Autoimmunity Reviews 6 (2007) 482 – 487

www.elsevier.com/locate/autrev

B cells in rheumatoid arthritis

Serena Bugatti, Veronica Codullo, Roberto Caporali, Carlomaurizio Montecucco ⁎
Chair and Division of Rheumatology, University of Pavia, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy
Received 16 December 2006; accepted 19 February 2007
Available online 16 March 2007

Abstract

Though its etiology remains unknown thus far, the role that autoimmune processes play in rheumatoid arthritis (RA)
pathogenesis has been widely proven. Given the easier accessibility of humoral components, the first feature of this contribution
to be recognized has been the occurrence of the so-called rheumatoid factor in a large proportion of RA patients. This antibody
recognizes the Fc portion of human IgG. By investigating RA pathologic processes and also through experimental models
where immune complexes play a fundamental role, many other autoantibodies have then come to our knowledge to be
associated with the disease. Their presence and persistence implies that clones of autoreactive B cells survive and proliferate in
RA patients under a continuous stimulation. Whether this is a mechanism of disease initiation or just an epiphenomenon is still
unclear but no doubt exists that autoantibodies represent a very useful tool in both diagnostic and prognostic terms. Being much
more than simple autoantibody producers, B cells are able to secrete many important cytokines and to efficiently present
antigens to T lymphocytes in the synovial environment. All of these functions are essential in the development of RA, and lately
have claimed attention as B cell depletion has become a common and effective strategy of treatment in RA.
© 2007 Elsevier B.V. All rights reserved.

Keywords: Rheumatoid arthritis; B lymphocytes; Autoantibodies; Lymphoid neogenesis

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
2. Autoantibody production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
2.1. Main autoantibody systems: genesis of RF and aCP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
2.2. Diagnostic and prognostic implications of RF and aCP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484
3. Autoantibody-independent role of B cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484
3.1. Tissue architecture of synovial B cells in RA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484
3.2. B cell activation and GC reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484
3.3. B cell-dependent T cell activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
3.4. B cells and cytokine production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
3.5. B cells and ectopic lymphoid neogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
4. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486

⁎ Corresponding author. Rheumatology, Chair and Division of Rheumatology, University of Pavia, IRCCS Fondazione Policlinico San Matteo,
Piazzale Golgi 2, 27100 Pavia, Italy. Tel.: +39 0 382 501878; fax: +39 0 382 503171.
E-mail address: montecucco@smatteo.pv.it (C. Montecucco).

1568-9972/$ - see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.autrev.2007.02.008
 S. Bugatti et al. / Autoimmunity Reviews 6 (2007) 482–487
Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .486
1. Introduction
Rheumatoid Arthritis (RA) is a chronic disorder that
mainly targets the synovial membrane of diarthrodial
joints but that can also have systemic manifestations [1].
Although considered for a long time a T cell/macrophage-
driven pathology, introduction of efficacious B cell-
targeted therapies with the use of an anti-CD20 monoclo-
nal antibody (Rituximab) [2] has re-opened the question of
B cell relevance in RA pathogenesis. Also thanks to
new acquisitions in both autoantibody-related and auto-
antibody-independent fields of research.
2. Autoantibody production
Many alterations in the physiologic process of B cell
tolerance have been described in RA. Normally, B cells
bearing receptors reacting with self-components are
counterselected at tolerance checkpoints both in bone
marrow and in the periphery through pathways that involve
receptor editing, apoptosis induction and anergy. It has been
shown that RA patients display a defective B cell tolerance
in more than one of these mechanisms [3]. Elevated BLyS
levels are found in sera or in synovial fluid of patients with
RA and BLyS may promote the inappropriate survival of B
cell clones [4]. Synovial production by terminally
differentiated plasma cells of both rheumatoid factor(s)
(RF) and anti-citrullinated proteins (aCP) has been
described together with the demonstration of clonal
expansion, somatic mutation and affinity maturation in
ectopic synovial germinal center (GC)-like structures [5].
Indirect proof of the incongruous activation of B lym-
phocytes in RA and of a persistent B cell receptor (BCR)
engagement is also the occurrence of malignant trans-
formation as shown by an increased proportion of diffuse
large B cell lymphomas (DLBCLs) in RA patients. Though
the mechanisms are not clear and likely multiple, this
alteration is mediated predominantly by an increased oc-
currence of the non-GC subtype of DLBCLs emphasizing
the role of activated peripheral B cells [6]. Under these
circumstances, B cells are pulled to produce a variable set
of autoantibodies (autoAbs). Their detection up to years
before the disease onset as for RF and aCP again suggests
that alterations in the B cell compartment occur at an early
stage of RA development [3].
Accumulation of genetic susceptibility and environ-
mental factors is also necessary for mounting this self-
reacting response and many HLA association have been
483
.
recognized [7]. Moreover, a haplotype of the gene enco-
ding the citrullinating enzymes peptidylarginine deimi-
nase (PAD) 4 was shown to be linked to RA, though this
association is highly susceptible to ethnic differences [8].
Even if a strong contribution of autoAbs has been ele-
gantly demonstrated in the pathogenic mechanism of
experimental models, e.g. anti-collagen II antibodies and
aCP in collagen-induced arthritis and anti-glucose-6-
phosphate isomerase in the K/BxN model, their role is far
from clear in the human disease. Main concerns are that RA
develops also in subjects that never come to display any
autoAb reactivity and that some of these autoAbs are not
disease-specific [1,8].
2.1. Main autoantibody systems: genesis of RF and aCP
RF binds the Fc portion of human IgG. It is found in up
to 80% of RA patients but it is quite unspecific as it is
detected in other autoimmune diseases, systemic infections,
and in up to 10% of healthy subjects [9]. Nevertheless
many differences exist between RF in health and disease.
The former is an IgM produced by B1 cells as a “natural
antibody” and shows polyreactivity and low affinity. RA–
RF instead undergoes Ig-associated gene rearrangement
and isotype switching as consequence of affinity matura-
tion and somatic hypermutation that RA B lymphocytes
experience under Th and synovial fibroblasts supervision
[1]. The nature of its binding to IgG–Fc involves an un-
conventional part of the BCR leaving space for another
(auto)antigen to be internalized, processed and presented to
T cells [9]. In support of this hypothesis comes the ability of
RF +B cells to be efficient antigen-presenting cells (APCs)
[10] and the demonstration that chromatin-containing im-
mune complexes stimulate RF +B cells synergistically en-
gaging the BCR and the innate immunity Toll-like
receptors (TLRs) [11]. This last finding is of striking
interest because it underscores the fundamental contribu-
tion of innate immunity to activation of the adaptive re-
ponse in an autoimmune setting.
Citrullination is the critical step for the recognition of a
bunch of proteins (fibrin, vimentin, fibronectin, collagen
type II), highly expressed in the synovial environment
during inflammation, by a group of autoAbs that speci-
fically occur in RA and referred as aCP [8]. Anticitrulline
immunity has recently offered evidences for a very interes-
ting etiologic model integrating autoimmunity with genetic
(the HLA–DR shared epitope) and environmental (smoke)
risk factors for RA [12]. It has been also shown that early
484 S. Bugatti et al. / Autoimmunity Reviews 6 (2007) 482–487
during disease progression aCP undergo isotype switching.
Contemporarily IgM–aCP persist during follow-up indi-
cating that this autoimmune response is continuously
reactivated during the course of arthritis [13].
2.2. Diagnostic and prognostic implications of RF and aCP
Despite there is no current way in clinical practice to
distinguish between “natural” and RA-associated RF, the
latter has a well-recognized role as clinical marker. It is part
of the ACR criteria for RA and, in prognostic terms,
identifies RA patients with a more severe disease function-
ally and radiographically, which also more frequently
experience extra-articular manifestations [10,14].
ACP are very specific for RA. They are found with a
significantly higher prevalence in sera of patients who
will develop severe radiological damage. ACP + patients
with undifferentiated arthritis have a chance of 90% to
progress to full-blown RA within 3 years [15].
In light of the growing use of new therapeutic agents in
RA, these autoAbs have acquired further importance. In
return, the effect of biologic treatments, and particularly of
B cell depletion, expand chances to shed light into their
pathogenetic role [2]. Efficacy of Rituximab has firstly
been proven in RF +patients and shown to parallel a sub-
stantial and sustained reduction of IgM-, IgG-and IgA-RF
levels [16]. Also, as shown for Rituximab and anti-TNFα,
RF and aCP levels decrease in response to treatment but RF
reduction is more pronounced and persistent during long-
term therapy suggesting a different regulation of these two
autoAbs systems [17]. Moreover, it has recently been
demonstrated that high pre-treatment levels of IgA–RF are
associated with poor response rate to the TNF-inhibitors in
advanced RA refractory to DMARDs [18].
3. Autoantibody-independent role of B cells
3.1. Tissue architecture of synovial B cells in RA
The activation events taking place within the rheuma-
toid synovium are mainly dependent on local interactions
and cell–cell contacts, thus assigning to tissue micro-
architecture a critical importance in orchestrating immune
responses.
B cells are a significant although not constant pop-
ulation in RA synovium. Indeed, B cell infiltration is
scanty in samples lacking a defined level of organization of
immune cells (diffuse synovitis) [19]. As opposed, B cells
constitute a considerable fraction of the inflammatory
infiltrate in samples characterized by large and well-
organized mononuclear aggregates (follicular and follicu-
lar with GCs synovitis) [19]. Here, three different B cell
subsets can be distinguished: terminally differentiated
plasma cells that surround the follicles; mature CD20+ B
cells in close interaction with CD4 + T cells; activated B
cells that have a GC phenotype and proliferate in a network
of follicular dendritic cells (FDCs). The enrichment of B
cells in follicular structures is not synovial-specific, as it is
recognized in other compartments, such as the subchondral
bone marrow of involved joints [20] and the lungs [21].
Importantly, the progressive enlargement of T–B cell
aggregates is paralleled by the acquisition of secondary
lymphoid organ-like features (a process known as
lymphoid neogenesis), such as lymphocyte compart-
mentalization within distinct areas, the constitution of a
specialized vascular apparatus and, finally, the organi-
zation of FDC networks (Fig. 1) [19].
It is still unclear whether the above described subsets of
synovial immune organization and B cell infiltration
(diffuse, follicular and follicular with GCs) represent stable
variants of the disease that occur in different patients, or
rather reflect distinct stages and responses to therapy.
Recent data seem to exclude a clear relationship between
lymphocyte microarchitecture and disease activity [22].
However, the frequent occurrence of lymphoid neogenetic
lesions in association to tissue damage [20,21] together
with the finding of a decrease in lymphoid neogenetic
features in patients treated with anti-TNF agents achieving
clinical response [22] strongly support an association of
synovial B cell aggregation with disease severity.
3.2. B cell activation and GC reaction
The establishment of a lymphoid-like architecture
within the synovial lesions, with B cells in close
interaction with T cells, resident cells and possibly
FDCs, provides the microenvironment in which B cell
activation and post-recombination processes of the BCR
can occur. The analysis of the V-gene repertoire ex-
pressed in synovial B cells has demonstrated that in
the inflamed synovium, besides B cell activation and
oligoclonal expansion, a GC reaction can take place [5].
Different patterns of synovitis have been shown to
correlate with biomarkers for B cell activity. Tissues
containing GCs and B cell aggregates have the highest
levels of IgG transcription if compared to samples with
diffuse infiltration [23]. Furthermore, GC synovitis have
increased levels of a proliferation-inducing ligand
(APRIL), which is a close homolog to BLyS and acts as
a modulator of peripheral B cell homeostasis promoting B
cell survival and differentiation [23].
Of note, B cell activation in RA synovitis occurs both
through T cell-dependent mechanisms (CD40–CD40L
ligation) and T-independent pathways (BLyS, TLRs).
 S. Bugatti et al. / Autoimmunity Reviews 6 (2007) 482–487
Fig. 1. Lymphoid organization in RA synovium. Sections of RA
synovium with a follicular pattern of infiltrating immune cells are
immunostained for CD20 (A), CD3 (B), CD21 (C), CD138 (D), PNAd
(E) and CXCL13 (F) antigens. Large size aggregates are characterized by
a secondary lymphoid organ-like architecture, with a central area of
CD20+ B cell enrichment (A) surrounded by a peripheral area of CD3 +
T cells (B) and a centrally located CD21+ follicular dendritic cell network
(C). CD138 + terminally differentiated plasma cells are situated at the
edge of the follicle (D). The ectopic lymphoid aggregates in RA synovitis
also develop a PNAd + specialized vascular apparatus (high endothelium
venules) (E) and are characterized by the in situ expression of secondary
lymphoid organ chemokines such as CXCL13 (F).
3.3. B cell-dependent T cell activation
Besides the effects of synovial lymphoid microarchi-
tecture on B cell activation, the establishment of B–T cell
contacts within ectopic follicles also provides the milieu in
which B cells can exert their immune functions on other
cells. Indeed, B cells can act as efficient APCs to stimulate
Tcells and to allow optimal development of memory in the
CD4 + T-cell population. Compared with non-specific
uptake associated with professional APCs, selective
uptake of antigen by antigen-specific B cells is markedly
superior. RF + B cells, in particular, are believed to play an
important role in antigen presentation [11]. They can take
up antigen–Ig immune complexes via their membrane Ig
receptors, which have RF specificity. B cells then process
and present peptides from the antigen, and thus induce
both T cell activation and T cell help [11].
An elegant demonstration that T cell response in RA
synovitis is dependent on B cells and on the lymphoid
485
organization comes from studies by Takemura and co-
workers [24]. Treatment with a monoclonal anti-CD20
antibody in SCID mice transplanted with RA synovial
tissue with GC formation led to disruption of GCs, loss of
FDC networks and impairment of T cell activation, with
fall in the production of T cell-derived cytokines.
3.4. B cells and cytokine production
As compared with other immune cells, B cells have not
typically been considered to be a major source of cytokines.
However, several lines of evidence have now established
that B cells can also produce a wide spectrum of cytokines
under inflammatory conditions. Notably, peripheral blood
B cells from healthy subjects are a source of IL-6, TNF and
lymphotoxin (LT) upon BCR and CD40 engagement [25].
There is now evidence that B cells may also play a
regulatory function by modulating the production of IL-10,
which can suppress harmful immune responses by
regulating Th1/Th2 balance and directly dampening innate
cell-mediated inflammatory responses [26].
The possible contribution of B cells in IL-10
production has been also highlighted in human RA.
Indeed, cytokine profile analysis has revealed higher
levels of transcription of IL-10 in follicular synovitis
compared to the diffuse pattern [27].
3.5. B cells and ectopic lymphoid neogenesis
In RA synovial tissue B cells are the major source of
LT–β, one of the members of the TNF superfamily. This
cytokine plays an important role in normal lymphoid orga-
nogenesis, together with the chemokine CXCL13, which is
a strong B cell attractant. Indeed, these two molecules drive
the interactions between mesenchymal and hematopoietic
cells in the first stages of lymphoid organ formation. Bind-
ing of LT to its receptor induces the expression of adhesion
molecules and of lymphoid chemokines (CCL19, CCL21,
CXCL12 and CXCL13) that regulate lymphocyte homing
and compartmentalization in lymphoid tissues [28].
Similarly, transgenic expression of CXCL13 in non-lymp-
hoid tissues is sufficient to activate a sequence of events that
lead to B and T cell recruitment and segregation [29].
A reactivation of the developmental pathway driven by
LT–β and CXCL13 has been thought to act up-stream the
lymphoid neogenetic process in RA. Indeed, CXCL13 and
LT–β have emerged as the two most important indepen-
dent predictive factors in the formation of ectopic GCs in
RA in a multivariate analysis [30]. Furthermore, CXCL13
production and expression strongly associate with aggre-
gates of growing dimensions, its presence correlating in a
qualitative and quantitative fashion to synovial infiltrating
486 S. Bugatti et al. / Autoimmunity Reviews 6 (2007) 482–487
B cells [19]. The major cellular source of LT–β in synovial
lesions has been demonstrated to be represented by a
subset of mantle-zone B cells [30] while CXCL13 is
produced by different cell populations [30,31].
4. Concluding remarks
B cells functions are pleiotropic in RA. They contri-
bute to production of autoAbs, antigen presentation and
cytokine production. All these functions have been dis-
sected also through the analysis of the synovial tissue
microarchitecture where B cells can find a niche to con-
solidate their alternative activation pathways and effec-
tively collaborate with other resident and hemopoietic
cells. Specifically treating RA with B cell-directed ther-
apies thus means not just to deplete their compartment but
also to interfere with the complex network that B cell
establish with the other principal cell types known to be
involved in the pathogenetic processes of RA.
Take-home messages
• B cells in RA show many features of an altered state
of activation whose discovery has greatly contributed
to clarify the autoimmune background that leads to
development of the disease.
• Autoantibodies, and mainly rheumatoid factor(s) and
anti-citrullinated proteins, have been implicated in
some of RA pathogenic events but also are useful
biomarkers in diagnosis and prognosis and have
shown correlations with response to treatment.
• It is now established that B cells have many more func-
tions in RA than just producing autoantibodies. They are
also very potent antigen-presenting cells and play a
critical role in the activation of T cells. Furthermore, B
cells do not only respond to but also produce cytokines.
• The cross-talk between B cells and infiltrating and
resident cells in rheumatoid synovitis is guaranteed by
the establishment of a complex microarchitecture that
morphologically and functionally reproduces some
features of secondary lymphoid organs (a process
known as lymphoid neogenesis).
• B cells themselves contribute to the production of
factors that orchestrate synovial lymphoid neogen-
esis, such as lymphotoxin.
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Vaccination with selected synovial T cells in rheumatoid arthritis.

This pilot clinical study was undertaken to investigate the role of T cell vaccination in the induction of regulatory
immune responses in patients with rheumatoid arthritis (RA). Chen G. et. al. (Arthritis Rheum 2007; 56: 453-463).
Autologous synovial T cells were selected for pathologic relevance, rendered inactive by irradiation, and used for
vaccination. Fifteen patients received T cell vaccination via 6 subcutaneous inoculations over a period of 12
months. T cell vaccination led to induction of CD4+ Tregs and CD8+ cytotoxic T cells specific for T cell vaccine.
There was selective expansion of CD4+Vβ2+ Tregs that produced interleukin-10 (IL-10) and expressed a high
level of transcription factor FoxP3, which coincided with depletion of over-expressed BV14+ T cells in treated
patients. CD4+ IL-10-secreting Tregs induced by T cell vaccination were found to react specifically with peptides
derived from IL-2 receptor α-chain. The expression level of FoxP3 in CD4+ T cells and increased inhibitory
activity of CD4+CD25+ Tregs were significantly elevated following T cell vaccination. The observed regulatory
immune responses collectively correlated with clinical improvement in treated patients. These findings suggest that
T cell vaccination induces regulatory immune responses that are associated with improved clinical and laboratory
variables in RA patients.

Interleukin-6 and chemokines in the neuropsychiatric manifestations of systemic lupus erythematosus.

To define the cytokine and chemokine profile in cerebrospinal fluid (CSF) from patients with neuropsychiatric
systemic lupus erythematosus (NPSLE). Forty-two SLE patients who had been hospitalized because of NP
manifestations were studied. Fragoso-Loyo H. et. al. (Arthritis Rheum 2007; 56: 1242-50). Patients were evaluated
at hospitalization and 6 months later; a CSF sample was obtained at each evaluation. As controls, CSF from 6 SLE
patients with septic meningitis, 16 SLE patients with no history of NP manifestations (non-NPSLE), and 25
patients with non-autoimmune disease were also studied. Soluble molecules, including cytokines interleukin-2 (IL-
2), IL-4, IL-6, IL-10, TNFα, and IFNγ and chemokines (monocyte chemotactic protein 1 (MCP-1), RANTES, IL-
18, monokine induced by IFNγ (MIG), and interferon-γ-inducible 10-kd protein (IP-10), were measured with the
use of cytometric bead array kits. CSF levels of the following molecules were significantly increased in NPSLE
patients as compared with non-NPSLE and non-autoimmune diseases control patients, respectively: IL-6 (32.7 vs
3.0 and 2.96 pg/ml), IL-8 (102.8 vs 29.97 and 19.7 pg/ml), IP-10 (888.2 vs 329.7 [p not significant] and 133.6 pg/
ml). RANTES, MCP-1, were not significantly different and MIG (35.4 vs 11.4 and 3.5 pg/ml). Low levels of IL-2,
IL-4, IL-10 and TNFα were found in all groups. Six months later and in the absence of NP manifestations, all
elevated molecule levels except RANTES, in patients with NPSLE had decreased significantly, and no differences
were noted between the NPSLE and non-NPSLE groups. Thus, a CNS response composed of IL-6 and
chemokines, but not Th1/Th2 cytokines, is associated with NP manifestations in SLE patients.