Contents
8.1 Introduction . . . . 117
8.2 Ultrastructural Changes in the Epidermis . . 117 8.2.1 Stratum Corneum . . . . 117
8.2.2 Viable Keratinocytes . . . . 118
8.2.2.1 Irritant Contact Dermatitis . . . . 118
8.2.2.2 Allergic Contact Dermatitis . . . . 121
8.2.3 Langerhans Cells . . . . 121
8.2.3.1 Allergic Contact Dermatitis . . . . 122
8.2.3.2 Irritant Contact Dermatitis . . . . 122
8.3 Ultrastructural Changes in the Dermis . . . 124
8.4 Ultrastructural Changes in Chronic Contact Dermatitis . . . . 124
8.5 Summary . . . . 125
References . . . . 125
8.1 Introduction
Electron microscopy has provided us with a valuable tool to investigate the cellular and subcellular effects of topical exposure to irritants and allergens, com- plementing histological examination at the light mi- croscope level. Most reported data are based on the use of conventional preparative techniques, but de- velopments such as post-fixation in ruthenium te- troxide to visualize intercellular lipids and the par- allel examination of semi-thin and ultra-thin resin- embedded samples have enhanced our understand- ing of the cellular changes that take place. It is impor- tant to remember, however, that electron microscopy gives us only a snapshot of a minute fraction of a skin biopsy. Therefore, studies employing small sample numbers, with limited scrutiny of each specimen, should be viewed with a degree of caution. This is particularly true for irritant contact dermatitis in- vestigations, where considerable inter-individual variation in the intensity of the response to chemicals occurs, and where the cellular damage inflicted is rarely uniform across the application site.
In the sections which follow, ultrastructural changes seen in skin exposed to irritants and aller- gens are described. With the exception of the last sec- tion, which deals specifically with a recent study of chronic chromate hand dermatitis, the data refer to the effects of acute exposure.
8.2 Ultrastructural Changes in the Epidermis
The stratified nature of the epidermis, and the pres- ence of Langerhans cells and melanocytes in addi- tion to keratinocytes, presents a wide variety of bio- chemical and immunological targets for topically ap- plied irritants and allergens. Primary contact occurs at the outermost stratum corneum, which, depending on the chemical characteristics of the substance, may show ultrastructural evidence of damage. Diffusion into and penetration of the viable epidermal regions then take place. Again depending upon the chemical nature of the agent, as well as the severity of response and time of examination post-exposure, morpholog- ical indications of metabolic interruption may be seen.
8.2.1 Stratum Corneum
The outermost diffusion barrier of the skin, the stra- tum corneum, is a 20- to 30-cell-thick layer of flat, hexagonal, protein-rich corneocytes surrounded by intercellular lipids. Generally speaking, chemical irri- tants rather than allergens produce marked changes to its structure and behavior, as evidenced, biophysi- cally, by increased transepidermal water loss. Recent ultrastructural studies utilizing ruthenium tetroxide as a post-fixative have greatly increased our under- standing of the manner in which some irritant chem- icals interact with this region of the epidermis and contribute to the development of irritant contact der- matitis (ICD). The application of low concentrations of the anionic surfactant sodium lauryl sulfate (SLS) to normal human skin was found by Fartasch to re-
Ultrastructure of Irritant
and Allergic Contact Dermatitis
Carolyn M. Willis
8
sult not so much in an alteration of the existing lipid structure, but rather an alteration in the synthesis of new lipids [1]. Hence, disturbance of lamellar body lipid extrusion and transformation into lipid bilayers occurred, in the absence of any disruption to the intercellular lipid layers of the upper stratum corne- um. By way of contrast, acetone produced a different pattern of change. Epidermal lipid lamellae displayed disruption and loss of cohesion throughout the stra- tum corneum – the transformed, more nonpolar, la- mellar lipids showing greater disruption than the more polar lamellar body sheets [1]. A similar dis- ruption of stratum corneum intercellular bilayers was also seen in human skin patch-tested with water alone [2], which would have the effect, as pointed out by the investigators, of enhancing skin permeability and susceptibility to irritants.
쐽 Chemical irritants generally have a greater impact than allergens on the ultrastructure of the stratum corneum.
8.2.2 Viable Keratinocytes
The greatest diversity of ultrastructural effects on vi- able keratinocytes within the epidermis is undoubt- edly exerted by irritants, rather than by allergens.
While both induce varying degrees of spongiosis, clearly visible by both light and electron microscopy, chemical irritants also give rise to a heterogeneity of forms of intracellular damage that are time, dose and, in some cases, irritant dependent.
8.2.2.1 Irritant Contact Dermatitis
Two early studies provided some of the first evidence that irritants can damage the skin by different mech- anisms. A comparison between the effects of an acid and an alkali on human epidermis found that sodium hydroxide dissolved the contents of horny cells and disrupted tonofilament–desmosome complexes, while hydrochloric acid did not [3]. Similarly, in a comparative study of two lipid solvents, the response to acetone, which was characterized by intracellular edema of keratinized cells and vacuolation of spi- nous cells, was conspicuously different to that to ker- osene, in which the formation of large lacunae and cytolysis of spinous cells were seen [4]. In our own study, designed to systematically compare the mor- phological effects of six structurally unrelated irri- tants on normal human skin, electron microscopy al- so revealed significant differences in the nature of the cellular damage induced by different chemicals after 48 h of exposure [5]. Patch test reactions to SLS were characterized by parakeratotic cells in the upper epidermis, containing dense osmiophilic cyto- plasm with numerous lipid droplets and vesicles, but an absence of keratohyalin granules (Figs. 1, 2). In contrast, the cationic detergent benzalkonium chlo-
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Core Message
Fig. 1.
The interface between dark, osmiophilic, vesiculated, par- akeratotic cells in the upper epidermis and paler cells of the stratum spinosum in a 48-h patch test reaction to sodium lauryl sulfate (SLS) (4%)
ride produced distinct areas of necrosis (Fig. 3). Ap- plication of the 12-C-long chain fatty acid nonanoic acid resulted in the formation of tongues of dyskera- totic cells, largely composed of dense, wavy aggre- gates of osmiophilic keratin filaments associated with prominent intercellular desmosomes, and con- taining shrunken nuclei with condensed, marginated heterochromatin (Fig. 4). Exposure to dithranol pro- duced different changes again, namely markedly en- larged upper epidermal keratinocytes, containing finely dispersed filaments and ribosomes, and, in keeping with previous findings [6, 7], disrupted mi- tochondria (Fig. 5).
The concept of ultrastructural changes being irri- tant-dependent was further supported by a recent study of the effects of a wide variety of irritant chem- icals on the skin of hairless guinea pigs [8]. Although the skin changes described were not identical to those seen in human skin, partly perhaps as a result of concentration differences, it was clear, that again the nature of the epidermal damage elicited by SLS differed markedly from that of benzalkonium chlo- ride.
Fig. 2.Basal keratinocytes in a 48-h SLS (4%) patch test reac- tion, illustrating lipid droplet accumulation and prominent intracytoplasmic vesiculation
Fig. 3.An area of necrosis induced in the mid epidermis by 48-h patch testing with benzalkonium chloride (0.5%). Kerati- nocytes show extensive vacuolation, pyknotic nuclei, and dis- rupted organelles and membranes
Table 1.Ultrastructural changes induced in the viable epider- mis by acute exposure to selected irritants. Changes depend on the irritant, its concentration, and time
Irritant Ultrastructural changes
Sodium lauryl Spongiosis, vesiculation, nuclear/intra- sulfate cytoplasmic/mitochondrial vacuolation,
lipid droplet accumulation, hydropic swelling, decreased desmosomes with aggregation of tonofilaments Benzalkonium Nuclear/intracytoplasmic vacuolation, chloride nuclear pyknosis, mitochondrial swell-
ing, organelle disruption, hydropic swelling, spongiosis
Dithranol Hydropic swelling, mitochondrial mem- brane disruption, spongiosis, intracyto- plasmic vacuolation, dyskeratosis, apop- tosis, colloid bodies
Croton oil Marked spongiosis, intracytoplasmic vacuolation, pyknotic/enlarged nuclei Nonanoic acid Dyskeratosis, nuclear/intracytoplasmic
vacuolation, vesiculation, lipid droplet accumulation, pyknotic nuclei Acetone Acantholysis, spongiosis, nuclear/intra-
cytoplasmic edema and vacuolation
Sodium Disrupted tonofilament–desmosome hydroxide complexes
Combined human and animal data [3–12]
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Fig. 5.
Enlarged upper epidermal keratinocyte, with cytoplasm containing finely dispersed filaments and ribosomes and perinuclearly clustered mito- chondria, in a 48-h patch test reaction to dithranol (0.2%) Fig. 4.
Dyskeratotic upper epider- mal cells, containing dense, wavy aggregates of osmio- philic keratin filaments, pro- duced by 48-h patch testing with nonanoic acid (80%)
The ultrastructural changes to the viable cells in the epidermis variously described by investigators during the last three decades [3–10] (Table 1) are, in the main, indicative of autolysis or cytolysis, which would eventually lead to disintegration of the cell. In some cases, however, certain alterations, such as con- densation of chromatin and cytosol, clumping of tonofilaments and budding of membrane-bound cell fragments, may be suggestive of another form of cell death, that of apoptosis. Often ultrastructurally in- distinguishable from dyskeratotic cells in the early stages, apoptotic keratinocytes have been described in reactions to a number of well-studied irritants [11–13].
쐽 Structurally unrelated chemical irritants damage the skin by different mechanisms, which is reflected in the varying ultrastruc- tural changes seen in the epidermis. These changes also depend on concentration, time, intensity of reaction, and species.
8.2.2.2 Allergic Contact Dermatitis
Intercellular edema or spongiosis, characterized by dilated intercellular spaces, stretched or absent tono- filament–desmosome complexes and the aggrega-
tion of tonofilaments into short bundles, is a consis- tent feature of the viable epidermal layers in allergic contact dermatitis (ACD) (Fig. 6), and one that is de- tectable in sensitized individuals by electron micros- copy as early as 3 h after exposure to hapten [14].
Intracellular changes to keratinocytes, such as vac- uolation and endoplasmic reticulum dilatation, also occur, but since the majority of allergens are also in- trinsically irritant in nature, ascribing such changes with any degree of certainty to the process of sensiti- zation itself is very difficult. Indeed, in a study of chromium reactions in humans and guinea pig, the authors concluded that keratinocyte intracellular re- action patterns were nonspecific and could not be distinguished from those of vehicle or occlusion alone [15].
쐽 The predominant ultrastructural change in the epidermis of acute allergic contact der- matitis lesions is spongiosis.
8.2.3 Langerhans Cells
Much of the ultrastructural data relating to Langer- hans cell (LC) behavior in contact dermatitis focuses, not surprisingly, on ACD rather than ICD. Contradic- tory electron microscopy findings have emerged over
Core Message
Fig. 6.
Low-power micrograph of the lower region of the epi- dermis of a 48-h patch test reaction to nickel sulfate (5%). Spongiosis and exocy- tosis are the predominant features
Core Message
the years, however, stimulating debate on a number of issues, including whether overt cellular damage to LC is an inherent feature of allergic contact reactions, and the extent to which the changes seen are specific to ACD. Nevertheless, there is now no doubting the central role that this antigen-presenting, mononucle- ar cell occupies from an immunologic point of view [16]. As to whether LCs have a functional role in ICD also remains a matter of speculation, but, here, there is certainly a great deal of evidence of cellular dam- age to LC, most of which is likely to be nonspecific in origin.
8.2.3.1 Allergic Contact Dermatitis
As early as 1973, ultrastructural observations led to speculation that Langerhans cells might play a role in allergic contact reactions [17]. Close apposition to mononuclear cells was described as being an exclu- sive feature of ACD, and a variety of cellular changes suggestive of targeted physiological activity were seen. In the intervening years, numerous ultrastruc- tural studies designed to elucidate the behavior of LC
have been conducted, some of which are summarized in Table 2. From these, it would appear that there is early metabolic activation, as indicated by prominent rough endoplasmic reticulum and Golgi apparatus, during the early stages of induction and elicitation, followed later by degenerative changes, such as membrane disruption and condensation of nuclear chromatin (Fig. 7). In a rare ultrastructural study linking LC function and morphology more closely, Rizova et al. described an alteration in the pattern of endocytosis of major histocompatibility complex class II (HLA-DR) molecules specific to allergens.
Sensitizer-treated LCs internalized HLA-DR prefe- rentially in lysosomes collected near the nucleus, whereas irritant-treated and nontreated LCs inter- nalized the molecules in prelysosomes located near the cell membrane [27].
8.2.3.2 Irritant Contact Dermatitis
Current immunological evidence does not support the concept of any specific functional activities for LC during the evolution of ICD, other than perhaps
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Table 2.A summary of the major ultrastructural changes induced in Langerhans cells by selected chemical allergens. (DNCB Din- itrochlorobenzene,DNFB dinitrofluorobenzene)
Allergen(s) Langerhans cell changes Ref.
Various Apposition to mononuclear cells. Prominent rough endoplasmic reticulum and [17]
(human, 4–72 h) Golgi complexes, glycogen accumulation, presence of polyribosomes, lysosome-like projections, ruffled cell membranes. Disruption to membranes
DNCB (guinea pig, 2–48 h) Early cellular vacuolar and granular changes, with apposition to mononuclear cells. [18]
Later migration to/loss from the horny layer
Nickel, thiuram mix, Apposition to other cells, marked endocytosis with greatly increased cytoplasmic [19]
epoxy resin, neomycin content of vesicles, the latter having trilaminar membranes and specific granules.
(man, 72 h) Dark cytoplasmic vesicles (nickel). No evidence of cell damage
DNCB (guinea pig, Early activation (6 h), with prominent rough endoplasmic reticulum and Golgi, [20]
2 h to 14 days) and numerous lysosomes and vacuoles. After 12 h, cell damage, evidenced by disruption of cell membranes, etc.
Various (human, 3–168 h) Increased metabolic activity in some cells, with distended endoplasmic reticulum, [21]
pronounced microtubules and increased numbers of Birbeck granules.
Also occasional necrotic cells, with condensed chromatin and shrunken cytoplasm
Various (human, 3–72 h) No morphological changes indicative of damage [22]
Picryl chloride, DNFB 1–24 h, activation with enlargement of cell and nucleus and increase in [23]
(mouse, 1–96 h) mitochondria, Golgi and endoplasmic reticulum. After 48 h, degenerative changes
DNFB (induction) Activation from 15 min, with LC showing intense endocytotic activity – numerous [24]
(guinea pig, 15 min to 24 h) coated vesicles and Birbeck granules
Various (human, 72 h) Increased numbers of LC, increased synthesis and cell surface expression of HLA [25]
class II molecules
DNFB (mouse, 1–96 h) During induction phase, cellular and endocytotic activation. Degenerative changes, [26]
including membrane rupture, cytoplasmic edema and irregular condensation of nuclear chromatin, in the late elicitation phase
as a contributor to the milieu of inflammatory medi- ators, through their production and release of cyto- kines such as interleukin-1 (IL-1) [28]. Morphological evidence, however, certainly points to their partici- pation in ICD, which, within the epidermis, shows variability with respect to time, severity of insult, and
the chemical nature of the irritant applied [29]. Ta- ble 3 provides a summary of some of the ultrastruc- tural studies in this area, which provide evidence for LC being both activated (Fig. 8) and in a state of de- generation during the evolution of ICD. Earlier be- liefs that apposition of LC to mononuclear cells with-
Fig. 7.
Degenerative changes, in- cluding disrupted organelles and membranes, in a Lange- rhans cell within the epider- mis of a 48-h patch test reac- tion to nickel sulfate (5%).
Activated Langerhans cells were also present in the same biopsy sample
Table 3.A summary of the predominant ultrastructural changes induced in Langerhans cells by acute exposure to selected chem- ical irritants. These are irritant-, dose-, time- and species-dependent. (BC Benzalkonium chloride, CO croton oil, SLS sodium lau- ryl sulfate)
Irritant(s) Langerhans cell changes Ref.
Mercuric chloride, soap, No apposition to mononuclear cells. Glycogen accumulation [17]
SLS (human, 24–48 h)
Dithranol, nonanoic acid Apposition to mononuclear cells. Ultrastructural evidence of both stimulation and [30]
(human, 6–72 h) degeneration
Dithranol (human, 24–48 h) Fine structural changes in the mitochondria [31]
BC (human, 3–168 h) Evidence of both increased metabolic activity (distended endoplasmic reticulum [21]
and increased numbers of mitochondria and Birbeck granules) and necrosis (condensed chromatin and shrunken cytoplasm)
CO, BC, SLS (mice, 1–96 h) Degenerative changes, with mitochondrial swelling and irregular cytoplasmic [23]
vacuolization, followed by membrane disruption and disorganization of the cellular components. With low concentration of CO, prior activation of LC, with increased numbers of mitochondria and enlargement of nuclei
Six irritants of varying Varying numbers of damaged cells displaying vesiculation, loss of integrity of [29]
chemical structure organelles and membranes, condensed nuclear heterochromatin and lipid (human, 48 h) accumulation. Frequent activated LC, with numerous Birbeck granules in reactions
to benzalkonium chloride
in the epidermis was unique to ACD [17] have now been set aside, following numerous reports of its oc- currence also in ICD [31].
쐽 Langerhans cells within both allergic and irritant patch test reactions show ultrastructural evidence of both activation and degeneration.
8.3 Ultrastructural Changes in the Dermis Commonly seen changes within the dermis of both ACD and ICD lesions include edema and capillary dilatation, with disruption and degeneration of colla- gen being an additional feature of some irritant reac- tions [32]. In their recent light- and electron-micro- scopic investigation of the effects of a range of chem- ical irritants on the skin of hairless guinea pigs, Sue- ki and Kligman [8] observed variations in the dermis that were, to a degree, irritant-dependent. Exposure to SLS and to organic solvents affected the dermis relatively little. In contrast, benzalkonium chloride and various urticariogens and comedogenic agents induced marked dilation of lymphatic vessels, as well as capillaries. Increased numbers of granules within dermal mast cells were also described for the latter irritants, although this was not quantified in any way.
An earlier light and electron microscopy study of hairless mice revealed that many irritant chemicals cause, in addition to the above changes, enlargement or hyperplasia of sebaceous glands, with basal cells displaying morphological signs of enhanced meta- bolic activity, such as increases in rough endoplasmic reticulum and sebum droplets [33]. Ultrastructural evidence has also led to the belief that platelets lining the dermal venular endothelium during irritant reac- tions contribute significantly to the pathogenesis of the overall response, at least in mice, being closely linked to the formation of edema [34].
쐽 Edema and capillary dilatation are com- monly described ultrastructural features within the dermis of allergic and irritant patch test reactions.
8.4 Ultrastructural Changes in Chronic Contact Dermatitis
Little information is available regarding the ultra- structural changes associated with chronic contact dermatitis. This is largely because of the difficulty of accurately characterizing the disorder. Most clinical cases of chronic contact dermatitis are attributable to a complex admix of endogenously and exogenously derived provocation factors. Atopy often plays a role
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Fig. 8.
An activated Langerhans cell containing numerous Birbeck granules and wid- ened rough endoplasmic re- ticulum, induced by patch testing with benzalkonium chloride (0.5%). Within the same biopsy sample, Lange- rhans cells displaying de- generative changes were al- so seen
Core Message
Core Message
and even where sensitization to a relevant hapten is proven, the influence of concomitant irritant expo- sure is difficult to disentangle. However, recently, Shah and Palmer [35] attempted to document the variations in ultrastructural appearance of chronic occupational hand dermatitis linked to chromate al- lergy. Examination of a broad spectrum of clinical disease, in terms of intensity and duration, revealed cellular features within the epidermis common to other inflammatory dermatoses. These included marked spongiosis and intracellular vacuolation, particularly within the basal layers. However, the au- thors also described, for the first time in relation to chromate dermatitis, the presence of spindle-shaped granular cells, possibly mast cells, in the upper der- mis, closely opposed to the dermo-epidermal junc- tion.
쐽 More studies of chronic contact dermatitis are required to appreciate more fully the ultrastructural changes which take place.
8.5 Summary
The past two or three decades have seen the publica- tion of a wealth of information on the ultrastructural morphology of acute allergic and irritant contact dermatitis. Much still needs to be learnt, however, about the cellular features of the chronic forms of contact dermatitis. The introduction of modified tis- sue preparation techniques has greatly improved vis- ualization of the stratum corneum and increased our understanding of the damage caused by topical ex- posure to chemicals. However, the continued paucity of studies utilizing correlative functional and mor- phological techniques still limits the extent to which purely electron microscopic findings can be mean- ingfully translated into pathophysiological events.
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