b lymphocytes on the front line of autoimmunity

www.elsevier.com/locate/autrev

Autoimmunity Reviews 5

B lymphocytes on the front line of autoimmunity

Pierre Youinou *, Sophie Hillion, Christophe Jamin, Jacques-Olivier Pers,

Alain Saraux, Yves Renaudineau

Laboratory of Immunology, Brest University Medical School Hospital, BP824, F29609 Brest Cedex, France

Received 30 March 2005; accepted 6 June 2005

Available online 16 August 2005

Abstract

The paradigm that B cell response to self antigens (Ag) is promoted by antibodies (Ab) has become unsatisfactory.

Studies over the last decade have indeed revealed that B cells serve extraordinarily diverse functions within the immune

system other than Ab production. They normally play a role in the development in the regulation, as well as the activation of

lymphoid architecture, regulating dentritic cells and T cell subsets function through cytokine production. Receptor editing is

also essential in B cells and aids in preventing autoimmunity. Both abnormalities in the distribution of B cells subsets and

clinical benefit response to B cell depletion in autoimmune states illustrate their importance. Transgenic animal models have

demonstrated that sensitivity of B cells to Ag receptor cross-linking correlates to autoimmunity: negative signaling by CD5

and CD22 in maintaining tolerance through recruitment of phosphatase has thus been documented. In short, a new area has

been reached, whereby B lymphocytes return as a significant contributor to autoimmune disorders.

D 2005 Elsevier B.V. All rights reserved.

Keywords: B lymphocyte; Autoimmune disease; Dendritic cell; T lymphocyte; B cell antigen receptor; CD5

Contents

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1. Subpopulations of B lymphocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.1. Classification according to the expression of CD5 . . . . . . . . . . . . . . . . . . . . . .

1.2. B lymphocyte ontogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.3. Maturation of B cells in the germinal centers . . . . . . . . . . . . . . . . . . . . . . . . .

2. Various functions of B cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.1. Influence of B lymphocytes on neighboring cells . . . . . . . . . . . . . . . . . . . . . . .

2.2. B lymphocytes as antigen-presenting cells. . . . . . . . . . . . . . . . . . . . . . . . . . .

2.3. Polarized cytokine production by B cells . . . . . . . . . . . . . . . . . . . . . . . . . . .

1568-9972/$ - s

doi:10.1016/j.au

* Correspondi

E-mail addre

(2006) 215–221

ee front matter D 2005 Elsevier B.V. All rights reserved.

trev.2005.06.011

ng author. Tel.: +33 298 22 33 84; fax: +33 298 22 38 47.

ss: [email protected] (P. Youinou).

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P. Youinou et al. / Autoimmunity Reviews 5 (2006) 215–221216

3. The B cell tolerance and its breakdown . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.1. The BCR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.1.1. The Ag binds to the BCR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.1.2. Involvement in the tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.2. Coordinated and intricate mechanisms of self tolerance . . . . . . . . . . . . . . . . . . . .

3.2.1. Regulation of signaling thresholds. . . . . . . . . . . . . . . . . . . . . . . . . . .

3.2.2. Anergy in self-reactive B cells . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.2.3. Secondary changes in the BCR specificity . . . . . . . . . . . . . . . . . . . . . .

3.3. Tuning the response of the antigen receptor . . . . . . . . . . . . . . . . . . . . . . . . . .

3.3.1. The lipid raft (LR) model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.3.2. Cytokinic survival factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.3.3. Genetic regulation of CD5 expression . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . 220
Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

Nonorgan-specific autoimmune diseases, such as

systemic lupus erythematosus (SLE), rheumatoid arthri-

tis (RA), primary Sjogren’s syndrome (pSS) or systemic

sclerosis (SSc) are associated with humoral and cellular

abnormalities. Based on their predominance in SLE

kidneys, RA synovium and pSS exocrine glands, T

cells used to occupy central stage of these networks.

Considerable research has focused on disturbances in

this cell compartment [1], in such a way that connec-

tive tissue diseases (CTD) were ascribed to defective T

cell censorship. Meanwhile, B lymphocytes have re-

ceived limited support as candidate causal agents, their

effects were portrayed as the production of antibodies

(Ab). A host of autoAb have indeed been described [2],

of which some might be pathogenic.

There have, however, been major advances in the

parameters that influence the fate of autoreactive B

cells [3]. Consequently, several investigators made up

their mind to explain humoral abnormalities by their

intrinsic hyperactivity. CTD may thus arise from poly-

clonal B cell activation [4]. Characteristics suggestive

of breakdown of normal Ab regulation have even been

identified in the relatives of patients [5,6]. The propen-

sity for IgG production in the peripheral blood (PB) of

relatives is supported by the finding of enhanced pro-

duction in response to autoantigen (Ag).

Further complexity to autoimmunity was defined in

the B cell compartment. New subpopulations of B cells

must be delineated. Owing to recent insights into their

functions, it has became apparent that B cells accom-

plish various other tasks than the making of autoAb. B

cell tolerance and tolerance breakdown deserve to be

re-analyzed. Survival and selection of B lymphocytes

are determined by B cell Ag receptor (BCR) specific-

ity, but the signal transduction is tuned by co-receptors,

and downstream adjusted by protein tyrosine kinases

(PTK) and protein tyrosine phosphatases (PTP).

1. Subpopulations of B lymphocytes

1.1. Classification according to the expression of CD5

CD5 was shown to be a marker of a normal B lym-

phocyte subset [7]. An increased number of CD5-expres-

sing B cells has been reported in RA and pSS. Of note,

those pSS patients with monoclonal immunoglobulin

(Ig) had higher levels of CD5+ B cells than the remain-

der [8]. The CD5-expressing B lymphocytes are char-

acterized by the production of polyreactive autoAb,

and a propensity for malignant transformation. To

come full circle, leukemic cells can be induced to

release autoAb [9].

Still exists some controversy over their origins. The

activation view implies that the CD5+ B cells can be

generated from CD5�B cells [10], whereas the lineage

paradigm posits the existence of separate progenitors

for CD5+ and CD5�B cells [11]. A new nomenclature

for B cells has been launched that distinguishes B1

from B2 lymphocytes. The former encompass CD5+

B cells, whereas the latter account for the conven-

tional B cells. So have we proposed [7] that there may

be different reasons for B cells to express CD5. In this

respect, the B1 population has been subdivided into

Table 1

Mature B (Bm) lymphocyte subsets within germinal centers

Subpopulation IgD CD38 CD23 CD27

Bm1 (naıve) + � � �Bm2 (activated) + + + �Bm2V (germinal

center founder)

+ ++ + �

Bm3 (centroblast) � ++ � �Bm4 (centrocyte) � ++ � �Early Bm5 (antibody

or memory)

� + � �

Bm5 (antibody-

secreting cell)

� � � +

Complete absence of T cell infiltrates in MRL lpr/lpr mice homo

logous for the deletion JH/JH.

The IgM MRL/MpJ-Faslpr mice have a transgene encoding surface

immunoglobulins, but not permitting its secretion. They develop

nephritis characterized by cellular infiltration.

Refs [14–17].

P. Youinou et al. / Autoimmunity Reviews 5 (2006) 215–221 217

B1a and B1b subpopulations. B1b cells lack surface

CD5, but share other attributes of B1a cells.

1.2. B lymphocyte ontogenesis

B cells originate in the liver during foetal life and

in the bone-marrow (BM) after birth [11] where they

pass through a sequence of stages. The diversity of

the BCR repertoire results from the ordered rear-

rangement of the gene segments V, D and J of the

Ig heavy chain locus, and those of the gene segments

V and J of its light chain locus. Pro-B cells, once they

have productively rearranged their Ig genes, proceed

to the pre-B cell stage. These immature B lympho-

cytes emigrate to the periphery.

1.3. Maturation of B cells in the germinal centers

Those cells that have just reached secondary lym-

phoid organs (SLO) become transitional B lympho-

cytes. Only mature B lymphocytes enter the lymphoid

follicles (LF) to make up germinal centers (GC), and

participate in the immune response [12]. Subsequent

non-circulating B cells consist of marginal zone (MZ)

B cells and follicular B cells. Noteworthy is that,

within the MZ lymphocytes, subsets differentiate into

early Ab-forming cells, while others give rise to

GC with hypermutation and memory in response to

a T-dependent Ag [13]. Furthermore, they proliferate

within exocrine glands in murine pSS [14]. MZ lym-

phocytes would, therefore, be key in this disease. The

importance of the ongoing LF competition is supported

by ectopic GC at sites of inflammation in pSS, RA and

Hashimoto’s thyroiditis. AutoAb can even develop out-

side GC as recently established in the MRL lpr/lpr

mouse model of SLE [15].

IgD and CD38 have been useful in classifying de-

velopmental stages. Thus, 7 mature B (Bm) cell subpo-

pulations differ with respect to the expression of these

2 markers (Table 1). Naıve (IgD+ CD38�) Bm1, once

activated as (IgD+ CD38+) Bm2, differentiate into GC

founder (IgD+ CD38++) Bm2V, centroblasts Bm3 and

centrocytes (IgD� CD38++) Bm4 and terminate as

(IgD� CD38+), early Bm5 and (IgD� CD38�) ulti-

mate Bm5 cells, i.e. memory B cells which express

CD27 and plasma cells which do not. Their distribution

is skewed in autoimmune patients, with increased fre-

quencies of GC founder cells in pSS, and pre-germinal

-

GC and PC precursors in juvenile SLE. In contrast, the

number of memory B cells was reduced in pSS [16].

However, CD20+ CD38� B lymphocytes with defec-

tive proliferative responsiveness exist [17] in RA sy-

novial fluid.

2. Various functions of B cells

Studies using genetically modified MRL lpr/lpr

mice that lack B lymphocytes, revealed that nephritis

did not come up [18]. Spontaneous T cell activation

was inhibited in B-deficient mice, and there was no

lymphocytic infiltration. The same group [19] showed

that mice that had B cells with membrane but not

secreted Ig developed nephritis. Therefore, an essential

role for B lymphocytes may not be through autoAb. B

lymphocytes are, therefore, endowed with diverse

functions (Table 2).

2.1. Influence of B lymphocytes on neighboring cells

TNF-a, LT-a and LT-h are involved in initiating and

maintaining normal splenic architecture, as indicated

by the facts that LT-a, LT-h, TNF-a receptor-I and

TNF-a KO mice have abnormal splenic architecture.

Elegant studies are relevant to the role of B lympho-

cytes in dendritic cells (DC) ontogenesis in that they

showed that B cells induce the appearance of DC

through the expression of membrane LT-a. Such cells

Table 2

Functions of B cells, in addition to antibody production

1. Shaping of the splenic architecture: dendritic cells and T

lymphocytes.

2. Antigen presentation (in particular CD5-expressing and rheuma-

toid factor-making B cells).

3. Production of cytokines to trigger polarization of naıve T

lymphocytes into T helper (Th)1 or Th2.


are absent in the SLO of mice deprived of B lympho-

cytes [20].

2.2. B lymphocytes as antigen-presenting cells

In addition, B cells do function [21] as APC: an Ag-

specific B cell can take up, internalize, process and

present peptides to another cell. This would improve

T cell immunity, and amplify the final Ab response.

B1a cells are suitable to the membrane expression of

multispecific anti-self Ig, and therein appropriate to

stretch out self components to other B1, to B2 or to T

cells. Splenic B1a cells have behaved as potent APC

in that they induce 2-fold greater levels of lymph

mode T lymphocyte IFN-g release than B2 cells in

the NZBM2410 lupus mouse [22]. It has even been

claimed that B cells binding Ag/anti-Ag IgG/anti-IgG

Ab immune complexes via membrane RF present the

Ag [23]. This involves B lymphocyte synapses, and

aids in the generation of peptide-major histocompati-

bility complexes for T lymphocyte synapse formation

in a sort of relay race [24].

2.3. Polarized cytokine production by B cells

Cytokines have been implicated in disease activity

and the involvement of such and such organ. For

example, IL-10 is abundant in SLE. Given the ex-

pression of IL-10 receptors and their part in the

excessive cell function in SLE, dysregulation of B

cell activity could be independent of T cell help [25].

Such a cliche that there exists Th1 and Th2 has

been substantiated. These effector cells produce dis-

tinct spectra of cytokines compatible with the kind of

response required to particular Ag. Th1 cells secrete

IFN-g and IL-2, whereas Th2 cells produce IL-4, IL-5

and IL-6. An exciting issue is that recent studies prompt

that naıve B cells differentiate into B effector (Be)1 and

Be2 with different cytokine profiles [26].

3. The B cell tolerance and its breakdown

3.1. The BCR

3.1.1. The Ag binds to the BCR

The Ag encounter with the BCR is a checkpoint

for self tolerance. Recent work has brought about

new insights into the stoichiometry of its compo-

nents [27]. CD79a and CD79b are both necessary for

the BCR to proceed from the endoplasmic reticulum to

the cell surface, and their intra-cytoplasmic tails con-

tain immunoreceptor tyrosine-based activation motifs

(ITAM) which constitute docking sites for PTK. High-

affinity interactions between autoAg and membrane-

bound Ig result in apoptosis of immature B cells. The

ensuing affinity maturation for exoAg takes place in

the GC [28]: centroblasts undergo hypermutations, and

centrocytes emerge, either with low affinity cells that

endure apoptosis, or with high affinity for the Ag, with

cells that change into Ab forming cells. Activation with

Ag switches on a number of PTK, including Lyn and

btk which are src-family members, and syk which bears

homology to the T cell zeta-associated protein 70 [29].

3.1.2. Involvement in the tolerance

Contrasting advances have been described regard-

ing the positive selection of mature B lymphocytes by

autoAg. Recruitment of mature B cells into the recir-

culating pool is dependent on BCR engagement by

such autoAg [30]. Additional mechanisms of self tol-

erance in the periphery have led to silence mature B

cells that have dodged central tolerance. By down-

regulating BCR surface expression, leukemic B lym-

phocytes [31] still generate BCR-mediated survival

signals. Clearly, autoAg are involved, because most

of those targeted in SLE are clustered into apoptotic

bodies, and such an intracellular localization pre-

disposes for autoAb production [32].

3.2. Coordinated and intricate mechanisms of self

tolerance

3.2.1. Regulation of signaling thresholds

Co-receptors lift and lower the BCR threshold by

modulating the activation of molecules required for

transmitting a signal. The transduction machinery is

raised by CD19 and CD21, and dampened down by

CD22, CD72 and CD5. Ligation of CD5 results in


apoptosis of resting B cells, but not resting T cells [33],

while anti-CD5 extends the proliferative response of

activated B1a cells [34]. The CD32 receptors for the Fc

part of IgG is also involved in preventing the BCR

response. All these glycoproteins harbor ITAM and

immunoregulatory tyrosine-inhibiting motifs which

recruite PTP in order to reverse the effects of PTK,

viz SH2-containing protein tyrosine phosphatase

(SHP)-1 for CD5, and SH2-containing inositol poly-

phosphate 5-phosphatase for CD32.

This negative regulation is offset by commensurate

co-receptors, such as CD19 [35] that amplify the

signals. Enhancing the density of CD19 expression

renders B lymphocytes hyper-responsive to trans-

membrane signals and induce the production of

autoAb. As a result, modest increases in the expres-

sion or the effect of this complex may shift the

balance between tolerance and immunity to immunity.

So, patients with SSc overexpress CD19 by as few as

20% [36].

3.2.2. Anergy in self-reactive B cells

Tolerance is governed by BCR signaling thresh-

olds. Hippen et al [37] have demonstrated in double-

transgenic (Tg) mice (Fig. 1) that CD5 contributes to

maintain tolerance in anergic B cells: those B lym-

phocytes of mice Tg for anti-hen egg lysozyme

HEL-Ig TgmHEL Tg

DELETI

1

HEL-IgsHEL T

HEL-Ig TgsHEL TgCD5-/-3

Fig. 1. The anti-hen egg lysozyme (HEL) immunoglobulin (Ig) transgen

anergized if it is Tg for soluble (s) HEL, and activated if this anergy mod

(HEL) Ab and membrane HEL Ag undergo apoptosis

based on their robust activation. They rather become

anergic if the mice are Tg for soluble HEL, but this is

broken if B cell anergy is bred onto the CD5-KO

background.

3.2.3. Secondary changes in the BCR specificity

By altering the specificity of their BCR in the

BM, auto-reactive B cells may initiate new Ig light

chain rearrangements [38]. The system can thus get

rid of self-reactive BCR generated by recombination.

Those immature B cells that undergo receptor editing

transcribe recombinase-activating genes, RAG1 and

RAG2.

Nonetheless, Ag-receptor genes can be reactivated

in SLO. This is supported by secondary rearrange-

ments: for example, RAG1 and RAG2 may be re-

expressed in a subset of activated mature murine B

cells population within the GC. If, once re-expressed,

the RAG gene products are functional, an unfavorable

surface Ig receptor gains an additional chance to be

revised, and auto-reactive B cells arising by hypermu-

tations in the centroblast a chance to escape deletion.

The view that Ag receptor engagement turns off the

V(D)J recombination machinery in human tonsil B

cells for good, had since to be thoroughly re-visited

[39].

ON

Tgg ANERGY

2

RESPONSE

ic B cells are deleted if the mouse is Tg for membrane (m) HEL,

el is bred onto a CD5�/� mouse.

! The antigen encounter with the B cell receptor is an

essential check point.

! A potent cytokine is the B cell activating factor.

! B cell depletion has a role to play in the treatment of

autoimmune diseases.


3.3. Tuning the response of the antigen receptor

3.3.1. The lipid raft (LR) model

Following its engagement, the BCR, along with

proteins involved in signaling, partitions into LR of

the cell membrane [40]. One mechanism by which

CD19 and CD32 may modulate this process is to

prolong the BCR residency within the LR, or to

block the signal. This is strengthened by the report

that LR composition is altered in SLE, and our finding

that the BCR resides longer in the LR of pSS patients

than in normal controls.

3.3.2. Cytokinic survival factors

The fate of B cells is also controlled by survival

factors. One of the most potent of these cytokines is

BAFF. Its administration protects B lymphocytes from

apoptosis, and promotes CTD-specific autoAb pro-

duction. Furthermore, patients harbor elevated levels

of BAFF. They correlate with the titer of autoAb in

pSS [14].

3.3.3. Genetic regulation of CD5 expression

Wehave identified a novel regulatorymotif upstream

of the non-coding region of the cd5 gene: this was

termed E1B. Compared with the known exon 1, termed

E1A, it discloses a new level of CD5 regulation. The

E1B-containing transcripts encode a truncated protein

which is retained intracellularly. It follows that the

amount of E1A-containing transcripts is down-regula-

ted, and the protein membrane expression diminished.

Translocation of SHP-1 (which reduces the BCR sig-

nal) is prevented, and, thereby, activation of the cell.

B lymphocyte abnormalities irregularities are plenty

to be incorporated into the schemes. These data are in

the process of being translated into the clinic. At this

moment, it may be assumed that B lymphocyte deple-

tion from the pre-B to the mature B cell stages has a role

to play in the treatment.

Take-home messages

! Subpopulations of B lymphocytes have been

delineated.

! B cells serve a number of functions, in addition to

the antibody production.

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: prevalence and clinical significance.

of autoimmune disorders, most commonly systemic

in systemic sclerosis has been reported, most studies

little is known about other aPL in this disease. In the

4:1795-96), determined the prevalence and clinical

nti- B2GPI), and antibodies to phosphatidylserine-

derma. aPL were present in 8/25 patients. aCL were

n controls (24% vs 5%, odds ratio = 6[1.2-2.9], p =

een patients and controls. Interestingly, patients with

T more frequently than those without (37.5% vs 0%,

ence of all aPL was more common in patients with

linical manifestations of antiphospholipid syndrome

b lymphocytes on the front line of autoimmunity

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