• Cis- and trans-dimerization of HLA-DQα/DQβ chains produce molecules that influence the risk of relapse after transplantation.

  • The HLA-DQ heterodimer is a functional paradigm of the transplantation barrier.

HLA-DQ heterodimers increase the susceptibility to autoimmune diseases, but their role in hematopoietic cell transplantation is unknown. We tested the hypothesis that outcome after HLA-matched and HLA-DQ–mismatched hematopoietic cell transplantation is influenced by HLA-DQ heterodimers. Heterodimers were defined in 5164 HLA-matched and 520 HLA-DQ–mismatched patients and their transplant donors according to well-established crystallographic criteria. Group 1 (G1) heterodimers are any DQA1*02/03/04/05/06α paired with any DQB1*02/03/04β. Group 2 (G2) heterodimers are DQA1*01α paired with any DQB1*05/06β. Multivariable models identified significantly higher relapse risk in G1G2 and G2G2 compared with G1G1 HLA-matched patients with malignant disease; risk increased with an increasing number of G2 molecules. In HLA-DQ–mismatched transplantation for malignant diseases, matching or mismatching for G2 increased relapse risk. G2 lowered disease-free survival after both HLA-matched and HLA-DQ–mismatched transplantation. A paradigm based on HLA-DQ heterodimers provides a functional definition of the hematopoietic cell transplantation barrier and a means to lower risks for future patients.

1.
van Rood
JJ
,
van Leeuwen
A
,
Keuning
JJ
,
van Oud Alblas
AB
.
The serological recognition of the human MLC determinants using a modified cytotoxicity technique
.
Tissue Antigens.
1975
;
5
(
2
):
73
-
79
.
2.
Bodmer
JG
. Ia Serology. In:
Bodmer
WF
,
Batchelor
JR
,
Bodmer
,
JG
, eds.
Histocompatibility Testing 1977.
Copenhagen, Denmark
:
Munksgaard
,
1978
:
351
-
357
.
3.
Duquesnoy
RJ
,
Marrari
M
,
Annen
K
.
Identification of an HLA-DR-associated system of B-cell alloantigens
.
Transplant Proc.
1979
;
11
(
4
):
1757
-
1760
.
4.
Terasaki
PI
,
Park
MS
,
Bernoco
D
, et al
Overview of the 1980 International Histocompatibility Workshop. In:
Terasaki
PI
, ed.
Histocompatibility Testing 1980.
Los Angeles, CA
:
UCLA Tissue Typing Laboratory
,
1980
.
5.
McDevitt
HO
,
Bodmer
WF
.
HL-A, immune-response genes, and disease
.
Lancet.
1974
;
303
(
7869
):
1269
-
1275
.
6.
Thorsby
E
.
Invited anniversary review: HLA associated diseases
.
Hum Immunol.
1997
;
53
(
1
):
1
-
11
.
7.
Hill
AVS
.
The immunogenetics of human infectious diseases
.
Annu Rev Immunol.
1998
;
16
(
1
):
593
-
617
.
8.
Shiina
T
,
Hosomichi
K
,
Inoko
H
,
Kulski
JK
.
The HLA genomic loci map: expression, interaction, diversity and disease
.
J Hum Genet.
2009
;
54
(
1
):
15
-
39
.
9.
Erlich
H
,
Valdes
AM
,
Noble
J
, et al;
Type 1 Diabetes Genetics Consortium
.
HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families
.
Diabetes.
2008
;
57
(
4
):
1084
-
1092
.
10.
Sollid
LM
.
The roles of MHC class II genes and post-translational modification in celiac disease
.
Immunogenetics.
2017
;
69
(
8-9
):
605
-
616
.
11.
Chabas
D
,
Taheri
S
,
Renier
C
,
Mignot
E
.
The genetics of narcolepsy
.
Annu Rev Genomics Hum Genet.
2003
;
4
(
1
):
459
-
483
.
12.
Brown
JH
,
Jardetzky
TS
,
Gorga
JC
, et al
.
Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1
.
Nature.
1993
;
364
(
6432
):
33
-
39
.
13.
Parham
P
.
HLA, anthropology, and transplantation
.
Transplant Proc.
1993
;
25
(
1 Pt 1
):
159
-
161
.
14.
The Immuno Polymorphism Database (IPD)-ImMunoGeneTics (IMGT)/HLA Database
. Available at: https://www.ebi.ac.uk/ipd/imgt/hla/. Accessed 5 February 2022.
15.
Charron
DJ
,
Lotteau
V
,
Turmel
P
.
Hybrid HLA-DC antigens provide molecular evidence for gene trans-complementation
.
Nature.
1984
;
312
(
5990
):
157
-
159
.
16.
Kwok
WW
,
Nepom
GT
.
Structural and functional constraints on HLA class II dimers implicated in susceptibility to insulin dependent diabetes mellitus
.
Baillieres Clin Endocrinol Metab.
1991
;
5
(
3
):
375
-
393
.
17.
Tollefsen
S
,
Hotta
K
,
Chen
X
, et al
.
Structural and functional studies of trans-encoded HLA-DQ2.3 (DQA1*03:01/DQB1*02:01) protein molecule
.
J Biol Chem.
2012
;
287
(
17
):
13611
-
13619
.
18.
Kooy-Winkelaar
Y
,
van Lummel
M
,
Moustakas
AK
, et al
.
Gluten-specific T cells cross-react between HLA-DQ8 and the HLA-DQ2α/DQ8β transdimer
.
J Immunol.
2011
;
187
(
10
):
5123
-
5129
.
19.
van Lummel
M
,
van Veelen
PA
,
Zaldumbide
A
, et al
.
Type 1 diabetes-associated HLA-DQ8 transdimer accommodates a unique peptide repertoire
.
J Biol Chem.
2012
;
287
(
12
):
9514
-
9524
.
20.
Chow
IT
,
Gates
TJ
,
Papadopoulos
GK
, et al
.
Discriminative T cell recognition of cross-reactive islet-antigens is associated with HLA-DQ8 transdimer-mediated autoimmune diabetes
.
Sci Adv.
2019
;
5
(
8
):
eaaw9336
.
21.
Bach
FH
,
van Rood
JJ
.
The major histocompatibility complex--genetics and biology (first of three parts)
.
N Engl J Med.
1976
;
295
(
15
):
806
-
813
.
22.
Lee
SJ
,
Klein
J
,
Haagenson
M
, et al
.
High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation
.
Blood.
2007
;
110
(
13
):
4576
-
4583
.
23.
Fleischhauer
K
,
Shaw
BE
,
Gooley
T
, et al;
International Histocompatibility Working Group in Hematopoietic Cell Transplantation
.
Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: a retrospective study
.
Lancet Oncol.
2012
;
13
(
4
):
366
-
374
.
24.
Petersdorf
EW
,
Carrington
M
,
O’hUigin
C
, et al;
International Histocompatibility Working Group in Hematopoietic Cell Transplantation
.
Role of HLA-B exon 1 in graft-versus-host disease after unrelated haemopoietic cell transplantation: a retrospective cohort study
.
Lancet Haematol.
2020
;
7
(
1
):
e50
-
e60
.
25.
Fürst
D
,
Müller
C
,
Vucinic
V
, et al
.
High-resolution HLA matching in hematopoietic stem cell transplantation: a retrospective collaborative analysis
[published correction appears in Blood. 2014;123(11):1768].
Blood.
2013
;
122
(
18
):
3220
-
3229
.
26.
Little
A-M
,
Akbarzad-Yousefi
A
,
Anand
A
, et al
.
BSHI guideline: HLA matching and donor selection for haematopoietic progenitor cell transplantation
.
Int J Immunogenet.
2021
;
48
(
2
):
75
-
109
.
27.
Robinson
J
,
Halliwell
JA
,
Hayhurst
JD
,
Flicek
P
,
Parham
P
,
Marsh
SGE
.
The IPD and IMGT/HLA database: allele variant databases
.
Nucleic Acids Res.
2015
;
43
(
database issue
):
D423
-
D431
.
28.
Raymond
CK
,
Kas
A
,
Paddock
M
, et al
.
Ancient haplotypes of the HLA Class II region
.
Genome Res.
2005
;
15
(
9
):
1250
-
1257
.
29.
Trowsdale
J
,
Knight
JC
.
Major histocompatibility complex genomics and human disease
.
Annu Rev Genomics Hum Genet.
2013
;
14
(
1
):
301
-
323
.
30.
Battiwalla
M
,
Ellis
K
,
Li
P
, et al
.
HLA DR15 antigen status does not impact graft-versus-host disease or survival in HLA-matched sibling transplantation for hematologic malignancies
.
Biol Blood Marrow Transplant.
2012
;
18
(
8
):
1302
-
1308
.
31.
Schmidt
AH
,
Sauter
J
,
Baier
DM
, et al
.
Immunogenetics in stem cell donor registry work: The DKMS example (part 2)
.
Int J Immunogenet.
2020
;
47
(
2
):
139
-
148
.
32.
Horowitz
MM
,
Gale
RP
,
Sondel
PM
, et al
.
Graft-versus-leukemia reactions after bone marrow transplantation
.
Blood.
1990
;
75
(
3
):
555
-
562
.
33.
Yamamoto
F
,
Suzuki
S
,
Mizutani
A
, et al
.
Capturing differential allele-level expression and genotypes of all classical HLA loci and haplotypes by a new capture RNA-Seq method
.
Front Immunol.
2020
;
11
:
941
.
34.
Unanue
ER
,
Turk
V
,
Neefjes
J
.
Variations in MHC class II antigen processing and presentation in health and disease
.
Annu Rev Immunol.
2016
;
34
(
1
):
265
-
297
.
35.
van Lith
M
,
McEwen-Smith
RM
,
Benham
AM
.
HLA-DP, HLA-DQ, and HLA-DR have different requirements for invariant chain and HLA-DM
.
J Biol Chem.
2010
;
285
(
52
):
40800
-
40808
.
36.
Silva
DG
,
Socha
L
,
Correcha
M
,
Petrovsky
N
.
Elevated lymphocyte expression of CLIP is associated with type 1 diabetes and may be a useful marker of autoimmune susceptibility
.
Ann N Y Acad Sci.
2004
;
1037
(
1
):
65
-
68
.
37.
Busch
R
,
De Riva
A
,
Hadjinicolaou
AV
,
Jiang
W
,
Hou
T
,
Mellins
ED
.
On the perils of poor editing: regulation of peptide loading by HLA-DQ and H2-A molecules associated with celiac disease and type 1 diabetes
.
Expert Rev Mol Med.
2012
;
14
:
e15
.
38.
Siebold
C
,
Hansen
BE
,
Wyer
JR
, et al
.
Crystal structure of HLA-DQ0602 that protects against type 1 diabetes and confers strong susceptibility to narcolepsy
.
Proc Natl Acad Sci USA.
2004
;
101
(
7
):
1999
-
2004
.
39.
Zhou
Z
,
Jensen
PE
.
Structural characteristics of HLA-DQ that may impact DM editing and susceptibility to type-1 diabetes
.
Front Immunol.
2013
;
4
:
262
.
40.
van Lummel
M
,
Buis
DTP
,
Ringeling
C
, et al
.
Epitope stealing as a mechanism of dominant protection by HLA-DQ6 in type 1 diabetes
.
Diabetes.
2019
;
68
(
4
):
787
-
795
.
41.
Christopher
MJ
,
Petti
AA
,
Rettig
MP
, et al
.
Immune escape of relapsed AML cells after allogeneic transplantation
.
N Engl J Med.
2018
;
379
(
24
):
2330
-
2341
.
42.
Toffalori
C
,
Zito
L
,
Gambacorta
V
, et al
.
Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation
.
Nat Med.
2019
;
25
(
4
):
603
-
611
.
43.
Alonso
MC
,
Navarrete
C
,
Solana
R
,
Torres
A
,
Pena
J
,
Festenstein
H
.
Differential expression of HLA-DR and HLA-DQ antigens on normal cells of the myelomonocytic lineage
.
Tissue Antigens.
1985
;
26
(
5
):
310
-
317
.
44.
Fernández-Viña
MA
,
Klein
JP
,
Haagenson
M
, et al
.
Multiple mismatches at the low expression HLA loci DP, DQ, and DRB3/4/5 associate with adverse outcomes in hematopoietic stem cell transplantation
.
Blood.
2013
;
121
(
22
):
4603
-
4610
.
45.
Ollila
HM
,
Fernández-Viña
M
,
Mignot
E
.
HLA-DQ allele competition in narcolepsy: a comment on Tafti et al. DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe
.
Sleep (Basel).
2015
;
38
(
1
):
147
-
151
.
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