Key Points

  • FcγRIIA, an IC receptor, promotes nephritis and thrombosis in lupus.

  • FcγRIIA expression modifies the platelet transcriptome and accelerates platelet activation in lupus.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease characterized by deposits of immune complexes (ICs) in organs and tissues. The expression of FcγRIIA by human platelets, which is their unique receptor for immunoglobulin G antibodies, positions them to ideally respond to circulating ICs. Whereas chronic platelet activation and thrombosis are well-recognized features of human SLE, the exact mechanisms underlying platelet activation in SLE remain unknown. Here, we evaluated the involvement of FcγRIIA in the course of SLE and platelet activation. In patients with SLE, levels of ICs are associated with platelet activation. Because FcγRIIA is absent in mice, and murine platelets do not respond to ICs in any existing mouse model of SLE, we introduced the FcγRIIA (FCGR2A) transgene into the NZB/NZWF1 mouse model of SLE. In mice, FcγRIIA expression by bone marrow cells severely aggravated lupus nephritis and accelerated death. Lupus onset initiated major changes to the platelet transcriptome, both in FcγRIIA-expressing and nonexpressing mice, but enrichment for type I interferon response gene changes was specifically observed in the FcγRIIA mice. Moreover, circulating platelets were degranulated and were found to interact with neutrophils in FcγRIIA-expressing lupus mice. FcγRIIA expression in lupus mice also led to thrombosis in lungs and kidneys. The model recapitulates hallmarks of human SLE and can be used to identify contributions of different cellular lineages in the manifestations of SLE. The study further reveals a role for FcγRIIA in nephritis and in platelet activation in SLE.

REFERENCES

1.
Carter
EE
,
Barr
SG
,
Clarke
AE
.
The global burden of SLE: prevalence, health disparities and socioeconomic impact
.
Nat Rev Rheumatol
.
2016
;
12
(
10
):
605
-
620
.
2.
Crampton
SP
,
Morawski
PA
,
Bolland
S
.
Linking susceptibility genes and pathogenesis mechanisms using mouse models of systemic lupus erythematosus
.
Dis Model Mech
.
2014
;
7
(
9
):
1033
-
1046
.
3.
Muskardin
TLW
,
Niewold
TB
.
Type I interferon in rheumatic diseases
.
Nat Rev Rheumatol
.
2018
;
14
(
4
):
214
-
228
.
4.
Niewold
TB
.
Connective tissue diseases: targeting type I interferon in systemic lupus erythematosus
.
Nat Rev Rheumatol
.
2016
;
12
(
7
):
377
-
378
.
5.
Craft
JE
.
Dissecting the immune cell mayhem that drives lupus pathogenesis
.
Sci Transl Med
.
2011
;
3
(
73
):
73ps9
.
6.
Flores-Mendoza
G
,
Sansón
SP
,
Rodríguez-Castro
S
,
Crispín
JC
,
Rosetti
F
.
Mechanisms of tissue injury in lupus nephritis
.
Trends Mol Med
.
2018
;
24
(
4
):
364
-
378
.
7.
Pieterse
E
,
van der Vlag
J
.
Breaking immunological tolerance in systemic lupus erythematosus
.
Front Immunol
.
2014
;
5
:
164
.
8.
Bazzan
M
,
Vaccarino
A
,
Marletto
F
.
Systemic lupus erythematosus and thrombosis
.
Thromb J
.
2015
;
13
(
1
):
16
.
9.
Scherlinger
M
,
Guillotin
V
,
Truchetet
ME
, et al
.
Systemic lupus erythematosus and systemic sclerosis: all roads lead to platelets
.
Autoimmun Rev
.
2018
;
17
(
6
):
625
-
635
.
10.
Abdel Galil
SM
,
Edrees
AM
,
Ajeeb
AK
,
Aldoobi
GS
,
El-Boshy
M
,
Hussain
W
.
Prognostic significance of platelet count in SLE patients
.
Platelets
.
2017
;
28
(
2
):
203
-
207
.
11.
Cervera
R
,
Khamashta
MA
,
Font
J
, et al;
European Working Party on Systemic Lupus Erythematosus
.
Morbidity and mortality in systemic lupus erythematosus during a 5-year period. A multicenter prospective study of 1,000 patients
.
Medicine (Baltimore)
.
1999
;
78
(
3
):
167
-
175
.
12.
Fernández
M
,
Alarcón
GS
,
Apte
M
,
Andrade
RM
,
Vilá
LM
,
Reveille
JD
;
LUMINA Study Group
.
Systemic lupus erythematosus in a multiethnic US cohort: XLIII. The significance of thrombocytopenia as a prognostic factor
.
Arthritis Rheum
.
2007
;
56
(
2
):
614
-
621
.
13.
Koupenova
M
,
Clancy
L
,
Corkrey
HA
,
Freedman
JE
.
Circulating platelets as mediators of immunity, inflammation, and thrombosis
.
Circ Res
.
2018
;
122
(
2
):
337
-
351
.
14.
Linge
P
,
Fortin
PR
,
Lood
C
,
Bengtsson
AA
,
Boilard
E
.
The non-haemostatic role of platelets in systemic lupus erythematosus
.
Nat Rev Rheumatol
.
2018
;
14
(
4
):
195
-
213
.
15.
Semple
JW
,
Italiano
JE
Jr.
,
Freedman
J
.
Platelets and the immune continuum
.
Nat Rev Immunol
.
2011
;
11
(
4
):
264
-
274
.
16.
Melki
I
,
Tessandier
N
,
Zufferey
A
,
Boilard
E
.
Platelet microvesicles in health and disease
.
Platelets
.
2017
;
28
(
3
):
214
-
221
.
17.
Duffau
P
,
Seneschal
J
,
Nicco
C
, et al
.
Platelet CD154 potentiates interferon-alpha secretion by plasmacytoid dendritic cells in systemic lupus erythematosus
.
Sci Transl Med
.
2010
;
2
(
47
):
47ra63
.
18.
Ferro
D
,
Basili
S
,
Roccaforte
S
, et al
.
Determinants of enhanced thromboxane biosynthesis in patients with systemic lupus erythematosus
.
Arthritis Rheum
.
1999
;
42
(
12
):
2689
-
2697
.
19.
Kato
K
,
Santana-Sahagún
E
,
Rassenti
LZ
, et al
.
The soluble CD40 ligand sCD154 in systemic lupus erythematosus
.
J Clin Invest
.
1999
;
104
(
7
):
947
-
955
.
20.
Lellouche
F
,
Martinuzzo
M
,
Said
P
,
Maclouf
J
,
Carreras
LO
.
Imbalance of thromboxane/prostacyclin biosynthesis in patients with lupus anticoagulant
.
Blood
.
1991
;
78
(
11
):
2894
-
2899
.
21.
Nagahama
M
,
Nomura
S
,
Ozaki
Y
,
Yoshimura
C
,
Kagawa
H
,
Fukuhara
S
.
Platelet activation markers and soluble adhesion molecules in patients with systemic lupus erythematosus
.
Autoimmunity
.
2001
;
33
(
2
):
85
-
94
.
22.
Marchesi
D
,
Parbtani
A
,
Frampton
G
,
Livio
M
,
Remuzzi
G
,
Cameron
JS
.
Thrombotic tendency in systemic lupus erythematosus
.
Lancet
.
1981
;
1
(
8222
):
719
.
23.
Lood
C
,
Tydén
H
,
Gullstrand
B
, et al
.
Platelet-derived S100A8/A9 and cardiovascular disease in systemic lupus erythematosus
.
Arthritis Rheumatol
.
2016
;
68
(
8
):
1970
-
1980
.
24.
Nhek
S
,
Clancy
R
,
Lee
KA
, et al
.
Activated platelets induce endothelial cell activation via an interleukin-1β pathway in systemic lupus erythematosus
.
Arterioscler Thromb Vasc Biol
.
2017
;
37
(
4
):
707
-
716
.
25.
Lood
C
,
Amisten
S
,
Gullstrand
B
, et al
.
Platelet transcriptional profile and protein expression in patients with systemic lupus erythematosus: up-regulation of the type I interferon system is strongly associated with vascular disease
.
Blood
.
2010
;
116
(
11
):
1951
-
1957
.
26.
Huber
C
,
Rüger
A
,
Herrmann
M
,
Krapf
F
,
Kalden
JR
.
C3-containing serum immune complexes in patients with systemic lupus erythematosus: correlation to disease activity and comparison with other rheumatic diseases
.
Rheumatol Int
.
1989
;
9
(
2
):
59
-
64
.
27.
Bruhns
P
,
Iannascoli
B
,
England
P
, et al
.
Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses
.
Blood
.
2009
;
113
(
16
):
3716
-
3725
.
28.
Nimmerjahn
F
,
Ravetch
JV
.
Fcgamma receptors as regulators of immune responses
.
Nat Rev Immunol
.
2008
;
8
(
1
):
34
-
47
.
29.
Clynes
R
,
Dumitru
C
,
Ravetch
JV
.
Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis
.
Science
.
1998
;
279
(
5353
):
1052
-
1054
.
30.
Park
SY
,
Ueda
S
,
Ohno
H
, et al
.
Resistance of Fc receptor-deficient mice to fatal glomerulonephritis
.
J Clin Invest
.
1998
;
102
(
6
):
1229
-
1238
.
31.
Bolland
S
,
Yim
YS
,
Tus
K
,
Wakeland
EK
,
Ravetch
JV
.
Genetic modifiers of systemic lupus erythematosus in FcgammaRIIB(-/-) mice
.
J Exp Med
.
2002
;
195
(
9
):
1167
-
1174
.
32.
Duits
AJ
,
Bootsma
H
,
Derksen
RHWM
, et al
.
Skewed distribution of IgG Fc receptor IIa (CD32) polymorphism is associated with renal disease in systemic lupus erythematosus patients
.
Arthritis Rheum
.
1995
;
38
(
12
):
1832
-
1836
.
33.
Takai
T
.
Roles of Fc receptors in autoimmunity
.
Nat Rev Immunol
.
2002
;
2
(
8
):
580
-
592
.
34.
Bruhns
P
.
Properties of mouse and human IgG receptors and their contribution to disease models
.
Blood
.
2012
;
119
(
24
):
5640
-
5649
.
35.
Bruhns
P
,
Jönsson
F
.
Mouse and human FcR effector functions
.
Immunol Rev
.
2015
;
268
(
1
):
25
-
51
.
36.
Huang
ZY
,
Chien
P
,
Indik
ZK
,
Schreiber
AD
.
Human platelet FcγRIIA and phagocytes in immune-complex clearance
.
Mol Immunol
.
2011
;
48
(
4
):
691
-
696
.
37.
Worth
RG
,
Chien
CD
,
Chien
P
,
Reilly
MP
,
McKenzie
SE
,
Schreiber
AD
.
Platelet FcgammaRIIA binds and internalizes IgG-containing complexes
.
Exp Hematol
.
2006
;
34
(
11
):
1490
-
1495
.
38.
Arman
M
,
Krauel
K
.
Human platelet IgG Fc receptor FcγRIIA in immunity and thrombosis
.
J Thromb Haemost
.
2015
;
13
(
6
):
893
-
908
.
39.
Qiao
J
,
Al-Tamimi
M
,
Baker
RI
,
Andrews
RK
,
Gardiner
EE
.
The platelet Fc receptor, FcγRIIa
.
Immunol Rev
.
2015
;
268
(
1
):
241
-
252
.
40.
Watanabe
H
,
Garnier
G
,
Circolo
A
, et al
.
Modulation of renal disease in MRL/lpr mice genetically deficient in the alternative complement pathway factor B
.
J Immunol
.
2000
;
164
(
2
):
786
-
794
.
41.
McKenzie
SE
,
Taylor
SM
,
Malladi
P
, et al
.
The role of the human Fc receptor Fc γ RIIA in the immune clearance of platelets: a transgenic mouse model
.
J Immunol
.
1999
;
162
(
7
):
4311
-
4318
.
42.
Zhi
H
,
Rauova
L
,
Hayes
V
, et al
.
Cooperative integrin/ITAM signaling in platelets enhances thrombus formation in vitro and in vivo
.
Blood
.
2013
;
121
(
10
):
1858
-
1867
.
43.
Zhi
H
,
Dai
J
,
Liu
J
, et al
.
Platelet activation and thrombus formation over IgG immune complexes requires integrin aIIbβ3 and lyn kinase
.
PLoS One
.
2015
;
10
(
8
):
1
-
14
.
44.
Stolla
M
,
Stefanini
L
,
André
P
, et al
.
CalDAG-GEFI deficiency protects mice in a novel model of Fcγ RIIA-mediated thrombosis and thrombocytopenia
.
Blood
.
2011
;
118
(
4
):
1113
-
1120
.
45.
Reilly
MP
,
Taylor
SM
,
Hartman
NK
, et al
.
Heparin-induced thrombocytopenia/thrombosis in a transgenic mouse model requires human platelet factor 4 and platelet activation through FcgammaRIIA
.
Blood
.
2001
;
98
(
8
):
2442
-
2447
.
46.
Beutier
H
,
Hechler
B
,
Godon
O
, et al
.
Platelets expressing IgG receptor FcγRIIA/CD32A determine the severity of experimental anaphylaxis
.
Sci Immunol
.
2018
;
3
(
22
):
eaan5997
.
47.
Cloutier
N
,
Allaeys
I
,
Marcoux
G
, et al
.
Platelets release pathogenic serotonin and return to circulation after immune complex-mediated sequestration
.
Proc Natl Acad Sci U S A
.
2018
;
115
(
7
):
E1550
-
E1559
.
48.
Flaumenhaft
R
,
Dilks
JR
,
Richardson
J
, et al
.
Megakaryocyte-derived microparticles: direct visualization and distinction from platelet-derived microparticles
.
Blood
.
2009
;
113
(
5
):
1112
-
1121
.
49.
Mobarrez
F
,
Fuzzi
E
,
Gunnarsson
I
, et al
.
Microparticles in the blood of patients with SLE: size, content of mitochondria and role in circulating immune complexes
.
J Autoimmun
.
2019
;
102
:
142
-
149
.
50.
Rifle
G
,
Chevet
D
,
Justrabo
E
.
Extracapillary glomerulonephritis [in French]
.
Rev Prat
.
1991
;
41
(
24
):
2437
-
2445
.
51.
Zhuang
H
,
Szeto
C
,
Han
S
,
Yang
L
,
Reeves
WH
.
Animal models of interferon signature positive lupus
.
Front Immunol
.
2015
;
6
:
291
.
52.
Freishtat
RJ
,
Natale
J
,
Benton
AS
, et al
.
Sepsis alters the megakaryocyte-platelet transcriptional axis resulting in granzyme B-mediated lymphotoxicity
.
Am J Respir Crit Care Med
.
2009
;
179
(
6
):
467
-
473
.
53.
Middleton
EA
,
Rowley
JW
,
Campbell
RA
, et al
.
Sepsis alters the transcriptional and translational landscape of human and murine platelets
.
Blood
.
2019
;
134
(
12
):
911
-
923
.
54.
Robles-Carrillo
L
,
Meyer
T
,
Hatfield
M
, et al
.
Anti-CD40L immune complexes potently activate platelets in vitro and cause thrombosis in FCGR2A transgenic mice
.
J Immunol
.
2010
;
185
(
3
):
1577
-
1583
.
55.
Amirkhosravi
A
,
Boulaftali
Y
,
Robles-Carrillo
L
, et al
.
CalDAG-GEFI deficiency protects mice from FcγRIIa-mediated thrombotic thrombocytopenia induced by CD40L and β2GPI immune complexes
.
J Thromb Haemost
.
2014
;
12
(
12
):
2113
-
2119
.
56.
Gray
MW
.
Mosaic nature of the mitochondrial proteome: implications for the origin and evolution of mitochondria
.
Proc Natl Acad Sci U S A
.
2015
;
112
(
33
):
10133
-
10138
.
57.
Joseph
JE
,
Harrison
P
,
Mackie
IJ
,
Isenberg
DA
,
Machin
SJ
.
Increased circulating platelet-leucocyte complexes and platelet activation in patients with antiphospholipid syndrome, systemic lupus erythematosus and rheumatoid arthritis
.
Br J Haematol
.
2001
;
115
(
2
):
451
-
459
.
58.
Helyer
BJ
,
Howie
JB
.
Renal disease associated with positive lupus erythematosus tests in a cross-bred strain of mice
.
Nature
.
1963
;
197
(
4863
):
197
.
59.
Andrews
BS
,
Eisenberg
RA
,
Theofilopoulos
AN
, et al
.
Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains
.
J Exp Med
.
1978
;
148
(
5
):
1198
-
1215
.
60.
Lood
C
,
Arve
S
,
Ledbetter
J
,
Elkon
KB
.
TLR7/8 activation in neutrophils impairs immune complex phagocytosis through shedding of FcgRIIA
.
J Exp Med
.
2017
;
214
(
7
):
2103
-
2119
.
61.
Gardiner
EE
,
Karunakaran
D
,
Arthur
JF
, et al
.
Dual ITAM-mediated proteolytic pathways for irreversible inactivation of platelet receptors: de-ITAM-izing FcgammaRIIa
.
Blood
.
2008
;
111
(
1
):
165
-
174
.
62.
Oikonomopoulou
K
,
Ricklin
D
,
Ward
PA
,
Lambris
JD
.
Interactions between coagulation and complement—their role in inflammation
.
Semin Immunopathol
.
2012
;
34
(
1
):
151
-
165
.
63.
Bergtold
A
,
Gavhane
A
,
D’Agati
V
,
Madaio
M
,
Clynes
R
.
FcR-bearing myeloid cells are responsible for triggering murine lupus nephritis
.
J Immunol
.
2006
;
177
(
10
):
7287
-
7295
.
64.
Jönsson
F
,
Mancardi
DA
,
Kita
Y
, et al
.
Mouse and human neutrophils induce anaphylaxis
.
J Clin Invest
.
2011
;
121
(
4
):
1484
-
1496
.
65.
Nishi
H
,
Tsokos
GC
,
Mayadas
TN
, et al
.
Neutrophil Fc g RIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases
.
J Clin Invest
.
2017
;
127
(
10
):
3810
-
3826
.
66.
Båve
U
,
Magnusson
M
,
Eloranta
ML
,
Perers
A
,
Alm
GV
,
Rönnblom
L
.
Fc gamma RIIa is expressed on natural IFN-alpha-producing cells (plasmacytoid dendritic cells) and is required for the IFN-alpha production induced by apoptotic cells combined with lupus IgG
.
J Immunol
.
2003
;
171
(
6
):
3296
-
3302
.
67.
Boylan
B
,
Gao
C
,
Rathore
V
,
Gill
JC
,
Newman
DK
,
Newman
PJ
.
Identification of FcgammaRIIa as the ITAM-bearing receptor mediating alphaIIbbeta3 outside-in integrin signaling in human platelets
.
Blood
.
2008
;
112
(
7
):
2780
-
2786
.
68.
Li
J
,
van der Wal
DE
,
Zhu
G
, et al
.
Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia
.
Nat Commun
.
2015
;
6
(
1
):
7737
.
69.
Manzano
EM
,
Sanz
RJ
,
Haslam
SM
, et al
.
Platelet protein glycosylation in immune thrombocytopenia
.
Blood
.
2018
;
132
(
suppl 1
):Abstract
2437
.
70.
Lefrançais
E
,
Ortiz-Muñoz
G
,
Caudrillier
A
, et al
.
The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors
.
Nature
.
2017
;
544
(
7648
):
105
-
109
.
71.
Campbell
RA
,
Schwertz
H
,
Hottz
ED
, et al
.
Human megakaryocytes possess intrinsic antiviral immunity through regulated induction of IFITM3
.
Blood
.
2019
;
133
(
19
):
2013
-
2026
.
72.
Furie
B
,
Furie
BC
.
The molecular basis of platelet and endothelial cell interaction with neutrophils and monocytes: role of P-selectin and the P-selectin ligand, PSGL-1
.
Thromb Haemost
.
1995
;
74
(
1
):
224
-
227
.
73.
Ehlers
R
,
Ustinov
V
,
Chen
Z
, et al
.
Targeting platelet-leukocyte interactions: identification of the integrin Mac-1 binding site for the platelet counter receptor glycoprotein Ibalpha
.
J Exp Med
.
2003
;
198
(
7
):
1077
-
1088
.
74.
Flick
MJ
,
LaJeunesse
CM
,
Talmage
KE
, et al
.
Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin alphaMbeta2 binding motif
.
J Clin Invest
.
2007
;
117
(
11
):
3224
-
3235
.
75.
Constantinescu-Bercu
A
,
Grassi
L
,
Frontini
M
,
Salles-Crawley
II
,
Woollard
K
,
Crawley
JT
.
Activated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2
.
eLife
.
2020
;
9
:
9
.
76.
Perper
SJ
,
Westmoreland
SV
,
Karman
J
, et al
.
Treatment with a CD40 antagonist antibody reverses severe proteinuria and loss of saliva production and restores glomerular morphology in murine systemic lupus erythematosus
.
J Immunol
.
2019
;
203
(
1
):
58
-
75
.
77.
Kawai
T
,
Andrews
D
,
Colvin
RB
,
Sachs
DH
,
Cosimi
AB
.
Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand
.
Nat Med
.
2000
;
6
(
2
):
114
-
114
.
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