132

Letters to the Editor / Journal of Dermatological Science 56 (2009) 128139

represent a founder effect [6]. Exons 5, 11, and 15 are clustered

with HPS1 mutations [4]. Different clinical HPS1 phenotypes were
associated with different HPS1 frameshifts, which suggested that
differentially truncated HPS1 polypeptides may have different
effects on the cellular function [3]. The c.1932delC mutation leads
to a longer HPS1 protein that a novel 79-residue peptide replaces
the wild-type 56-residue peptide after the mutation site at D644
(Fig. 1D). Although the predicted protein keeps most of the
sequence of wild-type HPS1, the presence of oculocutaneous
albinism suggests the loss-of-function effect on melanocytes and
renders the functional importance of the C-terminal 56 residues of
HPS1 protein. Similarly, the p.L668P missense mutation, located at
the C-terminus of HPS1, abolishes its assembly into BLOC-3,
indicating the functional importance of the HPS1 C-terminus [6].
This mutation may cause the unique clinical features as neither
prolonged bleeding time nor bleeding tendency was observed in
this patient. Further studies on the function of the C-terminus of
HPS1 will reveal the underlying mechanism. Follow-up observations are warranted to document the severity of the symptoms in
her adulthood.
Our success in the identication of the HPS1 mutation in the
OCA patients suggests the necessary of the mutational screening of
the HPS genes in the unidentied patients without mutations in
TYR, OCA2, TYRP1, and SLC45A2. The identication of HPS1 patient
in the OCA population implicates the underestimation of HPS
frequency in Chinese ethnicity.
Acknowledgements
This work was supported in part by National Natural Science
Foundation of China (Nos. 30525007 and 30730049), Natural
Science Foundation of Beijing (No. 7092040), and Capital Medical
Development Foundation (No. 2007-3111).

[2] Li W, Feng Y, Hao C, Guo X, Cui Y, He M, et al. The BLOC interactomes form a
network in endosomal transport. J Genet Genomics 2007;34:66982.
[3] Oh J, Bailin T, Fukai K, Feng GH, Ho L, Mao J, et al. Positional cloning of a gene for
HermanskyPudlak syndrome, a disorder of cytoplasmic organelles. Nat Genet
1996;14:3006.
[4] Li W, He M, Zhou HL, Bourne JW, Liang P. Mutational data integration in geneoriented les of HermanskyPudlak syndrome database. Hum Mutat
2006;27:4027.
[5] Suzuki T, Ito S, Inagaki K, Suzuki N, Tomita Y, Yoshino M, et al. Investigation on
the IVS5 + 5G>a splice site mutation of HPS1 gene found in Japanese patients
with HermanskyPudlak syndrome. J Dermatol Sci 2004;36:1068.
[6] Ito S, Suzuki T, Inagaki K, Suzuki N, Takamori K, Yamada T, et al. High frequency
of HermanskyPudlak syndrome type 1 (HPS1) among Japanese albinism
patients and functional analysis of HPS1 mutant protein. J Invest Dermatol
2005;125:71520.
[7] Vincent LM, Adams D, Hess RA, Ziegler SG, Tsilou E, Golas G, et al. Hermansky
Pudlak syndrome type 1 in patients of Indian descent. Mol Genet Metab 2009
[Epub ahead of print].
[8] Lee AC, Poon KH, Lo WH, Wong LG. Chronic ulcerative gastroduodenitis as a rst
gastrointestinal manifestation of HermanskyPudlak syndrome in a 10-yearold child. World J Gastroenterol 2008;14:293941.
[9] Hutton SM, Spritz RA. Comprehensive analysis of oculocutaneous albinism
among non-Hispanic caucasians shows that OCA1 is the most prevalent OCA
type. J Invest Dermatol 2008;128:244250.
[10] Oh J, Ho L, Ala-Mello S, Amato D, Armstrong L, Bellucci S, et al. Mutation analysis
of patients with HermanskyPudlak syndrome: a frameshift hot spot in the HPS
gene and apparent locus heterogeneity. Am J Hum Genet 1998;62:5938.

Aihua Weia,b, Shi Lianb, Lejin Wangc, Wei Lia,*

Key Laboratory of Molecular Developmental Biology,
Institute of Genetics and Developmental Biology,
Chinese Academy of Sciences, Datun Rd,
Chaoyang District, Beijing 100101, China
b
Department of Dermatology, Xuan Wu Hospital,
Capital Medical University, Beijing, China
c
Department of Ophthalmology, Peking University Third Hospital,
Beijing, China
a

*Corresponding author. Tel.: +86 10 6484 8212;

fax: +86 10 6484 8212
E-mail address: wli@genetics.ac.cn (W. Li)

References
[1] Huizing M, Gahl WA. Disorders of vesicles of lysosomal lineage: the HermanskyPudlak syndromes. Curr Mol Med 2002;2:45167.

14 May 2009
doi:10.1016/j.jdermsci.2009.07.007

Letter to the Editor

Morphological relationship between nerve bers and Langerhans cells in the epidermis of psoriasis vulgaris and lichen
simplex chronicus
To the Editor,
It is generally accepted that skin is a target organ of the stress
reaction [1,2]. There is a close correlation between psoriasis
vulgaris (PV), lichen simplex chronicus (LSC) and certain psychoneural factors. Both PV and LSC are associated with psychologic
disorders and can be aggravated by anxiety or depression.
Quantitative analysis of nerve bers in the lesions of PV provides
morphological evidence for the functional role of nervous system
in PV [3]. However, quantitative analysis of nerve bers in the
lesions of LSC and morphological relationship between nerve bers
and LCs in the lesions of PV and LSC have not been reported.
Totally 51 patients with PV, 24 patients with LSC and 24 normal
controls were enrolled upon completion of the consent form
(Table 1). Besides lesional skin, additional biopsies were taken
from normal-appearing skin of the opposite side of the same
patients as non-lesional skin. Lidocaine was used for local
anesthesia.

Incisional biopsy was embedded in OCT Compound and

cryosectioned at 12 mm. Labeled avidinbiotin streptavidin
horseradish peroxidase technique was employed to stain the
nerve bers [4]. Double labeled immunouorescence was performed [5]. Briey, uoresceinisothiocynate labeled mouse antihuman CD1a monoclonal antibody IgG (1:100; Serotec, UK) was
used to stain the LCs. Anti-neurolament H 200 kD rabbit serum
(1:100; Serotec, UK) was used to stain the nerves. The total length
of nerve bers was analyzed using an image analysis system (spot
version 3.5.9, Olympus, Japan) [6]. Five elds of 20 times vision
were randomly selected. The results were expressed as the
mean  SD mm. The contacts between LCs and nerve bers were
measured by a confocal laser scanning microscope (Leica, Germany).
A total of 50 LCs were randomly chosen and counted. The percent of
contacts between the red uorescent bers and green uorescent LCs
was calculated as described [7]. The nal results were expressed as
mean  SD. Two researchers did the counting in a blind way. Realtime PCR (Takara TP800) was carried out to examine the expression of
mRNA of nerve growth factor (NGF) in the epidermis (separated by
EDTA) of the lesional skin of LSC and PV. The sequence of primers for
NGF (142 bp) and b-actin (162 bp) were 50 -TCAGCGTCCGGACCCAATA-30 and 50 -CACAGAGCCTCGCCTTTG-30 , respectively.

Letters to the Editor / Journal of Dermatological Science 56 (2009) 128139

Table 1
Demographical data from patients with psoriasis vulgaris (PV) and lichen simplex
chronicus (LSC).
PV

LSC

Normal controls

Total No.
Male
Female
Age range (year)
Average age (year)

51
36
15
1562
33.5  10.3

24
15
9
1971
35.9  14.2

24
13
11
1952
32.3  9.3

Biopsy sites
Torso
Neck
Extremities

28
0
23

0
14
10

6
7
11

133

Table 2
Total length of nerve bers and neural-LC contacts in lesions and non-lesional skin
of patients with psoriasis vulgaris (PV) and lichen simplex chronicus (LSC).
Biopsy specimen

No. of cases

Total
length (mm)

Nerual-LC
contacts (%)

Normal Controls

24

206.6  64.2

22.5  5.9

PV
Non-lesional skin
Lesions

51
51

209.3  60.4
325.1  85.3**

23.2  6.2
50.1  4.5**

LSC
Non-lesional skin
Lesions

24
24

204.8  56.2
337.3  91.9**

24.4  7.7
57.2  8.1**

**
P < 0.01; non-lesional skin is the normal-appearing skin of the opposite side of
the same patient.

Table 3
Real-time PCR results of NGF mRNA expression in lesions and non-lesional skin of patients with psoriasis vulgaris (PV) and lichen simplex chronicus (LSC).

b-Actin

Normal controls
Non-lesional skin of PV
PV lesions
Non-lesional skin of LSC
LSC lesions

NGF

Quantitative value

Relative expression
quantity

Quantitative value

Corrected
quantitative value

257.0  18.5
282.6  21.3
362.5  30.6
313.0  55.3
382.5  23.4

1.0
1.1
1.4
1.2
1.5

1123.5  362.1
1614.2  358.8
2396.7  572.0
1858.9  396.2
2796.9  576.4

1123.5  362.1
1345.2  299.0
1711.9  408.6
1549.1  330.2
1864.6  378.3

t value

5.17
6.02
3.07
6.93

Relative expression
quantity
1.0
1.2
1.5
1.4
1.7

Note: t value refers to the statistical signicance between PV or LSC lesion groups and non-lesional skin of PV or LSC groups, respectively, and the statistical signicance
between PV or LSC lesion groups and normal controls, respectively. All the P value are less than 0.01.

A two-tailed Students t-test and chi-square criterion were used

to analyze the data. P < 0.05 was considered statistically signicant.
The total length of never bers substantially increased in both
LSC and PV lesions (Fig. 1a and d) compared with normal controls
(Fig. 1c) and the normal-appearing skin (or non-lesional skin) of
the patients with LSC (Fig. 1b) and PV (Fig. 1e). Fig. 2 presents the
typical uorescence of overlapping images of LCs and never bers
in the epidermis of the patients with LSC, PV and normal controls.
The length of nerve bers in the lesions of PV and LSC was
signicantly longer than that in both normal controls (P < 0.01)
and the normal-appearing skin of the patients (P < 0.01) (Table 2).
In addition, the percentage of contacts between nerve bers
and LCs in the lesions of patients with PV and LSC was signicantly
higher than that in the normal-appearing skin of the patients
(P < 0.01) and normal controls (P < 0.01) (Table 2). The expressions of mRNA of NGF in the lesional skin of LSC and PV were
signicantly upregulated than those in the normal-appearing
skin (P < 0.01) and those in the normal controls (P < 0.01)
(Table 3).

In this study, we have demonstrated that the length of nerve

bers in the epidermal lesions of PV and LSC is signicantly longer
than that in normal-appearing skin of the patients and normal
controls. The increased length of nerve bers indicates a
hyperplasia of nerve bers and a possible enhanced modulating
effect of nervous system on the cutaneous immunity in PV and LSC.
On the other hand, some inammatory cells in PV and LSC are
known to secrete NGFs [8]. Patients with PV and LSC exacerbate
when psychologically stressed out. Whether the effects act via
altering the function of LCs has not been reported. Our study, for
the rst time, provides morphological evidence of the contacts
between intraepidermal nerve bers and LCs in PV and LSC.
Furthermore, the number of contacts between the nerve bers and
LCs in the lesions of PV or LSC is signicantly elevated than that in
the normal-appearing skin and normal controls, which suggests
that LCs may serve as one of the target cells on which psychoneural
factors act in PV and LSC. The neurotrophic effects of LCs may also
be enhanced by the interactions with nerve bers [8].
It is well accepted that the neural system plays a crucial role in
PV and LSC by acting on the immune cells through neurotrans-

Fig. 1. Representative images of IHC staining of nerve bers (200). Nerve bers are shown in dark brown color and pointed out by arrows. (a) The lesion of a patient with LSC.
(b) The normal-appearing skin of the same patient with LSC. (c) The skin from a normal control. (d) The lesion of a patient with PV. (e) The normal-appearing skin of the same
patient with PV.

134

Letters to the Editor / Journal of Dermatological Science 56 (2009) 128139

Fig. 2. Representative uorescent images of contacts between LCs and nerve bers (200). LCs are in bright green color (upper traces); nerve bers are in red color (middle
traces); the overlapping contacts of LCs and nerve bers are in yellow color (lower traces). (a) 13: the lesion of a patient with LSC. (b) 13: the normal-appearing skin of the
same patient with LSC. (c) 13: the skin from a normal control. (d) 13: the lesion of a patient with PV. (e) 13: the normal-appearing skin of the same patient with PV.

mitters and that the optimal management of these dermatoses is

the mitigation of co-existent emotional stressors. Reynolds et al.
showed that the PKC-beta positive epidermal LC number was
signicantly reduced, whereas the CD1a positive epidermal LC
number was unchanged [9]. Their results may support our point of
view that the increased number of contacts between LCs and nerve
bers in this study are not due to an increased number of nerve
bers and LCs.
External irritation is well known to cause signicant changes in
nerve bers within the skin. In order to rule out the possibility that
the changes of nerve bers are secondary to external irritations, we
have performed the same experiment using the lesional skin of
several inammatory diseases including prurigo nodularis, lichen
amyloidosis, lichen striatus and keloid. The length of nerve bers
and percentage of nerver ber-LC contacts in the lesions of these
disorders are similar to those of the normal control group
(unpublished data).
Acknowledgments
We thank Dr. Stephen I. Katz for reviewing the manuscript. This
work was supported by the Program for Innovative Research Team
in University (IRT0760) from the Ministry of Education of China.
References
[1] Arck PC, Slominski A, Theoharides TC, Peters EM, Paus R. Neuroimmunology of
stress: skin takes center stage. J Invest Dermatol 2006;126:1697704.
[2] Roosterman D, Goerge T, Schneider SW, Bunnett NW, Steinhoff M. Neuronal
control of skin function: the skin as a neuroimmunoendocrine organ. Physiol
Rev 2006;86:130979.
[3] Naukkarinen A, Nickoloff BJ, Farber EM. Quantication of cutaneous sensory
nerves and their substance P content in psoriasis. J Invest Dermatol 1989;92:
1269.

[4] Dalsgaard CJ, Bjorklund H, Jonsson CE, Hermansson A, Dahl D. Distribution of

neurolament-immunoreactive nerve bers in human skin. Histochemistry
1984;81:1114.
[5] Hosoi J, Murphy GF, Egan CL, et al. Regulation of Langerhans cell function by
nerves containing calcitonin gene-related peptide. Nature 1993;363:15963.
[6] Jarvikallio A, Harvima IT, Naukkarinen A. Mast cells, nerves and neuropeptides
in atopic dermatitis and nummular eczema. Arch Dermatol Res 2003;295:27.
[7] Raychaudhuri SP, Raychaudhuri SK. Role of NGF and neurogenic inammation
in the pathogenesis of psoriasis. Prog Brain Res 2004;146:4337.
[8] Torii H, Yan Z, Hosoi J, Granstein RD. Expression of neurotrophic factors and
neuropeptide receptors by Langerhans cells and the Langerhans cell-like cell
line XS52: further support for a functional relationship between Langerhans
cells and epidermal nerves. J Invest Dermatol 1997;109:58691.
[9] Reynolds NJ, Yi JY, Fisher GJ, Cooper KD, Voorhees JJ, Grifths CE. Downregulation of Langerhans cell protein kinase C-beta isoenzyme expression in
inammatory and hyperplastic dermatoses. Br J Dermatol 1995;133:15767.

Shaoshan Cuia,1
Ting Xiaoa,1
Yan Wanga
Hongguang Lua
Yakun Wanga
Xing-Hua Gaoa
Huachen Weib
Hong-Duo Chena,*
a
Department of Dermatology, No.1 Hospital of China Medical
University, 155 North Nanjing Street, Shenyang 110001, China
b
Department of Dermatology, Mount Sinai School of Medicine,
New York, NY 10013, USA
*Corresponding author. Tel.: +86 24 83282642;
fax: +86 24 83282633
E-mail address: chenhd@cae.cn (Hong-Duo Chen)
1
Both authors contributed equally to this paper.
5 March 2009
doi:10.1016/j.jdermsci.2009.07.009