In this issue of Blood, Tanimura et al describe an interaction between certain human leukocyte antigen (HLA) class II alleles and misfolded β2-glycoprotein I (β2GPI). This complex is expressed on the surface of HLA class II–expressing placental endothelial cells, and it is a target for the autoantibodies against β2GPI seen in patients with antiphospholipid syndrome (APS), providing a mechanistic basis for pregnancy-related morbidity in these patients.1 

In antigen-presenting cells, HLA class II molecules present peptide antigens derived from extracellular proteins by the endocytic pathway to the CD4 T cells via the peptide-binding groove.2  Following their assembly in the endoplasmic reticulum with an invariant chain (Ii), the Ii/HLA class II complexes are transported to a late endosomal compartment called the major histocompatibility complex (MHC) class II compartment. Here, Ii is proteolytically processed and removed, allowing peptide loading to the antigen-binding groove in the HLA class II complex. The HLA class II complex is then transported to the plasma membrane to present the peptide cargo to CD4 T cells.

In previous publications, these authors have shown that the HLA class II molecules can also transport certain intact misfolded proteins such as the immunoglobulin G heavy chain from the endosomal compartment to the cell surface.3,4  Compared with HLA class I molecules, the peptide-binding groove of HLA class II molecules is open, and it can accommodate longer peptides. By using 293T cells transfected with complementary DNAs for β2GPI and HLA class II complex, the authors showed that misfolded β2GPI was bound to HLA class II molecules inside the cell. This interaction presumably occurs in the endosomal compartment, and the complex is transported to the cell surface. The binding of the β2GPI/HLA class II complex depends on the HLA-DR alleles. Certain APS-susceptible alleles such HLA-DR7 and HLA-DR4 bound to β2GPI more effectively than other alleles. Although these studies were performed in transfected 293T cells with forced expression, the authors demonstrated the association of β2GPI/HLA class II complex on endothelial cells in the placenta of patients with APS but not in the placenta of patients without APS. HLA class II–bound misfolded β2GPI is not only a target of antibody-induced injury but is also a potent inducer of antigen-specific B cells and may play a role in the persistence of these antibodies in APS patients.

These novel findings raise several interesting questions, which have a direct bearing on the mechanism of the procoagulant state associated with APS. Endothelial cells, the most extensively studied target, express class II antigens only after stimulation. This raises the question of whether only inflamed endothelial cells are the targets of the antiphospholipid antibodies. However, most patients with APS do not have evidence of vasculitis or other inflammatory conditions. Macrophages, the professional antigen-presenting cells, express HLA class II molecules and internalize β2GPI/phosphatidylserine–containing vesicles and platelet microparticles,5  and they can potentially express this epitope on their surface. In monocytes, antiphospholipid antibodies induce tissue factor, the major initiator of the coagulation system.6  Furthermore, the HLA class II molecules can transmit outside-in signals by triggering multiple pathways,7  and several signal transduction cascades have been shown in endothelial activation by β2GPI–dependent antiphospholipid antibodies.8 

Despite a large number of studies on this subject, the precise mechanism of the procoagulant state in APS is still elusive.9  The Tanimura et al study provides yet another potential cell surface receptor for β2GPI that may be involved in the induction of the procoagulant state.

Conflict-of-interest disclosure: The author declares no competing financial interests.

REFERENCES

REFERENCES
1
Tanimura
 
K
Jin
 
H
Suenaga
 
T
, et al. 
β2-Glycoprotein I/HLA class II complexes are novel autoantigens in antiphospholipid syndrome.
Blood
2015
, vol. 
125
 
18
(pg. 
2835
-
2844
)
2
Neefjes
 
J
Jongsma
 
ML
Paul
 
P
Bakke
 
O
Towards a systems understanding of MHC class I and MHC class II antigen presentation.
Nat Rev Immunol
2011
, vol. 
11
 
12
(pg. 
823
-
836
)
3
Jiang
 
Y
Arase
 
N
Kohyama
 
M
, et al. 
Transport of misfolded endoplasmic reticulum proteins to the cell surface by MHC class II molecules.
Int Immunol
2013
, vol. 
25
 
4
(pg. 
235
-
246
)
4
Jin
 
H
Arase
 
N
Hirayasu
 
K
, et al. 
Autoantibodies to IgG/HLA class II complexes are associated with rheumatoid arthritis susceptibility.
Proc Natl Acad Sci USA
2014
, vol. 
111
 
10
(pg. 
3787
-
3792
)
5
Thiagarajan
 
P
Le
 
A
Benedict
 
CR
Beta(2)-glycoprotein I promotes the binding of anionic phospholipid vesicles by macrophages.
Arterioscler Thromb Vasc Biol
1999
, vol. 
19
 
11
(pg. 
2807
-
2811
)
6
Kornberg
 
A
Blank
 
M
Kaufman
 
S
Shoenfeld
 
Y
Induction of tissue factor-like activity in monocytes by anti-cardiolipin antibodies.
J Immunol
1994
, vol. 
153
 
3
(pg. 
1328
-
1332
)
7
Al-Daccak
 
R
Mooney
 
N
Charron
 
D
MHC class II signaling in antigen-presenting cells.
Curr Opin Immunol
2004
, vol. 
16
 
1
(pg. 
108
-
113
)
8
Meroni
 
PL
Borghi
 
MO
Raschi
 
E
Tedesco
 
F
Pathogenesis of antiphospholipid syndrome: understanding the antibodies.
Nat Rev Rheumatol
2011
, vol. 
7
 
6
(pg. 
330
-
339
)
9
Chaturvedi
 
S
McCrae
 
KR
Recent advances in the antiphospholipid antibody syndrome.
Curr Opin Hematol
2014
, vol. 
21
 
5
(pg. 
371
-
379
)