Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2758_Библиотеки_им_академика_М_И_Перельмана
.pdf
Histopathology ofCutaneous
https://t.me/medicina_free
Adverse Drug Reactions
NicolasOrtonne
1 Introduction
This chapter focuses on the histopathological
manifestations of cutaneous adverse drug reactions (CADRs) driven by immune-mediated lymphocyte reactivity. These disorders are triggered
by T lymphocytes reactive to the culprit drug and
subsequently recruited into the skin: CADRs thus
represent a model of delayed hypersensitivity
(Zanni etal. 1998). Although the pathophysiology of CADR is complex, studies focusing on
genetic predisposition to drug allergy, T-cell
functioning and keratinocyte apoptosis have
informed our understanding of the biology which
underpins these reactions. In particular, the
development of epidermal necrolysis is inuenced by a genetic risk linked to the presence of
a particular HLA variant (Hung et al. 2005;
Chessman et al. 2008), while the disorder is
mediated through the action of cytotoxic proteins
produced by effector T-cells and factors which
can activate apoptosis and necroptosis pathways
in target keratinocytes (Nassif et al. 2004; de
Araujo etal. 2011; Chung etal. 2008).
2 Inammatory Patterns
inCADR
As described by Ackerman, the two main histopathological presentations encountered in
CADRs are the spongiotic and interface dermatitis patterns (Ackerman 1997). The psoriasiform
pattern is usually not seen in classical CADRs.
2.1 Spongiotic Reaction Pattern
From a histological point of view, the spongiotic
reaction pattern in CADRs is similar to that seen
in other eczematous dermatoses, such as atopic
eczema, contact dermatitis and viral maculopapular rashes. In the acute phase there is conuent
spongiosis which forms vesicles containing exocytosed lymphocytes and Langerhans cells
(Fig. 1). The spongiotic pattern is frequent in
maculopapular drug rashes and drug reaction
with eosinophilia and systemic symptoms
(DRESS). Chronic and sometimes widespread
eczematous reactions have been described in
older patients taking commonly prescribed medicines, such as anti-hypertensive drugs (especially
calcium channel blockers, angiotensin- converting
enzyme inhibitors) (Joly etal. 2007).
N. Ortonne (*)
Department of Pathology, Henri Mondor Hospital
and Paris Est Creteil University, Creteil, France
e-mail: nicolas.ortonne@aphp.fr
© Springer Nature Switzerland AG 2022
H. Y. Lee, D. Creamer (eds.), Drug Eruptions, Updates in Clinical Dermatology,
https://doi.org/10.1007/978-3-031-09388-3_3
53
54
https://t.me/medicina_free
a b
N. Ortonne
Fig. 1 Eczematous reaction pattern. (a) Acute phase
eczema showing foci of spongiosis, characterized by the
enlargement of inter-keratinocyte spaces and vesicles containing mononuclear inammatory cells. There is a dermal perivascular inltrate composed of lymphocytes.
2.2 Interface Dermatitis Pattern
The characteristic feature of the interface dermatitis pattern is epidermal attack by lymphocytes.
Other cytotoxic cell populations, such as dendritic plasmacytoid cells, can also be involved in
this epidermal assault. The classical inammatory dermatosis associated with an interface dermatitis histological pattern is lichen planus
(Wenzel etal. 2006).
The interface dermatitis pattern is variably
associated with the following features:
• Inltration of the deep layers of the epidermis
by lymphocytes and other mononuclear cells
(macrophages/dendritic plasmacytoid cells).
• Keratinocyte death producing apoptotic bod-
ies (Civatte or colloid bodies) with the release
of melanin pigment from their cytoplasm into
the epidermis and dermis.
• Vacuolization of the dermoepidermal junction
due to cell death and mononuclear cell
exocytosis.
Two main types of interface dermatitis pattern
can be identied morphologically: the vacuolar
form and the classical form (Ackerman 1997).
The vacuolar form is characterized by vacuolization of the basal layer of the epidermis with occasional apoptotic keratinocytes and a scanty
lymphocytic inltrate (Fig. 2a). This pattern is
Haematoxylin and eosin ×200. (b) Vesicle at high magnication containing numerous Langerhans’ cells which are
recognized by their clear and irregularly shaped nuclei
and moderately abundant eosinophilic cytoplasm.
Haematoxylin and eosin ×400
encountered in acute cutaneous lupus erythematosus and acute graft-versus-host disease. The
classical form, which occurs most commonly in
lichen planus, is typied by an abundant lymphocytic inltrate with more marked keratinocyte
apoptosis (Fig.2b).
A third variant of the interface dermatitis pattern can be considered, one which occurs in the
most severe form of CADR: Stevens–Johnson
syndrome/toxic epidermal necrolysis (SJS/
TEN) (Fig.2c). In this entity, keratinocyte apoptosis is predominant, in the form of conuent
clusters of dead cells. Keratinocyte apoptosis
explains the skin detachment in SJS/TEN,
referred to as epidermal necrolysis (EN), and is
caused by loss of cellular junctions between
neighbouring apoptotic cells. The lymphocyte
inltrate can be quite moderate or even minimal
in SJS/TEN reecting the concept that direct
contact with cytotoxic effector lymphocytes is
not necessary to kill keratinocytes. However,
soluble pro-apoptotic mediators, such as Fas
ligand, granulysin, interferon and TNF-alpha
may be involved, along with phenotypic modications of keratinocytes, leading to death ligand
expression (Arnold et al. 1999). Certain proinammatory cytokines promote keratinocyte
expression of pro-apoptotic ligands, such as Fas
ligand (Abe etal. 2003), and induces the death
of neighbouring cells. The role of the necroptosis process, recently identied in SJS/TEN, may
ab
Histopathology ofCutaneous Adverse Drug Reactions
https://t.me/medicina_free
c
55
Fig. 2 Interface dermatitis reaction pattern. (a) Vacuolar
interface dermatitis with lymphocyte exocytosis, vacuolization of the epidermal basal layer, occasional apoptotic
bodies and scattered lymphocytes in the supercial dermis. Haematoxylin and eosin ×200. (b) Classical lichenoid interface dermatitis with a dense lymphocytic inltrate
occupying the supercial dermis and extending to the der-
also partly explain pathomechanisms of the disorder (Saito etal. 2014). Necroptosis is characterized by a breakdown of the integrity of cell
membranes with release of alarmins, which in
mal–epidermal junction with numerous apoptotic bodies.
Haematoxylin and eosin ×100. (c) Aggressive ID, illustrating “acute syndrome of apoptotic pan-epidermolysis”
(ASAP), with conuent apoptotic keratinocytes and scattered lymphocytes in the supercial dermis and basal layers of the epidermis. Haematoxylin and eosin ×200
may characterize all the above entities, in which
common cellular and/or molecular effectors
occur downstream of drug, auto-immune, alloimmune and infectious triggers, respectively.
turn induce the death of other cells and recruitment of effector T-cells.
The term “acute syndrome of apoptotic pan-
epidermolysis” (ASAP) was rst introduced in
3 Non-specic Histological
Aspects ofCutaneous ADRs
2004 by Ting etal. to describe an aggressive form
of lupus erythematosus showing an EN-like
pattern on histology (Ting etal. 2004). We, and
others, have shown that other skin diseases can
present histologically with an EN pattern, including DRESS (Ortonne etal. 2015), erythema multiforme (Amode etal. 2018), lupus erythematosus
(Ting etal. 2004), acute graft-versus-host disease
and contact reactions with Nigella sativa oil
(Gaudin etal. 2018). A similar cytotoxic pathway
Pathologists with a reductionist vision of CADR
histopathology are inclined to limit their diagnoses by the presence of eosinophils and/or apoptotic keratinocytes. These two elements are
neither constant nor specic for a drug-induced
dermatosis. In many forms of CADR eosinophils
are absent, as are apoptotic keratinocytes.
Conversely, numerous non-drug rashes are distinguished by one or other of these features.
56
ab
https://t.me/medicina_free
N. Ortonne
Thus, histology is not usually considered as a
major diagnostic criterion for CADR. As an
example, a “non-suggestive” histology as a negative criterion for DRESS is the sole histological
feature mentioned in the DRESS diagnostic system published by Kardaun etal. (2013). However,
dermatopathology is an extremely important tool
in discriminating severe CADRs from non-drug
dermatoses. In a patient with extensive skin
detachment, histology will distinguish TEN from
staphylococcal scalded skin syndrome or from an
autoimmune bullous disorder.
The following sections outline the major histopathological features found in classical CADR
entities. It remains uncertain whether individual
manifestations represent distinct clinicalpathological entities or different aspects of a disease spectrum. In a retrospective study of 216
cases of CADRs overlap cases were rare, suggesting the validity of separate, discrete druginduced disorders (Bouvresse etal. 2012).
4 Drug-Induced Exanthem
The drug-induced exanthem, also known as a
maculo-papular rash, is the commonest form of
CADR and tends to show non-specic histological features (Hunziker etal. 1997). The dermatopathology may reveal only a perivascular
lymphocytic inltrate in the upper part of the dermis (Fig.3a), and for this reason a skin biopsy is
often not performed. Nonetheless, histopathological assessment may help to differentiate a
drug-induced exanthem from other conditions
presenting with an exanthem and a modest dermal lymphocytic inltrate, such as cutaneous
angioimmunoblastic T-cell lymphoma (AITL),
secondary syphilis, or autoimmune disorders
(lupus erythematosus, dermatomyositis). Of note
is the similarity, at the histological level, between
a viral exanthem and a drug-induced exanthem.
A drug aetiology is more likely with a spongiotic
reaction pattern and/or a multi-focal interface
c
Fig. 3 Histological aspects of the drug-induced exanthem. (a) Drug-induced exanthem characterised by a
slight perivascular inltrate in the supercial dermis.
Haematoxylin and eosin ×25. (b) Drug-induced exanthem
with spongiotic reaction pattern: conuent spongiosis and
lymphocyte exocytosis. Haematoxylin and eosin ×200. (c)
Drug-induced exanthem with an interface dermatitis, lymphocytes inltrating the basal layers of the vacuolized epidermis and a few apoptotic keratinocytes. There is an
abundant perivascular lymphocytic inltrate in the supercial dermis. Haematoxylin and eosin ×200
ab
cd
Histopathology ofCutaneous Adverse Drug Reactions
https://t.me/medicina_free
57
dermatitis pattern (Fig.3b, c) (Deschamps et al.
2020; Gerson et al. 2008). From a histological
point of view, this supports the existence of a
spectrum linking drug-induced exanthem with
DRESS, the latter being regarded by some
authors as a more severe expression of the former
(Pinto Gouveia etal. 2016; Ortonne 2016).
5 Drug Reaction
withEosinophilia
andSystemic Symptoms
(DRESS)
The histological picture of DRESS is highly
variable and reects the wide range of skin
manifestations macroscopically. However, a
lymphocytic inltrate is constant and, as with
drug-induced exanthems, may be the sole feature (Fig.4a). A spongiotic (Fig.4b) or interface dermatitis reaction pattern (Fig. 4c) can
occur, while pustular forms and keratinocyte
apoptosis may also be present (Fig.4d). Dermal
oedema and red blood cell extravasation are
often observed, reecting an increased microvascular permeability. Vasculitis is not a feature. The presence of several different
inammatory reaction patterns in a single
biopsy may be a clue to the diagnosis of DRESS
(Ortonne etal. 2015).
The inammatory cell inltrate in DRESS
varies. Lymphocytes are usually the predominant
cell type, but eosinophils may be prominent,
although this is not a predictive feature (Fig.5a).
Fig. 4 Various histopathological features of drug reaction
with eosinophils and systemic symptoms (DRESS). (a)
DRESS syndrome with a dense inltrate composed
mainly of lymphocytes in the supercial and mid dermis.
Epidermal changes are minimal. Haematoxylin and eosin
×100. (b) DRESS syndrome with a spongiotic reaction
pattern, showing intra-epidermal vesicles containing lymphocytes and Langerhans’ cells (arrow). Haematoxylin
and eosin ×200. (c) DRESS with interface dermatitis
showing a sub- epidermal band-like inltrate mainly composed of lymphocytes covering the dermal–epidermal
junction. Scattered apoptotic keratinocytes are present in
the epidermis. Haematoxylin and eosin ×200. (d) DRESS
syndrome overlapping with toxic epidermal necrolysis. A
cluster of apoptotic keratinocytes has resulted in complete
detachment of the epidermis. A dense inltrate is present
in the supercial dermis containing a few neutrophils and
nuclear debris. Haematoxylin and eosin ×100
58
ab
cd
https://t.me/medicina_free
N. Ortonne
Fig. 5 Eosinophils and visceral injury in DRESS. (a)
Dense dermal inammatory inltrate, mostly made of
lymphocytes with numerous widespread eosinophils, with
hyperplastic overlying epidermis. Eosinophils are associated with foci of collagen necrosis to yield “ame gures”
(inset). Haematoxylin and eosin ×100. (b) Severe hepatitis in a patient with DRESS showing dense inammatory
inltrate of the portal spaces, expanding into the liver lobules with areas of necrosis. The inltrate is made of lym-
Neutrophils can be seen, and, rarely, plasma
cells. The lymphocytic inltrate in DRESS may
be intense and show epidermotropism. Highly
activated T lymphocytes with an atypical appearance can also be seen making a differential diag-
phocytes, some of which are slightly enlarged or show
elongated nuclei, admixed with scattered eosinophils.
Haematoxylin and eosin ×200. (c) Necrotizing colitis in a
patient with DRESS.Areas of necrosis and ulceration of
the mucosa. Haematoxylin and eosin ×200. (d)
Necrotizing colitis in a patient with DRESS.A dense lymphocytic inltrate in the sub-mucosa with numerous
eosinophils and ame gures (arrows). Haematoxylin and
eosin ×200
the herpes viruses, including EBV (Seishima
et al. 2006). T-cells which are specic to EBV
peptides have been identied in many target tissues of DRESS, raising questions about disease
triggers (Picard etal. 2010).
nosis from T-cell lymphoma difcult.
Discriminating DRESS from cutaneous lymphomas (Sézary syndrome, angioimmunoblastic
T-cell lymphoma, aggressive CD8+ epidermotropic T-cell lymphoma) relies on phenotyping
6 Acute Generalized
Exanthematous Pustulosis
(AGEP)
and molecular studies.
The hallmark of DRESS is the systemic
involvement which includes acute hepatitis
(Fig. 5b), myocarditis, nephritis, pneumonitis
and colitis (Fig.5c, d). Another signicant characteristic is its association with reactivation of
In contrast to DRESS, acute generalized exanthematous pustulosis (AGEP) usually produces a
simple and characteristic histopathology (Halevy
et al. 2010). Sub-corneal, multilocular pustules
are typical, which are difcult to distinguish from
ac
Histopathology ofCutaneous Adverse Drug Reactions
https://t.me/medicina_free
b
59
Fig. 6 Acute generalized exanthematous pustulosis
(AGEP). (a) Early phase showing sub-corneal multilocular neutrophil pustule. Haematoxylin and eosin ×100. (b)
Late phase showing loss of pustule and elimination of the
pustular psoriasis (Fig. 6a, c). Subtle ndings
which point away from pustular psoriasis and
towards AGEP include the presence of eosino-
nuclear debris within a parakeratotic scale. Haematoxylin
and eosin ×100. (c) Active AGEP with sub-corneal pustule and a dense dermal inltrate. Haematoxylin and
eosin ×200
7 Stevens–Johnson Syndrome/
Toxic Epidermal Necrolysis
(SJS/TEN)
phils, necrotic keratinocytes, a mixed mid-dermal
interstitial and perivascular inltrate, and the
absence of tortuous or dilated blood vessels
(Kardaun etal. 2010). Histopathological diagnosis is aided by the biopsy of a fresh lesion; old
pustules are rapidly eliminated from the stratum
corneum (Fig.6b). The small size of AGEP pustules may enforce the need for multiple levels to
be cut to reveal the characteristic pathology.
SJS/TEN has a characteristic histological appearance. The disease is characterized by a massive
and conuent apoptosis of epidermal keratinocytes, sometimes including those of the hair or
sweat appendages. Keratinocyte death is so extensive that the epidermis detaches from the dermis
(epidermal necrolysis) (Fig.7). A dermal lymphocytic inltrate is always present but of varying
60
ab
https://t.me/medicina_free
N. Ortonne
c
Fig. 7 Stevens–Johnson syndrome/toxic epidermal
necrolysis (SJS/TEN). (a) Early lesion showing scattered
apoptotic keratinocytes and a minimal dermal lymphocytic inltrate. Haematoxylin and eosin ×200. (b)
Established SJS/TEN showing conuent epidermal apoptosis and epidermal detachment. Haematoxylin and eosin
density: often, it is scanty and with a paucity which
contrasts with the severity of epidermal pathology.
The density of the inltrate has no prognostic signicance (Valeyrie-Allanore etal. 2013).
×200. (c) Late lesion of SJS/TEN with regenerated epidermis underlying the detached, necrotic epidermis. In the
detached epidermis, there is evidence of secondary ischemic necrosis with keratinocyte pallor and vacuolization.
Haematoxylin and eosin ×200
that GBFDE can present with massive keratinocytes apoptosis, as is commonly seen in SJS/
TEN, or with spongiotic and/or interface dermatitis inammatory patterns. Cho et al. showed
that GBFDE and TEN are slightly different, with
more eosinophils and melanophages in GBFDE
8 Fixed Drug Eruption (FDE)
than TEN, and more granulysin + effector cells in
the epidermis in TEN than GBFDE (Cho etal.
A histopathological study of FDE demonstrated
necrotic keratinocytes, spongiosis, vacuolar
degeneration, eosinophils in 73% of cases, and
dermal melanophages in 55% (Weinborn et al.
2016). In a further study of generalized bullous
FDE (GBFDE) an interface dermatitis was
always present, eosinophils were seen in 87.5%
and dermal melanophages in all cases (Cho etal.
2014) (Fig. 8). Our studies have demonstrated
2014). Misukawa etal. and Shiohara etal. dem-
onstrated that memory CD8+ T cells were rapidly
activated after drug intake and were thereafter
maintained in the basal layer of lesional epider-
mis (Mizukawa and Shiohara 2010; Shiohara and
Mizukawa 2007; Mizukawa et al. 2002, 2008).
CD8+ T cells within the basal layer can be dem-
onstrated in late and “quiescent” skin lesions of
FDE (Fig.8c, d).
Histopathology ofCutaneous Adverse Drug Reactions
https://t.me/medicina_free
61
ab
cd
Fig. 8 Fixed drug eruption (FDE). (a) Bullous FDE with
detached epidermis showing apoptotic keratinocytes,
ischaemic necrosis and regenerated epidermis.
Haematoxylin and eosin ×100. (b) FDE showing an interface dermatitis with numerous lymphocytes inltrating
the vacuolized basal layers of the epidermis and scattered
apoptotic keratinocytes. Haematoxylin and eosin ×200.
9 Symmetrical Drug-Related
Intertriginous andFlexural
Exanthem (SDRIFE)
The histopathological features of SDRIFE have
not been studies in detail. In our experience,
SDRIFE shows a wide range of pathological patterns, including eczematous changes, sub-corneal
pustules, supercial dermal oedema and an inammatory inltrate which may contain lymphocytes,
neutrophils and eosinophils. The diagnosis of
SDRIFE is not made from the dermatopathology;
however, assessment of a skin biopsy can support
the diagnosis in the correct clinical setting.
(c) Quiescent FDE with numerous melanophages in the
supercial dermis with apparently normal overlying epi-
dermis. Haematoxylin and eosin ×200. (d) The same
sample as (c) showing a mild T-cell inltrate of CD8+
effector cells aligned along the basement membrane zone.
Anti-CD8 immunohistochemistry (DAB) ×200
10 Problems ofDierential
Diagnosis inDrug Eruption
Dermatopathology
Histopathological discrimination of SJS/TEN
from other conditions presenting with extensive
epidermal necrolysis is challenging. Severe cases
of erythema multiforme, lupus erythematosus,
dermatomyositis and GVHD can all share physi-
cal and dermatopathological manifestations with
SJS/TEN.In this acute scenario conrmation of
drug-induced SJS/TEN can only be achieved fol-
lowing a careful and informed synthesis of clini-
cal and dermatopathological features.
62
https://t.me/medicina_free
N. Ortonne
Similarly, dermatopathological differentiation
between a drug-induced exanthem, DRESS syndrome and a viral exanthem is difcult. This
diagnostic obstacle may reect the proposed role
of herpesvirus reactivation in DRESS, an hypothesis supported by the identication of EBVspecic clonal T-cells in DRESS-affected organs
(Picard etal. 2010). Some authors even suggest
that DRESS is a viral disease triggered by medication, a herpesvirus-drug synergy which is welldocumented by the eruption occurring in
infectious mononucleosis treated with penicillin.
Of greater concern is the differentiation of
DRESS from cutaneous T-cell lymphoma
(CTCL). Features shared by DRESS and T-cell
lymphomas include rash (especially erythroderma), lymphadenopathy, eosinophilia, and the
presence of circulating atypical lymphocytes.
Histologically, the inltrate in DRESS may be
composed of atypical lymphocytes, strongly
resembling those seen in Sezary syndrome
(Ortonne etal. 2015). The key features which discriminate DRESS from lymphoma include the
presence of inammatory alterations of the epidermis, the absence of pan-T-cell antigens loss,
the negative search for neoplastic T-cell markers,
such as CD158k/KIR3DL2in Sezary syndrome
(SS) (Ortonne etal. 2006, 2008) and TFH differentiation markers in angioimmunoblastic T-cell
lymphoma (AITL) (Leclaire Alirkilicarslan etal.
2017). DRESS patients will not possess a domi-
nant T-cell clone in the skin and blood. The lymphocyte inltrates in DRESS are usually enriched
in cytotoxic CD8+ effectors T-cells, some of
which correspond to the morphologically atypical cells. By contrast, the neoplastic T-cells in SS
and AITL are constantly CD4+. The mutational
landscape of AITL is well described and recurrent mutations affecting epigenetic regulators
(IDH2 p.R172K/S) or the small RhoA GTPase
(RHOA p.G17V) are recognized (SakataYanagimoto etal. 2014; Lemonnier etal. 2016).
Despite the problems in differential diagnosis,
dermatopathology plays a key role in the assessment of drug-induced skin disease. An understanding of common histopathological features
and disease patterns helps the physician both to
implicate medication as a trigger and to assign a
specic drug eruption diagnosis. A skin biopsy
and application of the dermatopathological principles outlined above have primacy in the management of all patients with a suspected cutaneous
adverse drug reaction.
References
Abe R, Shimizu T, Shibaki A, Nakamura H, Watanabe H,
Shimizu H.Toxic epidermal necrolysis and Stevens–
Johnson syndrome are induced by soluble Fas ligand.
Am J Pathol. 2003;162(5):1515–20.
Ackerman AB. Histologic diagnosis of inammatory
skin diseases: an algorithmic method based on pattern analysis. 2nd ed. Baltimore: Williams & Wilkins;
1997. p.943.
Amode R, Ingen-Housz-Oro S, Ortonne N, Bounfour T,
Pereyre S, Schlemmer F, etal. Clinical and histologic
features of mycoplasma pneumoniae-related erythema
multiforme: a single-center series of 33 cases compared with 100 cases induced by other causes. J Am
Acad Dermatol. 2018;79(1):110–7.
Arnold R, Seifert M, Asadullah K, Volk HD.Crosstalk
between keratinocytes and T lymphocytes via Fas/
Fas ligand interaction: modulation by cytokines. J
Immunol. 1999;162(12):7140–7.
Bouvresse S, Valeyrie-Allanore L, Ortonne N,
Konstantinou MP, Kardaun SH, Bagot M, etal. Toxic
epidermal necrolysis, DRESS, AGEP: do overlap
cases exist? Orphanet J Rare Dis. 2012;25(7):72.
Chessman D, Kostenko L, Lethborg T, Purcell AW,
Williamson NA, Chen Z, et al. Human leukocyte
antigen class I-restricted activation of CD8+ T cells
provides the immunogenetic basis of a systemic drug
hypersensitivity. Immunity. 2008;28(6):822–32.
Cho Y-T, Lin J-W, Chen Y-C, Chang C-Y, Hsiao C-H,
Chung W-H, et al. Generalized bullous xed drug
eruption is distinct from Stevens–Johnson syndrome/
toxic epidermal necrolysis by immunohistopathological features. J Am Acad Dermatol. 2014;70(3):539–48.
Chung W-H, Hung S-I, Yang J-Y, Su S-C, Huang S-P,
Wei C-Y, etal. Granulysin is a key mediator for disseminated keratinocyte death in Stevens–Johnson
syndrome and toxic epidermal necrolysis. Nat Med.
2008;14(12):1343–50.
de Araujo E, Dessirier V, Laprée G, Valeyrie-Allanore
L, Ortonne N, Stathopoulos EN, etal. Death ligand
TRAIL, secreted by CD1a+ and CD14+ cells in
blister uids, is involved in killing keratinocytes
in toxic epidermal necrolysis. Exp Dermatol.
2011;20(2):107–12.
Deschamps O, Ortonne N, Hüe S, Rodriguez C, Deschodt
C, Hirsch G, et al. Acute exanthemas: a prospective
study of 98 adult patients with an emphasis on cyto-
Соседние файлы в папке Библиотека им академика М.И. Перельмана