Fisher's Contact Dermatitis - 7th Edition

FISHER’S

CONTACT

DERMATITIS

7TH EDITION

Joseph F. Fowler, Jr., MD

Clinical Professor of Dermatology

Director of Occupational Dermatology

and Patch Test Clinic

University of Louisville, School of Medicine

Louisville, Kentucky

USA

Matthew J. Zirwas, MD

Ohio University

Columbus, OH

USA

Contact Dermatitis Institute

3400 E. McDowell Road

Phoenix, AZ 85008

Tel: 602-914-4267

Fax: 602-914-4269

Email: info@contactdermatitisinstitute.com

http://www.contactdermatitisinstitute.com/

Library of Congress Control Number: 2018956614

ISBN: 978-0-9773571-3-0

Printed and bound in the United States of America by Walsworth®

First printing February 2019

Cover Design: Yolieth Sanchez

© 2019 Contact Dermatitis Institute

All rights are reserved, whether the whole or part of the material. No part of this publication may be reproduced, translated, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopy, recording, or otherwise, without prior written permission from the publisher.

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Notice: The authors and publisher have made every effort to ensure that the patient care recommended herein, including choice of drugs and drug dosages, is in accord with the accepted standard and practice at the time of publication. However, since research and publication constantly change clinical standards, the reader is urged to check the product information sheet included in the package of each drug, which includes recommended doses, warnings, and contraindications. This is particularly important with new or infrequently used drugs. Any treatment regimen, particularly one involving medication, involves inherent risk that must be weighed on a case-by-case basis against the benefits anticipated. The reader is cautioned that the purpose of this book is to inform and enlighten; the information contained herein is not intended as, and should not be employed as, a substitute for individual diagnosis and treatment.

PREFACE TO FISHER’S 7TH EDITION

This seventh edition will have been published just over 50 years after the inestimable Alexander Fisher, MD, introduced his book Contact Dermatitis. It is likely that he did not expect that others would strive to continue his work and, in fact, add his name to the book’s title. Dr. Robert Rietschel and I did both when we wrote the text for the fourth edition. In the fourth through sixth editions, we attempted to update the work of Dr. Fisher and his collaborators while keeping some of the anecdotes and historical information that could be found only in the previous editions.

Now for this seventh edition, Dr. Reitschel has retired, and Dr. Matthew Zirwas has joined me as co-editor. We have retained some of Dr. Fisher’s wisdom of the ages, but much of the material is new and contributed by new authors. Although readers can now use on-line search engines to find contemporary information about contact dermatitis and patch testing, it is our hope that this volume will provide a concise one-stop location with comprehensive information on patch testing and the many causes of contact dermatitis. As of this writing, an online version is in the planning stages.

We dedicate this book to all who have taught us so much since Josef Jadassohn began patch testing in 1895 and to those on the front lines working, today and in the years to come, to identify contact allergens and to devise avoidance strategies for their patients. We also dedicate this book to our colleagues and family members who have been instrumental in its continuation: Dr. Alexander and Lilian Fisher, Dr. Robert and Connie Rietschel, Lynn Fowler, RN, and Dr. Jill Fichtel-Zirwas.

Joseph Fowler Jr., MD

Louisville, Kentucky

January 2019

List of Contributors

Khuzama Al Falah, MBBS, MMgt, SSC-Derm

Consultant Dermatologist

King Saud Medical City

Riyadh

Saudi Arabia

Amber Reck Atwater, MD

Dermatology Residency Program Director

Associate Professor of Dermatology

Director, Contact Dermatitis Clinic

Duke Dermatology

Durham, North Carolina

USA

Joel G. DeKoven, MD, MHSc, FRCPC

Associate Professor

Division of Dermatology

Department of Medicine

Sunnybrook Health Sciences Centre

and St. Michael’s Hospital

University of Toronto

Toronto

Canada

Salma Faghri de la Feld, MD

Assistant Professor

Department of Dermatology

Emory University School of Medicine

Atlanta, Georgia

USA

Vincent A. DeLeo, MD

Clinical Professor of Dermatology

Keck School of Medicine

University of Southern California

Los Angeles, California

and

Professor Emeritus, Dermatology

Icahn School of Medicine Mt. Sinai

New York, New York

USA

Joseph F. Fowler, MD

Clinical Professor of Dermatology

Director of Occupational Dermatology

and Patch Test Clinic

University of Louisville, School of Medicine

Louisville, Kentucky

USA

Anthony A. Gaspari, MD

Professor

Department of Dermatology and Cutaneous Biology

Sidney Kimmel Medical College of Thomas Jefferson

University

Philadelphia, Pennsylvania

USA

Carsten R. Hamann, MD, PhD

Dartmouth-Hitchcock Medical Center

Department of Dermatology

Lebanon, New Hampshire

USA

Curtis P. Hamann, MD

SmartPractice Dermatology

Contact Dermatitis Institute

Phoenix, Arizona

USA

Dathan J. Hamann, MD

Contact Dermatitis Institute

Phoenix, Arizona

USA

Previous address:

Division of Dermatology

Wexner Medical Center

The Ohio State University

Columbus, Ohio

USA

Stephen E. Helms, MD

Professor

Department of Dermatology

University of Mississippi Medical Center

Jackson, Mississippi

USA

Daniel Hogan, MD

Clinical Professor

Internal Medicine (Dermatology)

NOVA Southeastern University

College of Osteopathic Medicine

Fort Lauderdale, Florida

and

Chief of Dermatology

Bay Pines VA Healthcare System

Bay Pines, Virginia

USA

Marie Claude Houle, MDCM, FRCPC

Department of Dermatology

Hôtel-Dieu de Québec

CHU de Québec, Université Laval

Quebec City

Canada

Jeremy D. Jackson, MD

Associate Professor

Department of Dermatology

University of Mississippi Medical Center

Jackson, Mississippi

USA

Erin Lowe, DO

Department of Dermatology

NOVA Southeastern University/Largo Medical Center

Largo, Florida

USA

Jennifer H. Perryman, MD, MS

Greeley Skin Clinic

Greeley, Colorado

USA

Denis Sasseville, MD, FRCP

Division of Dermatology

McGill University Health Centre

Montreal

Canada

Peter C. Schalock, MD

Department of Surgery (Dermatology)

Geisel School of Medicine at Dartmouth

Hanover, New Hampshire

USA

Andrew Scheman, MD

Professor of Clinical Dermatology

Department of Dermatology

Northwestern University Feinberg School of Medicine

Chicago, Illinois

USA

Michael P. Sheehan, MD

Dermatology Physicians, Inc.

Columbus, Indiana

USA

Jonathan Silverberg, MD, PhD, MPH

Departments of Dermatology, Preventive Medicine,

and Medical Social Sciences

Northwestern University Feinberg School of Medicine

Chicago, Illinois

USA

Ainah Tan, MD

Department of Dermatology

Northwestern University Feinberg School of Medicine

Chicago, Illinois

USA

Jacob P. Thyssen, MD, PhD, DmSci

Professor

Department of Dermatology and Allergy

Herlev and Gentofte University Hospital

University of Copenhagen

Denmark

Matthew J. Zirwas, MD

Ohio University

Columbus, Ohio

USA

Table of Contents

Part 1 The Basics of Contact Dermatitis

Chapter 1: Pathogenesis of Allergic Contact Hypersensitivity

Chapter 2: Practical Aspects of Patch Testing

Chapter 3: Clinical Aspects of Contact Dermatitis

Chapter 4: Non-Eczematous Reactions to Cutaneous Contactants

Chapter 5: Hand Eczema

Part 2 The Basics of Contact Dermatitis

Chapter 6: Allergy to Topical Medications

Chapter 7: Topical Corticosteroids

Chapter 8: Medical Devices, Implants, and Equipment

Chapter 9: Preservatives and Vehicles in Cosmetics and Toiletries

Chapter 10: Textile and Footwear Dermatitis

Chapter 11: Fragrance Allergy

Chapter 12: Cutting Oils, Solvents, Petrolatum, Coal-Tar Products, Gases, and Propellants

Chapter 13: Plastics, Adhesives, and Synthetic Resins

Chapter 14: Allergies to Rubber and Other Elastomers

Chapter 15: Medical Devices, Implants, and Equipment

Chapter 16: Food Additives and Dyes

Chapter 17: Gums, Rosin, and Natural Resins

Chapter 18: Allergic Sensitization to Plants

Chapter 19: Photocontact Dermatitis

Chapter 20: Contact Stomatitis and Cheilitis

Chapter 21: Occupational Dermatitis

Chapter 22: Treatment of Contact Dermatitis

Index

Part 1

The Basics of

Contact Dermatitis

Chapter 1

Pathogenesis of Allergic Contact Hypersensitivity

Anthony A. Gaspari, MD

Executive Summary

Allergic contact dermatitis is an example of a type IV hypersensitivity reaction. Skin-derived antigen-presenting cells such as Langerhans cells play a role in the education of allergen-specific T-lymphocytes. Other cutaneous dendritic cell subsets also play a role in the sensitization and elicitation phases of allergic contact dermatitis. A multitude of T-lymphocyte subsets (defined by their cytokine profiles) act as effector and regulatory cells. Whereas T-lymphocytes convey memory and specificity in response to hapten sensitization, the emerging role of innate immunity (toll-like receptors, inflammasome, innate immune cells) is critical for the natural adjuvancy of most chemical sensitizers. Xenobiotics that cause allergic contact dermatitis trigger danger signals to the innate immune system that are similar to those elicited by microbial infections.

Predictive testing for risk assessment of novel chemicals is a challenging task for industry and regulators charged with protecting the general population from xenobiotics that have a potential to cause skin sensitization when used in topical formulations. Beyond the local lymph node assay (which involves the use of mice), there are emerging in vitro assays (peptide depletion assay, dendritic cell activation assays, in silico testing), which rely on knowledge of cellular and biochemical pathways involved in the formation, processing, and recognition of haptens by the immune system. The state of the art is that a panel of in vitro predictive assays will be necessary to identify chemicals with sensitizing potential. Despite advances in toxicologic sciences, the need for in vivo animal testing and screening of human volunteers has not yet been eliminated.

Abbreviations Used

ASC - apoptosis associated speck-like protein containing a caspase recruitment domain

ATP - adenosine triphosphate

CD - cluster designation

CGRP - calcitonin gene-related peptide

GPMT - guinea pig maximization test

h-CLAT - human cell line activation test

HLA - human leukocyte antigen

ICAM - intercellular adhesive molecule

Ig - immunoglobulin

IL - interleukin

LLNA - local lymph node assay

MCI - methylchloroisothiazolinone

MHC - major histocompatibility complex

MI - methylisothiazolinone

MUSST - myeloid U937 skin sensitization test

RNA - ribonucleic acid

TAP - transporter associated with antigen processing

Th - helper T cell

TLR - toll-like receptor

TNF - tumor necrosis factor

Allergic contact dermatitis is an example of a type IV hypersensitivity reaction. It is a T cell-driven process that begins when haptens contact Langerhans cells in the epidermis. Early events in the development of allergic contact dermatitis include penetration of the hapten through the stratum corneum, covalent conjugation to self-proteins, formation of an antigenic moiety, uptake by skin-associated dendritic cells, and education of allergen-specific T cells in the skin and local lymph node.

During the education of T cells, signals derived from the antigen-presenting cell (such as cytokines), as well as the hapten itself, polarize T cells into different subsets of helper T cells (Th). In humans, these polarized subsets produce a distinctive cytokine profile of interferons (IFN) and interleukins (IL) [e.g., Th1 (IFN-γ), Th2 (IL-4), Th9 (IL-9), Th17 (IL-17)] when stimulated with antigen. When appropriately stimulated, Langerhans cells migrate to regional lymph nodes. There, antigen is processed by antigen-presenting cells, which educate T cells to be specifically reactive to the presented allergen. Based on their cluster of designation (CD), the T cells that respond when an individual is re-exposed to an allergen are known as CD8+ T cells (cytotoxic T cells). CD8+ T cells are under the control of subsets of CD4+ T cells (helper T cells). A role has also been proposed for B cell participation in allergic contact dermatitis, and an animal model devoid of T and B cells has been found to demonstrate allergic contact dermatitis using natural killer cells.

Neurologic factors have also been found to play an important role in allergic contact dermatitis. Destroying the nerve fibers to draining lymph nodes can abolish the reaction. The neuropeptides, substance P, neurokinin A, and calcitonin gene-related peptide (CGRP) and their receptors, all play regulatory roles. T-regulatory cells play a critical role in downregulating the contact sensitivity reaction. IL-10 production by these cells is one of the underlying mechanisms, and there is also a cell-to-cell, contact-dependent, cytokine-independent mechanism. Skin memory of contact dermatitis may be due to the chemokine, CCL27, which causes retention of a specific type of T cell in the skin where the allergen was encountered.

Jadassohn, who described contact allergy to mercury in 1895, can be considered the ‘‘father’’ of contact dermatitis.¹ Earlier, and indeed for some years thereafter, contact hypersensitivity was essentially unknown except by a few workers in dermatology.²–⁵In 1927 Landsteiner published studies regarding antigens containing ‘‘simple chemical compounds.’’⁶ In 1929 Sulzberger published one of the earliest American works on the subject.⁷

Another important development was the recognition of the close similarity between contact allergy and delayed-type hypersensitivity to microbial antigens, which followed the findings of Landsteiner and Chase that both contact allergy to small molecular allergens and delayed-type hypersensitivity to microbial antigens could be passively transferred with lymphocytes in guinea pigs.⁸,⁹ This finding precipitated an era in which many investigators considered contact allergy and microbial allergy to be based on identical mechanisms. Despite many important fundamental similarities, however, certain differences between these forms of allergy were always evident.¹⁰,¹¹

Teleologically, one assumes that cell-mediated hypersensitivity serves the purpose of defending the body against foreign antigens such as those derived from bacteria, fungi, viruses, and foreign tissues and against autologous tumor antigens and other undesirable autologous antigens. Although cell-mediated hypersensitivity to these antigens helps to preserve the body’s integrity, allergic contact hypersensitivity to small molecular allergens (which, in fact, is hypersensitivity to autologous proteins made ‘‘foreign’’ by forming a complex with small molecular compounds) is damaging to the skin. In a sense, therefore, contact allergy can be considered a deviant form of cell-mediated hypersensitivity. The newest concept of allergic contact dermatitis is that xenobiotic chemicals are recognized as foreign because they activate innate immunity, mimicking danger signals similar to those engaged during a bacterial infection.¹²

Clinically, histologic evaluation of potential contact dermatitis is useful primarily to eliminate other conditions that could be confused with contact dermatitis. On the basis of a biopsy, contact dermatitis cannot be differentiated from other types of spongiotic dermatitis. From a research perspective, biopsies obtained within about 8 hours of induction may show some differences between allergic contact dermatitis and irritant contact dermatitis. In a clinical situation, however, a biopsy is usually performed several days after onset of disease. By then the histologic changes associated with irritant contact dermatitis and allergic contact dermatitis may appear almost identical.

Contact dermatitis is usually differentiated from other types of dermatitis on the basis of clinical findings, knowledge of exposure to potential allergens or irritants, and diagnostic patch testing. The histopathologic appearance of contact dermatitis overlaps with that of other forms of dermatitis and is seldom helpful in distinguishing the various forms of dermatitis. Both irritant and allergic contact dermatitis, however, have certain histopathologic features that sometimes add weight to the evidence in favor of the diagnosis.

Predictive testing is important in risk assessment during the preclinical evaluation of chemicals to which human subjects will be exposed in the form of skin care products. The rationale for all forms of predictive testing is derived from a profound understanding of the critical control points of allergic contact dermatitis. While in vivo assays such as the local lymph node assay (LLNA) are the current industry standard, a battery of in vitro tests can be used to study aspects of the allergic contact dermatitis cascade, such as hapten formation; dendritic-cell activation (maturation and associated change in immunologic phenotype) in response to hapten exposure; and the ability of activated dendritic cells to educate naive T cells in vitro, causing them to proliferate and secrete cytokines (as thought to occur in the local lymph node). In the next 10 years, it may be possible to make risk-assessment decisions without animal data by using a tiered, flexible, pathway-driven panel of predictive in vitro assays derived from advances in the immunology, biochemistry, and toxicology of allergic contact dermatitis. Ultimately, the value of these predictive tests will be validated by observations in populations of patients exposed to these chemicals.

OVERVIEW OF MECHANISMS OF HYPERSENSITIZATION

Contact allergens are small molecular substances, typically less than 500 Da.¹³ Because of their small size, they penetrate the skin barrier, which is relatively impermeable to large molecules under normal circumstances, and reach the living layers of the skin. To induce contact allergy, these substances must be presented to T lymphocytes in an immunologically effective ‘‘processed’’ form. This role is performed by antigen-presenting cells, principally epidermal Langerhans cells, and other dendritic cells. Dendritic cells located in the epidermis are commonly referred to as Langerhans cells while those in the dermis belong to a more heterogenous group.¹⁴

The heterogenous population of dendritic cells can be differentiated based on anatomical location, immunological function (i.e., antigen uptake, processing, and presentation to T cells) and surface marker expression. Several different subsets of dendritic cells exist in healthy skin.¹⁴ Langerhans cells, the major dendritic cell population in the epidermis, possess unique organelles known as the Birbeck granules, which are composed of granules of langerin (CD207).¹⁵ Other than staining positive for langerin, Langerhans cells also express major histocompatibility complex (MHC) Class II, CD11c, and CD1a (only in humans). In steady state, Langerhans cells remain in the epidermis and renew in the tissue by proliferating in situ. Initially, Langerhans cells were thought to be the only langerin+ cells in the skin. Later, langerin+ dendritic cells were identified in the dermis along with the better-known langerin- dermal dendritic cells.¹⁶ Finally, a small number of plasmacytoid dendritic cells, which were identified in the dermis of healthy individuals, are increased in allergic contact dermatitis and psoriasis.¹⁷

Knowledge of Langerhans cells expanded rapidly after identification of langerin and the subsequent generation of mouse models that permitted selective ablation of Langerhans cells.¹⁸ It is now appreciated that Langerhans cells may induce tolerogenic responses in the steady state. Langerhans cell ablation did not affect the duration of the T-cell response in skin contact hypersensitivity and, in a separate study, resulted in a stronger immune response. Together, the findings suggested that Langerhans cells may play an anti-inflammatory role in contact hypersensitivity. The tolerogenic role of Langerhans cells is not restricted to the contact hypersensitivity model. In an ultraviolet radiation model, Langerhans cells appear to be essential for regulatory T-cell induction.¹⁹ While most of these findings were obtained from studies of mice, they also are true for human Langerhans cells, which favor the generation of regulatory T cells under homeostatic conditions.²⁰

To interact with antigen presented by Langerhans cells during both induction of hypersensitivity and elicitation of a reaction, the T lymphocytes must possess surface antigen receptors (‘‘idiotypes’’) that are complementary to the physicochemical features of the antigen presented in the context of self-MHC molecules. Furthermore, the antigen-presenting cells must bear immune response-associated antigens for which the T lymphocytes possess receptors. The T lymphocytes also must be activated by IL-1, which is released from Langerhans cells and keratinocytes.

It was initially assumed that in a steady state skin contains very few T cells and that most T cells present during disease were recruited from the bloodstream.²¹ These assumptions, however, are not the case because αβ T cells with a memory phenotype regularly populate the human skin.²² In the epidermis T cells are usually found in the basal layer near Langerhans cells, and CD8+ T cells predominate. In the dermis, CD4+ T cells are more abundant than CD8+ T cells. Normal human skin is home to around 2 billion T cells, most of which (~80%) are classical αβ T cells that exhibit an effector memory phenotype as determined by the expression of CD45RO (and L-selectin-).²³,²⁴ Based on immunohistochemical staining, a large population of skin-resident T cells have been identified near vessels and skin appendages. Not surprisingly, T cells in the skin express molecules such as cutaneous lymphocyte antigen, CCR4 (C-C motif chemokine receptor 4), and other addressin molecules that allow the T cells to home to the skin. A small percentage of regulatory T cells has also been identified in human skin.²⁵

Under ordinary conditions, exposure to contact allergens sets two competing mechanisms in motion. One mechanism is mediated by effector T lymphocytes and leads to a state of hypersensitivity that becomes clinically manifest as an eczematous skin reaction. The other mechanism is mediated by suppressor cells now known as T regulatory cells (CD4+ T cells) that express CD25, thereby suppressing effector T cells and leading to relative or complete tolerance of the allergen. At any given time and site, the state of reactivity of the skin is principally the result of the balance between effector and suppressor cells present. T cells from patients who are clinically tolerant of nickel produce suppressive cytokines such as IL-10 when stimulated in vitro. This finding suggests that immune tolerance to xenobiotics is an active process and not merely a lack of reactivity.²⁵

Innate Immunity

The skin is heavily armed with innate immune mechanisms. There are physical barriers such as the stratum corneum, antimicrobial peptides, complement system, cell-associated toll-like receptors, and the inflammasome (an intracellular system for recognizing microbial infections). Emerging evidence suggests that innate immunity plays a critical role in the early molecular events underlying contact dermatitis. Toll-like receptors (TLRs) are a family of receptors that recognize pathogen-associated molecular patterns found on microorganisms (i.e., bacteria, parasites, viruses and fungi). Evolutionarily, TLRs are conserved in vertebrates and recognize a wide variety of ligands, including lipids, lipoproteins, proteins, and nucleic acids.²⁶ TLRs trigger specific biological responses. In addition to pathogen-associated molecular patterns, TLRs also recognize damage-associated molecular patterns, or self-molecules released during necrotic cell death. These ligands comprise a diverse set of proteins, nucleic acids, and glycosaminoglycans, including heat shock proteins, HMGB1 (high mobility group box 1), ribonucleic acid (RNA), deoxyribonucleic acid, hyaluronan, and heparin sulfate.²⁷

A crucial role for TLR2 and TLR4 has been described in the contact hypersensitivity experimental model of allergic contact dermatitis.²⁸ TLR2 and TLR4 appear to recognize endogenous ligands in the skin. One candidate is low molecular weight breakdown products of high molecular weight hyaluronic acid.¹² Low molecular weight hyaluronic acid activates dendritic cells in vitro via TLR2 and TLR4.²⁹ In addition, reactive oxygen species, which are produced in response to haptens, can induce the breakdown of hyaluronic acid. Importantly, blockade of the function of hyaluronic acid in germ-free mice significantly reduces sensitization,²⁹ which confirms a role for degraded hyaluronic acid as an endogenous activator of TLR2/4 signaling in contact hypersensitivity.

Human TLR4 (hTLR4) is the crucial receptor for nickel-induced pro-inflammatory gene expression.³⁰ Nickel allergy in humans appears to be an accident of nature. Binding of nickel to human TLR4, but not of the natural ligand lipopolysaccharide, requires the presence of two nonconserved histidines (H) in hTLR4: H456 and H458. These histidines are absent from mouse TLR4, which explains why mice fail to develop contact hypersensitivity to nickel.³⁰

A second recognition system for pathogen-associated molecular patterns involves the formation of an intracellular complex of proteins termed the inflammasome.³¹ The inflammasome complex includes proteins of the NLR (nucleotide-binding domain and leucine-rich repeat containing) gene family that sense foreign pathogen-associated molecular patterns or endogenous ligands through an incompletely understood mechanism. Engagement of these receptors signals through the adaptor protein ASC (apoptosis associated speck-like protein containing a caspase recruitment domain) to activate pro-caspase 1, which cleaves pro-interleukin-1β (pro-IL-1β) and pro-IL-18 into active forms. Since one outcome of TLR signaling is increased expression of messenger RNA for IL-1β, the TLR and inflammasome systems can work coordinately to induce inflammatory cytokines.

The importance of this system in responding to haptens is demonstrated by the reduction of hypersensitization to trinitrochlorobenzene and dinitrofluorobenzene in ASC-/-, NALP3-/- (NACHT domain-, leucine-rich repeat-, and PYD-containing protein 3), and caspase1-/- mice.³² At least in the case of trinitrochlorobenzene, inflammasome activation also depends on the adenosine triphosphate (ATP) receptor, P2X7.³³ This finding suggests that inflammasome activation is an indirect result of cell damage and release of ATP. Interestingly, dinitro-

thiocyanobenzene is a weak sensitizer that can induce tolerance to the structurally related hapten, dinitrofluorobenzene. Dinitrothiocyanobenzene does not induce inflammasome-mediated secretion of active IL-1 and IL-18.³⁴ Artificial inflammasome induction with sodium lauryl sulfate or co-administration of IL-1β converts dinitrothiocyanobenzene into a sensitizer. Therefore, inflammasome activation may be a feature common to all sensitizing haptens.

Innate immune cells such as natural killer T cells (a hybrid cell between a TCR (T-cell receptor)-bearing conventional T cell and a natural killer cell), which recognize glycolipids, are important in mouse contact hypersensitivity: Absence of this cell type severely impairs contact hypersensitivity.³⁵ In allergic contact dermatitis in humans, natural killer T-cells accumulate 100-fold greater than in the peripheral blood.³⁶ In the skin, they migrate into the epidermis and can mediate cytotoxicity against CD1d-bearing keratinocytes. They thus play a role in the inflammatory reaction underlying allergic contact dermatitis. Another even more primitive cell type is the natural killer cell, which lacks an antigen receptor, and is thought to play a role in anti-viral and anti-tumor host defense. In contact hypersensitivity, this cell type can substitute for conventional T cells in severe combined immune deficient mice (which lack conventional T and B cells).³⁷ This intriguing finding has yet to be confirmed in humans.

Contact Allergens

Typically, only small molecular compounds (<500 Da) can penetrate the horny layer into the living layers of the epidermis. Yet, to induce and elicit contact allergy, an antigen with a molecular weight of at least 5,000 Da is required. Antigenicity is accomplished by the conjugation of small molecules with autologous proteins present in the skin. Other requirements for antigenicity are the appropriate number of antigenic determinants and the appropriate tertiary structural features in the resulting molecule. Activation of the innate immune response is also part of this process. Sensitization is more easily induced when the skin barrier is compromised by dermatitis or ulceration.

It was originally thought that such conjugates were formed with the fibrous proteins of pro-keratins, keratins, procollagens and collagens, epidermal cell membranes, or soluble tissue and serum proteins. Although a role for these conjugates cannot be dismissed, it now appears that conjugation primarily occurs with cell membrane proteins during ‘‘processing’’ by the antigen-presenting Langerhans cells.

Linkage to the protein moiety is frequently covalent; for example, the epsilon-amino group of lysine and the sulfhydryl groups of cystine and cysteine have been suggested as binding sites for certain allergens. Often, however, it is difficult to predict the sensitizing capacity of a substance on the basis of its chemical structure. Some of the most common contact allergens, such as nickel, chromates, and other metal salts, do not form covalent bonds with proteins; that they can combine in some form with components of Langerhans cells provides a reasonable explanation for their allergenicity.³⁸ Current research suggests that a ‘‘successful’’ contact allergen causes an increase in the size of Langerhans cells along with an increase of Ia (MHC) molecules and co-stimulatory (second signal) molecules on the surfaces of Langerhans cells. In addition, the allergen may induce the migration of Langerhans cells to lymph nodes.³⁹ Langerhans cells migrate from the epidermis not only when exposed to allergens but also when exposed to toxic concentrations of irritants.⁴⁰

Genetic Factors

Susceptibility to the development of contact sensitivity is controlled genetically. The mode of inheritance in guinea pigs is autosomal and irregularly dominant.⁴¹ Different strains of guinea pigs can make an immune response to different contact allergens. For example, one strain responds to potassium dichromate and beryllium fluoride but not to mercuric chloride, whereas another strain responds to mercuric chloride but responds poorly to potassium dichromate and beryllium fluoride.⁴² These differences apparently relate to different hapten-amino acid linkages.

Exposure to ultraviolet-B inhibits contact sensitivity in certain strains of mice but not in other genetically distinct strains.⁴³,⁴⁴ Tumor necrosis factor-α (TNF-α) may be an important mediator of these effects.⁴⁵ Cellular death receptors such as the TNF-α receptor and Fas play a role in ultraviolet-induced immune suppression by leading to apoptosis of epidermal cells such as Langerhans cells and keratinocytes.⁴⁶

Studies of the mode of inheritance in humans are still inadequate, but the limited data suggest that genetic factors also control susceptibility to sensitization to particular allergens.⁴⁷ European studies have compared the frequency of human leukocyte antigens (HLAs) in patients with allergic contact dermatitis, usually to nickel, with local controls.⁴⁸-⁵⁰ Several studies have purported to show the increased occurrence of one or two HLA types in patients. However, for reasons that are obscure, no two studies have found the same HLA antigen to be increased in a statistically significant fashion. Among the antigens reported to be increased to some degree are HLA-B7, -B21, -B12, -Bw22, -B35,

-B40, -DR4, and -DRw6. Because the expression of the HLA antigen system is essential for the development of allergic contact dermatitis, it is tempting to search for associations between them.

Gene products of the transporter associated with antigen processing genes (TAP), TAP-1 and TAP-2, are involved in antigen processing. In a Finnish study, nickel-allergic persons were much more likely to possess the TAP-2B gene allele and much less likely to be TAP-2C positive than nonallergic subjects.⁵¹ These findings further support the likelihood of inborn genetic factors regulating the development of contact allergy across individuals.

In a study examining the genetic basis of susceptibility to contact allergy, polymorphisms in cytokine genes in individuals with multiple contact allergens were compared to those in individuals without eczema or contact allergy. Carriers of TNFα-308*1/2(*GA) and TNFα-308*2.2(*A/A), both TNFα genes, were more likely to be polysensitized.⁵² Another role for genetic polymorphism in contact dermatitis in humans has been identified. Susceptibility to para-phenylenediamine sensitization was related to genotype coding for rapid acetylation in 52.9% of patients with contact dermatitis compared with 37% of control subjects. The frequency of the NAT2*4 allele (N-acetyltransferase-2) and NAT2*4/*4 genotype, which code for rapid acetylation, was significantly higher in the patients with contact dermatitis (p = 0.003).⁵³

Antigen Presentation

T lymphocytes cannot interact directly with a contact antigen even when they possess the appropriate surface receptors for that antigen. The antigen must first be ‘‘processed’’ and then presented in suitable form on the surface of Langerhans cells that bear immune response-associated surface antigens [HLA-DR in humans;⁵⁴ class II MHC, called Ia (immune associated antigen), in mice] for which the T lymphocytes have the specific receptors. To induce contact allergy, the allergen is displayed in close association with these antigens or perhaps becomes conjugated with them.⁵⁵,⁵⁶ Random T lymphocytes circulating through the epidermis, dermis, dermal lymphatics, and regional lymph nodes can become apposed to the Langerhans cells, but only T lymphocytes, which have the complementary receptors for the contact antigen that is being presented, can become irreversibly apposed.

Langerhans Cells

Epidermal Langerhans cells have properties that make them particularly well suited to serve the function of presenting contact allergens. They have a pronounced capacity to bind small molecular compounds, among them well-recognized contact allergens, to their surface.³⁸ Their capacity for this binding exceeds that of peripheral blood macrophages.⁵⁷ Similar antigen-presenting cells found in the spleen, lymph nodes, and Langerhans cells are all derived from bone marrow precursors.

The antigen-processing capacity of Langerhans cells first involves plasma membrane changes with endocytosis of the antigen and digestion of proteins to active peptides in acidic organelles.⁵⁸,⁵⁹ At this time Birbeck granule expression increases, apparently in relation to antigen processing. As processing continues, the morphology of the Langerhans cells changes to a more dendritic cell type, which is associated with enhanced antigen-presenting capacity.

Experimental proof of the antigen-presenting functions of Langerhans cells derives from studies in inbred guinea pigs and mice and from the demonstration in mice that antigen presentation cannot occur in the absence of adequate numbers of functionally intact Langerhans cells at sites of exposure to the allergen.⁶⁰

Irradiation with ultraviolet-B or application of a topical corticosteroid reduces the density of Langerhans cells in skin and inhibits induction of contact sensitization.³⁹ In vitro cyclosporine A inhibits the antigen-presenting capability of Langerhans cells, apparently without affecting cell surface expression of Ia molecules.⁶¹

Induction of Contact Allergy

Soon after contact with an allergen, various cytokines that enhance the development of contact sensitivity are released.⁶² IL-1B increases the level of intercellular adhesive molecule-1 (ICAM-1). Other molecules, which facilitate interaction with CD4+ T cells, are then expressed on the surface of the Langerhans cells.

Within 24 hours of antigen application, Langerhans cells migrate to regional lymph nodes. There, they present the antigen to compatible T lymphocytes. The T lymphocytes must bear receptors for the complementary MHC protein as well as receptors for the contact allergen. Ultrastructural observations indicate that the contact allergens reside on the surfaces of Langerhans cells as well as in the intracytoplasmic Birbeck granules.⁶³ In the lymph nodes, certain T lymphocytes become physically apposed to the Langerhans cells, thereby facilitating transfer of antigen. These T cells are CD4+ and CD45RA+ and may be referred to as Th-0 cells.⁶⁴ Other cytokines, including transforming growth factor-β, IL-6, and IL-12, are important at this stage of sensitization. Lack of IL-12 can prevent development of Th-1 cells, which cause allergic contact dermatitis, and therefore may allow tolerance to the particular allergen to develop.⁶⁵ Through clonal proliferation, a subset of T lymphocytes capable of responding to the particular antigen upon future exposure is produced. Seven to 10 days are required before the number of these specific T lymphocytes is sufficient to cause contact dermatitis. Thereafter, contact dermatitis can be elicited by patch test or routine exposure.

Effector and Suppressor Cells

As discussed, exposure of individuals who are genetically susceptible to sensitization to a specific contact allergen sets in motion two competing mechanisms, that is, allergic sensitization mediated by effector cells and specific immunologic tolerance mediated by suppressor cells. In an unsensitized individual, oral or parenteral administration of an antigen can lead to reduced immune reactivity, whereas topical application of the same allergen may cause contact sensitization.⁶⁶ In experiments on guinea pigs, Landsteiner and Chase demonstrated the key role played by lymphocytes as the source and carriers of the hypersensitivity in contact allergy.⁹ Peritoneal exudate cells, predominantly lymphocytes, from contact-allergic donor animals, injected intraperitoneally or intravenously into recipient animals that had not previously been sensitized, passively transferred the hypersensitivity. In humans, however, such passive transfer experiments have yielded contradictory results. Both failure and success have been reported with intracutaneous and intravenous passive transfer of sensitized cells.⁶⁶-⁷⁰ The immunologic changes that ensue during the early days after a sensitizing exposure usually have a lasting impact on the outcome of the competition between effector and suppressor lymphocytes. The state of specific allergic hypersensitivity may last indefinitely. Once established, it cannot be deliberately altered, except for transient hyposensitization. Contact hypersensitivity is often thought to wane spontaneously in the elderly. In some patients, hypersensitivity wanes spontaneously at a much earlier age (sometimes within a few years of sensitization) despite continued exposure to the specific contact allergen. This seemingly contradictory finding remains unexplained. Contact allergy can develop from earliest infancy to old age, but it is most common in intermediate age groups.

The spleen plays an important role in generating suppressor cells.⁷¹ Tolerance, once established, apparently persists indefinitely in humans. In laboratory animals, tolerance can be broken deliberately with cyclophosphamide.⁷²,⁷³

The induction of contact allergy is sometimes referred to as the afferent phase and elicitation as the efferent phase. Vocanson and colleagues reviewed the role of various factors involved in the study of contact dermatitis in mouse models.⁷⁴ Most of this mouse work was done with strong sensitizers, such as 2,4-dinitrochlorobenzene and oxazolone. However, weak haptens, such as dyes, preservatives, perfumes, metal ions, and drugs, are the common haptens in human medicine. During the afferent phase, CD8+ T cells in draining lymph nodes are primed. During the efferent phase, these cells are recruited to the site of hapten challenge. In mice CD8+ T cells are the effector cells in weak allergens. Cells that downregulate contact dermatitis to strong haptens in animal models include various CD4+ T cell subsets. Th2 cells, IL-10-producing Tr1 cells, and natural CD4+CD25+ T cells have been implicated in downregulation. Vocanson and colleagues further found that both natural and hapten-induced CD4+CD25+ T cells regulate the CD8+ T cell response to a weak hapten (such as fragrances).⁷⁴ The sensitizing potential of haptens correlated with their pro-inflammatory properties. This association provided the activation of the skin-innate immunity required for differentiation and mobilization of dendritic cells from skin to lymph node and the priming of CD8+ T cell precursors. Since factors in the control of the development of allergic contact dermatitis include frequency, dose, duration, and route of administration of hapten; genetic polymorphisms of xenobiotic-metabolizing enzymes; and environmental factors such as psychological stress, CD8+ cytotoxic lymphocytes are implicated in the elicitation of contact dermatitis.⁷⁴ CD4+ T cells perform regulatory functions, but CD8+ T cells can mediate contact hypersensitivity, even in the absence of the CD4+ cells. Skin biopsies obtained 3 days after patch testing show that IL-12 is present in the cytoplasm of dermal dendritic cells, macrophages and Langerhans cells. IL-12 can also be found in keratinocytes in the presence of cellular exocytosis and spongiosis. IL-12 is thought to enhance the activation of cytotoxic lymphocytes and plays an important role in contact dermatitis.⁷⁴,⁷⁵

The focus of immunologists on T cell and B cell factors in contact hypersensitivity was questioned by O’Leary and colleagues, who demonstrated substantial contact hypersensitivity to 2,4-dinitroflurobenzene and oxazolone in mice devoid of T and B cells. Natural killer cells were believed to account for this phenomenon.³⁷ The role of B cells has been clarified in mouse models, and a role for IL-5 in activating eosinophils and B-1 cells has been described. The B-1 cell-derived antigen-specific immunoglobulin M (IgM) antibodies recruit effector T cells into skin. Infiltration of antigen-nonspecific mononuclear cells and polymorphonuclear cells follows.⁷⁶

Generalization of Contact Sensitivity

Antigen presentation by Langerhans cells to T lymphocytes has been thought to occur primarily in the lymph nodes. Whether antigen presentation also occurs in the skin is uncertain.⁷⁷ As stated, T cells residing in the skin (termed T-effector memory cells) accumulate and persist in the skin after an infection or immunization.²³,²⁴ This phenomenon is thought to be important in fixed drug eruption, psoriasis, and cutaneous T-cell lymphoma. Accumulation of allergen-specific T cells in the dermis also likely occurs after allergic contact dermatitis and may explain recall reactions when previous sites of contact dermatitis flare during patch testing. During this period of proliferation in laboratory animals, regional lymph nodes enlarge. There, allergen-specific T cells undergo further proliferation, which accounts for the production of large numbers of specifically sensitized effector cells and T memory cells. Their descendants enter the collecting sinus of the lymph node and from there are transferred to the blood, where they circulate to other parts of the lymphoid system.⁷⁸ This finding explains why almost invariably the entire surface of the body becomes hypersensitive to a contact allergen.

Localized Differences in Sensitivity

Contact sensitivity usually involves the entire integument, but differences in the degree of sensitivity at different skin sites are relatively common. For example, the site of originally induced sensitization and sites of previous exposure to a particular allergen (e.g., from patch testing) are often more sensitive than other areas.⁷⁹ The underlying mechanism has not been elucidated, but one theory postulates that clones of sensitized cells establish themselves in the dermis during an encounter with an allergen. Re-exposure to the allergen may trigger interaction with and proliferation of the clones of specifically sensitized cells at these previously exposed sites, thus accounting for their increased reactivity.

Elicitation of Reactions

After sensitization has occurred, re-exposure to the specific allergen leads to a series of events that eventually results in the inflammatory response clinically recognized as eczematous dermatitis. Histologically, this condition is characterized by spongiosis and lymphocytes in the epidermis and by lymphocytes, histiocytes, and varying numbers of eosinophils and basophils in the papillary dermis. The spongiosis may be partially attributable to the destructive effects of hapten-specific cytotoxic effector cells on keratinocytes and Langerhans cells.⁸⁰ The presence of eosinophils and basophils points to the participation of IgE antibodies and of cutaneous basophil hypersensitivity in the production of contact allergic reactions.⁸¹,⁸² Basophils are sources of transforming growth factor-β and therefore may play a role in downregulating expression of allergic contact dermatitis.

Elicitation of allergic contact dermatitis in a sensitized individual starts with antigen uptake and presentation by Langerhans cells and other cutaneous dendritic cell populations. T lymphocytes specifically reactive to the allergen in question accumulate at the site of exposure. It is unclear whether this accumulation is related to localized retention or proliferation of the specific T cells once they arrive at the site or to their preferential migration to the site.⁸³ Kalish, however, believes that migration of T lymphocytes is random and therefore that on-site retention or proliferation is likely.³⁹ Antigen-specific T cells compose 1% or fewer of the total T-cell population of the site, but this percentage is still 10 to 100 times greater than that present in the circulation.

Both antigen-specific and nonspecific T cells produce inflammatory mediators once they arrive on-site. TNF-β has direct cytotoxic effects on epidermal cells. It also induces ICAM-1 on keratinocytes, which aids binding of lymphocytes. Gamma-interferon, which induces both ICAM-1 and HLA-DR antigen expression on keratinocytes, further facilitates attachment by lymphocytes. Various interleukins stimulate growth and activation of T lymphocytes and attract neutrophils. Granulocyte-monocyte colony-stimulating factor activates monocytes and neutrophils.⁸⁴-⁸⁶

Mast Cells and Basophils

Mast cells and basophils are routinely found at sites of allergic contact dermatitis and are usually confined to the upper dermis. They release histamine, serotonin, and leukotrienes.⁸⁷ Pruritus and vascular dilation leading to tissue edema may result. Leukotrienes attract both neutrophils and lymphocytes. Mast cells and basophils, however, are not essential for the development of allergic contact dermatitis as demonstrated by its development in most cell-deficient mice.⁸⁸

Keratinocytes

Keratinocytes are not passive bystanders in the process of allergic contact dermatitis. Multiple cytokines are produced and/or released by damaged or ‘‘activated’’ keratinocytes. These cytokines include interleukin and granulocyte-monocyte colony-stimulating factor, with the function noted above. ICAM-1 is expressed in damaged but not normal keratinocytes, and it aids T-cell attachment. Furthermore, involved keratinocytes produce HLA-DR antigens in the cell surface, thereby allowing attachment of autoreactive T lymphocytes. Keratinocytes can serve as targets for cytotoxic T cells; that is, they can present hapten on self-class I MHC and are lysed as a result of this antigen presentation. Ia+ keratinocytes can also present haptens to T-helper cells, inducing clonal anergy (T-cell tolerance), thus competing with dendritic cells for antigen presentation to epidermotropic T cells and dampening allergic contact dermatitis.⁸⁹,⁹⁰ This mechanism may be involved in the maintenance of peripheral tolerance.

IL-1, which was one of the first cytokines identified from keratinocytes, enhances the activation of accessory dendritic cells, which, in turn, activates resting T lymphocytes.⁹¹ IL-5, also expressed by keratinocytes, further stimulates T-cell proliferation. IL-8 is another keratinocyte product that has a strong chemotactic effect on T cells. Nozaki and colleagues have published an excellent review of cytokine effects.⁹²

Neurologic Factors

Neuropeptides may influence the development of allergic contact dermatitis because nerve fibers of skin are in direct contact with Langerhans cells.⁹³ In response to epicutaneously applied allergens, unmyelinated sensory neurons release cutaneous neuropeptides, including substance P (also known as neurokinin 1), neurokinin A, and CGRP. Substance P may increase allergic contact dermatitis by increasing levels of TNF-α and IL-2. Substance P stimulates its principal receptor, neurokinin 1R. The result includes the release of IL 1 and the immunologic cascade. A second receptor, neurokinin-2R, also exists. Allergic contact dermatitis is augmented when neurokinin 2R is blocked and decreased when it is stimulated. Conversely, blocking neurokinin-1R decreases allergic contact dermatitis while stimulating neurokinin-1R increases it. Neurokinin A seems to work with neurokinin-2R, and substance P works with neurokinin-1R. Both substance P and neurokinin A are released when allergen is applied. Capsaicin-mediated depletion of neuropeptides in the skin of mice abolishes contact sensitivity to 2,4-dinitrochlorobenzene. Furthermore, destroying the nerve fibers to draining lymph nodes can abolish the reaction to 2,4-dinitrochlorobenzene.⁹³ CGRP may decrease allergic contact dermatitis by stimulating production of IL-10.⁹⁴,⁹⁵

The interplay between the immune system and cutaneous nerves was explored by injecting CGRP and a CGRP-antagonist into human skin before challenge with substances that induce immediate, delayed, and irritant reactions. At low doses, inhibition of CGRP inhibited delayed reactions but not immediate or irritant reactions; high doses exerted the opposite effect on delayed reactions. These findings imply a role for CGRP in delayed immunologic reactions.⁹⁶

Inhibition of Contact Sensitivity

Antigen presentation will be inadequate if exposure to a contact allergen occurs at a skin site with an insufficient number of functionally intact Langerhans cells. Under such circumstances, the development of specific immunologic tolerance (unresponsiveness) is favored because production of effector T lymphocytes is greatly decreased or absent. Another consequence is that a greater amount of allergen reaches the central parts of the lymphoid system and induces the production of specific suppressor cells there. However, even when first exposure is by contact, a tolerogenic effect is exerted by the fraction of the allergen that bypasses the epidermal Langerhans cells and reaches the dermis, dermal lymphatics, and regional lymph nodes.⁹⁷,⁹⁸ The ultraviolet radiation-resistant antigen-presenting cell described by Granstein and colleagues must also be mentioned in this connection.⁹⁹

Under what circumstances can one expect inadequate antigen presentation and consequently suppressor cell predominance to occur? In laboratory animals certain skin sites have contained a relatively small number of Langerhans cells. For example, the tail skin of mice has approximately one-third the number of Langerhans cells compared to most other areas of the skin. Although variations in the number of Langerhans cells have been observed in different areas of the skin in humans, none has yet been found to be so deprived of these cells that it interferes with adequate antigen presentation.⁹⁹ A decrease in the number or functional ability of Langerhans cells or dysfunction of the T-lymphocyte systems can lead to diminished contact sensitivity. Ultraviolet radiation decreases the functional capability of Langerhans cells and may impair lymphocyte function but does not greatly reduce the actual numbers of Langerhans cells.³⁹,¹⁰⁰ Topical corticosteroid usage also results in functional impairment of Langerhans cells and suppression of patch test reactions.¹⁰¹ Systemic intake of corticosteroids may compromise T-lymphocyte function as well as Langerhans cells capability.¹⁰² Cyclosporine A impairs Langerhans cells function in vitro without cytotoxic effects on the Langerhans cells or T lymphocytes.¹⁰³ Langerhans cells function may be compromised in acquired immunodeficiency syndrome.¹⁰⁴ The failure of Langerhans cells to stain positively for membrane Ia antigens and ATPase has demonstrated this functional impairment. Although the number of Langerhans cells demonstrable by electron microscopy at such sites is either unchanged or only slightly reduced, many of the cells are functionally impaired. Immediately after a contact allergic reaction, the number of Langerhans cells is temporarily reduced. Whether this reduction is sufficient to interfere with antigen presentation is unknown. Recovery from functional impairment caused by glucocorticosteroids and ultraviolet radiation usually takes 1 to 2 weeks.

Although antihistamines inhibit mast cell and basophil function, they do not appreciably alter contact hypersensitivity. Likewise, immunosuppressive agents such as methotrexate do not seem to impair contact sensitivity, as measured by patch testing.

It is safe to assume that other undiscovered factors and diseases that can also interfere with antigen presentation by Langerhans cells must exist.

Downregulation of Contact Sensitivity by Regulatory T Cells

Control of contact sensitization is mediated by two types of T cells. One type of T cell releases IL-10, which impairs the normal release of IL-12 from mature dendritic cells responding to an antigen. This lack of IL-12 inhibits activation of effector T cells. This type of control is under the direction of IL-10-producing regulatory T cells or Tr1. The other T cell that exerts inhibitory activity on the contact sensitization reaction is the CD4+CD25+Treg cell. A cell-to-cell, contact-dependent, cytokine-independent mechanism is involved; however, under certain circumstances, these cells may also produce IL-10. The Treg cell is anergic to antigen but can suppress contact sensitization in normal and naive individuals, and it can partially suppress the expression of allergy in sensitized individuals.¹⁰⁵

IN VITRO TESTS

The interaction between antigen-bearing Langerhans cells and sensitized lymphocytes can be demonstrated in vitro. When sensitized T lymphocytes are cultured together with syngeneic Langerhans cells-enriched

epidermal cell suspensions in the presence of a specific allergen, they undergo an antigen-specific proliferative response.¹⁰⁶,¹⁰⁷ Preceding treatment of the epidermal cell suspension with antibodies against Ia antigens abolishes this in vitro response and demonstrates the important role played by the immune response-associated surface antigens in this interaction.

Several in vitro reactions, such as the lymphocyte transformation test and the macrophage migration inhibition test, often parallel clinical contact sensitivity. These in vitro tests are used in the evaluation of metal salt allergy in patients about to undergo surgical replacement of metal-containing implants. This test has also been applied to the assessment of metal allergy in patients with complications related to metal implants.¹⁰⁸ The results of these in vitro procedures, however, have not correlated with the results of in vivo exposures sufficiently to justify their routine clinical use. Furthermore, adequate test techniques have been developed for only a few contact allergens.

Systemic Administration of Contact Allergens

Exposure to contact allergens frequently occurs systemically, either by ingestion or injection, and, less frequently, by insertion into the body (e.g., surgical implants, intrauterine devices). Although first exposure to contact allergens by the systemic route usually favors the development of partial or complete specific tolerance, sometimes allergic contact sensitization occurs instead. Presumably, the explanation is that some allergen reaches the skin through the blood circulation and is taken up by antigen-presenting epidermal or lymph node Langerhans cells.

A completely different effect is exerted by contact allergens administered systemically after specific sensitization has already occurred. Under such circumstances, a clinical reaction may ensue, probably because of the uptake of the blood-borne contact allergen by antigen-presenting epidermal cells and subsequent interaction with specifically sensitized lymphocytes.

A Mechanism for Auto-Eczematization 

In a mouse model of contact dermatitis, the induction of sensitivity to a specific hapten resulted in T cell clones that not only recognized the hapten but also recognized keratinocyte antigens. This phenomenon, which resulted in a broader degree of reactivity than expected, was interpreted as a possible mechanism for auto-eczematization in humans, whereby auto-immunity would be triggered by the release of cryptic self- antigens during allergic contact dermatitis.¹⁰⁹ In this scenario, auto-eczematization would be the clinical manifestation of autoreactive T cells.

Hyposensitization

Hyposensitization, a state of decreased sensitivity, occurs in previously sensitized subjects and can sometimes be induced by intravenous administration of the allergen and by prolonged oral administration.¹¹⁰ The allergen then bypasses the epidermal Langerhans cells system and exerts a direct action on effector T lymphocytes. The suppression of hypersensitivity is antigen specific and is not mediated by suppressor cells, but the exact underlying mechanism is unknown. The possibility of a receptor blockade has been suggested.¹¹¹ In contrast to specific immunologic tolerance, which is mediated by suppressor cells and tends to be long-lasting, hypo-

sensitization usually is a short-lived effect.

Skin Memory

Application of patch tests to a patient’s back can recall or cause dermatitis to flare on other body surfaces previously exposed to the allergen and part of the patient’s clinical contact dermatitis. If a patch test site is re-exposed to the same allergen within 2 to 3 weeks, a reaction occurs within 4 to 6 hours rather than within 2 to 4 days. This phenomenon is allergen specific. Retesting has been suggested as a way to determine whether true cross-reactivity exists or whether co-reactivity is occurring.¹¹² It has been suggested that the mechanism for site-specific allergen skin memory is related to a chemokine (CCL27) that causes perivascular retention of CCR10+CD4+ T cells in the dermis at the site of patch testing.¹¹³ These cells are found at least 3 weeks after resolution of the patch test reaction and are believed to be responsible for the rapidity of reactions associated with rechallenge with the same or true cross-reacting allergens.

HISTOLOGICAL EVALUATION OF DERMATITIS

The histology of contact dermatitis is influenced by the allergen involved and the timing of when a skin specimen is obtained. Because contact dermatitis is usually a clinical diagnosis, histological analysis tends to play more of a role in research than treatment although it can help establish a diagnosis in patients with an atypical presentation or when the differential diagnosis is broad.

Allergic Contact Dermatitis

Cutaneous changes viewed by light microscopy depend on two factors—severity of the response to an allergen and time of biopsy after allergen exposure. The age of the lesion at biopsy (i.e., timing of the histologic study) dictates whether pathologic changes are acute, subacute, or chronic inflammatory changes. In turn, severity of response depends on both the potency of the allergen and the affected individual’s degree of immunologic sensitivity.

Biopsies of experimentally induced allergic contact dermatitis (e.g., to 1% 2,4-dinitrochlorobenzene) show changes 4 to 8 hours after allergen application.¹¹⁴ The earliest change is the appearance of a few lymphocytes perivascularly in the dermis. Within 6 to 8 hours, some lymphocytes migrate into the epidermis as the dermal infiltrate increases, and focal spongiosis (intercellular edema) occurs in the Malpighian and basal layers. Both findings peak 24 to 48 hours after application. A study comparing punch biopsies from allergic patch tests (with quaternium-15 or colophony) with irritant patch tests (with benzalkonium chloride) demonstrated follicular spongiosis in six of seven allergic reactions but in only one of seven irritant reactions.¹¹⁵ Vesiculation occurs when the focal areas of spongiosis coalesce. With severe reactions, occasional neutrophils may be seen, but their presence is rare compared to their frequency in irritant contact dermatitis. In acute experimental allergic contact dermatitis, eosinophils may be found in both the dermis and epidermis and, if present, suggest allergic contact dermatitis rather than another form of dermatitis. In clinical practice, however, eosinophils have not been shown to be predictive of allergic contact dermatitis.

At about 24 hours and perhaps even earlier, basophils begin to appear. They may comprise up to 15% of the infiltrate by day 3, at which time the number of tissue mast cells begins to increase. Whereas basophils enter the site from the blood, mast cells are formed by local replication, which accounts for their delayed appearance. Other changes within the 24- to 48-hour time frame may include increased vascular permeability, which results in rare erythrocyte extravasation and dermal papillary edema, and fibrin deposition in the reticular dermis.

After 48 to 72 hours, the activity of inflammation subsides. Rebuilding and clean-up processes occur with infiltration of macrophages needed for removal of keratinocyte debris.¹¹⁶ Although not histologically prominent when routine stains (e.g., hematoxylin and eosin) are used, special stains (e.g., terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, TUNEL) have shown significant apoptosis of keratinocytes during allergic contact dermatitis.¹¹⁷ The apoptosis occurs for multiple reasons: direct toxicity of the allergen to keratinocytes and to effector lymphocytes (CD8+ conventional T cells, natural killer T cells, or natural killer cells) that either produce cytokines such as TNF-α or lymphotoxin or that directly mediate cytotoxicity (Fas-mediated or performin-mediated killing) during the exocytosis of these inflammatory lymphocytes in the epidermis during allergic contact dermatitis.¹¹⁸ The apoptotic death of keratinocytes during allergic contact dermatitis is likely the source of keratinocyte debris.

In contrast to the above experimentally derived data, in a clinical setting suspected contact dermatitis is usually biopsied days or even months after onset. In this case, a pattern of subacute or chronic dermatitis, which may be impossible to distinguish from nummular dermatitis or lichen simplex chronicus, may be seen.¹¹⁹ The inflammatory infiltrate, again primarily lymphocytes and other mononuclear cells, is less prominent and, in fact, may be absent from the epidermis. In one study eosinophilic spongiosis was present in 28% of patients compared to 5% of controls, and dendritic fibrohistiocytic cells were present in 44% of patients compared to 24%.¹²⁰ In the dermis, a perivascular pattern is likely. Mild spongiosis and microvesicle formation may be seen, but these changes may be lacking in long-standing dermatitis. Chronically, acanthosis with hyperkeratosis and some parakeratosis may be seen. Apparent intracellular edema may be related to glycogen distribution. Upper dermal fibrosis may occur as the result of thickened collagen.

Irritant Contact Dermatitis

Compared to allergic contact dermatitis, experimentally induced irritant contact dermatitis has a very different histopathologic picture when biopsies are obtained the first day or two after exposure. This difference is expected because in irritant contact dermatitis the epidermal damage is caused directly by the toxic agent, whereas in allergic contact dermatitis the damage is due to the host’s immune reactions. Although irritant contact dermatitis varies with the strength and type of irritant, it usually develops much more quickly than allergic contact dermatitis.¹²¹ Within a few hours of exposure to a moderately strong irritant such as 10% 2,4-dinitrochlorobenzene, dermo-epidermal separation begins. By 24 hours, epidermal necrosis is observed, often with subepidermal blister formation.¹¹⁴ Lymphocytes are relatively rare in both the dermis and epidermis. In contrast, the bulk of the inflammatory infiltrate is composed of neutrophils, which first appear within 6 to 8 hours of exposure. In guinea pigs, basophils are much more plentiful in early allergic reactions compared to irritant reactions.¹²² Presumably, all allergens induce a similar immune response, but different irritants produce different histologic findings, depending on their mechanism of cell damage. For example, after 48 hours the cytotoxic agent dithranol produces balloon degeneration of the upper dermis with disruption of mitochondria, whereas the detergent sodium lauryl sulfate induces parakeratosis and intracytoplasmic vesicles and lipid vacuoles.

Unfortunately, these differences between early allergic and irritant contact dermatitis are rarely of clinical benefit because biopsies within the first few days of onset are seldom available. The histologic findings of a chronic low-grade irritant contact dermatitis may be identical to those described for allergic contact dermatitis. Although by no means pathognomonic, the presence of eosinophils might suggest allergic contact dermatitis, whereas the absence of exocytosis of lymphocytes might suggest irritant contact dermatitis.

Differentiating Contact Dermatitis from Other Dermatoses

Sometimes a biopsy may shed light on a confusing clinical picture to help determine if the diagnosis is within the broad category of dermatitis as opposed to some other entity. Acute irritant or allergic contact dermatitis, for example, may be simulated by bullous impetigo or a viral vesicular eruption such as herpes. The histologic pattern of these conditions is readily distinguished from contact dermatitis. Likewise, examination of a biopsy can suggest contact urticaria or urticarial vasculitis. Histologically, persistent or "dermal’’ contact dermatitis may be differentiated from infiltrative processes such as rosacea, a sarcoid, or cutaneous T-cell lymphoma. Generalized allergic contact dermatitis, as may be associated with formaldehyde allergy, for example, can be distinguished histologically from erythroderma related to psoriasis, a drug reaction, or Sézary syndrome. The histopathology of these other conditions is thoroughly reviewed in texts on that subject.

The histologic differential diagnosis of an acute spongiotic dermatitis includes many other entities besides allergic contact dermatitis. This phenomenon may be seen in erythema multiforme, pityriasis rosea, guttate parapsoriasis, spongiotic drug eruptions, reactions to arthropod bites, and dermatophytic infections (i.e., positive for fungal hyphae with a periodic acid-Schiff stain). For subacute spongiotic dermatitis, the histologic differential diagnosis includes pityriasis lichenoides, dermatophytic infections, spongiotic drug eruptions, and reactions to arthropod bites. For chronic dermatitis, the histologic differential diagnosis includes pellagra and other nutritional deficiencies, large plaque para-

psoriasis, mycosis fungoides, and psoriasis. All three types of spongiotic dermatitis have numerous differentiating clinical and histologic features, and readers are referred to a skin histopathology textbook for further information.¹²³

Unusual Histologic Patterns of Contact Dermatitis

Occasional cases of allergic contact dermatitis, either systemic or exogenous, may show histologic and clinical patterns simulating other diseases. Such cases include erythema multiforme, vasculitis, lichenoid tissue reaction, and granuloma formation.¹²⁴ These rare variants are reviewed in the chapters covering the allergens involved.

Confocal Microscopy of Contact Dermatitis

Reflectance confocal microscopy uses a low-power laser to scan intact skin. The resolution of the resulting image is similar to that obtained with routine histology. Acutely, changes seen in both allergic and irritant contact dermatitis are similar. Irritant contact dermatitis, however, shows greater disruption of the stratum corneum and parakeratosis.¹²⁵-¹²⁷ In 14 subjects exposed to the irritant sodium lauryl sulfate, more severe acute changes were detected in white skin than in black skin.¹³ In a study of 16 subjects with positive patch tests to various allergens, spongiosis and exocytosis at the level of the stratum spinosum correlated highly with allergic contact dermatitis compared to controls.¹⁴

PREDICTIVE TESTING FOR HUMAN CONTACT DERMATITIS

The identification of the sensitizing capacity of individual compounds or finished products can be undertaken in human or animal systems.