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 6
Fisher’s
CONTACT
DERMATITIS

Robert L. Rietschel, MD Joseph F. Fowler, Jr, MD

Professor of Clinical Medicine Clinical Professor of Dermatology
University of Arizona College of Medicine Director of Occupational Dermatology
Chief, Dermatology Service University of Louisville School of Medicine
Southern Arizona VA Health Care System Louisville, Kentucky
Tucson, Arizona

2008
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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 regulation 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.
 To Alex and his inspiration, Lillian.
You are both missed.
Alex, your wit and wisdom live on in the work you created.

To Connie, Eric, and Penny, a wonderful supportive family.

To Lynn, for all her love, friendship and support.

 CONTENTS
Preface

1. Pathogenesis of Allergic Contact Hypersensitivity 1

2. Practical Aspects of Patch Testing 11

3. Predictive Testing for Human Contact Dermatitis 30

4. Histology of Contact Dermatitis 35

5. Role of Age, Sex, Color of Skin, and Atopic Status 38

6. Regional Contact Dermatitis 66

7. Noneczematous Contact Dermatitis 88

8. Systemic Contact-Type Dermatitis 110

9. Medications and Medical Devices, and Implications for the Medical Community 125
10. Medications from Plants 175
11. Antiseptics and Disinfectants 190
12. Topical Antimicrobials 210
13. Antihistamines 230
14. Local Anesthetics and Topical Analgesics 239
15. Topical Corticosteroids 254

16. Preservatives and Vehicles in Cosmetics and Toiletries 266

17. Hand Dermatitis Due to Contactants: Special Considerations 319

18. Textiles and Shoes 339

19. Medical Devices, Implants, and Equipment 370

20. Fragrance Allergy 393

21. Allergic Sensitization to Plants 405

22. Photocontact Dermatitis 454

23. Paresthesia Due to Contactants 470

24. Occupational Dermatitis 484

25. Cutting Oils, Solvents, Petrolatum, and Coal-Tar Products 520

26. Gases and Propellants 534

27. Plastics, Adhesives, and Synthetic Resins 542

28. Food Additives and Dyes 566

29. Rubber 581

30. Gums, Rosin, and Natural Resins 605

31. Contact Urticaria 615

32. Metals 641

33. Contact Stomatitis and Cheilitis 700

34. Treatment of Contact Dermatitis 722

35. Specific Instructions for Patients with Common Contact Allergens 731

Appendix 743

Subject Index 809

 PREFACE

T
his is the first revision of Alexander Fisher’s book that the original author will not see.
We mourn Dr. Fisher’s passing and in this sixth edition we hope to honor his memory.
When we took over this task with the production of the fourth edition, Dr. Fisher
remarked that we had taken a classic and turned it into a masterpiece. While his very kind words
might have been something of an overstatement, his description of this book as a classic remains
appropriate and we have endeavored to maintain that tradition. Much of the history of contact
dermatitis remains in these pages, and we have changed Dr. Fisher’s original wording as little as
possible.

The organization of the book has been slightly modified in this edition. We have removed the
Aquatic Dermatoses chapter (since it was less an account of contact dermatitis than a reflection
of one of Dr. Fisher’s personal interests), and some chapters have been combined in an effort to
eliminate redundancy. A substantial amount of new information has been added and is to be
found in the body of the text rather than in tables. The "boxes" that were part of the first five
editions have been replaced by executive summaries to the chapters, since we felt that the boxes
were redundant to the text and not as complete. In addition, a mini-atlas has been added to
highlight some of the principles noted in various chapters.

It is inevitable that a computer search will turn up items that we have failed to include. However,
a computer search will not provide the context that this classic attempts to provide. Most of what
is "out there" has found a place "in here." We hope you will find this edition a useful alternative
to spending valuable hours at your computer in search of relevant information on contact
dermatitis.

Robert L. Rietschel, MD
Joseph F. Fowler, Jr, MD
G L O S S A RY OF COMMONLY
U S E D A BBREVIATIONS

ACD allergic contact dermatitis

acet acetone
alc alcohol
aq aqueous
as is undiluted
BP balsam of Peru (now called Myroxylon pereirae)
chlor chloroform
co castor oil
eth ethanol
FDA Food and Drug Administration
ICD irritant contact dermatitis
ICU immunologic contact urticaria
MP Myroxylon pereirae
pdr powder
NACDG North American Contact Dermatitis Group
oo olive oil
pet petrolatum
PPDA paraphenylediamine
RAST radioallergosorbent test
sat saturated
ROAT repeated open application test
CHAPTER 1

PATHOGENESIS OF ALLERGIC
CONTACT HYPERSENSITIVITY
EXECUTIVE SUMMARY
Allergic contact dermatitis is a T cell-driven process that begins when haptens come into contact with
Langerhans cells in the epidermis. When properly stimulated, Langerhans cells migrate to regional lymph
nodes. Here, antigen is processed by T lymphocytes, which become specifically reactive to the presented
allergen. The T cells that respond when the individual is re-exposed to the allergen are now known as
CD8+T cells and are under the control of subsets of CD4+ 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. Neuropeptides Substance P, neurokinin A,
and calcitonin gene-related peptide 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
mechanisms. A cell-to-cell, contact-dependent, cytokine-independent mechanism is also found. Skin memory of
contact dermatitis may be due to a chemokine (CCL27) that causes retention of a specific type of T cell in the
skin site where the allergen was encountered.

Jadassohn,1 who described contact allergy to mercury in against foreign antigens, like those derived from bacteria,
1895, can be considered the ‘‘father’’ of contact dermatitis. fungi, viruses, and foreign tissues, and against autolo-
Prior to this time, and indeed for some years thereafter, gous tumor antigens and other undesirable autologous
contact hypersensitivity was essentially unknown except antigens. However, although cell-mediated hypersensi-
by a few workers in dermatology.2–5 In 1927, Landsteiner6 tivity to these antigens in general helps to preserve the
published studies regarding antigens containing ‘‘simple body’s integrity, allergic-contact hypersensitivity to small
chemical compounds.’’ Sulzberger,7 in 1929, published molecular allergens (which, in fact, is hypersensitivity to
one of the earliest American works on the subject. autologous proteins made ‘‘foreign’’ by complexing with
Another important development was the recognition that small molecular compounds) is damaging to the skin. In
a close similarity existed between contact allergy and a sense, therefore, contact allergy can be considered a
delayed-type hypersensitivity to microbial antigens, after deviant form of cell-mediated hypersensitivity.
Landsteiner and Chase published their findings 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 As a matter
Overview
of fact, this finding precipitated an era in which many Contact allergens almost invariably are small-molecule
investigators considered contact allergy and microbial substances of less than 500 daltons (Da).12 Because of their
allergy to be based on identical mechanisms. Despite many small size, they penetrate the skin barrier, which is rela-
important fundamental similarities, however, certain differ- tively impermeable under normal circumstances to large
ences were always evident between these forms of allergy.10,11 molecules, and reach the living layers of the skin. In order
Teleologically, one assumes that cell-mediated hyper- to induce contact allergy, these substances must be pre-
sensitivity serves the purpose of defending the body sented by antigen-presenting cells, principally epidermal

1
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2 / Fisher’s Contact Dermatitis

Langerhans cells (LCs), and other dendritic cells, to T instances, however, it is difficult to predict the sensitizing
lymphocytes in an immunologically effective ‘‘processed’’ capacity of a substance on the basis of its chemical struc-
form. The effector cells, which mediate allergic contact ture. In the past it has not been adequately emphasized
hypersensitivity, are descendants of these T lymphocytes. that some of the most common contact allergens, like
In order to interact with antigen presented by the LCs nickel, chromates, and other metal salts, do not form
in the course of both induction of hypersensitivity and covalent bonds with proteins; the fact that they can com-
elicitation of a reaction, the T lymphocytes must possess bine in some form with components of LCs provides a
surface receptors (‘‘idiotypes’’) that are complementary reasonable explanation for their allergenicity.13 Current
to the physicochemical features of that antigen. Further- research suggests that a ‘‘successful’’ contact allergen
more, the antigen-presenting cells must bear immune causes an increase in the size of LCs along with an increase
response–associated antigens for which the T lympho- of Ia (major histocompatibility complex) molecules on
cytes possess receptors. The T lymphocytes must also be the LC surfaces. In addition, the allergen may induce LC
activated by interleukin-1 (IL-1), which is released from migration to lymph nodes.14 Langerhans cells migrate out
LCs and keratinocytes. of the epidermis not only when exposed to allergens, but
Under ordinary conditions, exposure to contact aller- also when exposed to toxic concentrations of irritants.15
gens sets in motion two competing mechanisms, the one
mediated by effector T lymphocytes and leading to a
state of hypersensitivity that becomes clinically manifest GENETIC FACTORS
as an eczematous skin reaction. The other is mediated by Susceptibility to the development of contact sensitivity is
suppressor cells and leads to relative or complete toler- genetically controlled. The mode of inheritance in guinea
ance of the allergen. The state of reactivity of the skin at pigs is autosomal and irregularly dominant.16 Different
any particular time and site is principally the result of the strains of guinea pigs can make an immune response to
existing balance between the effector and the suppressor different contact allergens. For example, one strain
cells present. responds to potassium dichromate and beryllium fluor-
ide, but not to mercuric chloride, whereas another strain
makes a response to mercuric chloride but responds
poorly to potassium dichromate and beryllium fluor-
Contact Allergens ide.17 These differences apparently relate to different
Normally, only small molecular compounds (<500 Da) hapten–amino acid linkages.
can penetrate through the horny layer into the living Other studies have shown that ultraviolet-B (UVB)
layers of the epidermis. Yet, in order to induce and elicit exposure inhibits contact sensitivity in certain strains of
contact allergy, an antigen with a molecular weight of at mice, but not in other genetically distinct strains.18,19 It
least 5,000 Da is required. Antigenicity is accomplished has been postulated that tumor necrosis factor-a (TNF-a)
by the conjugation of small molecules with autologous may be an important mediator of these effects.20
proteins present in the skin. Other requirements for Studies of the mode of inheritance in humans are still
antigenicity are the appropriate number of antigenic inadequate, but the very limited available data suggest that
determinants and the appropriate tertiary structural fea- here also genetic factors control susceptibility to sensitiza-
tures in the resulting molecule. Activation of the innate tion to particular allergens.21 A number of European stu-
immune response is also part of this process. Sensitiza- dies have compared the frequency of human leucocyte
tion is more easily induced when the skin barrier is antigens (HLA) antigens in patients with allergic contact
compromised by dermatitis or ulceration. dermatitis (ACD), usually to nickel, with local con-
It was originally thought that such conjugates were trols.22–24 Several studies have purported to show increased
formed with the fibrous proteins of prokeratins, keratins, occurrence of one or two HLA types in patients, but for
procollagens and collagens, epidermal cell membranes, reasons that are obscure, no two studies have found the
or soluble tissue, and serum proteins. Although a role for same HLA antigen to be increased in a statistically signifi-
these conjugates cannot be dismissed, it now appears that cant fashion. Among the antigens reported to be increased
conjugation takes place mainly with cell membrane pro- to some degree are HLA-B7, -B21, -B12, -Bw22, -B35, -B40,
teins in the course of ‘‘processing’’ by the antigen-pre- -DR4, and -DRw6. Because the expression of the HLA
senting LCs. antigen system is essential for the development of ACD, it
Linkage to the protein moiety is frequently covalent; is tempting to search for HLA-ACD associations.
for example, the epsilon-amino group of lysine and the Gene products of the TAP-1 and TAP-2 genes (trans-
sulfhydryl groups of cystine and cysteine have been sug- porter associated with antigen processing) are involved
gested as binding sites for certain allergens. In many in antigen processing. A Finnish study showed that
 Chapter 1 / Pathogenesis of Allergic Contact Hypersensitivity / 3

nickel-allergic persons were much more likely to possess time, apparently in relation to antigen processing. As
the TAP-2B gene allele and much less likely to be TAP- processing continues, LC morphology changes to a more
2C positive than nonallergic subjects.25 This study dendritic cell type, which is associated with enhanced
further supports the likelihood of inborn genetic factors antigen-presenting capacity.
regulating one’s ability to develop contact allergy. Experimental proof of the antigen-presenting func-
In a search for a genetic basis for susceptibility to tions of LCs derives from studies in inbred guinea pigs
contact allergy, a study was done looking at polymorph- and mice and from the demonstration in mice that anti-
isms in cytokine genes. Individuals with multiple contact gen presentation cannot take place in the absence of
allergens were compared to individuals without eczema or adequate numbers of functionally intact LCs at sites of
contact allergy. Carriers of TNFA-308*1/2(*GA) and exposure to the allergen.34
TNFA-308*2.2(*A/A), which are tumor necrosis factor Irradiation with UVB or application of a topical
alpha genes, were more likely to be polysensitized.26 corticosteroid reduces the density of LCs in skin and
Another role for genetic polymorphism in contact derma- inhibits induction of contact sensitization.14 In vitro
titis in humans has been identified. Susceptibility to p- cyclosporine A inhibits the antigen-presenting capability
phenylenediamine sensitization was related to genotype of LCs, apparently without affecting cell surface expres-
coding for rapid acetylation in 52.9% of patients with sion of Ia molecules.35
contact dermatitis and 37% of control subjects. The fre-
quency of the NAT2*4 allele and NAT2*4/*4 genotype,
which code for rapid acetylation, was significantly higher Induction of Contact Allergy
in the patients with contact dermatitis (p= 0.003).27
Shortly after contact with an allergen, various cytokines
are released that enhance the development of contact
ANTIGEN PRESENTATION sensitivity.36 Interleukin-1B (IL-1B) increases the level
It is not possible for T lymphocytes to interact directly with of intercellular adhesive molecule (ICAM-1). Other
the contact antigen even when they possess the appropriate molecules are then expressed on the LC surface, which
surface receptors for that antigen. The antigen must first be facilitates interaction with CD4+ T cells.
‘‘processed,’’ and then must be presented in suitable form on Within 24 hours of antigen application, LCs migrate to
the surface of LCs28 that bear immune response–associated regional lymph nodes. There they present the antigen to
surface antigens (HLA-DR in humans; called Ia in mice) for compatible T lymphocytes. The T lymphocytes must bear
which the T lymphocytes have the specific receptors. To receptors for complementary major histocompatibility
induce contact allergy, the allergen is displayed in close complex protein as well as receptors for the contact aller-
association with these antigens or perhaps becomes conju- gen. Ultrastructural observations indicate that the contact
gated with them.29,30 Random T lymphocytes circulating allergens reside on the surfaces of LCs as well as in the
through the epidermis, dermis, dermal lymphatics, and intracytoplasmic Birbeck granules.37 In the lymph nodes,
regional lymph nodes can become apposed to the LCs, but certain T lymphocytes become physically apposed to the
only T lymphocytes, which have the complementary recep- LCs facilitating transfer of antigen. These T cells are CD4+
tors for the contact antigen that is being presented, can and CD45RA+ and may be referred to as Th-0 cells.38
become irreversibly apposed. Other cytokines are important at this stage of sensitiza-
tion, including IL-6, TGF-B, and IL-12. Lack of IL-12 can
LANGERHANS CELLS prevent development of Th-1 cells, which cause ACD, and
Epidermal LCs have properties that make them particu- therefore may allow development of tolerance to the par-
larly well suited to serve the function of presenting con- ticular allergen.39 Through clonal proliferation, a subset of
tact allergens. They have a pronounced capacity to bind T lymphocytes is produced that will be capable of
small molecular compounds, among them well-recog- responding to the particular antigen when future exposure
nized contact allergens, to their surface.13 Their capacity occurs. It will be 7 to 10 days before there are sufficient
to do this binding is greater than that of peripheral blood numbers of these specific T lymphocytes to cause contact
macrophages.31 Similar antigen-presenting cells are dermatitis. After that time, elicitation of contact dermati-
found in the spleen and lymph nodes. These and LCs tis, by patch test or routine exposure, is possible.
are all derived from bone marrow precursors.
Antigen-processing capacity of LCs involves, first, plasma EFFECTOR AND SUPPRESSOR CELLS
membrane changes with endocytosis of the antigen and As noted previously, exposure of individuals who are
digestion of proteins to active peptides in acidic orga- genetically susceptible to sensitization to a specific con-
nelles.32,33 Birbeck granule expression increases at this tact allergen sets in motion two competing mechanisms,
4 / Fisher’s Contact Dermatitis

namely, allergic sensitization mediated by effector cells haptens in animal models include various CD4+ T cell
and specific immunologic tolerance mediated by sup- subsets. Th2 cells, IL-10-producing Tr1 cells, and natural
pressor cells. In an unsensitized individual, oral or par- CD4+CD25+ T cells have been implicated in down reg-
enteral administration of an antigen can lead to reduced ulation. Vocanson and colleagues further found that
immune reactivity, whereas the same allergen may cause CD4+CD25+ T cells both natural and hapten-induced
contact sensitization when applied topically.40 The key regulate the CD8+ T cell response to a weak hapten (such
role played by lymphocytes as the source and carriers of as fragrances). They found that the sensitizing potential of
the hypersensitivity in contact allergy was demonstrated haptens correlated to their proinflammatory properties.
by Landsteiner and Chase9 60 years ago in experiments This provided the activation of the skin-innate immunity
on guinea pigs. Peritoneal exudate cells, predominantly required for differentiation and mobilization of dendritic
lymphocytes, from contact-allergic donor animals, cells from skin to lymph node and the priming of CD8+ T
injected intraperitoneally or intravenously into recipient cell precursors. Since factors in the control of the devel-
animals that had not previously been sensitized, passively opment of allergic contact dermatitis include frequency,
transferred the hypersensitivity. In humans, however, dose, duration and route of administration of hapten,
such passive transfer experiments have yielded contra- genetic polymorphisms of xenobiotic-metabolizing
dictory results. Both failure and success have been enzymes, and environmental factors such as psychological
reported with intracutaneous and intravenous passive stress,48 CD8+ cytotoxic lymphocytes are now implicated
transfer of sensitized cells.41–45 The immunologic in the elicitation of contact dermatitis. CD4+ T cells per-
changes, which ensue during the early days following form regulatory functions, but CD8+ T cells can mediate
sensitizing exposure, usually have a lasting impact on contact hypersensitivity, even in the absence of the CD4+
the outcome of the competition between effector and cells. Skin biopsies taken 3 days after patch testing show
suppressor lymphocytes. The state of specific allergic that Interleukin-12 (IL-12) is present in the cytoplasm of
hypersensitivity may last indefinitely. Once established, dermal dendritic cells such as macrophages and Langer-
it cannot be deliberately altered, except for transient hans cells. IL-12 can also be found in keratinocytes where
hyposensitization. Contact hypersensitivity is thought to there is exocytosis of cells and spongiosis. It is thought that
often wane spontaneously in elderly people. In some IL-12 enhances the activation of cytotoxic lymphocytes
patients, this hypersensitivity wanes spontaneously at a and plays an important role in contact dermatitis.49
much earlier age (at times within a few years) despite The focus of immunologists on T cell and B cell factors
continued exposure to the specific contact allergen. As in contact hypersensitivity was questioned by O’Leary
yet, no explanation for this finding has been discovered. and colleagues, who demonstrated substantial contact
Contact allergy can develop from earliest infancy to old hypersensitivity to 2,4-dinitroflurobenzene and oxazo-
age, but it is most common in the intermediate age lone in mice devoid of T and B cells. Natural killer cells
groups. were believed to account for this phenomenon.50 The
The spleen plays an important role in generating sup- role of B cells has been clarified in mouse models. A role
pressor cells.46 Tolerance, once established, apparently for IL-5 in activating eosinophils and B-1 cells was
persists indefinitely in humans. In laboratory animals, recently described. The B-1 cell-derived antigen-specific
tolerance can be broken deliberately with cyclophospha- immunoglobulin M antibodies recruit effector T cells
mide.47 into skin. Infiltration of antigen-nonspecific mononuc-
The induction of contact allergy is sometimes referred lear cells and polymorphonuclear cells then follows.51
to as the afferent phase and elicitation as the efferent
phase. Vocanson and colleagues reviewed the role of var-
ious factors involved in the study of contact dermatitis in
mouse models. To summarize some of their observations, GENERALIZATION OF CONTACT
most mouse work is done with strong sensitizers, such as SENSITIVITY
2,4-dinitrochlorobenzene (DNCB) and oxazolone. How- Antigen presentation by LCs to T lymphocytes has been
ever, weak haptens such as dyes, preservatives, perfumes, thought to take place primarily in the lymph nodes.
metal ions, and drugs are the common haptens in human Whether antigen presentation occurs in the skin also is
medicine. In the afferent phase CD8+ T cells in draining uncertain.52 In laboratory animals, enlargement of the
lymph nodes are primed. The efferent phase results in the regional lymph nodes is observed during this period of
recruitment of these cells to the site of hapten challenge. proliferation. There they undergo further proliferation,
The authors of this study, showed that CD8+ T cells were which accounts for the production of large numbers of
the effector cells in weak allergens when studied in mice. specifically sensitized effector cells and T memory cells.
The cells that downregulate contact dermatitis to strong Their descendants enter the collecting sinus of the lymph
 Chapter 1 / Pathogenesis of Allergic Contact Hypersensitivity / 5

node and from there are transferred to the blood, which Both antigen-specific and nonspecific T cells produce a
then circulates them to other parts of the lymphoid number of inflammatory mediators once they arrive on-site.
system.53 This finding explains why all areas of the body’s Tumor necrosis factor b (TNF-b) has direct cytotoxic effects
surface almost invariably become hypersensitive to the on epidermal cells. In addition, it induces ICAM-1 on
contact allergen. keratinocytes, which aids binding of lymphocytes. g-Inter-
feron also induces ICAM-1 as well as HLA-DR antigen
expression on keratinocytes. This, too, facilitates attachment
LOCALIZED DIFFERENCES IN by lymphocytes. Various interleukins stimulate growth and
SENSITIVITY activation of T lymphocytes and attract neutrophils. Gran-
Contact sensitivity usually involves the entire integument, ulocyte-monocyte colony-stimulating factor (GM-CSF)
but it is not unusual to find differences in degree of sensi- activates monocytes and neutrophils.59–61
tivity at different skin sites. For example, a greater degree of
sensitivity is often present at the site of originally induced
sensitization and at other sites of previous exposure to the Mast Cells and Basophils
particular allergen, such as sites at which patch tests had
Mast cells and basophils are routinely found at sites of
been done.54 The mechanism for this has not yet been
ACD and are usually confined to the upper dermis. They
elucidated, but one theory is that clones of sensitized cells
release histamine, serotonin, and leukotrienes.62 Pruritus
have established themselves in the dermis during a pre-
and vascular dilation leading to tissue edema may result.
vious encounter with the allergen. Re-exposure to the
Leukotrienes act to attract both neutrophils and lympho-
allergen may then trigger interaction with and proliferation
cytes. Mast cells and basophils are not essential for the
of the clones of specifically sensitized cells at these parti-
development of ACD, however, as demonstrated by the
cular sites, thus creating the increased capability to react.
development of ACD in most cell-deficient mice.63

Elicitation of Reactions Keratinocytes

After sensitization has taken place, re-exposure to the spe- Keratinocytes are not passive bystanders in the process of
cific allergen leads to a series of events that eventually result ACD. Multiple cytokines are produced and/or released
in the inflammatory response clinically recognized as an by damaged or ‘‘activated’’ keratinocytes. These include
eczematous dermatitis. It is characterized histologically by interleukin and GM-CSF, with the function noted above.
spongiosis and lymphocytes in the epidermis and by lym- In addition, ICAM-1 is expressed in damaged but not
phocytes, histiocytes, and varying numbers of eosinophils normal keratinocytes and aids T-cell attachment.
and basophils in the papillary dermis (see Chapter 4). The Furthermore, involved keratinocytes produce HLA-DR
spongiosis, at least in part, could be due to the destructive antigens in the cell surface, which allows attachment of
effects of hapten-specific cytotoxic effector cells on kerati- autoreactive T lymphocytes.
nocytes and LCs.55 The presence of eosinophils and baso- IL-1, which was one of the first cytokines identified
phils points to the participation of IgE antibodies and of from keratinocytes, enhances the activation of accessory
cutaneous basophil hypersensitivity in the production of dendritic cells, which in turn activates resting T lympho-
contact allergic reactions.56,57 Basophils are sources of trans- cytes.64 IL-5, also expressed by keratinocytes, further
forming growth factor (TGF-b) and therefore may play a stimulates T-cell proliferation. IL-8 is another keratino-
role in downregulating expression of ACD. cyte product that has a strong chemotactic effect on T
Elicitation of ACD in a sensitized individual starts with cells. Nozaki and colleagues65 have prepared an excellent
antigen uptake and presentation by LCs. T lymphocytes review of currently understood cytokine effects.
specifically reactive to the allergen in question accumulate
at the site of exposure. It is uncertain whether this accu-
mulation is due to localized retention or proliferation of
the specific T cells once they have arrived at the site, or to
Neurologic Factors
preferential migration to the site.58 Kalish,14 however, feels Neuropeptides may influence ACD development,
that migration of T lymphocytes is random, and therefore because nerve fibers of skin are in direct contact with
on-site retention or proliferation is likely. Antigen-specific LCs.66 Unmyelinated sensory neurons release cutaneous
T cells make up only 1% or less of the total T-cell popula- neuropeptide in response to epicutaneously applied aller-
tion of the site, but this is still 10 to 100 times more than gens. These include Substance P, neurokinin A, and
are present in the circulation. calcitonin gene-related peptide (CGRP). Substance P
6 / Fisher’s Contact Dermatitis

may increase ACD by increasing levels of TNF-a and IL- (e.g., the tail skin of mice, which has approximately one-
2. Substance P stimulates its principal receptor, neuroki- third the number of LCs present in most other areas).
nin 1R. Substance P is also known as neurokinin 1 Although variations in the number of LCs have been
(NK1). The result includes the release of IL 1 and the observed in different areas of skin in humans, none has
immunologic cascade (previously discussed). A second been described to date that is so deprived of these cells
receptor exists, known as neurokinin 2R (NK-2R). Aller- that it interferes with adequate antigen presentation.72
gic contact dermatitis is augmented when NK 2R is A decrease in the number or functional ability of LCs or
blocked and decreased when NK-2R is stimulated. Con- a dysfunction of the T-lymphocyte systems can lead to
versely, blocking NK-1R decreases allergic contact der- diminished contact sensitivity. Ultraviolet radiation
matitis and stimulating NK-1R increases it. Neurokinin (UVR) decreases the functional capability of LCs and
A seems to work with NK-2R, and Substance P works may impair lymphocyte function.14,73 The actual num-
with NK-1R. Both Substance P and NKA are released bers of LCs are not greatly reduced by UVR. Topical
when allergen is applied. Consequently, it has been corticosteroid usage also results in functional impair-
shown in mice that capsaicin-mediated depletion of neu- ment of LCs and suppression of patch test reactions.74
ropeptides in skin abolishes DNCB contact sensitivity. In Systemic corticosteroid intake may compromise T-lym-
additional, destroying the nerve fibers to draining lymph phocyte function, as well as LC capability.75 Cyclosporine
nodes can abolish the DNCB reaction.66 Another neuro- A impairs LC function in vitro without cytotoxic effects
peptide, calcitonin gene-related peptide, may decrease on the LCs or T lymphocytes.76 LC function may be
ACD by stimulating IL-10 production.67,68 compromised in acquired immunodeficiency syn-
The interplay between the immune system and cuta- drome.77 The failure of LCs to stain positively for mem-
neous nerves was explored by injecting calcitonin gene- brane Ia antigens and adenosine triphosphatase (ATPase)
related peptide (CGRP) and a CGRP-antagonist into has demonstrated this functional impairment. It should
human skin prior to challenge with an immediate reac- be pointed out that, although the number of LCs,
tion, a delayed reaction, and irritant inducing substances. demonstrable by electron microscopy at such sites, is
At low doses, inhibition of CGRP resulted in inhibition either unchanged or only slightly reduced, many of them
of delayed but not of immediate or irritant reactions; at are functionally impaired. The number of LCs is tem-
high doses, the opposite effect was seen on delayed reac- porarily reduced immediately following a contact allergic
tions. This implies a role for CGRP in delayed immuno- reaction, but whether this reduction is sufficient to inter-
logic reactions.69 fere with antigen presentation is not known. Recovery
from functional impairment caused by glucocorticoster-
oids and UVR usually takes 1 to 2 weeks.
INHIBITION OF CONTACT SENSITIVITY Antihistamines, although they inhibit mast cell and
Adequate antigen presentation cannot take place when basophil function, do not appreciably alter contact
exposure to the contact allergen occurs at a skin site hypersensitivity. Likewise, immunosuppressives such as
that has an insufficient number of functionally intact methotrexate do not seem to impair contact sensitivity,
LCs. Under such circumstances, the development of as measured by patch testing.
specific immunologic tolerance (unresponsiveness) is It is safe to assume that other, as yet undiscovered
favored because production of effector T lymphocytes factors and diseases must exist that can also interfere
is greatly decreased or absent. Another consequence is with antigen presentation by LCs.
that more of the allergen then reaches the central parts
of the lymphoid system and induces the production of
specific suppressor cells there. However, even when first DOWNREGULATION OF CONTACT
exposure takes place by contact, a tolerogenic effect is SENSITIVITY BY REGULATORY T CELLS
exerted by that fraction of the allergen that bypasses the Control of contact sensitization is mediated by two types of
epidermal LCs and reaches the dermis, the dermal T cells. One type releases IL-10, which impairs the normal
lymphatics, and the regional lymph nodes.70 The ultra- release of IL-12 from mature dendritic cells that are
violet radiation–resistant antigen-presenting cell responding to an antigen. This lack of IL-12 inhibits activa-
described by Granstein and colleagues71 must also be tion of effector T cells. This type of control is under the
mentioned in this connection. direction of IL-10-producing regulatory T cell or Tr1. The
Under what circumstances can one expect inadequate other cell that exerts inhibitory activity on the contact
antigen presentation and consequently suppressor cell sensitization reaction is the CD4+CD25+Treg cell. A cell-
predominance to occur? Certain skin sites in laboratory to-cell, contact-dependent, cytokine-independent mechan-
animals have contained a relatively small number of LCs ism is involved, although under certain circumstances these
 Chapter 1 / Pathogenesis of Allergic Contact Hypersensitivity / 7

cells may produce IL-10 also. The Treg cell is anergic to that not only recognized the hapten but also recognized
antigen but can suppress contact sensitization in normal keratinocyte antigens. This phenomenon, which resulted
and naı̈ve individuals and partially suppress the expression in a broader degree of reactivity than expected, was seen
of allergy in the sensitized individual.78 as a possible mechanism for autoeczematization in
humans.81
IN-VITRO TESTS
The interaction between antigen-bearing LCs and sensi-
tized lymphocytes can be demonstrated in vitro. When HYPOSENSITIZATION
sensitized T lymphocytes are cultured together with syn- Hyposensitization, a state of decreased sensitivity, occurs in
geneic Langerhans cell–enriched epidermal cell suspen- previously sensitized subjects and can sometimes be
sions in the presence of the specific allergen, they undergo induced by intravenous administration of the allergen
an antigen-specific proliferative response.79,80 Preceding and by prolonged oral administration.82 The allergen then
treatment of the epidermal cell suspension with antibodies bypasses the epidermal Langerhans cell system and exerts
against Ia antigens abolishes this in-vitro response and a direct action on effector T lymphocytes. The suppression
demonstrates the important role played by the immune of hypersensitivity is antigen specific and is not mediated by
response–associated surface antigens in this interaction. suppressor cells, but its exact mechanism is unknown. The
Several in-vitro reactions, like the lymphocyte trans- possibility of a receptor blockade has been suggested.83
formation test and the macrophage migration inhibition Hyposensitization usually has a short-lived effect, in
test, often parallel clinical contact sensitivity. The results contrast to specific immunologic tolerance, which is
of these in-vitro procedures, however, do not yet corre- mediated by suppressor cells and tends to be long-lasting.
late with sufficient regularity with the results of in vivo
exposures to justify their regular clinical use. Also, ade-
quate test techniques have been worked out for only a SKIN MEMORY
few contact allergens. Application of patch tests to the back of a patient can
recall or cause a flare-up of dermatitis on other body
SYSTEMIC ADMINISTRATION OF surfaces that previously were exposed to the allergen
CONTACT ALLERGENS and part of the patient’s clinical contact dermatitis. If
Exposure to contact allergens takes place frequently by a patch test site is re-exposed to the same allergen
the ‘‘systemic’’ route, either by ingestion or by injection within 2 to 3 weeks, a reaction occurs in 4 to 6 hours
and on less frequent occasions by insertion into the body rather than 2 to 4 days. This phenomenon is allergen
(as in operative procedures and intrauterine devices). As specific, and the retest technique has been suggested as a
has been discussed earlier, first exposure to contact aller- way to evaluate whether true crossreactivity exists or
gens by the systemic route usually favors the develop- whether co-reactivity is occurring.84 It has been sug-
ment of partial or complete specific tolerance. In some gested that the mechanism for site-specific allergen skin
instances, however, allergic contact sensitization rather memory is related to a chemokine (CCL27) that causes
than tolerance occurs after such a first exposure. The retention of CCR10+CD4+ T cells perivascularly in the
explanation presumably is that some of the allergen has dermis at the site of patch testing.85 These cells are
reached the skin through the blood circulation and has found at least 3 weeks after resolution of the patch-test
then been taken up by antigen-presenting epidermal or reaction and are believed to be responsible for the rapid
lymph node LCs. reactions seen on rechallenge with the same or true
A completely different effect is exerted by contact crossreacting allergens.
allergens that are ‘‘systemically’’ administered after spe-
cific sensitization has already occurred. Under such cir-
cumstances, a clinical reaction may ensue, probably
because of take-up of the blood-borne contact allergen
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