Delayed type hypersensitivity to natural rubber latex is rare compared to IgE mediated immediate reactions. Binding of allergens to MHC Class II is a crucial step in the presentation of antigens to CD4+ T Cells responsible for delayed reactions. Computational prediction of MHC class II epitopes on thirteen known latex allergens using SMM-align method revealed strong binding with several alleles. This shows that latex allergens are capable of initiating delayed type hypersensitivity in susceptible individuals.&#xd;&#xa

Bell R. Eapen

English

Nature Precedings

Title: 
Delayed-Type  hypersensitivity  to  latex:  Computational  prediction  of  MHC  class  II 
epitopes on latex allergens
Author:
Bell Raj Eapen MD.
Category: Hypothesis
Affiliation:
Kaya Skin Clinic
Dubai, U.A.E.
Address for correspondence:
Dr. Bell Raj Eapen
PB No: 5239
Kaya Skin Clinic
Dubai, U.A.E.
Phone: 00971 4 3949004
Fax: 00971 4 3369083
Email: admin@dermatologist.co.in 
Total Number of Tables: 1
Running Head: Latex and MHC Class II
 
N
at
ur
e 
Pr
ec
ed
in
gs
 : 
hd
l:1
01
01
/n
pr
e.
20
09
.2
93
1.
1 
: P
os
te
d 
6 
M
ar
 2
00
9
Key words
Natural Rubber Latex, MHC Class II.
N
at
ur
e 
Pr
ec
ed
in
gs
 : 
hd
l:1
01
01
/n
pr
e.
20
09
.2
93
1.
1 
: P
os
te
d 
6 
M
ar
 2
00
9
Abstract
Delayed type hypersensitivity to natural rubber latex is rare compared to IgE mediated 
immediate  reactions.  Binding  of  allergens  to  MHC Class  II  is  a  crucial  step  in  the 
presentation  of  antigens  to  CD4+  T  Cells  responsible  for  delayed  reactions. 
Computational prediction of MHC class II epitopes on thirteen known latex allergens 
using SMM-align method revealed strong binding with several alleles. This shows that 
latex  allergens  are  capable  of  initiating  delayed  type  hypersensitivity  in  susceptible 
individuals.
N
at
ur
e 
Pr
ec
ed
in
gs
 : 
hd
l:1
01
01
/n
pr
e.
20
09
.2
93
1.
1 
: P
os
te
d 
6 
M
ar
 2
00
9
 Background
Natural  rubber  latex  (NRL)  derived  from  the  rubber  tree  (Hevea  brasiliensis)  is  an 
important  allergen  causing  mostly  IgE  mediated  immediate  reactions  like  urticaria, 
angioedema  and  asthma.  [1]  The  existence  of  a  true  NRL  induced  delayed  type 
hypersensitivity  (type IV) is  still  debated.  Delayed type hypersensitivity  reactions  are 
attributed to additives like thiurams and carbamates. [2] The coexistence of the type I and 
type IV patterns and entities like protein contact dermatitis  [3] further complicate the 
issue. However incidence of true type IV hypersensitivities ranging from 1.2 to 6% has 
been reported following the introduction of an NRL containing patch test series. [4] 
During the sensitization phase of contact hypersensitivity, epidermal Langerhans'  cells 
internalise the allergen, migrate to the regional lymph node and present the processed 
allergen bound to MHC Class II molecules to CD4 T cells. MHC Class II binding site 
consists of a groove open at both ends and several pockets binding peptides with 13 to 25 
residues. [5] MHC molecules exhibit high degree of genetic variation which enables them 
to bind variety of peptides. 
As IgE from latex-sensitive patients bind to several proteins, there is still no consensus 
on  which  latex  proteins  are  antigenic.  However  information  on  thirteen  officially 
accepted latex allergens designated serially from Hev b 1 to 13 is available from the 
online repository www.allergen.org and are summarized in Table 1. [6,[7]
We tried to computationally predict the MHC class II epitopes on these antigens using 
SMM-align method. SMM-align is a novel stabilization matrix alignment method based 
N
at
ur
e 
Pr
ec
ed
in
gs
 : 
hd
l:1
01
01
/n
pr
e.
20
09
.2
93
1.
1 
: P
os
te
d 
6 
M
ar
 2
00
9
on scoring matrices that evaluate the contribution to binding of different residues in a 
peptide. [8] T cells are likely to recognize MHC binding peptides and initiate a cellular 
response. [9]
Methodology
The protein sequences of all thirteen allergens were downloaded from www.allergen.org 
and were added to a single file. This file was used for MHC Class II epitope prediction 
with  the  publicly  available  SMM-align  server  using  default  parameters.  The  server 
returns IC50 prediction scores (concentration of competing ligand which displaces 50% 
of the specific ligand) covering fourteen HLA DR alleles for each nanomer within the 
query peptide. Allergens with at least one nanomer with IC50 value less than fifty were 
considered as binders.
Results
Strong binding to one or more alleles was shown by all allergens except Hev b 5. Hev b 2 
was the most promiscuous allergen binding several alleles. DRB1*0101 was the most 
commonly bound allele. Results are summarized in Table 1.
Discussion
NRL  is  an  allergen  causing  mostly  IgE  mediated  immediate  type  hypersensitivity. 
Though there  have been significant advances in molecular  biology of latex allergens, 
their  ability  to  initiate  delayed-type  hypersensitivity  has  been  subject  to  debate. 
Computational  prediction  of  MHC  class  II  binding  regions  on  latex  allergens  adds 
credence to reports of type IV contact hypersensitivity to NRL. [4] 
N
at
ur
e 
Pr
ec
ed
in
gs
 : 
hd
l:1
01
01
/n
pr
e.
20
09
.2
93
1.
1 
: P
os
te
d 
6 
M
ar
 2
00
9
Prediction of MHC binding peptides is a commonly employed step in the identification of 
T cell epitopes. [9] MHC epitope related data is available from several databases like 
SYFPEITHI, [10] MHCBN [11] and IEDB [12]. Several algorithms like ARB [13] and 
SMM-align [8] are available for prediction of MHC class II binding peptides. Algorithms 
for scanning promiscuous peptides that can bind multiple MHC class II molecules are 
also available.  [14]  Promiscuous peptides are important  for  vaccine development and 
immunotherapy. [5] In our study Hev b 2 bound to six out of fourteen tested HLA DR 
alleles.
 
Conclusion
Most of the characterized latex allergens contain segments which can strongly bind MHC 
class II alleles and are capable of initiating delayed type hypersensitivity without a hapten 
in susceptible individuals. Certain promiscuous allergens like Hev b 2 bind to several 
MHC  alleles  making  them  ideal  candidates  for  immunotherapy.  [15]  However 
computational prediction of MHC binding has limited accuracy and clinical validation is 
essential.
 
References
1 Reunala T et al.,. Latex allergy and skin. Curr Opin Allergy Clin Immunol 4: 397-
401 (2004) [PMID: 15349039]
2 Miri S et al.,. Prevalence of type I allergy to natural rubber latex and type IV 
allergy  to  latex  and  rubber  additives  in  operating  room  staff  with  glove-related 
symptoms. Allergy Asthma Proc 28: 557-63 (2007) [PMID: 18034975]
N
at
ur
e 
Pr
ec
ed
in
gs
 : 
hd
l:1
01
01
/n
pr
e.
20
09
.2
93
1.
1 
: P
os
te
d 
6 
M
ar
 2
00
9
3 Doutre MS. Occupational contact urticaria and protein contact dermatitis. Eur J 
Dermatol 15: 419-24 (2005) [PMID: 16280292]
4 Sommer  S  et  al.,.  Type  IV  hypersensitivity  reactions  to  natural  rubber  latex: 
results of a multicentre study. Br J Dermatol 146: 114-7 (2002) [PMID: 11841376]
5 Wang  P  et  al.,.  A  systematic  assessment  of  MHC  class  II  peptide  binding 
predictions  and evaluation of a consensus approach.  PLoS Comput Biol  4:  e1000048 
(2008) [PMID: 18389056]
6 Breiteneder  H  et  al.,.  Molecular  and  immunological  characteristics  of  latex 
allergens. Int Arch Allergy Immunol 116: 83-92 (1998) [PMID: 9652300]
7 Wagner  S et  al.,.  Hevea brasiliensis  latex allergens:  current  panel and clinical 
relevance. Int Arch Allergy Immunol 136: 90-7 (2005) [PMID: 15627782]
8 Nielsen M et al.,. Prediction of MHC class II binding affinity using SMM-align, a 
novel stabilization matrix alignment method. BMC Bioinformatics 8: 238 (2007) [PMID: 
17608956]
9 Sette  A  et  al.,.  The  relationship  between  class  I  binding  affinity  and 
immunogenicity of potential cytotoxic T cell epitopes. J Immunol 153: 5586-92 (1994) 
[PMID: 7527444]
10 Schuler  MM  et  al.,.  SYFPEITHI:  database  for  searching  and  T-cell  epitope 
prediction. Methods Mol Biol 409: 75-93 (2007) [PMID: 18449993]
11 Bhasin M et al.,. MHCBN: a comprehensive database of MHC binding and non-
binding peptides. Bioinformatics 19: 665-6 (2003) [PMID: 12651731]
12 Peters B et al.,. The immune epitope database and analysis resource: from vision 
to blueprint. PLoS Biol 3: e91 (2005) [PMID: 15760272]
13 Bui HH et al.,. Automated generation and evaluation of specific MHC binding 
predictive tools: ARB matrix applications. Immunogenetics 57: 304-14 (2005) [PMID: 
15868141]
N
at
ur
e 
Pr
ec
ed
in
gs
 : 
hd
l:1
01
01
/n
pr
e.
20
09
.2
93
1.
1 
: P
os
te
d 
6 
M
ar
 2
00
9
14 Zhang  GL  et  al.,.  MULTIPRED:  a  computational  system  for  prediction  of 
promiscuous  HLA binding  peptides.  Nucleic  Acids  Res  33:  W172-9  (2005)  [PMID: 
15980449]
15 Tabar AI et al.,. Specific immunotherapy with standardized latex extract versus 
placebo in latex-allergic patients. Int Arch Allergy Immunol 141: 369-76 (2006) [PMID: 
16943675]
 Table 1: Latex allergens and binding MHC Class II alleles
Allergen Biochemical Name Alleles  showing  strong 
binding  predicted  by 
SMM-Align
Heb b 1 Rubber Elongation 
Factor
DRB1*0101
DRB1*1302
Hev b 2 Beta-1,3-
glucanase
DRB1*0101
DRB1*0701
DRB1*0901
DRB1*1302
DRB1*1501
DRB4*0101
Hev b 3 Small  rubber 
particle protein
DRB1*0101
DRB1*1302
Hev b 4 Lecithinase 
homologue
DRB1*0101
DRB1*0401
DRB1*1302
Hev b 5 Acidic protein -
Hev b 6 Hevein precursor DRB1*0101
DRB1*0404
DRB1*0701
DRB1*1302
Hev b 7 Patatin-like 
protein
DRB1*0101
DRB1*1302
DRB1*1501
N
at
ur
e 
Pr
ec
ed
in
gs
 : 
hd
l:1
01
01
/n
pr
e.
20
09
.2
93
1.
1 
: P
os
te
d 
6 
M
ar
 2
00
9
Hev b 8 Profilin DRB1*0101
Hev b 9 Enolase DRB1*0101
DRB1*1302
Hev b 10 Superoxide 
dismutase (Mn)
DRB1*0101
DRB1*1302
Hev b 11 Class I Chitinase DRB1*0101
DRB1*0404
Hev b 12 Lipid  transfer 
protein
DRB1*0101
DRB1*0404
Hev b 13 Esterase DRB1*0101
N
at
ur
e 
Pr
ec
ed
in
gs
 : 
hd
l:1
01
01
/n
pr
e.
20
09
.2
93
1.
1 
: P
os
te
d 
6 
M
ar
 2
00
9


MULTIPRED: a computational system for prediction of promiscuous HLA binding peptides.

Occupational contact urticaria and protein contact dermatitis.

Delayed-Type hypersensitivity to latex: Computational prediction of MHC class II epitopes on latex allergens

http://precedings.nature.com/documents/2931/version/1

Delayed-Type hypersensitivity to latex: Computational prediction of MHC class II epitopes on latex allergens

Abstract

Similar works

Full text

Available Versions

Nature Precedings