Key Points

  • CD27/CD70 deficiencies are IEIs characterized by EBV-associated immune dysregulation including HLH, lymphoproliferation, and malignancy.

  • The excellent outcome following HSCT in cases with CD27/CD70 deficiency supports its timely use particularly in patients with lymphoma.

Abstract

Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity (IEIs) characterized predominantly by Epstein-Barr virus (EBV)-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation, and malignancy. A comprehensive understanding of the natural history, immune characteristics, and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected the clinical information of 49 patients from 29 families (CD27, n = 33; CD70, n = 16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority of patients (90%) were EBV+ at diagnosis, but only ∼30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one patients (43%) developed autoinflammatory features including uveitis, arthritis, and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.

REFERENCES

1.
Zamora
MR
.
DNA viruses (CMV, EBV, and the herpesviruses)
.
Semin Respir Crit Care Med
.
2011
;
32
(
4
):
454
-
470
.
2.
Rickinson
AB
,
Long
HM
,
Palendira
U
,
Münz
C
,
Hislop
AD
.
Cellular immune controls over Epstein-Barr virus infection: new lessons from the clinic and the laboratory
.
Trends Immunol
.
2014
;
35
(
4
):
159
-
169
.
3.
Thorley-Lawson
DA
,
Gross
A
.
Persistence of the Epstein-Barr virus and the origins of associated lymphomas
.
N Engl J Med
.
2004
;
350
(
13
):
1328
-
1337
.
4.
Taylor
GS
,
Long
HM
,
Brooks
JM
,
Rickinson
AB
,
Hislop
AD
.
The immunology of Epstein-Barr virus-induced disease
.
Annu Rev Immunol
.
2015
;
33
:
787
-
821
.
5.
Tangye
SG
.
Genetic susceptibility to EBV infection: insights from inborn errors of immunity
.
Hum Genet
.
2020
;
139
(
6-7
):
885
-
901
.
6.
Tangye
SG
,
Latour
S
.
Primary immunodeficiencies reveal the molecular requirements for effective host defense against EBV infection
.
Blood
.
2020
;
135
(
9
):
644
-
655
.
7.
Bibas
M
,
Antinori
A
.
EBV and HIV-related lymphoma
.
Mediterr J Hematol Infect Dis
.
2009
;
1
(
2
):
e2009032
.
8.
Young
LS
,
Rickinson
AB
.
Epstein-Barr virus: 40 years on
.
Nat Rev Cancer
.
2004
;
4
(
10
):
757
-
768
.
9.
Tangye
SG
.
XLP: clinical features and molecular etiology due to mutations in SH2D1A encoding SAP
.
J Clin Immunol
.
2014
;
34
(
7
):
772
-
779
.
10.
Li
FY
,
Chaigne-Delalande
B
,
Su
H
,
Uzel
G
,
Matthews
H
,
Lenardo
MJ
.
XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus
.
Blood
.
2014
;
123
(
14
):
2148
-
2152
.
11.
Tangye
SG
,
Palendira
U
,
Edwards
ES
.
Human immunity against EBV-lessons from the clinic
.
J Exp Med
.
2017
;
214
(
2
):
269
-
283
.
12.
Latour
S
,
Fischer
A
.
Signaling pathways involved in the T-cell-mediated immunity against Epstein-Barr virus: lessons from genetic diseases
.
Immunol Rev
.
2019
;
291
(
1
):
174
-
189
.
13.
Alosaimi
MF
,
Hoenig
M
,
Jaber
F
, et al
.
Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency
.
J Allergy Clin Immunol
.
2019
;
144
(
2
):
574
-
583.e5
.
14.
Latour
S
,
Winter
S
.
Inherited immunodeficiencies with high predisposition to Epstein-Barr virus-driven lymphoproliferative diseases
.
Front Immunol
.
2018
;
9
:
1103
.
15.
Nolte
MA
,
van Olffen
RW
,
van Gisbergen
KP
,
van Lier
RA
.
Timing and tuning of CD27-CD70 interactions: the impact of signal strength in setting the balance between adaptive responses and immunopathology
.
Immunol Rev
.
2009
;
229
(
1
):
216
-
231
.
16.
Borst
J
,
Hendriks
J
,
Xiao
Y
.
CD27 and CD70 in T cell and B cell activation
.
Curr Opin Immunol
.
2005
;
17
(
3
):
275
-
281
.
17.
Hendriks
J
,
Gravestein
LA
,
Tesselaar
K
,
van Lier
RA
,
Schumacher
TN
,
Borst
J
.
CD27 is required for generation and long-term maintenance of T cell immunity
.
Nat Immunol
.
2000
;
1
(
5
):
433
-
440
.
18.
Hendriks
J
,
Xiao
Y
,
Borst
J
.
CD27 promotes survival of activated T cells and complements CD28 in generation and establishment of the effector T cell pool
.
J Exp Med
.
2003
;
198
(
9
):
1369
-
1380
.
19.
Munitic
I
,
Kuka
M
,
Allam
A
,
Scoville
JP
,
Ashwell
JD
.
CD70 deficiency impairs effector CD8 T cell generation and viral clearance but is dispensable for the recall response to lymphocytic choriomeningitis virus
.
J Immunol
.
2013
;
190
(
3
):
1169
-
1179
.
20.
Avery
DT
,
Ellyard
JI
,
Mackay
F
,
Corcoran
LM
,
Hodgkin
PD
,
Tangye
SG
.
Increased expression of CD27 on activated human memory B cells correlates with their commitment to the plasma cell lineage
.
J Immunol
.
2005
;
174
(
7
):
4034
-
4042
.
21.
van Montfrans
JM
,
Hoepelman
AI
,
Otto
S
, et al
.
CD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia
.
J Allergy Clin Immunol
.
2012
;
129
(
3
):
787
-
793.e6
.
22.
Salzer
E
,
Daschkey
S
,
Choo
S
, et al
.
Combined immunodeficiency with life-threatening EBV-associated lymphoproliferative disorder in patients lacking functional CD27
.
Haematologica
.
2013
;
98
(
3
):
473
-
478
.
23.
Alkhairy
OK
,
Perez-Becker
R
,
Driessen
GJ
, et al
.
Novel mutations in TNFRSF7/CD27: Clinical, immunologic, and genetic characterization of human CD27 deficiency
.
J Allergy Clin Immunol
.
2015
;
136
(
3
):
703
-
712.e10
.
24.
Izawa
K
,
Martin
E
,
Soudais
C
, et al
.
Inherited CD70 deficiency in humans reveals a critical role for the CD70-CD27 pathway in immunity to Epstein-Barr virus infection
.
J Exp Med
.
2017
;
214
(
1
):
73
-
89
.
25.
Kishore
R
,
Gupta
A
,
Gupta
AK
,
Kabra
SK
.
Novel mutation in the CD27 gene in a patient presenting with hypogammaglobulinemia, bronchiectasis and EBV-driven lymphoproliferative disease
.
BMJ Case Rep
.
2020
;
13
(
2
):
e233482
.
26.
Abolhassani
H
,
Edwards
ES
,
Ikinciogullari
A
, et al
.
Combined immunodeficiency and Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency
.
J Exp Med
.
2017
;
214
(
1
):
91
-
106
.
27.
Caorsi
R
,
Rusmini
M
,
Volpi
S
, et al
.
CD70 deficiency due to a novel mutation in a patient with severe chronic EBV infection presenting as a periodic fever
.
Front Immunol
.
2018
;
8
:
2015
.
28.
Kruger
Renate
,
Martin
Emmanuelle
,
Dmytrus
Jasmin
, et al
.
CD70 deficiency associated with chronic Epstein-Barr virus infection, recurrent airway infections and severe gingivitis in a 24-year-old woman
.
Front Immunol
. In press.
29.
Edwards
ESJ
,
Bier
J
,
Cole
TS
, et al
.
Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity
.
J Allergy Clin Immunol
.
2019
;
143
(
1
):
276
-
291.e6
.
30.
Pillay
BA
,
Avery
DT
,
Smart
JM
, et al
.
Hematopoietic stem cell transplant effectively rescues lymphocyte differentiation and function in DOCK8-deficient patients
.
JCI Insight
.
2019
;
5
:
5
.
31.
Avery
DT
,
Kane
A
,
Nguyen
T
, et al
.
Germline-activating mutations in PIK3CD compromise B cell development and function
.
J Exp Med
.
2018
;
215
(
8
):
2073
-
2095
.
32.
Payne
K
,
Li
W
,
Salomon
R
,
Ma
CS
.
OMIP-063: 28-color flow cytometry panel for broad human immunophenotyping [published online ahead of print 16 April 2020]
.
Cytometry A
.
doi:10.1002/cyto.a.24018
.
33.
Tangye
SG
,
Liu
YJ
,
Aversa
G
,
Phillips
JH
,
de Vries
JE
.
Identification of functional human splenic memory B cells by expression of CD148 and CD27
.
J Exp Med
.
1998
;
188
(
9
):
1691
-
1703
.
34.
Teplyakov
A
,
Obmolova
G
,
Malia
TJ
,
Gilliland
GL
.
Crystal structure of CD27 in complex with a neutralizing noncompeting antibody
.
Acta Crystallogr F Struct Biol Commun
.
2017
;
73
(
Pt 5
):
294
-
299
.
35.
Tosato
F
,
Bucciol
G
,
Pantano
G
, et al
.
Lymphocytes subsets reference values in childhood
.
Cytometry A
.
2015
;
87
(
1
):
81
-
85
.
36.
Schatorjé
EJ
,
Gemen
EF
,
Driessen
GJ
,
Leuvenink
J
,
van Hout
RW
,
de Vries
E
.
Paediatric reference values for the peripheral T cell compartment
.
Scand J Immunol
.
2012
;
75
(
4
):
436
-
444
.
37.
Garcia-Prat
M
,
Álvarez-Sierra
D
,
Aguiló-Cucurull
A
, et al
.
Extended immunophenotyping reference values in a healthy pediatric population
.
2019
;
96
(
3
):
223
-
233
.
38.
Klein
U
,
Rajewsky
K
,
Küppers
R
.
Human immunoglobulin (Ig)M+IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B cells
.
J Exp Med
.
1998
;
188
(
9
):
1679
-
1689
.
39.
Sallusto
F
,
Lenig
D
,
Förster
R
,
Lipp
M
,
Lanzavecchia
A
.
Two subsets of memory T lymphocytes with distinct homing potentials and effector functions
.
Nature
.
1999
;
401
(
6754
):
708
-
712
.
40.
Callan
MF
,
Tan
L
,
Annels
N
, et al
.
Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr virus In vivo
.
J Exp Med
.
1998
;
187
(
9
):
1395
-
1402
.
41.
Hislop
AD
,
Annels
NE
,
Gudgeon
NH
,
Leese
AM
,
Rickinson
AB
.
Epitope-specific evolution of human CD8(+) T cell responses from primary to persistent phases of Epstein-Barr virus infection
.
J Exp Med
.
2002
;
195
(
7
):
893
-
905
.
42.
Bomken
S
,
van der Werff Ten Bosch
J
,
Attarbaschi
A
, et al
.
Current understanding and future research priorities in malignancy associated with inborn errors of immunity and DNA repair disorders: the perspective of an interdisciplinary working group
.
Front Immunol
.
2018
;
9
:
2912
.
43.
Coquet
JM
,
Middendorp
S
,
van der Horst
G
, et al
.
The CD27 and CD70 costimulatory pathway inhibits effector function of T helper 17 cells and attenuates associated autoimmunity
.
Immunity
.
2013
;
38
(
1
):
53
-
65
.
44.
Jacobs
J
,
Deschoolmeester
V
,
Zwaenepoel
K
, et al
.
CD70: An emerging target in cancer immunotherapy
.
Pharmacol Ther
.
2015
;
155
:
1
-
10
.
45.
Wajant
H
.
Therapeutic targeting of CD70 and CD27
.
Expert Opin Ther Targets
.
2016
;
20
(
8
):
959
-
973
.
46.
Boleto
G
,
Allanore
Y
,
Avouac
J
.
Targeting costimulatory pathways in systemic sclerosis
.
Front Immunol
.
2018
;
9
:
2998
.
47.
Starzer
AM
,
Berghoff
AS
.
New emerging targets in cancer immunotherapy: CD27 (TNFRSF7)
.
ESMO Open
.
2020
;
4
(
suppl 3
):
e000629
.
48.
de Miranda
NF
,
Georgiou
K
,
Chen
L
, et al
.
Exome sequencing reveals novel mutation targets in diffuse large B-cell lymphomas derived from Chinese patients
.
Blood
.
2014
;
124
(
16
):
2544
-
2553
.
49.
Riether
C
,
Schürch
CM
,
Bührer
ED
, et al
.
CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia
.
J Exp Med
.
2017
;
214
(
2
):
359
-
380
.
50.
Scholtysik
R
,
Nagel
I
,
Kreuz
M
, et al
.
Recurrent deletions of the TNFSF7 and TNFSF9 genes in 19p13.3 in diffuse large B-cell and Burkitt lymphomas
.
Int J Cancer
.
2012
;
131
(
5
):
E830
-
E835
.
51.
Park
GB
,
Kim
YS
,
Lee
HK
, et al
.
Endoplasmic reticulum stress-mediated apoptosis of EBV-transformed B cells by cross-linking of CD70 is dependent upon generation of reactive oxygen species and activation of p38 MAPK and JNK pathway
.
J Immunol
.
2010
;
185
(
12
):
7274
-
7284
.
52.
Lucchini
G
,
Marsh
R
,
Gilmour
K
, et al
.
Treatment dilemmas in asymptomatic children with primary hemophagocytic lymphohistiocytosis
.
Blood
.
2018
;
132
(
19
):
2088
-
2096
.
53.
Balashov
D
,
Shcherbina
A
,
Maschan
M
, et al
.
Single-center experience of unrelated and haploidentical stem cell transplantation with TCRαβ and CD19 depletion in children with primary immunodeficiency syndromes
.
Biol Blood Marrow Transplant
.
2015
;
21
(
11
):
1955
-
1962
.
54.
Bertaina
A
,
Merli
P
,
Rutella
S
, et al
.
HLA-haploidentical stem cell transplantation after removal of αβ+ T and B cells in children with nonmalignant disorders
.
Blood
.
2014
;
124
(
5
):
822
-
826
.
55.
Shah
RM
,
Elfeky
R
,
Nademi
Z
, et al
.
T-cell receptor alphabeta(+) and CD19(+) cell-depleted haploidentical and mismatched hematopoietic stem cell transplantation in primary immune deficiency
.
J Allergy Clin Immunol
.
2018
;
141
(
4
):
1417
-
1426.e1
.
56.
Prunotto
G
,
Offor
UT
,
Samarasinghe
S
, et al
.
HSCT provides effective treatment for lymphoproliferative disorders in children with primary immunodeficiency [published online ahead of print 1 May 2020]
.
J Allergy Clin Immunol
.
doi:10.1016/j.jaci.2020.03.043
.
57.
Fox
TA
,
Chakraverty
R
,
Burns
S
, et al
.
Successful outcome following allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency
.
Blood
.
2018
;
131
(
8
):
917
-
931
.
58.
Morris
EC
,
Albert
MH
.
Allogeneic HSCT in adolescents and young adults with primary immunodeficiencies
.
Front Pediatr
.
2019
;
7
:
437
.
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