach to this process is that of the physiologist with an acquired interest in mucosal immunology, and therefore he provides a unique insight into immunophysiology of intestinal electrolyte transport. Using Ussing chamber studies to measure electrolyte transport across the colon of experimental animals, Dr. Powell provides evidence that products of the cyclooxygenase pathway can increase net fluid secretion. These effects can be blocked by cyclooxygenase inhibitors, such as indomethacin. The stimulus for increased secretion may be mediated via (1) a receptor-effector (cAMP-mediated) response as with prostaglandin E2 (PGE2), or (2) by activation of enteric nerves (PGI2). He further refines the observation by citing recently generated data that suggest the phenomenon may be a two-step process involving first the fibroblastic sheath surrounding intestinal epithelial cells and second the enterocyte. He suggests that inflammatory mediators released by one cell type (e.g., platelet-activating factors, PAF, elaborated by the mast cell after an IgE-mediated response) might in turn activate another inflammatory cell (e.g., the phagocyte) by virtue of shared cell membrane receptors for that agonist. Furthermore, evidence exists that mesenchymal cells (fibroblasts and endothelial cell) can release mediators that stimulate prostaglandin release from these inflammatory cells, suggesting yet another pathway for electrolyte secretion in enterocytes. These intriguing hypotheses add new dimension to our understanding of immunologic inflammatory-mediated epithelial cell responses.

The next chapter, entitled Immune Regulation of Intestinal Arachidonic Acid Metabolism: Effects on Intestinal Water and Electrolyte Transport, by Drs. Chang and Musch, provides further primary data that support the notion that products of inflammation can affect water and electrolyte transport in the intestine. These authors list the tissues within the intestine capable of secreting arachidonic acid (AA) metabolites. They describe the cellular mechanisms for immune regulation of AA release and metabolism and, finally, using human colon cancer cell lines (T-84, etc.), describe the specific mechanism of action of AA metabolites on intestinal secretion. They also stress that these metabolites can provide (1) a direct stimulus to enterocytes via receptor-effector mechanisms (e.g., cAMP) or (2) an indirect stimulus via enteric nerves and neurotransmitter release. Furthermore, they describe experiments that suggest that AA metabolites, most notably LTB4, may provide chemotactic attraction of inflammatory cells to the intestine. These migrating inflammatory cells may in turn release mediators that directly affect enterocytes or indirectly stimulate further release of AA, providing a vicious cycle response. These same AA metabolites may also alter intestinal blood flow and smooth muscle motility, which further contributes to altered epithelial function and an additional vicious cycle of an ongoing stimulus to further inflammation and chemostasis.

Professor D. Grant Gall, a pediatric gastroenterologist and endocrinologist with a long-standing research interest in intestinal mucosal immune responses to allergens and microorganisms, describes the pathophysiologic basis for intestinal symptoms after anaphylaxis in the chapter entitled Gastrointestinal Anaphylaxis: Effect on Gastric and Intestinal Function. In this chapter, Dr. Gall concentrates on IgE-mediated injury to the stomach and small intestine and suggests that the gastrointestinal response to injury represents an appropriate adaptation to the insult and is not a nonspecific disordered response. He further suggests that the repertoire of responses to injury by the gut is limited and therefore mediated through a few common mechanisms. In an animal model of intestinal anaphylaxis, Dr. Gall describes the gastric response to mucosal anaphylaxis. As a result of allergen stimulus to IgE-mediated mast cell degranulation, acid secretion increases and gastric emptying is delayed. These effects are attributed to histamine release and are viewed as protective of the host by theoretically increasing protein allergen denaturation and delaying allergen release into the small intestine. Using the same animal model, Dr. Gall describes an increase in electrolyte and water secretion into the small intestine and colon. These responses are again attributed to mast cell degranulation and are collectively caused by 5-hydroxytryptamine (5-HT) release acting through type 2 receptors on enterocytes. The 5-HT response is modified by cyclooxygenase and lipooxygenase metabolites and platelet-activating factors. Of interest is the observation that in food-antigen-mediated anaphylaxis, histamine and enteric neuron pathways appear not to contribute to secretion of electrolytes and water. The author also provides direct evidence for altered intestinal myoelectric and motor activity after antigen-mediated anaphylaxis. Finally, he reviews the intestinal response to chronic anaphylaxis. This includes diarrhea, growth failure, ongoing mast cell denaturation, and subtle changes in villous height and crypt depth at the ultrastructural level.

Dr. Kim E. Barrett, an internationally known mast cell biologist, specifically examines mast cell mediator effects on the T84 cell line, in the chapter entitled, Acute and Chronic Control of Colonic Chloride Secretion by Mast Cell Mediators. Dr. Barrett suggests that in addition to the regulatory influences on crypt cell secretion of chloride ion mediated by neurocrine, endocrine, and paracrine systems, the mucosal immune systems can function to modulate epithelial function, and this immune process may be integrated with other regulator processes. Using an in vitro human cancer cell line (T84) to quantitate chloride secretion, Dr. Barrett can best determine the specific role of mast cell mediators in this process. She then provides evidence that mast cell mediators can have a direct effect on enterocyte secretion of Cl– ion. She demonstrates that histamine, adenosine, and the prostaglandin metabolite PGD2 induce chloride secretion of T84 cells. In contrast, leukotrienes, platelet-activating factor, and a number of cytokines had no acute effects on T84 cell chloride secretion, suggesting that these mediators may function in a two-step fashion mediated by an intermediate cell type, such as the fibroblast. She then reviews a variety of intracellular mechanisms for chloride secretion, including a receptor-mediated stimulus of phosphatidylinositol turnover and increased cAMP levels. When presented in combination, mast cell mediators may produce an additional stimulus to Cl– secretion by a different intracellular mediator. In a chronic model of T84 chloride secretion, mast cell mediators vary after secretion by paracellular, as well as transcellular, pathways. Finally, Dr. Barrett discusses the implications of these findings for inflammatory diarrhea. She suggests that mast cell mediators chronically released during inflammation may contribute to diarrheal symptoms associated with other regulatory processes.

REFERENCES

Brown, A.M. FASEB J. 1991; 5:2175–2179.

Harari, Y., Russell, D.A., Castro, G.A. J. Immunol. 1987; 138:1250–1255.

Lake, A.M., Bloch, K.J., Neutra, M.R., Walker, W.A. J. Immunol. 1979; 122:834–837.

Kagnoff, M.F.Sleisenger M., Fortran J., eds. Gastrointestinal Disease: Pathophysiology, Diagnosis, and Management. W. B. Saunders: Philadelphia, 1989; 114–144.

Perdue, M.H., Gall, D.G. Am. Physiol. Soc. 1986; G427–G431.

Powell, D.W.Schultz, S.G., Field, M., Frizzell, R.A., Rauner, B.B., eds. Handbook of Physiology; IV. American Physiology Society, Bethesda, Maryland, 1991:591–641.

Scott, R.B., Diamant, S.C., Gall, D.G. Am. Jour. Physiol. 1988; G505–G511.

Stead, R.H., Dixon, M.F., Bramwell, N.H., Riddell, R.H., Bienenstock, J. Gastroenterology. 1989; 97:575–585.

Strober, W., James, S.P. JAMA. 1987; 288:2962–2969.

Sullivan, K., Field, M. Schultz, S.G., Field, M., Frizzell, R.A., Rauner, B.B., eds. Handbook of Physiology; IV. American Physiology Society, Bethesda, Maryland, 1991:287–301.

Walker, W.A., Wu, M., Isselbacher, K.J., Bloch, K.J. Gastroenterology. 1975; 69:1223–1229.

Wasserman, S.I., Barrett, K.E., Huott, P.A., Beuerlein, G., Kagnoff, M.F., Dharmsathaphorn, K. Am. Physiol. Soc. 1988; C53–C62.

1

Immunological Regulation of Epithelial Function

Gilbert A. Castro,     Department of Physiology and Cell Biology, University of Texas Medical School, Houston, Texas

Publisher Summary

This chapter focuses on the immunological regulation of epithelial function. Evidence that sensitized lymphocytes from gut-associated lymphoid tissues (GALT) enter lymph capillaries and travel via the mesenteric lymph nodes, thoracic duct, and bloodstream to populate mucosae of the gastrointestinal (GI) and other tracts gives rise to the concept of the common mucosal immune system (MIS). Mucosae of the GI tract consist of epithelium overlying a basement membrane, capillaries, loose connective tissue, nerves, and smooth muscle. The mucosal immune system comprises components of connective tissue, the mononuclear phagocyte system—the reticuloendothelial system, and GALT. Gut epithelium, as a secretor of IgA and as an antigen processor and T-cell regulator, functions in the afferent and efferent arms of the MIS, suggesting that GALT might appropriately be called gut-associated lymphoepithelial tissue. The enteric nervous system (ENS) modulates the transduction and amplification of antigenic signals. Extrinsic nerves and hormones are suspected to modulate immunophysiological phenomena in gut mucosa.

I. Introduction

II. Discovery—Evidence of Immune Regulation of Epithelial Function

III. Integration— Patterns That Connect

IV. Application—Protection, Reconstruction, Attenuation, and Augmentation of Mucosal Immune Responses

References

I INTRODUCTION

A Theme—Connectedness

Many of the ideas and research pursuits of the author relating to the immunological regulation of epithelial function (Castro, 1982) were outgrowths of a graduate-level course developed and taught about two decades age. The course was entitled The Physiologic and Immunologic Nature of Parasitism. Parasitism, by its nature, involves the integration of two organisms. The course was designed in an attempt to capture the natural shifts in host and parasite physiological systems that occur during the infectious process, when two organisms become connected. This process is one of coadaptation. In the host, physiologic adaptation may involve the reconstruction of disintegrated systems or the development and expression of newly integrated ones. The immune system provides plasticity for the latter.

The power of the integrative approach in understanding vital processes is underscored in a monograph entitled Physiological Integrations in Action, which was published by Adolf in 1982. In addressing physiologists, Adolf implies, pedagogically, that the integrative approach is a way of thinking that is usually not fully developed nor appreciated until late in one’s research career when mental reviews of a life’s work reveal common threads that connect pools of information that, at one time, were viewed in isolation. He recommends that the integrated way of thinking be put into practice to guide research efforts early on, because integration is the nature of physiology.

Contributions made through the integrated approach are considered from a philosophical perspective in a treatise on Scholarship Revisited by Boyer (1991). He views the discovery, integration, application, and teaching of information as scholarly endeavors that can stand independently but that are also connected. For example, by applying newfound knowledge, theory and practice vitally interact, and one renews the other.

Integration means, in part, making connections across the disciplines, placing specialties in larger context, illuminating or interpreting data in a revealing way. Through connectedness research is ultimately made authentic (Van Doren, 1959).

There is a current and natural tendency to focus on interdisciplinary and integrative studies, long on the edge of academic life, in response to both new intellectual questions and pressing human problems (Boyer, 1991). This tendency is a clear indication that something is happening to the way we think about the way we think (Geertz, 1980).

B Approach—Discovery, Integration, Application

Immunophysiology of the gut, as addressed by a consideration of immunological regulation of epithelial function, is an interdisciplinary and integrative term that acknowledges a way we have begun to think about mucosal immunity. Studies of allergic responses in parasitized hosts, together with parallel studies performed by several investigative teams and involving nonparasite systems (see Castro, 1990, for review), have, during the last decade, established that the mucosal immune system controls or regulates physiological processes in epithelial cells. To describe the state of the art in this area would entail a description of the works of all contributors to this section and of contributors to other sections of this volume. Because much of the state-of-the-art work will be described firsthand by other contributors, my aim is to focus on the general state of the field with regard to three topics:

1. Types of information that demonstrate, unambiguously, that the immune system regulates epithelial function in the gut.

2. Interpretation of current information to identify patterns that connect and, thereby, develop generalities and concepts that contribute to our understanding of homeostasis and disease processes.

3. Potential applications of newfound knowledge.

I am hopeful that in the end my presentation supports the notion of Olszewski, (1988) that the future of immunology should properly be an era of immunophysiology with emphasis on immunoregulation.

II DISCOVERY—EVIDENCE OF IMMUNE REGULATION OF EPITHELIAL FUNCTION

A Structural Connections

Evidence that sensitized lymphocytes from gut-associated lymphoid tissues (GALT) enter lymph capillaries and travel via the mesenteric lymph nodes, thoracic duct, and bloodstream to populate mucosae of the gastrointestinal (GI) and other tracts (McDermott and Bienenstock, 1979) gives rise to the concept of the common mucosal immune system.

Mucosae of the GI tract consist of epithelium overlying a basement membrane, capillaries, loose connective tissue, nerves, and smooth muscle. The mucosal immune system (MIS) comprises components of connective tissue, the mononuclear phagocyte system (the reticuloendothelial system), and GALT (see Castro, 1989a). Gut epithelium, as a secretor of IgA (Underdown and Schiff, 1986) and as an antigen processor and T-cell regulator (Bland and Warren, 1986; Mayrhofer et al., 1983; Leonilda et al., 1990), functions in the afferent and efferent arms of the MIS, suggesting that GALT might appropriately be called gut-associated lymphoepithelial tissue (Bockman et al., 1983). The enteric nervous system (ENS) modulates the transduction and amplification of antigenic signals (Castro, 1988). Extrinsic nerves and hormones are suspected to modulate immunophysiological phenomena in gut mucosa (Castro, 1989b).

The structural relationship between the immunological system, the nervous system, and epithelial cells in intestinal mucosa are illustrated in Figure 1 by spatial associations among mast cells, nerves, and enterocytes. As demonstrated later, functional interactions among these three elements provide concrete evidence of immunological regulation of epithelial functions.

Fig. 1 Spatial relationship between a mast cell (arrow), nerve (arrowhead), and epithelial cell (E). Light micrograph inset. Original photomicrography by Leon Garretson, The University of Texas Medical School at Houston.

B Functional Connections

Attempts to determine the regulatory role of the immune system on epithelial functions involve two major approaches. The first is to apply chemical agents, or inflammatory mediators, to GI tissues and assess their effects on function. The second is to apply antigen to previously sensitized tissues and determine physiological changes that are evoked.

1 Stimulation of Mucosal Tissue with Inflammatory Mediators

The first approach, already noted, rests on the assumption that inflammatory mediators are released endogenously during antigen-stimulated reactions. The rationale is that cells of the immune system and their paracrine secretions also have roles in inflammation. In other words, inflammatory mediators are equated with so-called immune agonists.

A convenient way to visualize the connection between inflammatory mediators and immune agonists is to consider the inflammatory changes that associate with types I–IV hypersensitivity reactions. These four types can be distinguished, in part, based on (a) their time of onset after antigenic challenge, (b) their requirements for antibodies, and (c) the cells involved (Coombs and Gell, 1975). The accumulation of these cells and the attending functional changes represent various degrees of inflammation within a spectrum of acute to chronic.

Type I hypersensitivity (anaphylaxis) is dependent on the interaction of antigen with anaphylactic antibody (IgE or IgG subclasses) bound to amine-containing cells such as mast cells and basophils. Type II involves complement- and antibody-dependent cellular cytotoxicity (ADCC) that results in the lysis of target cells. Type III (Arthus reaction) is characterized by the formation of antigen–antibody complexes that activate complement and attract neutrophiles. Type IV involves antigen-activated T cells that release lymphokines, which, in part, cause local proliferation of lymphocytes and taxis of myeloid cells. The rapid onset of types I–III reactions categorizes them as immediate hypersensitivities, while the relatively slow expression of type IV labels it as delayed hypersensitivity (Roitt et al., 1985).

Considerably more is known about functional changes evoked by anaphylaxis or type I hypersensitivity compared with type II–IV hypersensitivities. Type II–IV reactions are more difficult to study than type I because their onset is less predictable. Difficulty also arises from the fact that more than one of these reactions may occur concurrently and may also be preceded by a type I reaction. For example, the antigen–antibody complexes that characterize the Arthus reaction attract neutrophils chemotactically from leaky capillaries. Both chemotaxis and enhanced capillary permeability may be effected through mast cell mediators released via a type I hypersensitivity reaction.

The application of exogenous agonists to study effects of immune elements on electrolyte transport is helpful in elucidating the cellular and subcellular pathways involved in immune-mediated changes in physiology and in determining whether the action of a putative immune agonist on the effector tissue is direct or indirect (Wasserman et al., 1988; Barrett et al., 1990). A factor that must be considered in drawing conclusions from this approach is that an observed effect might not represent what occurs in response to local antigenic stimulation. Also, responses of epithelial cells to stimulants may be different in inflamed compared to noninflamed tissues (Harari and Castro, 1991). The paracrine nature and influence of various inflammatory mediators on electrolyte absorption and secretion and the significance of this influence have been comprehensively reviewed by Powell (1991).

2 Stimulation of Mucosal Tissue with Antigen

To establish an immunophysiological role for a specific mediator, it is necessary to demonstrate that an observed effector response (e.g., altered epithelial function) results from antigenic challenge and is mediated by the secretion of the paracrine or cytokine in question. Furthermore, it must be verified that the antigen-induced change is dependent on prior sensitization and is specific with regard to responsiveness to the triggering antigen. In short, once a response is observed, it is necessary, in essence, to follow Koch’s postulates to establish that a specific cytokine or paracrine is responsible for that response.

Several lines of evidence derived from the latter approach link altered epithelial function in the GI tract to a defined immunological trigger. The most clearly elucidated examples involve type I hypersensitivity. Intestinal anaphylaxis is associated with epithelial damage and sloughing (Perdue et al., 1984; Miller et al., 1986). Mucus secretion from goblet cells has been attributed to anaphylaxis, but this remains a controversial issue (Lake et al., 1980; Perdue et al. 1984; Miller et al., 1986). In several host–parasite interactions, acute, anaphylaxis-induced changes in gut epithelium are followed by chronic, T-cell-dependent inflammation in the lamina propria, villous atrophy, crypt elongation, and goblet cell hyperplasia (Castro, 1989b). The strongest direct evidence of antigen-induced changes in epithelial function comes from a variety of in vitro and acute in vivo experiments involving anaphylactically mediated changes in ion transport in the jejunum, ileum, and colon of guinea pigs, rats, and mice (see Table I, taken from Castro, 1990).

TABLE I

Reported Changes in Electrolyte Transport Triggered by Local Anaphylaxisa