Food Allergy E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 2157

Veröffentlichungsjahr: 2013

Beschreibung

Food Allergy is a unique book which uses a scientific approach to cover both pediatric and adult adverse reactions to foods and food additives. Following the successful formula of the previous editions, Food Allergy has established itself as the comprehensive reference for those treating patients with food allergy or suspected allergy.

This fifth edition has been thoroughly revised and updated. It is a practical, readable reference for use in the hospital or private practice setting. Each of the chapters is capable of standing alone, but when placed together they present a mosaic of the current ideas and research on adverse reactions to foods and food additives.

The book covers basic and clinical perspectives of adverse reactions to food antigens, adverse reactions to food additives and contemporary topics, including a review of the approaches available for diagnosis. Food Allergy is directed toward clinicians, nutritionists and scientists interested in food reactions and will be an invaluable resource for all those working in this field.

Leseprobe

Contents

Cover

Title Page

Copyright

List of Contributors

Preface to the Fifth Edition

Abbreviations

Part 1: Adverse Reactions to Food Antigens: Basic Science

Chapter 1: The Mucosal Immune System

Introduction

Mucosal immunity is associated with suppression: the phenomena of controlled inflammation and oral tolerance

The nature of antibody responses in the gut-associated lymphoid tissue

The anatomy of the gut-associated lymphoid tissue: antigen trafficking patterns

References

Chapter 2: The Immunological Basis of IgE-Mediated Reactions

Introduction

Route of sensitization

Allergen uptake in the intestine

T-cell response in IgE-mediated allergy

B-cell response in IgE-mediated allergy

Allergen-specific IgG and IgA

Genes and environment

Innate immune recognition of allergens

Allergic inflammation

IgE receptors

Mast cells

Basophils

Eosinophils

Conclusion

References

Chapter 3: The Immunological Basis of Non-IgE-Mediated Reactions

Introduction

Development of food allergy

Gut anatomy

Defense mechanisms

Oral tolerance

Antigen transport

Antigen processing and presentation

T cells

Eosinophils

Food protein-induced enterocolitis and proctocolitis

Celiac disease

Allergic eosinophilic esophagitis and gastroenteritis

Conclusions

Acknowledgment

References

Chapter 4: Food Allergens—Molecular and Immunological Characteristics

Introduction

Food allergen protein families

Food allergens of animal origin (Table 4.2)

Food allergens of plant origin (Table 4.3)

Allergen databases

What does this mean?

Acknowledgment

References

Chapter 5: Biotechnology and Genetic Engineering

Introduction

Plant biotechnology

Roundup Ready soybeans: a case study in food safety assessment

General assessment strategy for food allergy

Allergy assessment summary: Roundup Ready soybeans

Trends in the science of risk assessment

Value of measuring allergen expression levels as part of the allergy risk assessment of biotech crops

Removing allergens from foods

International consensus: a common strategy

Conclusion and future considerations

References

Chapter 6: Food Allergen Thresholds of Reactivity*

Definition of threshold

Thresholds for sensitization versus elicitation

Clinical determination of individual threshold doses

Clinical correlates of thresholds of reactivity

MEDs for specific foods

Usefulness of individual thresholds for reactivity

Food industry and regulatory uses of threshold information

Conclusions

References

Chapter 7: Immunological Tolerance

Introduction

Organization of the gastrointestinal immune system

Gastrointestinal antigen uptake

Assessment of oral tolerance

Site of tolerance induction

Effector mechanisms of oral tolerance

Gastrointestinal antigen presentation: the role of dendritic cells

Factors affecting development of oral tolerance

Conclusion

References

Chapter 8: In Vitro Diagnostic Methods in the Evaluation of Food Hypersensitivity

Introduction

Food-specific antibody assays

Indications for allergen-specific IgE testing

IgG and IgA antibody detection in celiac disease

Food allergens

Allergenic food components

Food allergen epitopes

Predictive quantitative allergen-specific IgE levels

Analytes and assays with little or no confirmed value in the diagnosis of food allergy

Laboratory considerations

Summary

References

Part 2: Adverse Reactions to Food Antigens: Clinical Science

Chapter 9: Theories on the Increasing Prevalence of Food Allergy

Introduction

References

Chapter 10: The Spectrum of Allergic Reactions to Foods

Introduction

IgE-mediated reactions

Non-IgE-mediated reactions

Adverse food reactions associated with eosinophilic disease

Conditions associated with multiple immune mechanisms

Summary

References

Chapter 11: Cutaneous Reactions: Atopic Dermatitis and Other IgE- and Non-IgE-Mediated Skin Reactions

Introduction

Immunopathophysiology of AD

Role of food allergy in AD

Epidemiology of food allergy in AD

Diagnosis of food hypersensitivity in patients with AD

Management

Natural history of food hypersensitivity

Conclusions

References

Chapter 12: Oral Allergy Syndrome

Introduction

Epidemiology

Clinical features

Molecular basis/pathogenesis

Allergens

Pollen-food syndromes

Diagnosis

Management

Future directions

Conclusions

References

Chapter 13: The Respiratory Tract and Food Hypersensitivity

Introduction

Epidemiology

Respiratory presentations of food allergy

Allergens

Routes of exposure

What is the link between the respiratory tract and food hypersensitivity?

Managing a patient presenting with food-induced respiratory symptom

Summary and conclusions

References

Chapter 14: Anaphylaxis and Food Allergy

Introduction

Definitions

Prevalence

Etiology

Diagnosis

Treatment

Prognosis

References

Chapter 15: Infantile Colic and Food Allergy

Introduction

Epidemiology of colic

Infantile and parental factors associated with infantile colic

Infantile colic and gastrointestinal disorders

Dietary treatment of colic

Conclusion

References

Chapter 16: Eosinophilic Esophagitis, Gastroenteritis, and Colitis

Eosinophilic esophagitis

Eosinophilic gastroenteritis (gastroenterocolitis)

Eosinophilic proctocolitis

References

Chapter 17: Gluten-Sensitive Enteropathy

Introduction

Etiology

Epidemiology

Natural history of celiac disease

Clinical presentation

Diagnostic tests for celiac disease

Treatment

Prevention

Mortality in celiac disease

References

Chapter 18: Food Protein-Induced Enterocolitis and Enteropathies

Introduction

Food protein-induced enterocolitis syndrome

Food protein-induced enteropathy

Iron deficiency anemia

Conclusion

References

Chapter 19: Occupational Reactions to Food Allergens

Introduction

Definitions/classifications

Prevalence and incidence

Risk factors

Agents associated with allergic occupational diseases of food workers

Relationship of sensitization routes: inhalation at the workplace versus ingestion at home

Diagnosis

Prognosis

Prevention and treatment

Conclusions

References

Part 3: Adverse Reactions to Foods: Diagnosis

Chapter 20: IgE Tests: In Vitro Diagnosis

Introduction

Common diagnostic test methods for the quantitative measurement of food allergen-specific IgE

Total IgE

Component-resolved diagnosis with individual food allergens and allergenic peptides

Food allergen-specific IgE and the atopic march

References

Chapter 21: In Vivo Diagnosis: Skin Testing and Challenge Procedures

Introduction

Skin prick tests

Additional diagnostic steps prior to OFCs

The history and physical examination

Diagnostic elimination diets

Oral food challenges

Summary

References

Chapter 22: Atopy Patch Testing for Food Allergies

Introduction

History

History: atopic dermatitis

History: eosinophilic esophagitis

History: food protein-induced enterocolitis syndrome

Unanswered questions

Conclusion

References

Chapter 23: Elimination Diets and Oral Food Challenges

Introduction

Historical background

Food elimination diets

Oral food challenges

Summary

References

Chapter 24: General Approach to Diagnosing Food Allergy and the Food Allergy Guidelines

Why is it important to systematically diagnose food allergy?

Moving from focused history-taking to focused in vivo and in vitro testing

Using skin and blood tests to follow patients over time

References

Chapter 25: Hidden and Cross-Reacting Food Allergens

Introduction

Hidden food allergens

Cross-reacting food allergens

Cross-reactions among specific foods/food families

Summary and management

References

Chapter 26: Controversial Practices and Unproven Methods in Allergy

Introduction

Definitions

“Controversial” tests

Unproven tests

Inappropriate tests

Unproven therapy

Urine autoinjections

Inappropriate therapy

Conclusion

References

Part 4: Adverse Reactions to Food Additives

Chapter 27: Asthma and Food Additives

Introduction

Evaluating asthma studies

Conclusions

References

Chapter 28: Urticaria, Angioedema, and Anaphylaxis Provoked by Food Additives

Mechanisms of additive-induced urticaria, angioedema, and anaphylaxis

Study design for food additive challenges in patients with urticaria/angioedema

Individual additives in acute urticaria: description, challenges, and testing

Food additive sensitivity in chronic idiopathic urticaria/angioedema

Recommendations for food additive challenge protocols in patients with urticaria, angioedema, and/or anaphylaxis

Conclusion

References

Chapter 29: Sulfites

Introduction

Clinical manifestations of sulfite sensitivity

Prevalence

Mechanisms

Diagnosis

Treatment

Food and drug uses

Fate of sulfites in foods

Likelihood of reactions to sulfited foods

Avoidance diets

Conclusion

References

Chapter 30: Monosodium Glutamate

The fifth taste: L-glutamate

Monosodium glutamate and neurotoxicity

MSG symptom complex

MSG and the FDA

Conclusion

References

Chapter 31: Tartrazine, Azo, and Non-Azo Dyes

Urticaria/angioedema reactions associated with tartrazine and other dyes

Asthma associated with tartrazine and other dyes

Anaphylaxis from ingestion of dyes

Atopic dermatitis and cutaneous reactions to tartrazine

Contact dermatitis to tartrazine and azo dyes

Other cutaneous reactions to tartrazine and azo dyes

Hyperkinesis and tartrazine

Conclusions

References

Chapter 32: Adverse Reactions to the Antioxidants Butylated Hydroxyanisole and Butylated Hydroxytoluene

Toxicology

Asthma/rhinitis

Urticaria

Dermatitis

Mechanisms

Unsubstantiated effects

Summary

References

Chapter 33: Adverse Reactions to Benzoates and Parabens

Benzoates and parabens as food and beverage additives

Benzoates, parabens, and associations with chronic urticaria–angioedema

Benzoates, parabens, and associations with asthma

Benzoates, parabens, and anaphylaxis

Benzoates, parabens, and dermatitis

Miscellaneous reactions

Summary and conclusions

References

Chapter 34: Food Colorings and Flavors

Food colorings

Food flavorings

Summary

References

Part 5: Contemporary Topics in Adverse Reactions to Foods

Chapter 35: Pharmacologic Food Reactions

Introduction

Vasoactive amines

Monoamines

Methylxanthines

Capsaicin

Ethanol

Myristicin

Psoralen

Solanine and chaconine

Glycyrrhetinic acid

Oleocanthal

References

Chapter 36: The Management of Food Allergy

Introduction

Allergen avoidance

Allergen identification

Label reading

Cross-contact

Cooking

Psychosocial impact

Teens and young adults: high-risk patients

Management of food allergy at school

Eating away from home

Special occasions

References

Chapter 37: The Natural History of Food Allergy

Introduction

Studies on the development of food allergy

Studies on the loss of food allergy

Milk allergy

Egg allergy

Peanut allergy

Tree nuts allergy

Other foods

Food allergy in adults

Follow-up of the food-allergic child

Conclusions

References

Chapter 38: Prevention of Food Allergy

Introduction

Methodological challenges

Onset of sensitization and food allergy

Maternal diet (during pregnancy and/or breast-feeding) and the prevention of food allergy

Complementary infant feeding and the prevention of food allergy

Combined maternal and infant dietary measures and the prevention of food allergy

Routes of sensitization, cross sensitization, and oral tolerance induction

Unpasteurized milk, probiotics, and prebiotics

Nutritional supplements

Conclusions

References

Chapter 39: Diets and Nutrition

Introduction

Label reading

Food preparation safety

Resources

Nutrition

Dietary reference intakes

Baked milk and egg

Summary

References

Chapter 40: Food Toxicology

Intoxications caused by synthetic chemicals in foods

Intoxications caused by naturally occurring chemicals in foods

Metabolic food disorders

References

Chapter 41: Seafood Toxins

Introduction

Background

Common intoxications associated with fish

Common intoxications associated with shellfish

Conclusions

Acknowledgment

References

Chapter 42: Neurologic Reactions to Foods and Food Additives

Migraine headache

Epilepsy

Vertigo

Hemiplegia

Gluten sensitivity and neurological abnormalities

References

Chapter 43: Experimental Approaches to the Study of Food Allergy

Animal models of IgE-mediated food allergy

Experimental approaches using human specimens

Conclusions

References

Chapter 44: Food Allergy: Psychological Considerations and Quality of Life

Introduction

Psychological impact and quality of life

Psychosocial support of patients and families with food allergy

Food allergy and psychological disorders

Approach to the patient with psychological symptoms attributed to food allergy

References

Chapter 45: Foods and Rheumatologic Diseases

Introduction

Rheumatoid arthritis

Diet in the etiology of RA

Genetics in the etiology of RA—the potential interaction with food

Food allergy/intolerance in RA

Potential mechanisms of food intolerance/allergy RA

Dietary omega-3 supplementation and RA

Probiotics for the treatment of arthritis

Summary

Appendix

References

Chapter 46: Approaches to Therapy in Development

Immunotherapeutic approaches for treating food allergy

Allergen-specific immunotherapy

Oral immunotherapy

Immunotherapy with modified recombinant engineered food proteins

Allergen-nonspecific therapy

Conclusions

References

Index

This edition first published 2014 © 2008, 2010, 2014 by John Wiley & Sons, Ltd Chapter 3 © Hirsh D Komarow

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Library of Congress Cataloging-in-Publication Data

Food allergy (John Wiley & Sons, Ltd.) Food allergy : adverse reactions to foods and food additives / edited by Dean D. Metcalfe, Hugh A. Sampson, Ronald A. Simon, Gideon Lack. – Fifth edition. p. ; cm. Includes bibliographical references and index. ISBN 978-0-470-67255-6 (cloth : alk. paper) – ISBN 978-1-118-74414-7 (ePub) – ISBN 978-1-118-74416-1 (ePdf) – ISBN 978-1-118-74417-8 (eMobi) – ISBN 978-1-118-74418-5 I. Metcalfe, Dean D., editor of compilation. II. Sampson, Hugh A., editor of compilation. III. Simon, Ronald A., editor of compilation. IV. Lack, Gideon, editor of compilation. V. Title. [DNLM: 1. Food Hypersensitivity. 2. Food Additives–adverse effects. WD 310] RC596 616.97′5–dc23 2013017942

A catalogue record for this book is available from the British Library.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

Cover image: Generated by Christian Radauer and Heimo Breiteneder, Medical University of Vienna, Austria

Cover design by Andrew Magee Design Ltd

List of Contributors

Maria Laura Acebal, JD

Board Director and Former CEO

FARE: Food Allergy Research and Education (formerly The Food Allergy & Anaphylaxis Network (FAAN))

Washington, DC, USA

Shradha Agarwal, MD

Assistant Professor of Medicine

Division of Allergy and Clinical Immunology

Icahn School of Medicine at Mount Sinai

New York, NY, USA

Katrina J. Allen, MD, PhD

Professor of Paediatrics

Murdoch Childrens Research Institute;

The University of Melbourne Department of Paediatrics;

Department of Allergy and Immunology

Royal Children's Hospital

Melbourne, VIC, Australia

Matthew Aresery, MD

Allergist

Maine General Medical Center

Augusta, ME, USA

James L. Baldwin, MD

Associate Professor

Division of Allergy and Clinical Immunology

University of Michigan

Ann Arbor, MI, USA

Gary A. Bannon, PhD

Global Regulatory Sciences and Affairs

Monsanto

St Louis, MO, USA

Joseph L. Baumert, PhD

Assistant Professor Co-Director

Food Allergy Research and Resource Program

Department of Food Science and Technology

Food Allergy Research and Resource Program

University of Nebraska

Lincoln, NE, USA

M. Cecilia Berin, PhD

Associate Professor of Pediatric Allergy and Immunology

Icahn School of Medicine at Mount Sinai

New York, NY, USA

Kirsten Beyer, MD

Professor of Experimental Pediatrics

Charité Universitätsmedizin Berlin

Klinik für Pädiatrie m.S. Pneumologie und Immunologie

Berlin, Germany

Stephan C. Bischoff, MD

Professor of Medicine

Director, Institute of Nutritional Medicine and Immunology

University of Hohenheim

Stuttgart, Germany

John V. Bosso, MD

Affiliate Faculty Member

Columbia University College of Physicians and Surgeons;

Chief, Allergy and Immunology

Nyack Hospital

Nyack, NY, USA

Heimo Breiteneder, PhD

Professor of Medical Biotechnology

Department of Pathophysiology and Allergy Research

Medical University of Vienna

Vienna, Austria

A. Wesley Burks, MD

Curnen Distinguished Professor and Chairman

Department of Pediatrics

University of North Carolina

Chapel Hill, NC, USA

Robert K. Bush, MD

Emeritus Professor

Division of Allergy, Immunology, Pulmonary, Critical Care, and Sleep Medicine

Department of Medicine

University of Wisconsin School of Medicine and Public Health

Madison, WI, USA

André Cartier, MD

Clinical Professor of Medicine

Université de Montréal

Hôpital du Sacré-Coeur de Montréal

Montreal, QC, Canada

Soheil Chegini, MD

Attending Physician

Exton Allergy and Asthma Associates

Exton, PA, USA

Leslie G. Cleland, MD, FRACP

Director of Rheumatology

Rheumatology Unit

Royal Adelaide Hospital

Adelaide, SA, Australia

Ma. Lourdes B. de Asis, MD

Allergy and Asthma Consultants of Rockland and Bergen West

Nyack, NY, USA

Raymond C. Dobert, PhD

Global Regulatory Sciences and Affairs

Monsanto, St. Louis, MO, USA

George Du Toit, MD

Consultant in Paediatric Allergy

King's College London

Clinical Lead for Allergy Service

Guy's and St Thomas' NHS Foundation Trust

St Thomas' Hospital

London, UK

John M. Fahrenholz, MD

Division of Allergy, Pulmonary and Critical Care Medicine

Vanderbilt University Medical Center

Nashville, TN, USA

David M. Fleischer, MD

Associate Professor of Pediatrics

University of Colorado Denver School of Medicine

Division of Pediatric Allergy and Immunology

National Jewish Health

Timothy J. Franxman, MD

Fellow

Division of Allergy and Clinical Immunology

University of Michigan

Ann Arbor, MI, USA

Roy L. Fuchs, phD

Global Regulatory Sciences and Affairs

Monsanto, St. Louis, MO, USA

Matthew J. Greenhawt, MD, MBA, FAAP

Assistant Professor

Division of Allergy and Clinical Immunology

Food Allergy Center

University of Michigan Medical School

Ann Arbor, MI, USA

Marion Groetch, MS, RD, CDN

Director of Nutrition Services

The Elliot and Roslyn Jaffe Food Allergy Institute

Division of Allergy and Immunology

Department of Pediatrics

Icahn School of Medicine at Mount Sinai

New York, NY, USA

Robert G. Hamilton, PhD, D.ABMLI

Professor of Medicine and Pathology

Departments of Medicine and Pathology

Johns Hopkins University School of Medicine

Baltimore, MD, USA

Ralf G. Heine, MD, FRACP

Department of Allergy & Immunology

Royal Children's Hospital, Melbourne, VIC, Australia

Murdoch Childrens Research Institute, Melbourne, Australia

Department of Paediatrics

The University of Melbourne, Melbourne, Australia

David J. Hill, MD, FRACP

Senior Consultant Allergist

Murdoch Childrens Research Institute

Melbourne, VIC, Australia

Jonathan O'B. Hourihane, DM, FRCPI

Professor of Paediatrics and Child Health

University College Cork, Ireland

Sangeeta J. Jain, MD

Section of Clinical Immunology, Allergy and Rheumatology

Tulane University Health and Sciences Center

New Orleans, LA, USA

Stacie M. Jones, MD

Professor of Pediatrics

Chief, Division of Allergy and Immunology

University of Arkansas for Medical Sciences and Arkansas Children's Hospital

Little Rock, AR, USA

Hirsh D. Komarow, MD

Staff Clinician

Laboratory of Allergic Diseases

National Institute of Allergy and Infectious Diseases

National Institutes of Health

Bethesda, MD, USA

Jennifer J. Koplin, PhD

Postdoctoral Research Fellow

Murdoch Childrens Research Institute

Royal Children's Hospital

Melbourne, VIC, Australia

Samuel B. Lehrer, PhD

Research Professor of Medicine, Emeritus

Tulane University

New Orleans, LA, USA

Donald Y.M. Leung, MD, PhD

Professor of Pediatrics

University of Colorado Denver School of Medicine

Edelstein Family Chair of Pediatric Allergy and Immunology

National Jewish Health

Chris A. Liacouras, MD

Professor of Pediatrics

Division of Gastroenterology and Nutrition

The Children's Hospital of Philadelphia

Philadelphia, PA, USA

Jay Lieberman, MD

Assistant Professor

Department of Pediatrics

The University of Tennessee Health Sciences Center

Memphis, TN, USA

Madhan Masilamani, PhD

Assistant Professor of Pediatric Allergy and Immunology

Icahn School of Medicine at Mount Sinai

New York, NY, USA

Lloyd Mayer, MD

Professor of Medicine and Immunobiology

Division of Allergy and Clinical Immunology

Immunology Institute

Icahn School of Medicine at Mount Sinai

New York, NY, USA

E.N. Clare Mills, PhD

Professor

Manchester Institute of Biotechnology

University of Manchester

Manchester, UK

Michelle Montalbano, MD

Advanced Allergy and Asthma, PLLC

Silverdale, WA, USA

Amanda Muir, MD

Fellow, Pediatric Gastroenterology

Division of Gastroenterology and Nutrition

The Children's Hospital of Philadelphia

Philadelphia, PA, USA

Anne Muñoz-Furlong, BA

Founder and CEO

The Food Allergy and Anaphylaxis Network

Fairfax, VA, USA

Joseph A. Murray, MD

Professor of Medicine

Mayo Clinic

Rochester, MN, USA

Kari Nadeau, MD, PhD, FAAAAI

Associate Professor

Division of Immunology and Allergy

Stanford Medical School and Lucile Packard Children's Hospital

Stanford, CA, USA

Jennifer A. Namazy, MD

Division of Allergy, Asthma and Immunology

Scripps Clinic

San Diego, CA, USA

Julie A. Nordlee, MS

Clinical Studies Coordinator

Department of Food Science and Technology

Food Allergy Research and Resource Program

University of Nebraska

Lincoln, NE, USA

Anna Nowak-Węgrzyn, MD

Associate Professor of Pediatrics

Department of Pediatrics, Allergy and Immunology

Jaffe Food Allergy Institute

Icahn School of Medicine at Mount Sinai

New York, NY, USA

Raymond M. Pongonis, MD

Division of Allergy, Pulmonary and Critical Care Medicine

Vanderbilt University Medical Center

Nashville, TN, USA

Graham Roberts, DM, MA, BM BCh

Professor and Consultant in Paediatric Allergy and Respiratory Medicine

University Hospital Southampton NHS Foundation Trust

Southampton, UK

David M. Robertson, MD

Allergist/Immunologist

Hampden County Physician Associates

Springfield, MA, USA;

Clinical Assistant Professor of Pediatrics

Tufts University School of Medicine

Boston, MA, USA

Alberto Rubio-Tapia, MD

Assistant Professor of Medicine

Division of Gastroenterology and Hepatology

Mayo Clinic

Rochester, MN, USA

David R. Scott, MD

Fellow, Division of Allergy, Asthma and Immunology

Scripps Clinic

San Diego, CA, USA

Gernot Sellge, MD PhD

Clinical and Research Fellow

University Hospital Aachen

Department of Medicine III

Aachen, Germany

Scott H. Sicherer, MD

Professor of Pediatrics

The Elliot and Roslyn Jaffe Food Allergy Institute

Division of Allergy and Immunology

Department of Pediatrics

Icahn School of Medicine at Mount Sinai

New York, NY, USA

Maxcie M. Sikora, MD

Alabama Allergy and Asthma Center

Birmingham, AL, USA

Lisa K. Stamp, FRACP, PhD

Professor and Rheumatologist

University of Otago–Christchurch

Christchurch, New Zealand

Lauren Steele, BA

Doris Duke Clinical Research Fellow

Division of Allergy and Immunology Department of Pediatrics

Icahn School of Medicine at Mount Sinai

New York, NY, USA

Donald D. Stevenson, MD

Senior Consultant

Division of Allergy, Asthma and Immunology

Scripps Clinic

La Jolla, CA, USA

Von Ta, MD

Research Fellow

Division of Immunology and Allergy

Stanford Medical School and Lucile Packard Children's Hospital

Stanford, CA, USA

Steve L. Taylor, PhD

Professor

Department of Food Science and Technology

Co-Director, Food Allergy Research and Resource Program

University of Nebraska

Lincoln, NE, USA

Ashraf Uzzaman, MD

Saline Allergy Asthma Sinus Specialists

Saline, MI, USA

Julie Wang, MD

Associate Professor of Pediatrics

Jaffe Food Allergy Institute

Department of Pediatrics

Icahn School of Medicine at Mount Sinai

New York, NY, USA

Jason M. Ward, PhD

Global Regulatory Sciences and Affairs

Monsanto, St. Louis, MO, USA

Richard W. Weber, MD

Professor of Medicine

National Jewish Health

Professor of Medicine

University of Colorado Denver School of Medicine

Denver, CO, USA

Laurianne G. Wild, MD

Section of Clinical Immunology, Allergy and Rheumatology

Tulane University Health and Sciences Center

New Orleans, LA, USA

Katharine M. Woessner, MD

Program Director

Allergy, Asthma and Immunology Training Program

Scripps Clinic Medical Group

San Diego, CA, USA

Robert A. Wood, MD

Professor of Pediatrics and International Health

Director, Pediatric Allergy and Immunology

Johns Hopkins University School of Medicine

Baltimore, MD, USA

Preface to the Fifth Edition

It is the privilege of the editors to present the fifth edition of Food Allergy: Adverse Reactions to Foods and Food Additives. As in the first four editions, we have attempted to create a book that in one volume would cover pediatric and adult adverse reactions to foods and food additives, stress efforts to place adverse reactions to foods and food additives on a sound scientific basis, select authors to present subjects on the basis of their acknowledged expertise and reputation, and reference each contribution thoroughly. Hugh, Ron, and I as co-editors of the fifth edition are pleased to be joined by Professor Gideon Lack, Head of the Children's Allergy Service at Guy's and St Thomas' NHS Foundation Trust, and Professor of Pediatric Allergy at King's College London, who brings a unique perspective to the understanding of the evolution of the food allergic state.

The growth in knowledge in this area continues to be gratifying and is reflected in the diversity of subject matter in this edition. Again, this book is directed toward clinicians, nutritionists, and scientists interested in food reactions, but we also hope that patients and parents of patients interested in such reactions will find the book to be a valuable resource. The chapters cover basic and clinical perspectives of adverse reactions to food antigens, adverse reactions to food additives, and contemporary topics. Basic science begins with overview chapters on immunology with particular relevance to the gastrointestinal tract as a target organ in allergic reactions and the properties that govern reactions initiated at this site. Included are chapters relating to biotechnology and to thresholds of reactivity. This is followed by chapters reviewing the clinical science of adverse reactions to food antigens from the oral allergy syndrome to cutaneous disease, and from eosinophilic gastrointestinal disease to anaphylaxis. The section on diagnosis constitutes a review of the approaches available for diagnosis, and their strengths and weaknesses. Adverse reactions to food additives include chapters addressing specific clinical reactions and reactions to specific agents. The final section on contemporary topics includes discussions of the pharmacologic properties of food, the natural history and prevention of food allergy, diets and nutrition, neurologic reactions to foods and food additives, psychological considerations, and adverse reactions to seafood toxins.

Each of the chapters in this book is capable of standing alone, but when placed together they present a mosaic of the current ideas and research on adverse reactions to foods and food additives. Overlap is unavoidable but, we hope, is held to a minimum. Ideas of one author may sometimes differ from those of another, but in general there is remarkable agreement from chapter to chapter. We, the editors, thus present the fifth edition of a book that we believe represents a fair, balanced, and defensible review of adverse reactions of foods and food additives.

Dean D. Metcalfe Hugh A. Sampson Ronald A. Simon Gideon Lack

About the cover: The cover picture shows the structure of the vicilin and major peanut allergen Ara h 1 (Protein Data Bank accession number 3s7i). Vicilins are a large family of seed storage proteins that contains many important allergens from legumes, tree nuts, and seeds. The picture was generated by Christian Radauer and Heimo Breiteneder, Department of Pathophysiology and Allergy Research, Medical University of Vienna, Austria.

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Adverse Reactions to Food Antigens: Basic Science

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The Mucosal Immune System

Shradha Agarwal & Lloyd Mayer

Division of Clinical Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Key Concepts

The gastrointestinal tract is the largest lymphoid organ in the body. The mucosal immune system is unique in its ability to suppress responses against commensal flora and dietary antigens.The mucosal immune system is characterized by unique cell populations (intraepithelial lymphocytes, lamina propria lymphocytes) and antigen-presenting cells (epithelial cells, tolerized macrophages, and dendritic cells) that contribute to the overall nonresponsive state.Numerous chemical (extremes of pH, proteases, bile acids) and physical (tight junctions, epithelial membranes, mucus, trefoil factors) barriers reduce antigen access to the underlying mucosal immune system (nonimmune exclusion).Secretory IgA serves as a protective barrier against infection by preventing attachment of bacteria and viruses to the underlying epithelium (immune exclusion).Oral tolerance is the active nonresponse to antigen administered via the oral route. Factors affecting the induction of oral tolerance to antigens include the age and genetics of the host; the nature, form, and dose of the antigen; and the state of the mucosal barrier.

Introduction

An allergic response is thought to be an aberrant, misguided, systemic immune response to an otherwise harmless antigen. An allergic response to a food antigen then can be thought of as an aberrant mucosal immune response. The magnitude of this reaction is multiplied several fold when one looks at this response in the context of normal mucosal immune responses, that is, responses that are suppressed or downregulated. The current view of mucosal immunity is that it is the antithesis of a typical systemic immune response. In the relatively antigen pristine environment of the systemic immune system, foreign proteins, carbohydrates, or even lipids are viewed as potential pathogens. A coordinated reaction seeks to decipher, localize, and subsequently rid the host of the foreign invader. The micro- and macroenvironment of the gastrointestinal (GI) tract is quite different, with continuous exposure to commensal bacteria in the mouth, stomach, and colon and dietary substances (proteins, carbohydrates, and lipids) that, if injected subcutaneously, would surely elicit a systemic response. The complex mucosal barrier consists of the mucosa, epithelial cells, tight junctions, and the lamina propria (LP) containing Peyer's patches (PP), lymphocytes, antigen-presenting macrophages, dendritic cells (DCs), and T cells with receptors for major histocompatibility complex (MHC) class I- and II-mediated antigen presentation. Pathways have been established in the mucosa to allow such nonharmful antigens/organisms to be tolerated [1,2]. In fact, it is thought that the failure to tolerate commensals and food antigens is at the heart of a variety of intestinal disorders (e.g., celiac disease and gluten [3,4], inflammatory bowel disease, and normal commensals [5–7]). Those cells exist next to a lumen characterized by extremes of pH replete with digestive enzymes. Failure to maintain this barrier may result in food allergies. For example, studies in murine models demonstrated that coadministration of antacids results in breakdown of oral tolerance implying that acidity plays a role in the prevention of allergies and promotion of tolerance [8,9]. Thus, it makes sense that some defect in mucosal immunity would predispose a person to food allergy. This chapter will lay the groundwork for the understanding of mucosal immunity. The subsequent chapters will focus on the specific pathology seen when the normal immunoregulatory pathways involved in this system are altered.

Mucosal immunity is associated with suppression: the phenomena of controlled inflammation and oral tolerance

As stated in the introduction, the hallmark of mucosal immunity is suppression. Two linked phenomena symbolize this state: controlled/physiologic inflammation and oral tolerance. The mechanisms governing these phenomena are not completely understood, as the dissection of factors governing mucosal immunoregulation is still evolving. It has become quite evident that the systems involved are complex and that the rules governing systemic immunity frequently do not apply in the mucosa. Unique compartmentalization, cell types, and routes of antigen trafficking all come together to produce the immunosuppressed state.

Controlled/physiologic inflammation

The anatomy of the mucosal immune system underscores its unique aspects (Figure 1.1). There is a single layer of columnar epithelium that separates a lumen replete with dietary, bacterial, and viral antigens from the lymphocyte-rich environment of the underlying loose connective tissue stroma, called the lamina propria. Histochemical staining of this region reveals an abundance of plasma cells, T cells, B cells, macrophages, and DCs [2, 10–12]. The difference between the LP and a peripheral lymph node is that there is no clear-cut organization in the LP and cells in the LP are virtually all activated memory cells. While the cells remain activated, they do not cause destruction of the tissue or severe inflammation. The cells appear to reach a stage of activation but never make it beyond that stage. This phenomenon has been called controlled/physiologic inflammation. The entry and activation of the cells into the LP is antigen driven. Germ-free mice have few cells in their LP. However, within hours to days following colonization with normal intestinal flora (no pathogens), there is a massive influx of cells [13–16]. Despite the persistence of an antigen drive (luminal bacteria), the cells fail to develop into aggressive, inflammation-producing lymphocytes and macrophages. Interestingly, many groups have noted that cells activated in the systemic immune system tend to migrate to the gut. It has been postulated that this occurs due to the likelihood of reexposure to a specific antigen at a mucosal rather than a systemic site. Activated T cells and B cells express the mucosal integrin α4β7 which recognizes its ligand, MadCAM [13–20], on high endothelial venules (HEV) in the LP. They exit the venules into the stroma and remain activated in the tissue. Bacteria or their products play a role in this persistent state of activation. Conventional ovalbumin-T-cell receptor (OVA-TCR) transgenic mice have activated T cells in the LP even in the absence of antigen (OVA) while OVA-TCR transgenic mice crossed on to a RAG-2-deficient background fail to have activated T cells in the LP [21]. In the former case, the endogenous TCR can rearrange or associate with the transgenic TCR generating receptors that recognize luminal bacteria. This tells us that the drive to recognize bacteria is quite strong. In the latter case, the only TCR expressed is that which recognizes OVA and even in the presence of bacteria no activation occurs. If OVA is administered orally to such mice, activated T cells do appear in the LP. So antigen drive is clearly the important mediator. The failure to produce pathology despite the activated state of the lymphocytes is the consequence of suppressor mechanisms in play. Whether this involves regulatory cells, cytokines, or other, as yet undefined, processes is currently being pursued. It may reflect a combination of events. It is well known that LP lymphocytes (LPLs) respond poorly when activated via the TCR [22,23]. They fail to proliferate although they still produce cytokines. This phenomenon may also contribute to controlled inflammation (i.e., cell populations cannot expand, but the cells can be activated). In the OVA-TCR transgenic mouse mentioned above, OVA feeding results in the influx of cells. However, no inflammation is seen even when the antigen is expressed on the overlying epithelium [24]. Conventional cytolytic T cells (class I restricted) are not easily identified in the mucosa and macrophages respond poorly to bacterial products such as lipopolysaccharide (LPS) because they downregulate a critical component of the LPS receptor, CD14, which associates with Toll-like receptor-4 (TLR-4) and MD2 [25]. Studies examining cellular mechanisms regulating mononuclear cell recruitment to inflamed and noninflamed intestinal mucosa demonstrate that intestinal macrophages express chemokine receptors but do not migrate to the ligands. In contrast, autologous blood monocytes expressing the same receptors do migrate to the ligands and chemokines derived from LP extracellular matrix [26]. These findings imply that monocytes are necessary in maintaining the macrophage population in noninflamed mucosa and are the source of macrophages in inflamed mucosa. All of these observations support the existence of control mechanisms that tightly regulate mucosal immune responses.

FIGURE 1.1 Hematoxylin and eosin stain of a section of normal small intestine (20×). Depicted is the villi lined with normal absorptive epithelium. The loose connective tissue stroma (lamina propria) is filled with lymphocytes, macrophages, and dendritic cells. This appearance has been termed controlled or physiologic inflammation.

Clearly, there are situations where the inflammatory reaction is intense, such as infectious diseases or ischemia. However, even in the setting of an invasive pathogen such as Shigella or Salmonella, the inflammatory response is limited and restoration of the mucosal barrier following eradication of the pathogen is quickly followed by a return to the controlled state. Suppressor mechanisms are thought to be a key component of this process as well.

Oral tolerance

Perhaps the best-recognized phenomenon associated with mucosal immunity and equated with suppression is oral tolerance (Figure 1.2) [27–32]. Oral tolerance can be defined as the active, antigen-specific nonresponse to antigens administered orally, characterized by the secretion of interleukin (IL)-10 and transforming growth factor beta (TGF-β) by T lymphocytes. Many factors play a role in tolerance induction and there may be multiple forms of tolerance elicited by different factors. The concept of oral tolerance arose from the recognition that we do not frequently generate immune responses to foods we eat, despite the fact that they can be quite foreign to the host. Disruption in oral tolerance results in food allergies and food intolerances such as celiac disease. Part of the explanation for this observation is trivial, relating to the properties of digestion. These processes take large macromolecules and, through aggressive proteolysis and carbohydrate and lipid degradation, render potentially immunogenic substances nonimmunogenic. In the case of proteins, digestive enzymes break down large polypeptides into nonimmunogenic di- and tri-peptides, too small to bind to MHC molecules. However, several groups have reported that upwards of 2% of dietary proteins enter the draining enteric vasculature intact [33]. Two percent is not a trivial amount, given the fact that Americans eat 40–120 g of protein per day in the form of beef, chicken, or fish.

Box 1.1 Factors affecting the induction of oral tolerance.

Age of host (reduced tolerance in the neonate)Genetics of the hostNature of the antigen (protein → carbohydrate → lipid)Form of the antigen (soluble → particulate)Dose of the antigen (low dose → regulatory T cells; high dose → clonal deletion or anergy)State of the barrier (decreased barrier → decreased tolerance)

FIGURE 1.2 Comparison of immune responses elicited by changing the route of administration of the soluble protein antigen ovalbumin. (a) The outcome of systemic immunization. Mice generate both T-cell and antibody responses. (b) If mice are fed OVA initially, systemic immunization fails to generate a T- or B-cell response. (c) When T cells are transferred from mice initially fed OVA antigen to naïve mice, systemic immunization fails to generate a T- or B-cell response. Tolerance is an active process since it can be transferred by either PP CD4+ T cells (Strober, Weiner) or splenic CD8+ T cells (Waksman). These latter findings suggest that there are multiple mechanisms involved in tolerance induction. Adapted from Chehade M, Mayer L. Oral tolerance and its relation to food hypersensitivities. J Allergy Clin Immunol 2005; 115:3--12; quiz 13.

The key question then is: How do we regulate the response to antigens that have bypassed complete digestion? The answer is oral tolerance. Its mechanisms are complex (Box 1.1) and depend on age, genetics, nature of the antigen, form of the antigen, dose of the antigen, and the state of the mucosal barrier.

Several groups have noted that oral tolerance is difficult to achieve in neonates [34]. This may relate to the rather permeable barrier that exists in the newborn and/or the immaturity of the mucosal immune system. The limited diet in the newborn may serve to protect the infant from generating a vigorous response to food antigens. However, several epidemiological studies have suggested that delayed introduction may contribute to food allergies [35,36], though these studies were retrospective and difficult to control. Thus, recent guidelines for introduction of allergenic solid foods were revised to reflect that insufficient evidence exists to support delayed weaning as a strategy to prevent allergies [37]. In contrast, early introduction may also not be the solution to prevent food allergies as there may exist a time for immune regulation to mature. Interestingly, in humans, despite the relatively early introduction of cow's milk (in comparison to other foods) it remains one of the most common food allergens in children [38]. A study by Strobel demonstrated enhancement of immunologic priming in neonatal mice fed antigen in the first week of life, whereas tolerance developed after waiting 10 days to introduce antigen [39].

The next factor involved in tolerance induction is the genetics of the host. Berin et al. examined allergic sensitization in TLR4+ and TLR4− mice on two genetic backgrounds, C3H and Balb/c, and found Th2 skewing in TLR4-deficient C3H mice compared with TLR4-sufficient C3H mice. This pattern of Th2 skewing was not observed in TLR4-deficient mice on a Balb/c background [40]. Lamont et al. [41] published a report detailing tolerance induction in various mouse strains using the same protocol. Balb/c mice tolerize easily while others failed to tolerize at all. Furthermore, some of the failures to tolerize were antigen specific; upon oral feeding, a mouse could be rendered tolerant to one antigen but not another. This finding suggested that the nature and form of the antigen also play a significant role in tolerance induction.

Protein antigens are the most tolerogenic while carbohydrates and lipids are much less effective in inducing tolerance [42]. The form of the antigen is critical; for example, a protein given in soluble form (e.g., OVA) is quite tolerogenic whereas, once aggregated, it loses its potential to induce tolerance. The mechanisms underlying these observations have not been completely defined but appear to reflect the nature of the antigen-presenting cell (APC) and the way in which the antigen trafficks to the underlying mucosal lymphoid tissue. Insolubility or aggregation may also render a luminal antigen incapable of being sampled [2]. In this setting, nonimmune exclusion of the antigen would lead to ignorance from lack of exposure of the mucosa-associated lymphoid tissue (MALT) to the antigen in question. One study examining the characteristics of milk allergens involved in sensitization and elicitation of allergic response demonstrated that pasteurization led to aggregation of whey proteins but not casein and that the formation of aggregates changed the path of antigen uptake, away from absorptive enterocytes to PP. Subsequently, pasteurized β-lactoglobulin leads to enhanced IgE as well as Th2 cytokine responses in the initial sensitization step, and in contrast only soluble milk proteins triggered anaphylaxis in mice, since transepithelial uptake across the small intestinal epithelium was not impaired [43].

Lastly, prior sensitization to an antigen through extraintestinal routes affects the development of a hypersensitivity response. For example, sensitization to peanut protein has been demonstrated by application of topical agents containing peanut oil to inflamed skin in children [44]. Similar results were obtained by Hsieh's group in epicutaneous sensitized mice to the egg protein ovalbumin [45].

The dose of antigen administered during a significant period early in life is also critical to the form of oral tolerance generated. In addition, frequent or continuous exposure to relatively low doses typically results in potent oral tolerance induction. In murine models, high-dose exposure to antigen early in life can produce lymphocyte anergy while low doses of antigen appears to activate regulatory/suppressor T cells [38, 46, 47] of both CD4 and CD8 lineages. Th3 cells were the initial regulatory/suppressor cells described in oral tolerance [47–49]. These cells appear to be activated in the PP and secrete TGF-β. This cytokine plays a dual role in mucosal immunity; it is a potent suppressor of T- and B-cell responses while promoting the production of IgA (it is the IgA switch factor) [34, 50–52]. An investigation of the adaptive immune response to cholera toxin B subunit and macrophage-activating lipopeptide-2 in mouse models lacking the TGF-βR in B cells (TGFβRII-B) demonstrated undetectable levels of antigen-specific IgA-secreting cells, serum IgA, and secretory IgA (SIgA) [53]. These results demonstrate the critical role of TGF-βR in antigen-driven stimulation of SIgA responses in vivo. The production of TGF-β by Th3 cells elicited by low-dose antigen administration helps explain an associated phenomenon of oral tolerance, bystander suppression. As mentioned earlier, oral tolerance is antigen specific, but if a second antigen is coadministered systemically with the tolerogen, suppression of T- and B-cell responses to that antigen will occur as well. The participation of other regulatory T cells in oral tolerance is less well defined. Tr1 cells produce IL-10 and appear to be involved in the suppression of graft-versus-host disease (GVHD) and colitis in mouse models, but their activation during oral antigen administration has not been as clear-cut [54–56]. Frossard et al. demonstrated increased antigen-induced IL-10-producing cells in PP from tolerant mice after β-lactoglobulin feeding but not in anaphylactic mice suggesting that reduced IL-10 production in PP may support food allergies [57]. There is some evidence for the activation of CD4+CD25+ regulatory T cells during oral tolerance induction protocols but the nature of their role in the process is still under investigation [58–61]. Experiments in transgenic mice expressing TCRs for OVA demonstrated increased numbers of CD4+CD25+ T cells expressing cytotoxic T-lymphocyte antigen 4 (CTLA-4) and cytokines TGF-β and IL-10 following OVA feeding. Adoptive transfer of CD4+CD25+ cells from the fed mice suppressed in vivo delayed-type hypersensitivity responses in recipient mice [62]. Furthermore, tolerance studies done in mice depleted of CD25+ T cells along with TGF-β neutralization failed in the induction of oral tolerance by high and low doses of oral OVA suggesting that CD4+CD25+ T cells and TGF-β together are involved in the induction of oral tolerance partly through the regulation of expansion of antigen-specific CD4+ T cells [63]. Markers such as glucocorticoid-induced TNF receptor and transcription factor FoxP3, whose genetic deficiency results in an autoimmune and inflammatory syndrome, have been shown to be expressed CD4+CD25+ Tregs [64,65]. Lastly, early studies suggested that antigen-specific CD8+ T cells were involved in tolerance induction since transfer of splenic CD8+ T cells following feeding of protein antigens could transfer the tolerant state to naïve mice [66–69]. Like the various forms of tolerance described, it is likely that the distinct regulatory T cells defined might work alone depending on the nature of the tolerogen or in concert to orchestrate the suppression associated with oral tolerance and more globally to mucosal immunity.

As mentioned, higher doses of antigen lead to a different response, either the induction of anergy or clonal deletion. Anergy can occur through T-cell receptor ligation in the absence of costimulatory signals provided by IL-2 or by interactions between receptors on T cells (CD28) and counterreceptors on APCs (CD80 and CD86) [70]. Clonal deletion occurring via FAS-mediated apoptosis [71] may be a common mechanism given the enormous antigen load in the GI tract.

The last factor affecting tolerance induction is the state of the barrier. Several states of barrier dysfunction are associated with aggressive inflammation and a lack of tolerance. In murine models the permeability of the barrier is influenced by exposures to microbial pathogens such as viruses, alcohol, and nonsteroidal anti-inflammatory drugs, which can result in changes in gene expression and phosphorylation of tight junction proteins such as occludins, claudins, and JAM-ZO1, which have been associated with changes in intestinal mast cells and allergic sensitization [72,73]. Increased permeability throughout the intestine has been shown in animal models of anaphylaxis by the disruption of tight junctions, where antigens are able to pass through paracellular spaces [74–76]. More recently, mutations in the gene encoding filaggrin have been linked to the barrier dysfunction in patients with atopic dermatitis, which has been associated with increased prevalence of food allergy. Similarly, barrier defects associated with decreased filaggrin expression have been demonstrated in patients with eosinophilic esophagitis [77]. It is speculated that barrier disruption leads to altered pathways of antigen uptake and failure of conventional mucosal sampling and regulatory pathways. For example, treatment of mice with interferon gamma (IFN-γ) can disrupt the inter-epithelial tight junctions allowing for paracellular access by fed antigens. These mice fail to develop tolerance to OVA feeding [78,79]. However, as IFN-γ influences many different cell types, mucosal barrier disruption may be only one of several defects induced by such treatment.

Do these phenomena relate to food allergy? There is no clear answer yet, though both allergen-specific and nonspecific techniques to induce tolerance are being studied in clinical trials in food-allergic patients [80–83]. While these studies are interventional and may not provide insight into the mechanisms involved in the naturally occurring mucosal tolerance, they are valuable in determining successful treatment approaches to food-allergic patients.

The nature of antibody responses in the gut-associated lymphoid tissue

IgE is largely the antibody responsible for food allergy. In genetically predisposed individuals an environment favoring IgE production in response to an allergen is established. The generation of T-cell responses promoting a B-cell class switch to IgE has been described (i.e., Th2 lymphocytes secreting IL-4). The next question, therefore, is whether such an environment exists in the gut-associated lymphoid tissue (GALT) and what types of antibody responses predominate in this system.

Antibodies provide the first line of protection at the mucosal surface with IgA being the most abundant antibody isotype in mucosal secretions. In fact, given the surface area of the GI tract (the size of one tennis court), the cell density, and the overwhelming number of plasma cells within the GALT, IgA produced by the mucosal immune system far exceeds the quantity of any other antibody in the body. IgA is divided into two subclasses, IgA1 and IgA2, with IgA2 as the predominant form at mucosal surfaces. The production of a unique antibody isotype SIgA was the first difference noted between systemic and mucosal immunity. SIgA is a dimeric form of IgA produced in the LP and transported into the lumen by a specialized pathway through the intestinal epithelium (Figures 1.1–1.3) [84]. SIgA is unique in that it is anti-inflammatory in nature. It does not bind classical complement components but rather binds to luminal antigens, preventing their attachment to the epithelium or promoting agglutination and subsequent removal of the antigen in the mucus layer overlying the epithelium. These latter two events reflect “immune exclusion,” as opposed to the nonspecific mechanisms of exclusion alluded to earlier (the epithelium, the mucus barrier, proteolytic digestion, etc.). SIgA has one additional unique aspect—its ability to bind to an epithelial cell-derived glycoprotein called secretory component (SC), the receptor for polymeric Ig (pIgR) [85–88]. SC serves two functions: it promotes the transcytosis of SIgA from the LP through the epithelium into the lumen, and, once in the lumen, it protects the antibody against proteolytic degradation. This role is critically important, because the enzymes used for protein digestion are equally effective at degrading antibody molecules. For example, pepsin and papain in the stomach digest IgG into F(ab′)2 and Fab fragments. Further protection against trypsin and chymotrypsin in the lumen allows SIgA to exist in a rather hostile environment.

FIGURE 1.3 Depiction of the transport of secretory IgA (SIgA) and SIgM. Plasma cells produce monomeric IgA or IgM that polymerizes after binding to J chain. Polymeric immunoglobulins are secreted into the lamina propria and taken up by the polymeric Ig receptor (PIgR) or secretory component (SC) produced by intestinal epithelial cells and expressed on the basolateral surface. Bound SIgA or SIgM are internalized and transcytosed in vesicles across the epithelium and releases with SC into the intestinal lumen. SC protects the SIgA from degradation once in the lumen.

IgM is another antibody capable of binding SC (pIgR). Like IgA, IgM uses J chain produced by plasma cells to form polymers—in the case of IgM, a pentamer. SC binds to the Fc portions of the antibody formed by the polymerization. The ability of IgM to bind SC may be important in patients with IgA deficiency. Although not directly proven, secretory IgM (SIgM) may compensate for the absence of IgA in the lumen.

What about other Ig isotypes? The focus for years in mucosal immunity was SIgA. It was estimated that upwards of 95% of antibody produced at mucosal surfaces was IgA. Initial reports ignored the fact that IgG was present not only in the LP, but also in secretions [89,90]. These latter observations were attributed to leakage across the barrier from plasma IgG. However, recent attention has focused on the potential role of the neonatal Fc receptor, FcRn, which might serve as a bidirectional transporter of IgG [91,92]. FcRn is an MHC class I-like molecule that functions to protect IgG and albumin from catabolism, mediates transport of IgG across epithelial cells, and is involved in antigen presentation by professional APCs. FcRn is expressed early on, possibly as a mechanism to transport IgG from mother to fetus and neonate for passive immunity [93–95]. Its expression was thought to be downregulated after weaning, but studies suggest that it may still be expressed in adult lung, kidney, and possibly gut epithelium. Recent studies have explored the possibility of utilizing these unique properties of FcRn in developing antibody-based therapeutics for autoimmune diseases [96–98].