Role of toll-like receptors in primary Sjögren’s syndrome with a special emphasis
on B-cell maturation within exocrine tissues
, Laëtitia Le Pottier
, Valérie Devauchelle
, Jacques-Olivier Pers
, Pierre Youinou
EA2216 Immunology & Pathology and IFR 148 ScinBioS, Université Européenne de Bretagne, Université de Brest, Brest, France
CHRU Morvan, Brest, France
Received 26 January 2012
Accepted 28 January 2012
Be they follicular cells within the germinal centers (GCs) or marginal zone (MZ), all naïve mature B
lymphocytes need tonic signaling to stay alive. We reasoned that the same holds true for those B
lymphocytes that proliferate in the salivary glands (SGs) of patients with primary Sjögren’s syndrome.
Based on B cell inﬁltration, 11 SGs and three tonsil samples were selected for further examination. Tissue
sections were stained using CD20 combined with CD10, CD21, CD27, CD38 or IgD. They were also laser-
microdissected for quantitative RT-PCR of transcription factors, GC-speciﬁc activation-induced cytidine
deaminase (AID) and TLR9. Some B cell aggregates proved to be real GCs according to their membrane
markers, whereas others were clusters of transitional type II B cells. These contained mRNAs for Notch-2
and Blimp-1, but not for Pax-5, Bcl-6 and AID. Unanticipated was the ﬁnding of mRNAs for TLR9 in these
clusters of MZ B-cells, but not in the real GCs. Not only do TLR9 deliver sufﬁciency of tonic signaling to
keep B cells alive, but they also confer autoreactive B cells with an MZ-like phenotype. Thus, TLRs might
be targets for forthcoming biotherapies.
Ó 2012 Elsevier Ltd. All rights reserved.
Autoimmune epithelitis , designated Sjögren’s syndrome
(SS), is hallmarked by a disruption of acinar and ductal structures,
the subsequent lymphocytic inﬁltration of lacrimal and salivary
glands (SGs) and their ensuing dryness . This presents alone as
primary SS, or associated with other connective tissue diseases as
secondary SS. Some controversy persists over which type of
lymphocytes prevails , borne out by the view, for years, that T
cells are competent in their own to initiate the syndrome . Since
then, B cells have attracted interest, since, beyond the production of
antibodies (Abs) they accomplish various tasks [5e7].
An approach to assigning these functions to B-cell subsets is to
analyze their ontogeny. Immature B cells exit the bone marrow,
settle in secondary lymphoid organs and progress through
sequencial stages. They are ﬁrst CD21
delineated as transitional type 1 B lymphocytes (BT1). Upon B cell
antigen (Ag) receptor (BCR) engagement, they undergo apoptosis,
while, in the absence of Ag, they escape negative selection, evolve to
BT2 cells, and turn CD21
. The ﬁrst step is
spontaneous, but further progression requires B cell-activating
factor of the TNF family (BAFF) binding to the third receptor (BR3)
on B lymphocytes . Autoreactive BT2 cells are ineffective, relative
to the remainder, in their ability to enter the follicles (FOs) where
their maturation is assisted by BAFF. The possibility thus arises that
autoreactive B cells, including those harboring the idiotype recog-
nized by the 9G4 monoclonal Ab (mAb), circumvent this checkpoint.
The fate of B cells is thus determined by the afﬁnity of their BCRs to
local Ags, prior to transcription factor (TF) commitment. A weak
signal favors expression of Notch-2 receptors, increases the density
of BR3, conﬁnes the cells to the marginal zone (MZ), suppresses Bcl-6
and activates IRF-4 .In contrast, should the afﬁnity be strong, BT2
cells migrate to the FO, where Bcl-6 is upregulated, Pax-5 brought
into play, and germinal centers (GCs) initiated. As a result, the
activation-induced cytidine deaminase (AID) gene is transcribed,
and promotes somatic mutations and recombinations. Simulta-
neously, BR3 expression diminishes, functional inhibition of Pax-5
permits maturation of plasma cells (PCs), alongside silencing Bcl-6,
and Blimp-1 supports their generation .
Given their propensity to be activated in the MZ, preventing
autoreactive B cells from colonizing this site is essential. Thus,
Corresponding author. Immunology & Pathology, Brest University Medical
School Hospital, 5 Av Foch, BP824, F29609 Brest, France. Tel.: þ33 298 22 33 84;
fax: þ33 298 22 38 47.
E-mail address: firstname.lastname@example.org (C. Jamin).
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Journal of Autoimmunity
journal homepage: www.elsevier.com/locate/jautimm
0896-8411/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
Journal of Autoimmunity 39 (2012) 69e76