Immunology of Dermatophytosis

Sandro Rogerio Almeida

Received: 15 October 2007 / Accepted: 30 January 2008 / Published online: 14 May 2008
Springer Science+Business Media B.V. 2008
Abstract The immune response to infection by
dermatophytes ranges from a non-specic host mech-
anismtoa humoral andcell-mediatedimmune response.
The currently accepted view is that a cell-mediated
immune response is responsible for the control of
dermatophytosis. Indeed, some individuals develop a
chronic or recurrent infection mediated by the suppres-
sion of a cell-mediated immune response. The immune
response to Trichophyton is unusual in that this fungus
can elicit both immediate hypersensitivity (IH) and
delayed-type hypersensitivity (DTH) in different indi-
viduals when they are submitted to a skin test reaction.
Understanding the nature and function of the immune
response to dermatophytes is an exciting challenge that
might lead to novel approaches in the treatment and
immunological prophylaxis of dermatophytosis.
Keywords Dermatophytosis Immunology
Innate immunity Adaptive immunity
Introduction
The immune response against fungi ranges from
protective mechanisms that were already present
early in the evolution of multicellular organisms
(innate immunity) to sophisticated mechanisms
which are specically induced during infection and
disease (adaptive immunity) [1]. The understanding
of innate immunity against fungi has experienced
great progress throughout the past few years with the
discovery of Toll-like receptors and glucan receptors
such as dectin-1 and dectin-2. The interaction of
fungi with these receptors has been contributing to
the better comprehension of the innate response [2].
The study of the adaptive immune response against
fungi has shed light on T lymphocytes activation
during infection including the possibility to develop
vaccines [3].
The immunology of dermatophytosis is currently
poorly understood. Some recent works have focused
on T cell immunity against dermatophytes [4]. It is
now accepted that a cell-mediated immune response
is responsible for the control of infection by derma-
tophytes. On the other hand, susceptibility to chronic
dermatophytosis is associated with atopy and with
immediate type hypersensitivity [5]. The identica-
tion of the mechanism which induces the control of
disease is an interesting point to study in the
immunology of dermatophytosis.
Innate Immune Response
Professional phagocytes, consisting of neutrophils,
macrophages, and dendritic cells, have an essential
S. R. Almeida (&)
Department of Clinical and Toxicological Analysis,
Faculty of Pharmaceutical Sciences, Sao Paulo
University, Avenida Prof. Lineu Prestes, 580, Bloco 17,
Sao Paulo CEP 05508-900, Brazil
e-mail: sandroal@usp.br
1 3
Mycopathologia (2008) 166:277283
DOI 10.1007/s11046-008-9103-6
role in the initiation of the specic immune response.
Natural killer cells, gamma delta T cells, and non-
hematopoietic cells, such as epithelial and endothelial
cells, are also important for onsetting the immune
response.
Innate immunity is instrumental for the develop-
ment of adaptive cell-mediated immune responses
controlling mycotic infections or for disease progres-
sion [6, 7]. It participates in conferring phagocytic
cells their ability to ingest and/or inhibit fungal
growth, as well as in triggering an acute inammatory
reaction, or in presenting fungal antigens to T cells.
These cells could phagocytose fungal cells, initiate
antigen presentation, as well as secrete key cytokines
such as tumor necrosis factor-a (TNF-a and interleu-
kin (IL)-12, chemokines, and other molecules that
initiate the inammatory reaction and modulate the
infection.
Dermatophytes are a group of fungi that have the
capacity to invade keratinized tissues to produce
infection. However, the immune response against
dermatophytes begins with the interaction of the
fungus with the stratum corneum. Several authors
have demonstrated the release of IL-8 by keratinocytes
in the presence of dermatophyte antigens, such as
trichophytin, suggesting that these cells can contribute
to the induction of an acute response during infection
by dermatophytes [8]. The production of IL-8 by
keratinocytes induces the accumulation of neutrophils
in the stratum corneum. Shiraki et al. [9] showed that
Trichophyton tonsurans-infected keratinocytes
up-regulated the expression of IL-8 mRNA and
secreted IL-8 and IL-16. It therefore appears that
keratinocytes not only play an important structural
role in the formation of a physical barrier against
dermatophytes, but may also play an important
function in initiating a cutaneous inammatory
reaction.
After interaction with the stratum corneum, der-
matophytes might invade the keratinized tissues.
Incubation of fresh human serum with Trichophyton
rubrum increased the chemotaxis and adherence of
polymorphonuclear leukocytes (PMNL). Comple-
ment-opsonized spores, but not hyphae, were killed
by PMNL. This was conrmed by the lack of growth
in subsequent cultures [10].
Most of the studies on dermatophytes investigated
the role of T-cell-mediated immunity on the outcome
of infection. Few studies have addressed the role of
macrophages and neutrophils during the initial phase
of infection.
Human polymorphonuclear neutrophils and mono-
cytes play an important role in the host defenses against
fungi. Phagocytosis and enhancement of the respiratory
burst are the main mechanisms by which PMNL kill
fungi. The importance of neutrophils in the defense
against dermatophytes is evidenced by the observation
of a dense inltration of these cells in infected areas of
the skin [11]. Human neutrophils were highly toxic to
T. rubrum and Trichophyton quinckeanum after 2 h of
incubation at 37C. Cytotoxicity showed a linear target
to effector cell relationship. The cytotoxic effect was
largely mediated by oxidative intermediates derived
from the respiratory burst of the phagocytic cells.
However the cytotoxic activity of neutrophils was
transient. Long periods of incubation resulted in
increased fungal viability. Monocytes exerted a less
marked cytotoxic effect [12].
Recently, our group investigated the interaction of
T. rubrum conidia with peritoneal mouse macro-
phages [13]. We found that macrophages
phagocytose T. rubrum conidia and that this process
is inhibited by T. rubrum exoantigens or mannan.
Thus, it seems likely that fungal-derived carbohy-
drates are involved in the uptake of conidia. It is
known that carbohydrate-binding C-type lectin and
lectin-like receptors play an important role in the
immune system [14]. Mannan can bind either to the
mannose receptor or the b-glucan receptor [15]. We
also found that the phagocytosis of T. rubrum has
functional consequences for macrophages since it
resulted in a down-modulation of class II major
histocompatibility complex (MHC) antigens and in
the expression of co-stimulatory molecules. Further-
more, it induced the production of IL-10, a potent
anti-inammatory cytokine. Moreover, the ingested
T. rubrum conidia differentiated into hyphae that
grew and killed the macrophages after 8 h of culture.
These results indicate that fungal cells are able to
inhibit macrophage functions or to induce suppres-
sive cytokines that could favor fungal evasion from
host responses. However, we also found that
T. rubrum-infected macrophages produced high lev-
els of TNF-a, a prototypic pro-inammatory
cytokine. Even though fungal exoantigens inhibited
the phagocytosis of conidia, they did not induce a
signicant production of IL-10 or TNF-a by macro-
phages. Thus, it appears that fungal-derived
278 Mycopathologia (2008) 166:277283
1 3
carbohydrates that mediate phagocytosis do not
trigger, per se, cytokine production.
The immune system has evolved an elaborate
system of pathogen surveillance, the so-called path-
ogen-recognition receptors (PRRs), which can
recognize conserved structures in microbes [16]. A
novel class of PRRs is the Toll-Like receptors (TLRs)
[17]. During the past few years, extensive research
has demonstrated that TLRs are crucial for the
recognition of pathogenic microorganisms and for
the activation of an innate immune response [18].
Recent studies have demonstrated the involvement of
TLRs in the recognition of fungal pathogens such as
Candida albicans, Aspergillus fumigatus, and Cryp-
tococcus neoformans [19, 20].
Recent studies suggest that TLR 2-dependent
mechanisms induced by certain microorganisms
contribute to the evasion to or inhibition of the
immune response. For instance, Yersinia enterocol-
itica and C. albicans induce immunosuppression
through TLR 2-mediated IL-10 release [15, 21].
Similarly, A. fumigatus, during germination, induces
the production of IL-10 through TLR 2 signaling
[22]. It remains to be determined whether T. rubrum
infection activates TLR 2.
Recently, a b-glucan receptor present mainly in
macrophages and dendritic cells, dectin-1, was iden-
tied. Dectin-1 is a small type II transmembrane
receptor containing one lectin-like carbohydrate rec-
ognition domain, which recognizes b 1,3- and b 1,6-
linked glucans as well as intact yeasts. Dectin-1
mediates a cellular response to yeasts or conidia by
inducing the production of pro-inammatory cyto-
kines [23].
Another carbohydrate receptor, dectin-2, was also
identied recently. Sato et al. [24] showed that
dectin-2 preferentially binds to hyphae of various
fungal species, including T. rubrum. Dectin-2-ligated
hyphae or those cross-linked by antibodies induce the
phosphorylation of tyrosine, internalize a surrogate
ligand, activate nF-jB, and up-regulate the expres-
sion of TNF-a and IL-1ra (a IL-1 receptor antagonist)
in macrophages. Regarding Candida albicans, all the
carbohydrates unique to hyphae (not present in the
yeast cell wall) that were tested by Sato et al. [24] as
candidates for being a dectin-2 ligand, failed to
inhibit the selective binding of hyphae to dectin-2,
and inhibition was possible only with high dose
mannan, a result which is consistent with the fact that
dectin-2 can recognize high mannose structures.
However, the real participation of mannans as the
dectin-2 ligand is uncertain. In fungi like C. albicans,
both the yeast and hyphal forms contain mannans in
their cell wall. Therefore, a better display or even a
higher amount of some minor structures in cell wall
mannans of hyphae compared to yeast form, could
explain the preferential binding of dectin-2 to hyphal
structures.
Adaptive Immunity
Humoral Immunity
Several studies have shown that humoral immunity to
dermatophytes is not protective. However, antibodies
are detected in infected patients and animals [25, 26].
The production of antibodies occasionally occurs in
complications of dermatophytosis such as vasculitis
and urticaria. The possibility that dermatophyte
antigens serve as a non-specic adjuvant for the
production of IgE antibodies, resulting in allergic
disease, in predisposed individuals has been evalu-
ated. The antigenic composition of dermatophytes
was found to differ between species, but it was
characteristic and constant for different strains of the
same species. Partial cross-reactivity was detected
between different species [27].
The concentrations of antibodies against several
dermatophyte species have already been measured
using several different methods including immuno-
diffusion, ELISA, counterimmunoelectrophoresis,
and complement xation. Kaaman et al. [28] showed
a higher concentration of IgG antibodies against
dermatophyte antigens, measured by ELISA, in
infected individuals compared with that found in
uninfected controls. High levels of specic IgE and
IgG4 were detected in patients with chronic dermat-
ophytosis. On the other hand, Ig levels are low in
patients that present a positive delayed type hyper-
sensitivity (DTH) skin test [28].
Positive immediate (IgE mediated) hypersensitiv-
ity (IH) tests to Trichophyton extract are frequently
observed in subjects with chronic dermatophytosis.
These IgE antibody-mediated reactions are charac-
terized by a local wheal and are 5 to 20 min after the
injection of antigen into the skin. In this process, the
binding of antigen to IgE on the surface of mast cells
Mycopathologia (2008) 166:277283 279
1 3
results in cross-linking of IgE, which in turn, triggers
the degranulation of mast cells and the release of
histamine and other proinammatory mediators [29].
The IH skin test for Trichophyton is associated with
the presence of serum IgE and IgG against Tricho-
phyton antigens. Furthermore, IgG4 is the major
component of the IgG response. Thus, IH reactions to
dermatophytes bear the hallmarks of a Th2 response.
In this type of response, IL-4 produced by CD4 T
cells (Th2 cells) induces antibody isotype switching
to IgG4 and IgE [30].
Cell-mediated Immune Response
The more characteristic cell-mediated immune
response to dermatophytes is DTH. DTH is a form
of cell-mediated immunity in which the ultimate
effector cell is the activated macrophage. In the
classical DTH reaction, the activation of macro-
phages is mediated by gamma interferon (IFN-c)-
producing (Th1) CD4 T lymphocytes. These T cells
recognize and respond to foreign antigens presented
in the form of a complex of peptide and class II
MHC. This cell-mediated response is characterized
by indurations at the site of injection provoked by the
recruitment of cells into the skin associated to
deposition of brin, which is maximal at 48 h. A
positive DTH reaction to Trichophyton extract is
associated with lower titers of IgG directed toward
Trichophyton antigens and the absence of IgE or
IgG4 [31].
Several experiments have shown that the resolu-
tion of dermatophytosis is mediated by DTH [32].
The inability of an individual to develop an infection
after experimental inoculation when he presents a
positive DTH reaction and the development of DTH
involved with inammatory response in primary
infection argue with these hypotheses [33]. In con-
trast, IH skin tests are often associated with chronic
infection; this suggests that a humoral response to
Trichophyton is less protective than a cell-mediated
response [34].
Jones [36] showed that human volunteers infected
with dermatophytes presented two patterns of cellular
immune response. He observed that an acute inam-
matory response correlated with a positive DTH skin
test to trichophytin and clearing of the infection. In
contrast, chronic infection was associated with high
IH and low or waning DTH [35].
The dermatophyte antigens recognized by human
T lymphocytes and their degree of cross-reactivity
were analyzed by MacCarthy et al. [36]. These
authors generated dermatophyte-responsive T cell
lineages by means of an in vitro sensitization to crude
fungal extracts obtained from T. rubrum, T. tonsu-
rans, Microsporum canis, and Epidermophyton
occosum. The human T cells responded to fungal
extracts derived from these various dermatophyte
species, demonstrating the recognition of cross-reac-
tive antigens by human T cells. This cross-reactivity
was induced by a mannose-rich glycoprotein fraction
of dermatophytes.
Koga et al. [37] analyzed skin lesions caused by
dermatophytes in situ by immunohistochemistry and
observed a mixture of CD4- and CD8-positive T cells
in the dermal inltrates of the lesions. Considerable
numbers of CD1a-positive and CD68-positive cells
were detected in the upper dermis and the epidermis.
IFN-c-positive cells were present in the upper dermis
of lesion, suggesting that the skin lesions caused by
dermatophytes may be associated with a Th1
response [37].
Distinct subpopulations of helper T cells are known
to stimulate different immune response pathways [38]
and immunity to pathogens could be regulated by Th1
or Th2 subsets, which would ultimately determine the
outcome of the infection. Lymphokines produced by
Th1 lymphocytes are correlated to resistance against
some diseases, whereas lymphokines produced by Th2
cells can be associated to susceptibility [39]. Moreover,
the two preferential activation pathways, Th1 or Th2,
are usually antagonistic [40], resulting either in the
activation of the cellular immune response, which
would confer protection, or in a high production of
antibodies that would be correlated with disease.
Indeed, it has been proposed that, throughout the
course of the disease, there is a tendency toward the
activation of Th2 subsets, leading to an intense B cell
stimulation and inefcient macrophage activation [41].
Changes in the balance between Th1 and Th2
responses have been implicated in the progression of
several diseases associated with dermatophytosis,
notably HIV infection.
As shown for other diseases [42], many factors
may determine resistance or susceptibility to infec-
tion. The dose of the antigen, the type of antigen
presenting cells (APCs) and the nature of the co-
stimulatory microenvironment are postulated as
280 Mycopathologia (2008) 166:277283
1 3
polarizing factors in determining which immune
response pathway will be preferentially activated
[43, 44]. The population of APCs that are able to
activate class II MHC-restricted, CD4+ Th cells is
heterogeneous and includes B cells, macrophages,
and dendritic cells (DCs).
DCs have been described as initiators and modu-
lators of the immune response. Immature DCs, which
reside in most tissues and organs, actively capture
and process antigens [45]. Upon activation by
microbes, by the microbial cell wall component
lipopolysaccharide (LPS), or cytokines such as IL-1b,
granulocyte-macrophage colony-stimulating factor
(GM-CSF) and TNF-a, DCs migrate to lymph nodes
and the spleen, where they activate na ve antigen-
specic T cells. During this migration, they undergo a
process of maturation, which is a crucial step in the
development of DCs into fully potent APCs. During
maturation, DCs lose their ability to capture and
process antigens, increase their expression of class II
MHC, co-stimulatory molecules (CD40, CD80,
CD86) and adhesion molecules (CD54), and up-
regulate their production of cytokines such as IL-12.
This latter cytokine plays a key role in the induction
of cell-mediated immunity to intracellular pathogens
by triggering the production of IFN-c in natural killer
(NK) and T cells [46].
The activation of the appropriate CD4 Th subset is
important for the resolution of some diseases and
several studies have shown that different outcomes of
a disease can be obtained by inuencing the commit-
ment of precursors to either the Th1 or Th2 lineage. It
is therefore important to determine the factors which
may lead to the predominance of Th1 or Th2 in vivo.
However, the role of DCs in dermatophytosis has not
yet been investigated. With the knowledge that DCs
can initiate an immune response with the aid of na ve
T cells and that they also participate in Th cell
education [47], it is important to understand the role
played by DCs in dermatophytosis. This hypothesis is
currently under study in our laboratory.
The 29-kDa subtilase homologue, Tri r 2 derived
from T. rubrum, exhibits unique immunological
characteristics in its ability to yield positive IH and
DTH skin tests in different individuals. Patterns of T
cell epitope recognition were compared between IH
and DTH skin test groups and a peptide (aa 4160
p5) containing an immunodominant epitope associ-
ated with DTH, but not with IH response, was
identied [48]. The same authors observed that this
peptide is recognized in a permissive manner. The
strong T cell proliferative response to p5 in subjects
with DTH was due to the amino-terminal region. The
response stimulated by Tri r 2 was dominated by the
Th1 cytokine IFN-c in DTH-positive subjects. Para-
doxically, p5 induced the production of IL-5 and IL-
10 (Th2 type-cytokines) in DTH-positive, but not in
IH subjects. These observations argue against the
segregation of Th1 cells and Th2 cells with DTH and
IH responses, respectively. Instead, they suggest that
T cell repertoires associated with distinct immune
responses to Tri r 2 can be distinguished based on the
Th2 cytokine induction by DTH-associated major
epitopes localized in the amino-terminal region of the
molecule. These results suggest that delayed skin
responses induced by Trichophyton do not reect
classical DTH, but an alternative response.
Experimental animal models have been used to
study the role of cell-mediated immune response
during dermatophytosis. Green et al. [49] showed
that athymic (nude) rats that lack T-cell-mediated
immunity, could not clear Trichophyton mentagro-
phytes infections compared with genetically matched
euthymic control rats. Calderon and Hay [50] using
sublethally irradiated mice which were particularly
susceptible to Trichophyton infection, found that
regional lymph node cells from syngeneic acutely
infected donors conferred protection to irradiated
recipients. Thus, serum from the same donors did not
prevent infection of normal mice. The capacity of
lymphoid cells to transfer adoptive immunity was lost
after treatment with monoclonal anti-Thy-1.2 anti-
body and complement, suggesting the participation of
these cells in protection against infection [50].
There is some evidence that certain dermato-
phytes, such as T. rubrum, produce substances that
weaken the immune response. Mannan, a glycopro-
tein component of the fungal cell wall, may suppress
the inammatory response especially in atopic or
other persons susceptible to the mannan-induced
suppression of cell-mediated immune response. Blake
et al. [51] demonstrated that the incubation of
puried T. rubrum mannan with peripheral blood
mononuclear cells suppressed lymphoblast formation
and inhibited the lymphocyte proliferative response
to mitogens. Grando et al. [52] identied the mono-
cyte as the likely target cell for immunosuppresion.
They found that monocytes, not lymphocytes, bound
Mycopathologia (2008) 166:277283 281
1 3
uorescein isothiocyanate-mannan and that the sur-
face-bound ligand appeared to be internalized and
digested. This binding could interfere with accessory
cell functions of monocytes.
Conclusion
The severe dermatophytosis often seen in individuals
with AIDS attest to the importance of a cell-mediated
immune response in the control of this disease. Thus,
the inhibition of the T cell response contributes to the
development of the chronic form of the disease.
The development of a vaccine which has the
ability to induce a strong protective memory T-cell
response to dermatophytes could therefore be advan-
tageous over existing treatments. The molecular
characterization of dermatophyte antigens provides
us with invaluable tools to study the immunological
aspects of dermatophytosis and the identication of
peptides which preferentially stimulate Th1-response.
On the other hand, attention has been focused until
now on the role of T lymphocytes in host defenses in
humans as well as in experimentally infected animals.
However, it appears that further work should be
undertaken on the role of phagocytic cells and their
relevance to the control of these infections. Presen-
tation of antigen through antigen-presenting cells
such as macrophages and dendritic cells may deter-
mine the degree of interference with cell-mediated
immunity during dermatophytosis.
The denition of the immune mechanisms which
govern distinct immune responses against dermato-
phytes, may be pivotal in the understanding of the
host determinants of protective immunity.
References
1. Romani L. Immunity to fungal infection. Nat Rev.
2004;4:113.
2. Gantner BN, Simmons RM, Canavera SJ, Akinra S,
Underhill DM. Collaborative induction of inammatory
responses by Dectin-1 and Toll-like receptor 2. J Exp Med.
2003;197:111924.
3. Woodfolk JA, Platts-Mills TAE. The immune response to
dermatophytes. Res Immunol. 1998;149:43645.
4. Woodfolk JA, Platts-MILLS TAE. Diversity of the human
allergen-specic T cell repertoire associated with distinct
skin test reactions: delayed-type hypersensitivity-associated
major epitopes induce Th1-and Th2-dominated responses.
J Immunol. 2001;167:541219.
5. Woodfolk JA. Allergy and dermatophytes. Clin Microbiol
Rev. 2005;18:3043.
6. Romani L. Innate and adaptive immunity in Candida
albicans infections and saprophytism. J Leukoc Biol.
2000;68:1759.
7. Romani L. Immunity to Candida albicans: Th1, Th2 cells
and beyond. Curr Opin Microbiol. 1999;2:3637.
8. Grappel SF, Blank F. Role of keratinases in dermatophy-
tosis. I. Immune responses of guinea pigs infected with
Trichophyton mentagrophytes and guinea pigs immunized
with keratinases. Dermatologica. 1972;145:24555.
9. Shiraki Y, Ishibashi Y, Hiruma M, Nishikawa A, Ikeda S.
Cytokine secretion proles of human keratinocytes during
Trichophyton tonsurans and Arthroderma benhamiae
infections. J Med Microbiol. 2006;55:117585.
10. Dahl MV, Carpenter R. Polymorphonuclear leukocytes,
complement, and Trichophyton rubrum. J Invest Dermatol.
1986;86:13841.
11. Szepes E, Magyarlaki M, Battyani Z, Schneider I. Immu-
nohistological characterization of the cellular inltrate in
dermatophytosis. Mycoses. 1993;36:2036.
12. Calderon RA, Hay RJ. Fungicidal activity of human
neutrophils and monocytes on dermatophyte fungi, Trich-
ophyton quinckeanum and Trichophyton rubrum.
Immunology. 1987;61:28995.
13. Campos MRM, Russo M, Gomes E, Almeida SR. Stimu-
lation, inhibition and death of macrophages infected with
Trichophyton rubrum. Microbes Infect. 2006;8:3729.
14. Engele M, Stossel E, Castiglione K, Schwerdtner N,
Wagner M, Bolcskei P, Rollinghoff M, Stenger S. Induc-
tion of TNF in human alveolar macrophages as a potential
evasion mechanism of virulent Mycobacterium tuberculo-
sis. J Immunol. 2002;168:132837.
15. Netea MG, Sutmuller R, Hermann C, Van der Graaf CA,
Van der Meer JW, van Krieken JH, Hartung T, Adema G,
Kullberg BJ. Toll-like receptor 2 suppresses immunity
against Candida albicans through induction of IL-10 and
regulatory T cells. J Immunol. 2004;172:37128.
16. Shortman K, Lui YJ. Mouse and human dendritic cell
subtypes. Nat Rev Immunol. 2002;2:15161.
17. Pasare C, Medzhitov R. Toll-like receptors and acquired
immunity. Semin Immunol. 2004;16:236.
18. Kopp E, Medzhitov R. Recognition of microbial infection by
Toll-like receptors. Curr Opin Immunol. 2003;15:396401.
19. Villamon E, Gozalbo D, Roig P, O

Connor JE, Fradelizi D,

Gil ML. Toll-like receptor-2 is essential in murine defenses
against Candida albicans infections. Microbes Infect.
2004;6:17.
20. Braedel S, Radsak M, Einsele H, Latge J-P, Michan A,
Loefer J, Haddad Z, Grigoleit U, Schil H, Hebart H.
Aspergillus fumigatus antigens active innate immune cells
via Toll-like receptors 2 and 4. Br J Haematol. 2004;125:
3929.
21. Sing A, Rost D, Tvardovskaia N, Roggenkamp A, Wide-
mann A, Kirschning CJ, Aefelbacher M, Heesemann J.
Yersinia V-antigen exploits Toll-like receptor 2 and CD14
for interleukin-10-mediated immunosuppression. J Exp
Med. 2002;196:101724.
22. Netea MG, Warris A, Van der Meer JW, Fenton MJ,
Verver-Janssen TJ, Jacobs LE, Andresen T, Verweij PE,
Kullberg BJ. Aspergillus fumigatus evades immune
282 Mycopathologia (2008) 166:277283
1 3
recognition during germination through loss of toll-like
receptor-4-mediated signal transduction. J Infect Dis.
2003;188:3206.
23. Brown GD, Herre J, Williams DL, Willment JA, Marshall
ASJ, Gordon S. Dectin-1 mediates the biological effects of
b-glucans. J Exp Med. 2003;197:111924.
24. Sato K, Yang XL, Yudate T, Chung JS, Wu J, Luby-Phelps
K, Kimberly RP, Underhill D, Cruz PD Jr, Ariizumi K.
Dectin-2 is a pattern recognition receptor for fungi that
couples with the Fc receptor c chain to induce innate
immune responses. J Biol Chem. 2006;28:3885466.
25. Svejgaard E. Humoral antibody responses in the immu-
nopathogenesis of dermatophytosis. Acta Derm Venereol
Suppl (Stockh). 1986;121:8591.
26. Grappel SF, Blank F, Bishop CT. Circulating antibodies in
dermatophytosis. Dermatologica. 1972;144:111.
27. De Haan P, Wickler JR, Van Der Raay-Helmer EMH,
Boorsina DM. Antigens of dermatophytes, their charac-
terization using monoclonal antibodies. In: Kurstak E (ed.),
Immunology of fungal diseases. Marcel Dekker, Inc., New
York, 1989;11332.
28. Kaaman T, von Stedingk LV, von Stedingk M, Wasserman
J. ELISA-determined serological reactivity against puried
trichophytin in dermatophytosis. Acta Derm Venereol.
1981;61:313317.
29. Alonso A, Pionetti CH, Mouchian K, Albonico JF, Iraneta
SG, Potenza M, Iovannitti C. Hypersensitivity to Trichophy-
ton rubrum antigens in atopic and non-atopic podiatrists.
Allergol Immunopathol (Madrid). 2003;31:706 (in spanish).
30. Slunt JB, Taketomi EA, Woodfolk JA, Hayden ML, Plats-
Mills TAE. The immune response to Trichophyton tonsu-
rans: distinct T cell cytokine proles to a single protein
among subjects with immediate and delayed hypersensi-
tivity. J Immunol. 1996;157:51927.
31. Woodfolk JA, Slunt JB, Deuell B, Hayden ML, Platts-
Mills TA. Denition of a Trichophyton protein associated
with delayed hypersensitivity in humans: evidence for
immediate (IgE and IgG4) and delayed hypersensitivity to
a single protein. J Immunol. 1996;156:1695701.
32. Calderon RA. Immunoregulation of dermatophytosis. Crit
Rev Microbiol. 1989;16:33968.
33. Lepper AWD. Experimental bovine Trichophyton ver-
rucosum infection. The cellular responses in primary
lesions of the skin resulting from surface or intradermal
inoculation. Res Vet Sci. 1974;16:28798.
34. Hombo S, Jones HE, Artis WM. Chronic dermatophyte
infection: evaluation of the Ig class-specic antibodies
response reactive with polysaccharide and peptide antigens
derived from Trichophyton mentagrophytes. J Invest Der-
matol. 1984;82:28790.
35. Jones HE. Immune response and host resistance of human
to dermatophyte infection. J Am Acad Dermatol.
1993;28:S128.
36. MacCarthy KG, Blake JS, Johnson KL, Dahl MV, Kalish
RS. Human dermatophyte-responsive T cell lines recog-
nize cross-reactive antigens associated with mannose-rich
glycoproteins. Exp Dermatol. 1994;3:6671.
37. Koga T, Duan H, Urabe K, Furue M. Immunohistochem-
ical detection of interferon-gamma-producing cells in
dermatophytosis. Eur J Dermatol. 2003;11:1057.
38. Cherwinski HM, Schumacher JH, Brown JH, Mosmann
TR. Two types of mouse helper T cell clone. lll. Further
differences in lymphokine synthesis between Th1 and Th2
clones revealed by RNA hybridization, functionally
monospecic bioassays, and monoclonal antibodies. J Exp
Med. 1987;166:122944.
39. Nacy CA, Fortier AH, Pappas MG, Henry R. Susceptibility
of inbred mice to Leishmania infection: correlation of
susceptibility with in vitro defective macrophage micro-
bicidal activities. Cell Immunol. 1983;77:298307.
40. Mosmann TR, Moore KW. The role of IL-10 in crossre-
gulation of Th1 and Th2 response. Immunol Today.
1991;12:A4953.
41. Behin R, Mauel J, Sordat B. Leishmania tropica: patho-
genicity and in vitro macrophage function in strains of
inbred mice. Exp Parasitol. 1979;48:816.
42. McLeod R, Buschman E, Arbuckle LD, Skamene E.
lmmunogenetics in the analysis of resistance to intracel-
lular pathogens. Curr Opin Immunol. 1995;7:53952.
43. Bretscher PA, Wei G, Menon JN, Bielefeldt-Ohmann H.
Establishment of stable, cell-mediated immunity that
makes susceptible mice resistant to Leishmania major.
Science. 1992;257:53942.
44. Kuchroo VK, Prabhu M, Brown JA, Ranger AM, Zamvil
SS, Sobel RA. B71 and B72 costimulatory molecules
active differentially the Th1/Th2 developmental pathways:
application to autoimmune disease therapy. Cell. 1995;80:
70718.
45. Cella M, Sallusto F, Lanzavecchia A. Origin, maturation
and antigen presenting function of dendritic cells. Curr
Opin Immunol. 1997;9:106.
46. Furgier-Vivier I, Servet-Delprat C, Rivailler P, Rissoan M-
C, Liu Y-J, Rabourdin-Combe C. Measles virus suppresses
cell-mediated immunity by interfering with the survival
and functions of dendritic and T cells. J Exp Med.
1997;186:81323.
47. Reise Sousa C, Sher A, Kaye P. The role of dendritic cells
in the induction and regulation of immunity to microbial
infection. Curr Opin Immunol. 1999;11:3928.
48. Woodfolk JA, Sung SS, Benjamin DC, Lee JK, Platts-Mill
TA. Distinct human T cell repertoires mediate immediate
and delayed-type hypersensitivity to the Trichophyton
antigen, Tri r 2. J Immunol. 2000;165:437987.
49. Green F 3rd, Lee KW, Balish E. Chronic T. mentagro-
phytes dermatophytosis of guinea pig skin grafts on nude
mice. J Invest Dermatol. 1982;79:1259.
50. Calderon RA, Hay RJ. Cell-mediated immunity in exper-
imental murine dermatophytosis. II. Adoptive transfer of
immunity to dermatophyte infection by lymphoid cells
from donors with acute or chronic infections. Immunology.
1984;53:46572.
51. Blake JS, Dahl MV, Herron MJ, Nelson RD. An immun-
oinhibitory cell wall glycoprotein (mannan) from
Trichophyton rubrum. J Invest Dermatol. 1991;96:65761.
52. Grando SA, Hostager BS, Herron MJ, Dahl MV, Nelson
RD. Binding of Trichophyton rubrum mannan to human
monocytes in vitro. J Invest Dermatol. 1992;98:87680.
Mycopathologia (2008) 166:277283 283
1 3
Reproducedwith permission of thecopyright owner. Further reproductionprohibited without permission.