commentary

The results of the study by Schottelius

et al. (2010) raise the question of whether
tissue-specific differences in immune
responses are common in other cell signaling pathways and how they might
affect the inflammatory response. Their
report highlights the importance of studying the immune response in several models of tissue-specific inflammation before
concluding that a specific cellular signaling factor has pro- or anti-inflammatory
effects. Most interestingly, the results
could open new avenues for treating
specific tissues locally with signaling
factor antagonists and agonists. Such an
approach could provide more favorable
efficacy to side-effect ratios in treating
tissue-specific inflammatory disorders.
CONFLICT OF INTEREST

The authors state no conflict of interest.

References

Anderson DR, Hegde S, Reinhard E et al. (2005)

Aminocyanopyridine inhibitors of mitogen
activated protein kinase-activated protein kinase
2 (MK-2). Bioorg Med Chem Lett 15:158790
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Pyrrolopyridine inhibitors of mitogen-activated
protein kinase-activated protein kinase 2 (MK-2).
J Med Chem 50:264754
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26:44754
Ronkina N, Kotlyarov A, Dittrich-Breiholz O et al.
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Pyrrolo-pyrimidones: a novel class of MK2
inhibitors with potent cellular activity. Bioorg
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Schottelius AJ, Zgel U, Dcke W-D et al. (2010) The

role of mitogen-activated protein kinase-activated

protein kinase 2 in the p38/TNF- pathway of
systemic and cutaneous inflammation. J Invest
Dermatol 130:48191

Wu JP, Wang J, Abeywardane A et al. (2007)

The discovery of carboline analogs as potent
MAPKAP-K2 inhibitors. Bioorg Med Chem Lett
17:46649

See related article on pg 529

Genetic Influences on Human Body

Odor: From Genes to the Axillae
George Preti1,2 and James J. Leyden2
Several groups have identified the characteristic axillary odorants and how they
arrive on the skin surface, pre-formed, bound to water-soluble odorless precursors in apocrine secretions. In the current issue, Martin et al., (2010) describe
the relationship between the production of axillary odorants and variants in
the ABCC11 gene. Individuals who are homozygotic for a SNP (538G>A) were
found to have significantly less of the characteristic axillary odorants than either
individuals who were heterozygotic for this change or those who had the wildtype gene. The 538G>A SNP predominates in Asians who have nearly complete
loss of typical body odor. ABCC11 is expressed and localized in apocrine sweat
glands. These findings are remarkably similar to the ethnic distribution and
expression patterns for apocrine apoD, a previously identified carrier of a characteristic axillary odorant.
Journal of Investigative Dermatology (2010) 130, 344346. doi:10.1038/jid.2009.396

Human axillary odor (commonly

referred to as body odor) is caused by
a complex mixture of volatile organic
compounds that produce a characteristic odor that has been termed uniquely
human (Labows et al., 1982). The nature
and biogenesis of the odorants that constitute the axillary bouquet are the focus
of a multibillion-dollar industry that seeks
new products to counteract odor production and perception. In addition, axillary
secretions and odors contain human
primer pheromones that affect neuroendocrine rhythms, as well as modulator
pheromones that can affect mood (Preti
et al., 2003; also see Wysocki and Preti,
2009, for a review).
Research into the nature of body odor
began in the 1960s with the discovery
that axillary odor could be produced
by the interaction of odorless apocrine
secretions (collected by injecting dilute
epinephrine into the axilla after degerming the skin surface with alcohol) with

inoculation by gram-positive organisms

found on the skin surface (Shehadeh
and Kligman, 1963a,b). Subsequent
studies led by David Gower demonstrated the presence of volatile, odorous
C19-16 steroids5-androst-16-en-3ol (androstenol) and 5-androst-16-en3-one (androstenone)in the axillae.
These compounds were identified and
quantified by radioimmunoassay and
gas chromatographymass spectrometry techniques (see Rennie et al., 1991,
and Gower and Ruparelia, 1993, for
reviews). The urine/musk-like odors of
these compounds were thought by these
investigators and others (Labows et al.,
1979, 1982) to be suggestive of axillary
odor. Research from our laboratory (Zeng
et al., 1991, 1992, 1996a,b) as well as
from Natsch et al. (2003) subsequently
presented both organoleptic and analytical evidence that a mixture of C6C11
normal, branched, hydroxy- and unsaturated acids present in axillary sweat

1
Monell Chemical Senses Center, Philadelphia, Pennsylvania, USA and 2Department of Dermatology,
School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Correspondence: George Preti, Monell Chemical Sense Center, 3500 Market Street, Philadelphia,
Pennsylvania 19104, USA. E-mail: preti@monell.org or preti@pobox.upenn.edu

344 Journal of Investigative Dermatology (2010), Volume 130

commentary

Clinical Implications
Axillary odor is determined by variants in the ABCC11 gene, which
encodes an ATP-driven efflux pump protein.
Individuals who are homozygotic for a SNP (538G>A) in the proteins
polypeptide chain have significantly less of the characteristic axillary
odorants.
The 538G>A SNP predominates in Asians who have nearly complete loss
of typical body odor.

constitute the dominant, characteristic

axillary odors. In addition to this mixture of major odor constituents are trace
amounts of thio-alcohols (Natsch et al.,
2004; Troccaz et al., 2004; Hasegawa
et al., 2004) with high odor impact (low
olfactory threshold).
The precursors to axillary odor reside
in the apocrine glands (Shehadeh and
Kligman, 1963a,b; Zeng et al., 1992).
The characteristic axillary odor is formed
by the interaction of odorless, precursor
molecules found in apocrine secretions
with cutaneous, axillary microorganisms (Shehadeh and Kligman, 1963a;
Leyden et al., 1981; Zeng et al., 1991).
In addition, Zeng et al. (1992) demonstrated that the water-soluble portion of
apocrine secretions contains the odor
precursors and that one of the major
axillary odorants, 3-methyl-2-hexenoic
acid (3M2H), is carried to the skin surface bound to two proteins that have
been designated apocrine secretion
odor-binding proteins: ASOB1 (apparent molecular weight, 45 kDa) and
ASOB2 (apparent molecular weight, 26
kDa) (Spielman et al., 1995). Additional
research documented that the polypeptide chain of ASOB2 is identical to that of
apolipoprotein D (Zeng et al., 1996b), a
known member of the 2-microglobulin
superfamily of carrier proteins (also
known as lipocalins) that carry lipids in
the circulatory system (Flower, 1996). In
apocrine secretions, apolipoprotein D
(apoD) carries 3M2H, as demonstrated
by Spielman et al. (1995) and Zeng et
al. (1996a). Spielman et al. (1998) also
demonstrated that axillary biopsies
taken from both male and female volunteers exhibit specific immunoreactivity
for apocrine apoD localized to the apocrine gland. Finally, Zeng et al. (1996a)
employed in situ hybridization with an
oligonucleotide probe against apoD

mRNA using biopsied axillary tissue

to demonstrate that the message for
synthesis of this protein is specific to the
apocrine glands.
In this issue, Martin et al. (2010)
describe the relationship between
the production of axillary odorants
and variants in the ABCC11 gene.
Individuals who were homozygotic for
a single-nucleotide polymorphism (SNP)
(538G>A) that changes amino acid
180 in the resultant proteins polypeptide chain from glycine (G) to arginine
(R) were found to have a significantly
smaller amount of the characteristic
axillary odorants than either those who
were heterozygotic for this change or
those who had the wild-type gene. The
ABCC11 gene encodes an ATP-driven
efflux pump that plays an important
function in ceruminous apocrine glands
of the auditory canal. The 538G>A SNP
is associated with a dry white earwax
phenotype that is predominant in Asians
and rare in Africans and Europeans. This
same SNP predominates in Asians who
have nearly complete loss of typical body
odor. The ABCC11 protein is expressed
and localized in apocrine sweat glands
and appears to play a key role in the
secretion and/or formation of glutamine
precursors to axillary odorants.
When Jacoby et al. (2004) studied
the levels of apocrine apoD in a group
of subjects of different ethnic backgrounds, they reported that subjects of
Asian descent had diminished or nondetectable levels of apoD in axillary
skin extracts; in non-Asian subjects this
protein was easily detected. These data
are remarkably similar to those reported here by Martin et al. (2010) for the
ABCC11 gene and its expressed protein
(human ABC transporter) and raise the
question of whether a relationship exists
between apoD and this protein.

The collection method employed

by Martin et al. (2010) used exercise to
collect mixed axillary sweat, yielding
a combination of fluids from eccrine,
apocrine, and apoeccrine glands, when
present (Sato et al., 1987). The last are
hybrid sweat glands that have been
documented in the axillae of some individuals by Sato et al. (1987). The protein
levels reported by Martin et al. (2010) for
sweat from their strong odor producers
(GG homozygotics; ~1 mg/ml) are lower
than that reported for apocrine secretions by Spielman et al. (1998; ~4.2 mg/
ml) and Jacoby et al. (2004; 45 mg/ml).
This could indicate that substantial degradation of proteins may have occurred
in their samples. Interestingly, our studies with apocrine secretion (Zeng et al.,
1992; Spielman et al., 1995; Zeng et al.,
1996a,b), collected under sterile conditions, reported no glutamine-bound
precursors, suggesting that they may be
formed in the initial interactions between
cutaneous bacteria and protein-bound
odorants. For example, apoD has pyroglutamate as its N-terminal amino acid,
and Martin and colleagues collection
method allows ample time for (i) opening of the proteins callix (making 3M2H
and other acids carried within the protein available) and (ii) bacterial cleavage of the N-terminal pyroglutamate via
bacterial N-acyl-aminocyclase enzyme
(Natsch et al., 2003), which would liberate glutamate for interaction with 3M2H
and other acids, viz.
Bacterial
PyroglutamateN-acyl-aminocyclase +
N-apoD
and other enzymes

3M2H + G1n + peptide fragments

3M2HG1n + peptide fragments

Martin et al. (2010) did not explore

the discovery of apoD by Zeng et al.
(1996b) or its quantification in axillary
secretions by Jacoby et al. (2004) in relation to their findings. Consequently, the
relationship between the two proteins,
their expression in different ethnic
groups, and their regulation of axillary
odorant production constitute attractive
areas for future study.
www.jidonline.org 345

commentary

CONFLICT OF INTEREST

The authors state no conflict of interest.

References

Flower DR (1996) The lipocalin protein family:

structure and function. Biochem J 318:114
Gower DB, Ruparelia BA (1993) Olfaction in humans
with special reference to odorous 16-androstenes:
their occurrence, perception and possible social
psychological and sexual impact. J Endocrinol
137:16787
Hasegawa Y, Yabuki M, Matsukane M (2004)
Identification of new odoriferous compounds
in human axillary sweat. Chem Biodiversity
1:204250
Jacoby RB, Brahms JC, Ansari SA et al. (2004)
Detection and quantification of apocrine secreted
odor-binding protein on intact human axillary
skin. Int J Cosmet Sci 26:3746
Labows JN, Preti G, Hoelzle E et al. (1979) Steroid
analysis of human apocrine secretion. Steroids
34:24958
Labows JN, McGinley KJ, Kligman AM (1982)
Perspectives on axillary odor. J Soc Cosmet Chem
34:193202
Leyden JJ, McGinley KJ, Hoelzle K et al. (1981) The
microbiology of the human axillae and its relation
to axillary odors. J Invest Dermatol 77:4136
Martin A, Saathoff M, Kuhn F et al. (2010) A
functional ABCC11 allele is essential in the
biochemical formation of human axillary odor.
J Invest Dermatol 130:52940
Natsch A, Gfeller H, Gygax P et al. (2003) A
specific bacterial aminoacylase cleaves odorant
precursors secreted in the human axilla. J Biol
Chem 278:571827
Natsch A, Schmid J, Flachsmann F (2004)
Identification of odoriferous sulfanylalkanols
in human axilla secretions and their formation
through cleavage of cysteine precursors by a
C-S lyase isolated from axilla bacteria. Chem
Biodiversity 1:105872
Preti G, Wysocki CJ, Barnhart KT et al. (2003) Male
axillary extracts contain pheromones that affect
pulsatile secretion of luteinizing hormone
and mood in female recipients. Biol Reprod
68:210713
Rennie PJ, Gower DB, Holland KT (1991) In-vitro
and in-vivo studies of human axillary odour
and the cutaneous microflora. Br J Dermatol
124:596602
Sato K, Leidal R, Sato F (1987) Morphology and
development of an apoeccrine sweat gland in
human axillae. Am J Physiol 252:16680
Shehadeh N, Kligman AM (1963a) The effect of
topical antibacterial agents on the bacterial flora
of the axillae. J Invest Dermatol 40:6171
Shehadeh N, Kligman AM (1963b) The bacteria
responsible for apocrine odor, II. J Invest
Dermatol 41,15
Spielman AI, Zeng X-N, Leyden JJ et al. (1995)
Proteinaceous precursors of human axillary odor:
isolation of two novel odor binding proteins.
Experientia 51:407
Spielman AI, Harmony JAK, Stuart WD et al. (1998)
Identification
and
immunohistochemical
localization of protein precursors to human
axillary odor in apocrine gland secretions. Arch
Dermatol 134:8138

Troccaz M, Strakkenman C, Niclass Y et al. (2004)

3-Methyl-3-sulfanylhexan-1-ol as a major
descriptor for the human axilla-sweat odour
profile. Chem Bioversity 1:102235

Zeng X-N, Leyden JJ, Brand JG et al. (1992) An

investigation of human apocrine gland secretion
for axillary odor precursors. J Chem Ecol
18:103955

Wysocki CJ, Preti G (2009) Human pheromones:

whats purported, whats supported. A Sense of
Smell Institute White Paper <http://senseofsmell.
org/papers/Human_Pheromones_Final%20
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Zeng X-N, Leyden JJ, Spielman AI et al. (1996a)

Analysis of the characteristic human female
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Zeng X-N, Leyden JJ, Lawley HJ et al. (1991) Analysis

of the characteristic odors from human male
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Zeng C, Spielman AI, Vowels BR et al. (1996b)

A human axillary odorant is carried by
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93:662630

See editorial on page 321 and related article on pg 546

Some Light on
the Photobiology of Vitamin D
Antony R. Young1
In this issue, Bogh et al. report a study that begins to address the important public
health question of skin surface area and UVB exposure dose, related to erythema,
necessary to achieve a given level of vitamin D status. They demonstrate the importance of baseline vitamin D status in conducting such studies. A smaller substudy
suggests that skin pigment is not a barrier to vitamin D photosynthesis.
Journal of Investigative Dermatology (2010) 130, 346348. doi:10.1038/jid.2009.419

Introduction

The benefits of vitamin D and how best

to obtain and maintain optimal levels are highly controversial topics that
have enormous potential implications
for human health. Nature has provided
humans with two sources of vitamin D:
solar UVB radiation and diet. However,
most foods provide very little vitamin D,
especially in typical Western diets. The
exception is oily fish. Manmade interventions include food fortification in some
countries, supplementation, and the use
of tanning devices with UVB. Any discussion on vitamin D status should be based
on facts. There is a surprising lack of careful, published investigation (as opposed
to observation/extrapolation/calculation)
into the photobiology of vitamin D in
vivo and its interaction with skin color.
Furthermore, there is a lack of data that
compare the effects of UVR with other
approaches to maintaining vitamin D

status performed in the same laboratories

to minimize experimental variation.
The significance of this study

The study by Bogh et al. (2010, this issue)

is a welcome and timely addition to our
knowledge in the photobiology field.
The baseline data show that 85% of
182 people screened for the study were
either vitamin D (25(OH)D) insufficient
(67% < 50 nmol l-1) or deficient (18% <
25 nmol l-1) in Denmark at 56N during
the winter. The limitation of these definitions of vitamin D status is discussed
in this issues Editorial, by Reddy and
Gilchrest (2010). The backs and chests
of volunteers with skin types IVI were
exposed to three standard erythema
doses (SEDs) of UVB for 4 days over
1 week. The UVB source used was very
rich in the spectral region that converts
7-dehydrocholesterol to previtamin D
in the skin. The sites exposed represent

Division of Genetics and Molecular Medicine, St Johns Institute of Dermatology, Kings College London,
London, UK
1

Correspondence: Antony R. Young, King's College London, Division of Genetics and Molecular Medicine, St John's Institute of Dermatology, Tower Wing (9th floor), Guys Hospital, London SE1 9RT, UK.
E-mail: antony.r.young@kcl.ac.uk

346 Journal of Investigative Dermatology (2010), Volume 130