• In patients with active HLH, B-cell development and maturation are impaired along with a decrease in cTfh cells.

  • Control of T-cell activation during an active HLH state improves cTfh cell frequency and B-cell maturation.

Hemophagocytic lymphohistiocytosis (HLH) is characterized by hyperinflammation and multiorgan dysfunction. Infections, including the reactivation of viruses, contribute to significant disease mortality in HLH. Although T-cell and natural killer cell–driven immune activation and dysregulation are well described, limited data exist on the status of B-cell compartment and humoral immune function in HLH. We noted marked suppression of early B-cell development in patients with active HLH. In vitro B-cell differentiation studies after exposure to HLH-defining cytokines, such as interferon gamma (IFN-γ) and tumor necrosis factor, recapitulated B-cell development arrest. Messenger RNA sequencing of human CD34+ cells exposed to IFN-γ demonstrated changes in genes and pathways affecting B-cell development and maturation. In addition, patients with active HLH exhibited a marked decrease in class-switched memory B (CSMB) cells and a decrease in bone marrow plasmablast/plasma cell compartments. The decrease in CSMB cells was associated with a decrease in circulating T follicular helper (cTfh) cells. Finally, lymph node and spleen evaluation in a patient with HLH revealed absent germinal center formation and hemophagocytosis with associated lymphopenia. Reassuringly, the frequency of CSMB and cTfh improved with the control of T-cell activation. Taken together, in patients with active HLH, these changes in B cells may affect the humoral immune response; however, further immune studies are needed to determine its clinical significance.

1.
Ishii
E
.
Hemophagocytic lymphohistiocytosis in children: pathogenesis and treatment
.
Front Pediatr
.
2016
;
4
:
47
.
2.
Filipovich
AH
,
Chandrakasan
S
.
Pathogenesis of hemophagocytic lymphohistiocytosis
.
Hematol Oncol Clin North Am
.
2015
;
29
(
5
):
895
-
902
.
3.
Marsh
RA
,
Madden
L
,
Kitchen
BJ
, et al
.
XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease
.
Blood
.
2010
;
116
(
7
):
1079
-
1082
.
4.
Romberg
N
,
Vogel
TP
,
Canna
SW
.
NLRC4 inflammasomopathies
.
Curr Opin Allergy Clin Immunol
.
2017
;
17
(
6
):
398
-
404
.
5.
Jordan
MB
,
Hildeman
D
,
Kappler
J
,
Marrack
P
.
An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder
.
Blood
.
2004
;
104
(
3
):
735
-
743
.
6.
Das
R
,
Guan
P
,
Sprague
L
, et al
.
Janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis
.
Blood
.
2016
;
127
(
13
):
1666
-
1675
.
7.
Albeituni
S
,
Verbist
KC
,
Tedrick
PE
, et al
.
Mechanisms of action of ruxolitinib in murine models of hemophagocytic lymphohistiocytosis
.
Blood
.
2019
;
134
(
2
):
147
-
159
.
8.
Locatelli
F
,
Jordan
MB
,
Allen
C
, et al
.
Emapalumab in children with primary hemophagocytic lymphohistiocytosis
.
N Engl J Med
.
2020
;
382
(
19
):
1811
-
1822
.
9.
De Benedetti
F
,
Grom
A
,
Brogan
P
, et al
.
Efficacy and safety of emapalumab in macrophage activation syndrome
.
Ann Rheum Dis
.
2023
;
82
(
6
):
857
-
865
.
10.
Keenan
C
,
Nichols
KE
,
Albeituni
S
.
Use of the JAK inhibitor ruxolitinib in the treatment of hemophagocytic lymphohistiocytosis
.
Front Immunol
.
2021
;
12
:
614704
.
11.
Pagel
J
,
Beutel
K
,
Lehmberg
K
, et al
.
Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5)
.
Blood
.
2012
;
119
(
25
):
6016
-
6024
.
12.
Meeths
M
,
Entesarian
M
,
Al-Herz
W
, et al
.
Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2
.
Blood
.
2010
;
116
(
15
):
2635
-
2643
.
13.
Rohr
J
,
Beutel
K
,
Maul-Pavicic
A
, et al
.
Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases
.
Haematologica
.
2010
;
95
(
12
):
2080
-
2087
.
14.
Esmaeilzadeh
H
,
Bemanian
MH
,
Nabavi
M
, et al
.
Novel patient with late-onset familial hemophagocytic lymphohistiocytosis with STXBP2 mutations presenting with autoimmune hepatitis, neurological manifestations and infections associated with hypogammaglobulinemia
.
J Clin Immunol
.
2015
;
35
(
1
):
22
-
25
.
15.
Pachlopnik Schmid
J
,
Canioni
D
,
Moshous
D
, et al
.
Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency)
.
Blood
.
2011
;
117
(
5
):
1522
-
1529
.
16.
Pieper
K
,
Grimbacher
B
,
Eibel
H
.
B-cell biology and development
.
J Allergy Clin Immunol
.
2013
;
131
(
4
):
959
-
971
.
17.
Lounder
DT
,
Bin
Q
,
de Min
C
,
Jordan
MB
.
Treatment of refractory hemophagocytic lymphohistiocytosis with emapalumab despite severe concurrent infections
.
Blood Adv
.
2019
;
3
(
1
):
47
-
50
.
18.
LeBien
TW
,
Tedder
TF
.
B lymphocytes: how they develop and function
.
Blood
.
2008
;
112
(
5
):
1570
-
1580
.
19.
Miosge
LA
,
Goodnow
CC
.
Genes, pathways and checkpoints in lymphocyte development and homeostasis
.
Immunol Cell Biol
.
2005
;
83
(
4
):
318
-
335
.
20.
Carulli
G
,
Ottaviano
V
,
Guerri
V
, et al
.
Multiparameter flow cytometry to detect hematogones and to assess B-lymphocyte clonality in bone marrow samples from patients with non-Hodgkin lymphomas
.
Hematol Rep
.
2014
;
6
(
2
):
5381
.
21.
McKenna
RW
,
Washington
LT
,
Aquino
DB
,
Picker
LJ
,
Kroft
SH
.
Immunophenotypic analysis of hematogones (B-lymphocyte precursors) in 662 consecutive bone marrow specimens by 4-color flow cytometry
.
Blood
.
2001
;
98
(
8
):
2498
-
2507
.
22.
Sanz
I
,
Wei
C
,
Jenks
SA
, et al
.
Challenges and opportunities for consistent classification of human B cell and plasma cell populations
.
Front Immunol
.
2019
;
10
:
2458
.
23.
Corcione
A
,
Benvenuto
F
,
Ferretti
E
, et al
.
Human mesenchymal stem cells modulate B-cell functions
.
Blood
.
2006
;
107
(
1
):
367
-
372
.
24.
Ravelli
A
,
Minoia
F
,
Davi
S
, et al
.
2016 classification criteria for macrophage activation syndrome complicating systemic Juvenile idiopathic arthritis: a European League against rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative
.
Ann Rheum Dis
.
2016
;
75
(
3
):
481
-
489
.
25.
Henter
JI
,
Horne
A
,
Arico
M
, et al
.
HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis
.
Pediatr Blood Cancer
.
2007
;
48
(
2
):
124
-
131
.
26.
Chantepie
SP
,
Cornet
E
,
Salaun
V
,
Reman
O
.
Hematogones: an overview
.
Leuk Res
.
2013
;
37
(
11
):
1404
-
1411
.
27.
Roy
S
,
Guler
R
,
Parihar
SP
, et al
.
Batf2/Irf1 induces inflammatory responses in classically activated macrophages, lipopolysaccharides, and mycobacterial infection
.
J Immunol
.
2015
;
194
(
12
):
6035
-
6044
.
28.
Liu
M
,
Guo
S
,
Hibbert
JM
, et al
.
CXCL10/IP-10 in infectious diseases pathogenesis and potential therapeutic implications
.
Cytokine Growth Factor Rev
.
2011
;
22
(
3
):
121
-
130
.
29.
Honkala
AT
,
Tailor
D
,
Malhotra
SV
.
Guanylate-binding protein 1: an emerging target in inflammation and cancer
.
Front Immunol
.
2019
;
10
:
3139
.
30.
Farrar
MA
,
Schreiber
RD
.
The molecular cell biology of interferon-gamma and its receptor
.
Annu Rev Immunol
.
1993
;
11
:
571
-
611
.
31.
Halloran
PF
,
Miller
LW
,
Urmson
J
, et al
.
IFN-gamma alters the pathology of graft rejection: protection from early necrosis
.
J Immunol
.
2001
;
166
(
12
):
7072
-
7081
.
32.
Havenar-Daughton
C
,
Lindqvist
M
,
Heit
A
, et al
.
CXCL13 is a plasma biomarker of germinal center activity
.
Proc Natl Acad Sci U S A
.
2016
;
113
(
10
):
2702
-
2707
.
33.
Kumar
D
,
Rostad
CA
,
Jaggi
P
, et al
.
Distinguishing immune activation and inflammatory signatures of multisystem inflammatory syndrome in children (MIS-C) versus hemophagocytic lymphohistiocytosis (HLH)
.
J Allergy Clin Immunol
.
2022
;
149
(
5
):
1592
-
1606.e16
.
34.
Weiss
ES
,
Girard-Guyonvarc'h
C
,
Holzinger
D
, et al
.
Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome
.
Blood
.
2018
;
131
(
13
):
1442
-
1455
.
35.
Papadaki
HA
,
Kritikos
HD
,
Gemetzi
C
, et al
.
Bone marrow progenitor cell reserve and function and stromal cell function are defective in rheumatoid arthritis: evidence for a tumor necrosis factor alpha-mediated effect
.
Blood
.
2002
;
99
(
5
):
1610
-
1619
.
36.
Baratono
SR
,
Chu
N
,
Richman
LP
,
Behrens
EM
.
Toll-like receptor 9 and interferon-gamma receptor signaling suppress the B-cell fate of uncommitted progenitors in mice
.
Eur J Immunol
.
2015
;
45
(
5
):
1313
-
1325
.
37.
Yamada
G
,
Ogawa
M
,
Akagi
K
, et al
.
Specific depletion of the B-cell population induced by aberrant expression of human interferon regulatory factor 1 gene in transgenic mice
.
Proc Natl Acad Sci U S A
.
1991
;
88
(
2
):
532
-
536
.
38.
Young
HA
,
Klinman
DM
,
Reynolds
DA
, et al
.
Bone marrow and thymus expression of interferon-gamma results in severe B-cell lineage reduction, T-cell lineage alterations, and hematopoietic progenitor deficiencies
.
Blood
.
1997
;
89
(
2
):
583
-
595
.
39.
Popescu
M
,
Cabrera-Martinez
B
,
Winslow
GM
.
TNF-alpha contributes to lymphoid tissue disorganization and germinal center B cell suppression during intracellular bacterial infection
.
J Immunol
.
2019
;
203
(
9
):
2415
-
2424
.
40.
Borte
S
,
Meeths
M
,
Liebscher
I
, et al
.
Combined newborn screening for familial hemophagocytic lymphohistiocytosis and severe T- and B-cell immunodeficiencies
.
J Allergy Clin Immunol
.
2014
;
134
(
1
):
226
-
228
.
41.
Tesi
B
,
Davidsson
J
,
Voss
M
, et al
.
Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms
.
Blood
.
2017
;
129
(
16
):
2266
-
2279
.
42.
Allenspach
EJ
,
Soveg
F
,
Finn
LS
, et al
.
Germline SAMD9L truncation variants trigger global translational repression
.
J Exp Med
.
2021
;
218
(
5
):
e20201195
.
43.
Zhang
M
,
Yao
C
,
Cai
J
, et al
.
LRRK2 is involved in the pathogenesis of system lupus erythematosus through promoting pathogenic antibody production
.
J Transl Med
.
2019
;
17
(
1
):
37
.
44.
Allende
ML
,
Tuymetova
G
,
Lee
BG
,
Bonifacino
E
,
Wu
YP
,
Proia
RL
.
S1P1 receptor directs the release of immature B cells from bone marrow into blood
.
J Exp Med
.
2010
;
207
(
5
):
1113
-
1124
.
45.
Landreth
KS
,
Narayanan
R
,
Dorshkind
K
.
Insulin-like growth factor-I regulates pro-B cell differentiation
.
Blood
.
1992
;
80
(
5
):
1207
-
1212
.
46.
Clutter
SD
,
Fortney
J
,
Gibson
LF
.
MMP-2 is required for bone marrow stromal cell support of pro-B-cell chemotaxis
.
Exp Hematol
.
2005
;
33
(
10
):
1192
-
1200
.
47.
Gatto
D
,
Brink
R
.
B cell localization: regulation by EBI2 and its oxysterol ligand
.
Trends Immunol
.
2013
;
34
(
7
):
336
-
341
.
48.
Gatto
D
,
Paus
D
,
Basten
A
,
Mackay
CR
,
Brink
R
.
Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses
.
Immunity
.
2009
;
31
(
2
):
259
-
269
.
49.
Moir
S
,
Buckner
CM
,
Ho
J
, et al
.
B cells in early and chronic HIV infection: evidence for preservation of immune function associated with early initiation of antiretroviral therapy
.
Blood
.
2010
;
116
(
25
):
5571
-
5579
.
50.
Moir
S
,
Fauci
AS
.
Pathogenic mechanisms of B-lymphocyte dysfunction in HIV disease
.
J Allergy Clin Immunol
.
2008
;
122
(
1
):
12
-
19
. quiz 20-11.
51.
Tipton
TRW
,
Hall
Y
,
Bore
JA
, et al
.
Characterisation of the T-cell response to Ebola virus glycoprotein amongst survivors of the 2013-16 West Africa epidemic
.
Nat Commun
.
2021
;
12
(
1
):
1153
.
52.
Winslow
GM
,
Cooper
A
,
Reiley
W
,
Chatterjee
M
,
Woodland
DL
.
Early T-cell responses in tuberculosis immunity
.
Immunol Rev
.
2008
;
225
:
284
-
299
.
53.
Turka
LA
,
Linsley
PS
,
Lin
H
, et al
.
T-cell activation by the CD28 ligand B7 is required for cardiac allograft rejection in vivo
.
Proc Natl Acad Sci U S A
.
1992
;
89
(
22
):
11102
-
11105
.
54.
Merli
P
,
Caruana
I
,
De Vito
R
, et al
.
Role of interferon-gamma in immune-mediated graft failure after allogeneic hematopoietic stem cell transplantation
.
Haematologica
.
2019
;
104
(
11
):
2314
-
2323
.
55.
Vinuesa
CG
,
Linterman
MA
,
Yu
D
,
MacLennan
IC
.
Follicular helper T cells
.
Annu Rev Immunol
.
2016
;
34
:
335
-
368
.
56.
Breitfeld
D
,
Ohl
L
,
Kremmer
E
, et al
.
Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production
.
J Exp Med
.
2000
;
192
(
11
):
1545
-
1552
.
57.
Wong
CK
,
Wong
PT
,
Tam
LS
,
Li
EK
,
Chen
DP
,
Lam
CW
.
Elevated production of B cell chemokine CXCL13 is correlated with systemic lupus erythematosus disease activity
.
J Clin Immunol
.
2010
;
30
(
1
):
45
-
52
.
58.
Moura
RA
,
Fonseca
JE
.
JAK inhibitors and modulation of B cell immune responses in rheumatoid arthritis
.
Front Med (Lausanne)
.
2020
;
7
:
607725
.
59.
Gabr
JB
,
Liu
E
,
Mian
S
, et al
.
Successful treatment of secondary macrophage activation syndrome with emapalumab in a patient with newly diagnosed adult-onset Still's disease: case report and review of the literature
.
Ann Transl Med
.
2020
;
8
(
14
):
887
.
60.
Lo
MS
,
Zurakowski
D
,
Son
MB
,
Sundel
RP
.
Hypergammaglobulinemia in the pediatric population as a marker for underlying autoimmune disease: a retrospective cohort study
.
Pediatr Rheumatol Online J
.
2013
;
11
(
1
):
42
.
61.
Granata
G
,
Didona
D
,
Stifano
G
,
Feola
A
,
Granata
M
.
Macrophage activation syndrome as onset of systemic lupus erythematosus: a case report and a review of the literature
.
Case Rep Med
.
2015
;
2015
:
294041
.
62.
Calame
KL
.
Plasma cells: finding new light at the end of B cell development
.
Nat Immunol
.
2001
;
2
(
12
):
1103
-
1108
.
63.
Nguyen
DC
,
Joyner
CJ
,
Sanz
I
,
Lee
FE
.
Factors affecting early antibody secreting cell maturation into long-lived plasma cells
.
Front Immunol
.
2019
;
10
:
2138
.
64.
Fairfax
KA
,
Kallies
A
,
Nutt
SL
,
Tarlinton
DM
.
Plasma cell development: from B-cell subsets to long-term survival niches
.
Semin Immunol
.
2008
;
20
(
1
):
49
-
58
.
65.
de Benedetti
F
,
Massa
M
,
Robbioni
P
,
Ravelli
A
,
Burgio
GR
,
Martini
A
.
Correlation of serum interleukin-6 levels with joint involvement and thrombocytosis in systemic juvenile rheumatoid arthritis
.
Arthritis Rheum
.
1991
;
34
(
9
):
1158
-
1163
.
66.
Choy
EH
,
De Benedetti
F
,
Takeuchi
T
,
Hashizume
M
,
John
MR
,
Kishimoto
T
.
Translating IL-6 biology into effective treatments
.
Nat Rev Rheumatol
.
2020
;
16
(
6
):
335
-
345
.
67.
Enoksson
SL
,
Grasset
EK
,
Hagglof
T
, et al
.
The inflammatory cytokine IL-18 induces self-reactive innate antibody responses regulated by natural killer T cells
.
Proc Natl Acad Sci U S A
.
2011
;
108
(
51
):
E1399
-
1407
.
68.
Jego
G
,
Bataille
R
,
Pellat-Deceunynck
C
.
Interleukin-6 is a growth factor for nonmalignant human plasmablasts
.
Blood
.
2001
;
97
(
6
):
1817
-
1822
.
69.
Toubiana
J
,
Okada
S
,
Hiller
J
, et al
.
Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype
.
Blood
.
2016
;
127
(
25
):
3154
-
3164
.
70.
Chandrakasan
S
,
Chandra
S
,
Davila Saldana
BJ
,
Torgerson
TR
,
Buchbinder
D
.
Primary immune regulatory disorders for the pediatric hematologist and oncologist: a case-based review
.
Pediatr Blood Cancer
.
2019
;
66
(
5
):
e27619
.
71.
Kumar
D
,
Prince
C
,
Bennett
CM
, et al
.
T-follicular helper cell expansion and chronic T-cell activation are characteristic immune anomalies in Evans syndrome
.
Blood
.
2022
;
139
(
3
):
369
-
383
.
You do not currently have access to this content.
Sign in via your Institution