Review
Int Arch Allergy Immunol 2000;122:8–19
The Immune Response in Adenoids
and Tonsils
M.J.P. van Kempen a G.T. Rijkers b P.B. Van Cauwenberge a
a Department of Otorhinolaryngology, University Hospital of Ghent, Belgium;
b Department of Immunology, University Hospital for Children and Youth, Utrecht, The Netherlands
Key Words
Immune response W Tonsil W M-cell W Dendritic cell W
CD40/CD40L
Abstract
The adenoid and tonsils are lymphoid tissues located in
the pharynx that play an important role in host defense
against invading antigens of the upper respiratory tract.
Histologically, these structures consist of four well-
defined microcompartments which all participate in the
immune response: the cryptepithelium, the follicular ger-
minal center with the mantle zone and interfollicular
area. With the uptake of antigen by M-cells present in the
cryptepithelium a process is initiated which ultimately
results in the generation and dissemination of antigen-
specific memory and mainly dimeric IgA-producing ef-
fector B-lymphocytes. This process requires successful
cognate interactions between antigen-presenting cells
and lymphocytes and mutually between lymphocytes,
which depend not only on antigen-specific signals but
also on the expression of various complementary adhe-
sion and costimulatory molecules.
Copyright © 2000 S. Karger AG, Basel
© 2000 S. Karger AG, Basel
ABC 1018–2438/00/1221–0008$17.50/0
Fax + 41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/journals/iaa
Mucosa-Associated Lymphoid Tissue
Every breath we take and every swallow contains anti-
genic material. Although many inhaled or ingested anti-
gens are harmless, a significant portion will include a
potential danger, requiring the generation of rapid and
effective protective immune responses. Therefore, the
mucous membranes have developed an immune system
which differs anatomically and functionally from that of
the spleen and lymph nodes. This mucosal immune sys-
tem (mucosa-associated lymphoid tissue; MALT) consists
of lymphoid tissues that populate the internal surfaces of
the body, namely the upper and lower respiratory tract
(NALT, BALT), the gastrointestinal (GALT) and urogeni-
tal tract. In addition, it may include exocrine secretory
sites that are linked to these organs, such as the salivary
and lacrimal glands. The main function of these structures
is to sample antigens, have them surveyed locally by
immune cells in order to destroy them and generate effec-
tor and memory lymphocytes which can migrate to other
mucosal sites.
Nasopharyngeal-Associated Lymphoid Tissue
The lymphoid structures belonging to the NALT are
arranged in a specific circular orientation around the wall
of the throat, called Waldeyer’s ring (fig. 1). This ring con-
Correspondence to: Dr. M. van Kempen
Department of Otorhinolaryngology, University Hospital of Ghent
De Pintelaan 185
B–9000 Ghent (Belgium)
Tel. +32 9 240 23 32, Fax +32 9 240 49 93
Fig. 1. Schematic representation of Wal-
deyer’s ring. Adapted from Perry and Whyte
[5].
sists of the nasopharyngeal tonsil – or adenoid – attached
to the posterior wall of the pharynx, the paired tubal ton-
sils, situated at the pharyngeal ostia of the Eustachian
tubes, the paired palatine tonsils (PT) positioned in the
oropharynx and the lingual tonsil in the glosso-epiglottic
space. Various studies have demonstrated that these
structures are indeed engaged in antibody responses to
viral and bacterial pathogens that have a tropism to the
naso- or oropharynx, like respiratory syncytial virus
(RSV), Streptococcus pneumoniae, Haemophilus influen-
zae and ß-hemolytic streptococci [1, 2]. In an elegant
study on 27 individuals undergoing a tonsillectomy,
Quiding-Järbrink et al. [3] showed that preoperative in-
tranasal and intratonsillar vaccination with cholera toxin
induced a considerable vaccine-specific antibody secret-
ing cell response in adenoids and PTs while parenteral
immunization failed to evoke any tonsillar response. This
local B-cell response consisted of IgG- and IgA-type anti-
bodies and was followed by a systemic vaccine-specific
antibody response. Moreover, a second intratonsillar im-
munization evoked a larger vaccine-specific antibody-
secreting cell response in the previously primed tonsil.
These observations clearly demonstrate the capacity of
PTs and adenoids to serve as an inductive site for local
and distant antibody responses and to generate an immu-
nological memory independent of the systemic immune
system. The importance of the NALT is further illustrated
by reduced specific IgA antibody titers detected in naso-
pharyngeal secretions following tonsillectomy and ade-
noidectomy in children previously immunized with oral
live polio virus vaccine [4].
The Immune Response in Adenoids and
Tonsils
In order to better understand the generation of these
immune responses, we will review the immunological
characteristics of the adenoids and PTs.
Histological Features
In contrast to the spleen and lymph nodes, which
depend on antigenic delivery through afferent lymphatics,
both the anatomical localization and the histological orga-
nization of tonsils are particularly suited for the capture of
foreign material from epithelial surfaces. Macroscopical-
ly, the tonsillar surface is characterized by various narrow
epithelial channels, called crypts, which penetrate deep
into the underlying lymphoid tissue. These crypts consid-
erably increase the tonsillar surface area. While the oro-
pharyngeal surface of adult PTs is covered by approxi-
mately 45 cm2 of epithelium, the cryptoepithelial area is
about 4–5 times larger [5]. Crypts are also designed for
entrapping foreign material. The epithelium lining the
crypts differs from that mainly overlying the nasopharyn-
geal and palatine tonsils. Whereas a ciliated respiratory
and stratified squamous epithelium protects the adenoid
and PT, respectively, a nonuniform epithelium covers the
crypts. It is in this crypt- or lympho-epithelium that the
immune response is initiated.
In addition to the crypt epithelium, three other histo-
logically well-defined microcompartments can be distin-
guished that all participate in the immune response. Par-
allel to the crypt epithelium, numerous rounded aggre-
gates of mainly B-lymphocytes also called follicular ger-
minal centers can be found each surrounded by a crown-
Int Arch Allergy Immunol 2000;122:8–19 9
Fig. 2. Photomicrograph of the morphology
of the palatine tonsil. An immunohisto-
chemical stain for cytokeratin highlights the
cryptepithelium (red). Parallel to the crypt-
epithelium are aggregates of B-cell follicles,
each with its mantle zone facing the crypt.
T-cell areas are found between the follicles.
shaped mantle zone of dense, small lymphocytes and in-
between interfollicular areas which are predominantly
populated by T-lymphocytes (fig. 2).
Immunological Features of the
Microcompartments
The Lymphoepithelium
The lymphoepithelium consists not only of epithelial
cells but also of nonepithelial cells like lymphocytes, mac-
rophages and dendritic cells [6]. Approximately 50% of
the intraepithelial lymphocytes are immunoglobulin-pro-
ducing B-cells, whilst T-lymphocytes are relatively sparse
[7]. Low numbers of a specific T-cell population – the Á‰
T-cells – can be observed in the cryptepithelium [8; van
Kempen: unpubl. obs.]. This T-cell subset is possibly
involved in the tonsillar epithelial immunosurveillance as
it demonstrates cytolytic activity against antigenically
modified epithelial cells [9].
Interspersed between other epithelial cells resides a
unique population of epithelial cells: M-(membrane) cells.
The function of M-cells appears to be the uptake and
transport of antigen [10]. Originally, these specialized
cells were demonstrated in the Peyer’s patches of the
small bowel but others and our group have described
them as well in PT and adenoids [11–13]. Ultrastructur-
ally, M-cells are characterized by apical irregular micro-
folds, an abundant amount of cytoplasmic vesicles and
10 Int Arch Allergy Immunol 2000;122:8–19
a deep invaginated basolateral membrane forming a ‘cen-
tral hollow’ (fig. 3). These typical features all facilitate
antigen trapping and endocytic antigen uptake and short-
en the distance that transcytotic vesicles have to travel.
Our group found a close association between M-cells and
active lymphoid cells, the latter being trapped in the baso-
lateral hollow of the former, suggesting the antigen-han-
dling role of M-cells [14]. From in vitro studies on intesti-
nal epithelial cell lines it seems that M-cells do not process
the captured antigen during transport but deliver it intact
to underlying cells [10].
Until now, the origin of the M-cell is not clear. It has
been suggested that they develop from adjoining colum-
nar ciliated or nonciliated cells under the influence of
antigens or lymphocytes [15]. Recently, Kerneis et al. [16]
demonstrated the in vitro differentiation of small bowel
cryptoepithelial cells into M-cells under the influence of
soluble Peyer’s patches B-cell factors [16].
In order to induce an effective antigen-specific T-cell-
dependent immune response, the captured antigen has to
be processed into immunogenic peptides and presented in
the context of major histocompatibility (MHC) molecules
to a T-cell receptor (TCR). Since M-cells supposedly do
not process antigen and only weakly express MHC class
II, other cells are likely to be involved in antigen presenta-
tion [17]. For this purpose tonsils dispose of a diverse
population of professional antigen-presenting cells (APC),
which include macrophages, B-lymphocytes and dendritic
cells (DCs) that all express MHC class II molecules.
van Kempen/Rijkers/Van Cauwenberge
 Especially bone-marrow-derived DCs are very well
suited for priming naı̈ve T-lymphocytes. Their unique
morphology with numerous surface projections allows a
large contact area with responding T-lymphocytes [18].
Moreover, these highly mobile cells display a considerably
higher MHC expression than other APCs do [19]. Imma-
ture DCs located at sites of antigen entry display a strong
receptor-dependent and independent endocytic capacity,
allowing for efficient antigen processing and MHC class II
loading [20]. However, despite their high ability for cap-
turing antigen, immature DCs are weakly immunogenic
to T-cells. After perceiving a so-called ‘danger signal’, pro-
vided by bacterial product lipopolysaccharide (LPS) or
inflammatory cytokines (IL-1, TNF-·), an irreversible
DC maturation process is initiated which includes the loss
of endocytic activity and an enhanced T-cell stimulatory
capacity [21–23]. The maturing DCs home to T-cell areas
of secondary lymphoid organs where they ultimately prime
naı̈ve T-cells [20]. The functional alterations during the
DC maturation process are reflected in morphological
changes with the development of dendrites and alterations
in DC phenotype (fig. 4). To enable receptor-mediated
endocytosis, immature DCs display transmembrane mac-
rophage mannose receptors (MMRs), DEC-205 as well as
Fc-receptors [22]. Mature DCs, also called interdigitating
DCs (IDCs), lack these receptors but have a high density
of MHC class II molecules on their surface [20]. In ad-
dition, they express costimulatory molecules, like CD80
and CD86, formerly termed B7.1/B7.2 and accessory
Fig. 3. Adenoidal M-cell. The adenoidal ciliated epithelium is inter-
molecules, like intercellular adhesion molecule-1/CD54
rupted by the irregular microfolds of the M-cell. Two lymphocytes
(ICAM-1), lymphocyte function-associated antigen-3 are entrapped in the basolateral hollow of the M-cell. Reprinted with
(LFA-3), and CD70 that are required for optimal T-cell permission from Claeys et al. [13].
activation. Immunohistochemical studies on human PTs
elegantly demonstrated the two distinct DC subsets with
immature DCs in the lymphoepithelium and mature IDCs
predominantly localized in clusters within the interfollicu- immature DCs were shown to migrate in response to
lar T-cell areas [24, van Kempen: unpubl. obs.]. MIP-3· while mature DCs only responded to MIP-3ß
Interestingly, semiquantitative analysis of DC num- [28]. This altered chemokine response was found to be
bers in tonsils has shown significantly increased numbers related to a different chemokine receptor expression pat-
of HLA-DR+-S100+ DC in the lymphoepithelium in tern [29]. In agreement with these in vitro findings, in situ
hypertrophic PT and adenoids as well as in frequently hybridization studies on human PTs have shown that
infected tonsils compared to controls [25, 26]. These MIP-3· mRNA is predominantly expressed by inflamed
altered DC numbers are possibly related to an increased epithelium, a site known to be infiltrated by immature
DC recruitment. In fact, various inflammatory mediators DCs while the expression of MIP-3ß was restricted to T-
such as macrophage inflammatory protein (MIP)-3·, cell-rich areas whereto mature DCs home [28].
monocyte chemotactic protein (MCP)-3, complement-
derived C5a and platelet-activating factor (PAF) were The Interfollicular T-Cell Area
found to exert a strong chemotactic activity on DCs in The interfollicular area is predominantly populated by
vitro [27]. Recently, it was demonstrated that DC chemo- T-lymphocytes and also contains many high endothelial
kine responsiveness depends on their maturation status as venules (HEV). These specialized postcapillary venules

The Immune Response in Adenoids and Int Arch Allergy Immunol 2000;122:8–19 11
Tonsils
Fig. 4. Characterization of immature and
mature DCs. Adapted from Banchereau and
Steinman [20]. CCR6,7 = CC chemokine
receptor 6,7.
promote lymphocyte extravasation by a specific expres-
sion pattern of adhesion molecules. By demonstrating a
preferential expression of ICAM-1 on interfollicular ton-
sillar HEV, in conjunction with increased expression of
lymphocyte function-associated antigen-1 (LFA-1) ex-
pressing lymphocytes close to these HEV, Perry et al. [30]
suggested that the former functions as a promotor of lym-
phocyte extravasation into this area. However, other ad-
hesion molecules were also found to be active in the
recruitement of naı̈ve lymphocytes, in particular CD34
on tonsillar HEV and its ligand L-selectin, which is highly
expressed on virgin lymphocytes [31, 32].
Once in the tonsil, naı̈ve CD45RA+ T-lymphocytes
migrate through the interfollicular area, make contact
with and scan the surface of multiple antigen-presenting
cells (APCs) for their specific antigen. If the encounters
are unsuccessful, these T-lymphocytes return to the circu-
lation via the efferent lymph. A successful recognition
event between a T-lymphocyte and an APC leads to T-cell
retention and subsequent activation. For optimal antigen-
specific T-cell activation, at least two signals are required
[33]. The first signal is antigen-specific and is mediated
via TCR recognition of a peptide antigen bound to MHC
molecules expressed on the APC surface. The second, co-
stimulatory, signal is mediated by a number of receptor-
coreceptor pairs like CD80, CD86, both interacting with
the transiently expressed CD28 molecule on T-cells and
e.g. ICAM-1-binding LFA-1 [34]. The interaction of
MHC molecules with the TCR and the ligation of the var-
12 Int Arch Allergy Immunol 2000;122:8–19
ious costimulatory molecules with their cognate receptors
lead to a rapid upregulation of CD40 ligand (CD40L) on
the T-cell surface [35]. CD40L will in turn interact with
CD40 present on the APCs, thereby strengthening the
APC-T-cell contact [36]. Studies on naı̈ve T-cells have
shown that the magnitude of CD40L expression on indi-
vidual T-cells is determined by the extent of TCR ligation,
which in turn appears to be determined by antigenic pep-
tide affinity and APC costimulatory molecule expression
[35]. Although every professional APC constitutively ex-
presses CD40, resting macrophages and B-cells appear to
have little naı̈ve T-cell-stimulating activity [34, 37]. On
their surface, they express only a very restricted amount
of costimulatory molecules, insufficient to induce satis-
factory CD40L expression necessary for a primary T-cell
response. On the contrary, mature DCs, as mentioned
previously, express many accessory molecules and there-
fore seem to be responsible for primary T-cell activation
[38, 39].
The ligation of CD40 by CD40L firstly enhances IDC
costimulatory activity by upregulating the expression of
accessory molecules [36]. This further increases the capac-
ity of IDCs to induce T-cell proliferation. In addition,
CD40 triggering is a potent stimulus for cytokine and che-
mokine release such as IL-8, MIP-1· and TNF-· by acti-
vated DCs. Mature DCs have been shown to produce
extremely high levels of IL-12 following CD40 engage-
ment [40]. This cytokine directs the subsequent T-cell
response towards a Th1-type response [41]. Recently, Ris-
van Kempen/Rijkers/Van Cauwenberge
Fig. 5. Schematic representation of T- and
B-cell priming and activation in the interfol-
licular area.
soan et al. [42] introduced the concept of two lineage and
functionally distinct DC subsets, namely DC1 and DC2.
Upon CD40L activation, the DC1 subset, consisting of
myeloid DC, were found to produce high levels of IL-12
and to induce Th1-cell differentiation. On the other hand
lymphoid DCs representing the DC2 subset failed to pro-
duce detectable amounts of IL-12 following CD40 liga-
tion and initiated a Th2-type response. Interestingly, even
in the absence of IL-4 these DC2s were able to induce Th2
differentiation [43]. These findings suggest that, in addi-
tion to providing naı̈ve helper T-cells with antigen and
costimulatory signals, DCs also play an important role in
the polarization process. As a result of this interaction,
T-cells become activated, proliferate and differentiate
into a distinct T-cell subset.
A portion of the primed T-cells will leave the tonsils
either to become effector or memory cells. Indeed, even
without B cell triggering, short-lived T-cell memory re-
sponses to antigens can be generated [44]. Nevertheless, ex-
tensive T-cell proliferation and memory T-cell production
is only triggered following cognate interaction of primed
T-cells with B-cells. Therefore, some primed T- lympho-
cytes remain in the lymphoid tissue and particularly cluster
around the outer part of the extrafollicular zone.
At the outer parts of the extrafollicular zone naı̈ve B-
lymphocytes are found as well [24]. Following their devel-
opment in the bone marrow, naı̈ve B-lymphocytes, carry-
The Immune Response in Adenoids and
Tonsils
ing both surface IgM and IgD, continuously migrate into
the peripheral lymphoid tissues where they percolate
through to the T-cell-rich extrafollicular areas. In thymus-
dependent humoral immune responses these B-lympho-
cytes may transiently arrest here in order to survey any
trapped antigen [45]. The naı̈ve B-lymphocyte bearing a
B-cell antigen receptor (BCR) specific for the trapped
antigen will be retained and subsequently capture and
process the antigen. Recent data suggest that upon B-cell
antigen receptor triggering two closely related T-cell
chemoattractants, namely MIP-1· and MIP-1ß, are pro-
duced by tonsillar B-lymphocytes [46]. Activated CD4+
T-cells were found to actively migrate along this chemo-
tactic gradient, thus enabling cell-to-cell contact. The anti-
gen-specific B-cell subsequently interacts with the pre-
viously primed T-cell and receives accessory signals from
it (fig. 5). Apart from T-cell-derived cytokines, such as IL-
2, IL-4 and IL-5, these signals critically involve the liga-
tion of CD40 on B-cells to its counterreceptor CD40L,
expressed by the activated T-cell, and CD86/CD80-CD28
interactions [47]. This second B-cell activation signal
seems to be crucial for promoting B-cell proliferation, dif-
ferentiation as well as the immediate induction of im-
munoglobulin class switching. Indeed, experiments in
mice have shown that blocking the CD40 costimulatory
pathway by anti-CD40L completely inhibits germinal
center (GC) reactions and memory B-cell formation-
Int Arch Allergy Immunol 2000;122:8–19 13
Fig. 6. Phenotypic characteristics of the sev-
en human tonsillar B-cell subsets. FM = Fol-
licular mantle; DZGC = germinal center
dark zone; CB = centroblast; CC = centro-
cyte.
[48]. The importance of CD40 cross-linking for human
B-lymphocyte activation is further illustrated in the hy-
per-IgM syndrome where a mutation in the CD40L gene
results in a severe IgG and IgA deficiency [49].
In addition to direct intercellular T/B-cell contact and
T-cell factors, recent in vitro studies have suggested that
DCs also directly modulate B-cell growth and differentia-
tion [50]. In the presence of IL-2, DCs generated in vitro
were found to stimulate CD40-activated naı̈ve B-cells to
differentiate into plasma cells producing large amounts of
IgM, an effect mediated by IL-12. Moreover, DCs can
also regulate immunoglobulin class switching, as they
induced an IgA switch predominantly towards the IgA2
isotype in vitro [51]. Thus, in addition to T-cell activation
and polarization, DCs directly modulate B-cell growth
and differentiation. Therefore interfollicular-antigen-spe-
cific naı̈ve B-cell activation is preferably represented as a
‘ménage à trois’ rather than a dialogue between T- and
B-lymphocytes.
Following cognate interaction in the outer T-cell zone,
the activated B-cell proliferates in situ and migrates along
a chemotactic gradient either to the lymphoid follicle, to
become a germinal center founder cell, or remains extra-
follicular [44]. In the extrafollicular areas, the B-lympho-
cyte undergoes further clonal expansion and differentiates
into short-lived (2–3 days) low-affinity antibody secreting
plasma cells which migrate to distant sites [52]. The sub-
sequently produced, essentially IgM antibodies can bind
circulating antigen resulting in the formation of soluble
14 Int Arch Allergy Immunol 2000;122:8–19
immune complexes. Also the remaining primed T-cell
briefly proliferates in situ [44]. However, particularly dur-
ing the primary antigen response, most of the activated
T-cells first move into lymphoid follicles and proliferate
extensively there. Indeed, 1 week after antigen triggering,
antigen-specific T-cells are predominantly observed in the
tonsillar follicles [53]. Finally, it is assumed that once
antigen presentation has been achieved, the DCs will be
killed by T-cells or will die by apoptosis [54].
Follicular Germinal Center
During T-cell-dependent antigen responses, GCs de-
velop in primary lymphoid follicles resulting in the forma-
tion of secondary lymhoid follicles. These GCs provide a
specialized microenvironment where B-cells undergo ex-
tensive proliferation, somatic mutation, BCR affinity
maturation and immunoglobulin isotype switching re-
sulting in the formation of memory B-cells and plas-
ma cells. The various stages of B-cell maturation during
the GC reaction in human tonsils have phenotypically
been divided into seven distinct B-cell subsets by Liu et
al. [55] (fig. 6). The primary follicular B-cell population,
IgM+IgD+CD38–, has a naı̈ve phenotype, expresses the
apoptosis survival gene bcl-2 and lack apoptosis-inducing
genes such as Fas (CD95). On the contrary, tonsillar GC
B-cells are distinguished by their lack of surface IgD and
the expression of the GC marker CD38. B-cell blasts that
colonize the lymphoid follicle following a productive T-/
B-cell interaction in the extrafollicular region represent
van Kempen/Rijkers/Van Cauwenberge
a transitional subset. These GC founder cells display the
IgM+IgD+CD38+ phenotype and, in contrast to naı̈ve B-
lymphocytes, express the pro-apoptotic Fas molecule. Ap-
parently the T-/B-cell contact has sensitized these cells for
apoptosis.
Once intrafollicular, the activated B-cell blast starts to pro-
liferate rapidly for about 3 days giving rise to centroblasts
positive for the nuclear proliferation maker Ki-67 [56] (fig.
7). This intense CD40/CD40L-induced proliferation of
GC-B cell blasts seems to be promoted by a specific DC
subpopulation, called germinal center DC (GCDC) [57]. As
a consequence, this space-filling process will displace the
resting follicular B-lymphocytes to form a surrounding fol-
licular mantle. Approximately 4 days after antigenic stimu-
lation, the GC is fully developed and consists of a dark and a
light zone containing about 1.4 ! 104 cells [45].
In the dark zone, IgM–IgD–CD38+CD77+ centro-
blasts undergo intense somatic hypermutation in their
immunoglobulin variable region genes, giving rise to a
clone of nonproliferating IgM–IgD–CD38+CD77– cen-
trocytes [55]. These centrocytes display diversity in BCR
affinity and specificity, possibly including even some self-
reactive clones.
In order to prevent low-affinity and autoreactive mu-
tants from entering the memory B-cell pool, a positive
selection process is initiated in the basal light zone of the
GC. In this area, closely associated with GC B-cells, follic-
ular dendritic cells (FDCs) reside [58]. These FDCs char-
acteristically demonstrate numerous cell surface exten- Fig. 7. The tonsillar GC reaction. 1: Activation Ag-specific B-cells in
sions with complement and Fc-receptors [59]. At this time extrafollicular area; 2: CBs mutate their IgV genes and proliferate;
3: selection of highest-affinity CCs by competition for antigen bind-
point during the immune response, some of the previous-
ing on FDC; 4: selected CCs present FDC-derived antigenic peptides
ly formed immune complexes consisting of low affinity to GC T-cell; 5: rescued CCs differentiate into memory cells or plas-
antibodies, circulating antigen and complement compo- ma blasts expressing mutated Ig with increased affinity for the immu-
nents become deposited on FDCs [60]. Because of the nizing Ag; 6: nonselected CCs die by apoptosis and are devoured by
inability of FDC to process antigen, these complexes can stainable body macrophages. DZ = Dark zone; CB = centroblast;
LZ = light zone; CC = centrocyte; MZ = mantle zone; PC = plasma
be retained for a long period of time [61]. The diverse
cell; MC = memory cell.
populations of centrocytes will now compete for antigen
binding on the FDC [62, 63]. However, only those with
the highest affinity BCR will succeed and be selected.
Low-affinity mutants will fail to bind the antigen present- The rescued, high-affinity centrocytes will retain some
ed and will therefore die by apoptosis. Indeed, a high of the antigen from the immune complex, process it and
apoptosis index has been observed in this region [64]. The continue their affinity maturation in the apical part of the
mechanism by which FDCs rescue the selected centro- GC light zone where they are submitted to another selec-
cytes from apoptosis remains unknown, but possibly tion process. This involves the presentation of FDC-
involves complement component and adhesion molecule derived antigenic peptides in the context of MHC class II
expression. In fact, B-cell ligation onto FDCs was recently molecules by centrocytes to GC T-helper cells [62, 66].
demonstrated to be mediated by the adhesion molecules: These GC T-helper cells were found to be specific for the
ICAM-1 and vascular cell adhesion molecule-1 (CD106; initial antigen [67]. If the GC T-helper cell recognizes the
VCAM-1) that can bind B cells through LFA-1 and very peptide presented, a second B-/T-cell interaction will
late antigen-4 (VLA-4), respectively [65]. arise, resulting in a rapid upregulation of CD40L expres-

The Immune Response in Adenoids and Int Arch Allergy Immunol 2000;122:8–19 15
Tonsils
sion on these T-cells [44]. Indeed, immunohistochemical
staining of human tonsillar sections demonstrated a high
CD40L expression on germinal T-cells [68]. Since CD40/
CD40L ligation downregulates Fas expression, these high-
affinity GC B-cell blasts are rescued from their previously
programmed cell death [69]. However, irrelevant centro-
cytes will not encounter their cognate T-helper-cell and
consequently will die in situ by apoptosis. Furthermore
this cognate T-/B-cell interaction induces the release of
T-cell-derived cytokines, e.g. IL-4 and IL-10, which to-
gether with CD40L signaling, represent key elements for
the proliferation and isotype switch of high-affinity cen-
trocytes [70]. Indeed, antibody isotype switching was
found to occur in proximity of T-cells in the apical light
zone of the GC [71]. During this process, many B-cells
change antibody class from IgM to IgG and other isotypes
by switching of the immunoglobulin heavy chain constant
genes to downstream isotypes without altering their anti-
gen-binding specificity.
The thus generated high-affinity isotype switched cen-
trocytes differentiate into either memory B-cells or plas-
ma blasts of various isotypes. This differentiation process
also appears to be dependent, besides cytokines, on
CD40/CD40L interaction since prolonged CD40 signal-
ing induces IgD–CD38– memory B-cells while plasma
blasts are generated when CD40 signaling is removed
[72].
In a variable number of plasma blasts, a joining (J)-
chain gene is induced. This gene encodes a small cytoplas-
mic peptide, the J-chain, which plays a crucial role in the
formation of polymeric immunoglobulins (pIg) [73]. Al-
though this peptide can be coexpressed by all plasma
blasts regardless of their isotype, it only becomes incorpo-
rated with cytoplasmic IgA and IgM to form polymers:
pentameric IgM and dimeric IgA. Normally, the tonsillar
GC reaction induces a substantial number of immuno-
cytes (plasma blasts and plasma cells) with cytoplasmic
IgG (55–72%) and IgA (13–18%) and to a lesser extent
IgD and IgM [73]. Approximately 36% of the IgG, 29% of
the IgA and 55% of the IgM isotypes coexpress the J-chain
[74]. In children the switching process was found to
induce relatively more IgA isotypes associated with an
even higher percentage of J-chain expression. However, in
youngsters with recurrent tonsillitis, the capacity for J-
chain coexpression was shown to be significantly im-
paired [75].
Finally, most of the hypermutated, high-affinity mem-
ory B-cells emigrate, most likely directed by chemokines,
from the GC to extrafollicular compartments such as the
tonsillar crypt epithelium where they may continue to
16 Int Arch Allergy Immunol 2000;122:8–19
present antigen [76]. The plasma cell precursors also rap-
idly leave the GC to terminate their differentiation at
local extrafollicular or distant effector sites.
About 3–4 weeks after initial antigen exposure the GC
decreases in size. It then consists of a few antigen-specific
B-blasts approximate to FDCs [56]. Presumably, this
close spatial relation represents the site of long-term
memory B-cell renewal stimulated by the antigen-anti-
body complexes on FDCs. Furthermore, most of the anti-
gen-specific T-cells previously located at the apical light
and outer zone of the GC area leave the GC towards the
extrafollicular T-cell zone [44].
Associated Exocrine Sites
Due to the expression of specific adhesion molecules,
most of the tonsillar primed plasma blasts will selectively
migrate to secretory sites as the nasal mucosa, salivary
and lacrimal glands. At these effector sites, they will com-
plete their differentiation into immunoglobulin-produc-
ing plasma cells. Most of this immunoglobulin is in the
form of IgA polymers [73].
By the incorporation of the J-chain, pIgA as well as
pentameric IgM are able to bind to a unique epithelial
receptor protein complex, called transmembrane secreto-
ry component, which ensures the selective external trans-
port of these secretory immunoglobulins [77]. In coopera-
tion with innate defense mechanisms, these pIg perform
immune exclusion at these sites.
Secondary Immune Responses
In addition to generating antigen-specific primary T-
cell responses, tonsils are also capable of mounting sec-
ondary immune responses [78]. Histologically, this reac-
tion is characterized by a massive extrafollicular plasma
cell reaction and only a small GC reaction [45].
Whereas priming of naı̈ve T-cells is restricted to DCs,
it seems that other APCs, like memory or even resting B-
lymphocytes are able to activate memory T-cells [35].
This difference in T-cell responsiveness to antigenic stim-
ulation is presumably due to the higher levels of certain
accessory molecules, e.g. LFA-1 and CD28, expressed
by memory T-cells which allows a more avid interaction
with even weakly TCR-stimulating APCs [79]. In ad-
dition, compared to naı̈ve CD45RA+ T-cells, memory
CD45RO+ T-cells were found to require a lower level of
intracellular signaling necessary to initiate T-cell prolifer-
van Kempen/Rijkers/Van Cauwenberge
ation [80]. Furthermore unlike naı̈ve B-cells, memory
IgD–CD38– B cells can, following antigen uptake via
their sIg, rapidly upregulate the necessary costimulatory
molecules for T-cell activation [55]. All these factors,
combined with the close spatial relation between memory
B-cells and memory T-lymphocytes in the M-cell pockets
and other regions of the crypt epithelium, may explain the
rapid secondary immune response that can be observed
[81].
Interestingly, in vitro studies have demonstrated that
CD40-activated memory B-cells give rise to more plasma
cells and immunoglobulins compared to naı̈ve B-cells
whilst the latter generate larger numbers of nondifferen-
tiated activated B-cells [82]. Apparently, memory B-cells
have a decreased potential to generate new memory cells,
but preferentially undergo terminal differentiation into
plasma cells. These observations may explain how the
immune system controls the size of the memory cell popu-
lation and prevents its overexpansion. Furthermore, they
explain the extensive extrafollicular plasma cell reaction
and intense immune response observed in vivo following
secondary immunizations.
Conclusion
The adenoids and PT are organized lymphoepithelial
structures that play an important role in protecting the
upper respiratory tract region against incoming antigens.
Via their specialized cryptepithelium, foreign material
is sampled after which antigen-specific memory and effec-
tor B-cells, mainly producing pIgA with a J-chain, are gen-
erated and disseminated to nearby mucosal sites.
This function requires successful cognate interactions
between APC and lymphocytes and mutually between
lymphocytes, which depend on the expression of comple-
mentary adhesion and costimulatory molecules. In partic-
ular, CD40/CD40L ligation is of essential importance as
it induces GC formation, somatic mutation, positive
selection of high affinity mutants and isotype switching.
Even though our knowledge on the importance of ade-
noids and tonsils has enormously increased over the past
decade, further studies are needed to completely unravel
this complex immunological process and to better under-
stand pathological conditions.

References

1 Harabuchi Y, Hamamoto M, Shirasaki H, Asa-
kura K, Matsuyama H, Kataura A: Specific
immune response of the adenoids to a respira-
tory antigen. Am J Otolaryngol 1989;10:138–
142.
2 Rynell-Dagoo B: The immunological function
of the adenoid. Acta Otolaryngol 1976;82:196–
198.
3 Quiding-Järbrink M, Granström G, Nord-
ström I, Holmgren J, Czerkinsky C: Induction
of compartmentalized B-cell responses in hu-
man tonsils. Infect Immunol 1995;63:853–
857.
4 Ogra PL: Effect of tonsillectomy and adenoi-
dectomy on nasopharyngeal antibody response
to poliovirus. N Engl J Med;1971;284:59–64.
5 Perry M, Whyte A: Immunology of the tonsils.
Immunol today 1998;19:414–420.
6 Graeme-Cook F, Bhan AK, Harris NL: Immu-
nohistochemical characterization of intraepi-
thelial and subepithelial mononuclear cells of
the upper airways. Am J Pathol 1993;143:
1416–1422.
7 Tang X, Hori S, Osamura RY, Tsutsumi Y:
Reticular crypt epithelium and intra-epithelial
lymphoid cells in the hyperplastic human pala-
tine tonsil: An immunohistochemical analysis.
Pathol Int 1995;45:34–44.
8 Olofsson K, Hellström S, Hammarström M-L:
The surface epithelium of recurrent infected
palatine tonsils is rich in Á‰-T-cells. Clin Exp
Immunol 1998;111:36–47.
9 Yamanaka N, Yokoyama M, Kawaguchi T, Ta-
manaki K, Ishii H: Role of Á‰-T-cells in the pal-
atine tonsil. Acta Otolaryngol Suppl (Stock)
1996;523:90–93.
10 Neutra MR, Frey A, Kraehenbuhl J-P: Epithe-
lial M-cells: Gateways for mucosal infection
and immunization. Cell 1996;86:345–348.
11 Owen RL, Jones AL: Epithelial cell specializa-
tion within human Peyer’s patches: An ultra-
structural study of intestinal lymphoid follicles.
Gastroenterology 1974;66:189–203.
12 Karchev T, Kabakchiev P: M-cells in the epi-
thelium of the nasopharyngeal tonsil. Rhinolo-
gy 1984;22:201–210.
13 Claeys A, Cuvelier C, Quatacker J, van Cau-
wenberge P: Ultrastructural investigation of
M-cells and lymphoepithelial contacts in
naso-pharyngeal associated lymphoid tissue
(NALT). Acta Otolaryngol Suppl (Stock) 1996;
523:40–42.
14 Claeys A, Cuvelier C, Van Cauwenberge P:
Immunohistochemical analysis of the lym-
phoepithelium in human nasopharyngeal asso-
ciated lymphoid tissue (NALT). Acta Otolaryn-
gol Suppl (Stock) 1996;523:38–39.
15 Wolf JL, Bye WA: The membranous epithelial
(M) cell and the mucosal immune system.
Annu Rev Med 1984;35:95–112.
16 Kerneis S, Bogdanova A, Kraehenbuhl JP:
Conversion by Peyer’s patch lymphocytes of
human enterocytes into M cells that transport
bacteria. Science 1997;277:949–952.
17 Bjerke K, Brandtzaeg P: Lack of relation be-
tween expression of HLA-DR and secretory
component (SC) in follicle associated epithe-
lium of human Peyer’s patches. Clin Exp Im-
munol 1988;71:502–507.
18 Schuler G, Thurene B, Romani N: Dendritic
cells: From ignored cells to major players in T-
cell-mediated immunity. Int Arch Allergy Im-
munol 1997;112:317–322.
19 Inaba K, Pack M, Inaba M, Sakuta H, Isdell F,
Steinman RM: High levels of a major histo-
compatibility complex II- self peptide complex
on dentritic cells from the T cell area of lymph
nodes. J Exp Med 1997;186:665–672.
20 Banchereau J, Steinman RM: Dendritic cells
and the control of immunity. Nature 1998;392:
245–252.
21 Rescigno M, Granucci F, Citterio S, Foti M,
Ricciardi-Castagnoli P: Coordinated events
during bacteria-induced DC maturation. Im-
munol Today 1999;20:200–203.

The Immune Response in Adenoids and Int Arch Allergy Immunol 2000;122:8–19 17
Tonsils
22 Sallusto F, Cella M, Danieli C,Lanzavacchia A:
Dendritic cells use macropinocytosis and the
mannose receptor to concentrate macromole-
cules in the major histocompatibility complex
class II compartment: Downregulation by cyto-
kines and bacterial products. J Exp Med 1995;
182:389–400.
23 Cella M, Engering A, Pinet V, Pieters J, Lan-
zavacchia A: Inflammatory stimuli induce ac-
cumulation of MHC class II complexes on den-
dritic cells. Nature 1997;388:782–787.
24 Björk P, Flores-Romo L, Liu Y-J: Human in-
terdigitating dendritic cells directly stimulate
CD40-activated naı̈ve B cells. Eur J Immunol
1997;27:1266–1274.
25 Bani D, Gallo O, Fini-Storchi O: Intraepithe-
lial lymphocyte subpopulations and dendritic
accessory cells in normal and hypertrophic ade-
noids. Laryngoscope 1994;104:869–873.
26 Brodsky L, Frankel S, Gorfien J, Rossman J,
Noble B: The role of dendritic cells in the
development of chronic tonsillar disease in
children. Acto Otolaryngol Suppl (Stock) 1996;
523:98–100.
27 Sozzani S, Sallusto F, Luini W, Zhou D, Pie-
monti L, Allavena P, Van Damme J, Valitutti
S, Lanzavecchia A, Mantovani A: Migration of
dendritic cells in response to formylpeptides,
C5a, and a distinct set of chemokines. J Immu-
nol 1995;155:3292–3295.
28 Dieu M-C, Vanbervliet B, Vicari A, Bridon
JM, , Oldham E, Ait-Yahia S, Briere F, Zlotnik
A, Lebecque S, Caux C: Selective recruitment
of immature and mature dendritic cells by dis-
tinct chemokines expressed in different ana-
tomic sites. J Exp Med 1998;188:373–386.
29 Greaves DR, Wang W, Dairaghi DJ, Dieu M-
C, Saint-Vis B, Franz-Bacon K, Rossi D, Caux
C, McClanahan T, Gordon T, Zlotnik A, Schall
TJ: CCR6, a CC chemokine receptor that inter-
acts with macrophage inflammatory protein 3·
and is highly expressed in human dendritic
cells. J Exp Med 1997;6:837–844.
30 Perry ME, Brown KA, von Gaudecker B: Ul-
trastructural identification and distribution of
the adhesion molecules ICAM-1 and LFA-1 in
the vascular and extravascular compartments
of the human palatine tonsil. Cell Tissue Res
1992;268:317–326.
31 Puri KD, Finger EB, Gaudernack G, Springer
TA: Sialomucin CD34 is the major L-selectin
ligand in human tonsil high endothelial ven-
ules. J Cell Biol 1995;131:261–270.
32 Andoh N, Ohtani H, Kusakari C, Onodera A,
Hotta O, Tomiaka S, Nagura H: Expression of
E- and P-selectin by vascular endothelial cells
in human tonsils. Acta Otolaryngol Suppl
(Stock) 1996;523:52–54.
33 Bretscher P: The two-signal model of lympho-
cyte activation twenty-one years later. Immu-
nol Today 1992;13:74–76.
34 Croft M, Dubey C: Accessory molecule and
costimulation requirements for CD4 T-cell re-
sponse. Crit Rev Immunol 1997;17:89–118.
35 Jaiswal AI, Croft M: CD40 ligand induction on
T cell subsets by peptide-presenting B cells.
Implications for development of the primary T
and B cell response. J Immunol 1997;159:
2282–2291.
18 Int Arch Allergy Immunol 2000;122:8–19
36 Caux C, Massacrier C, Vanbervliet B, Dubois
B, Van Kooten C, Durand I, Banchereau J:
Activation of human dendritic cells through
CD40 cross-linking. J Exp Med 1994;180:
1263–1272.
37 Fuchs EJ, Matzinger P: B cells turn off virgin
but not memory T cells. Science 1992;258:
1156–1159.
38 Prickett TC, McKemnzie JL, Hart DN: Adhe-
sion molecules on human tonsil dendritic cells.
Transplantation 1992;53:483–490.
39 King PD, Katz DR: Human tonsillar dendritic
cell-induced T cell responses: Analysis of mo-
lecular mechanisms using monoclonal anti-
bodies. Eur J Immunol 1989;19:581–587.
40 Cella M, Scheidegger D, Palmer-Lehman K,
Lane P, Lanzavacchia A, Alber G: Ligation of
CD40 on dendritic cells triggers the production
of high levels of interleukin-12 and enhances T
cell stimulatory capacity: T-T help via APC
activation. J Exp Med 1996;184:747–752.
41 Heufler C, Koch F, Stanzl U, Topan G, Wy-
socka M, Trinchieri G, Enk A, Steinamn RM,
Romani N, Schuler G: Interleukin-12 is pro-
duced by dendritic cells and mediates T helper
1 development as well as interferon-gamma
production by T helper 1 cells. Eur J Immunol
1996;26:659–668.
42 Rissoan MC, Soumelis V, Kadowaki N,
Grouard G, Briere F, de Waal Malefyt R, Liu
YJ: Reciprocal control of T helper cell and den-
dritic cell differentiation. Science 1999;283:
1183–1186.
43 Kalinksi P, Hilkens CM, Snijders A, Snijde-
wint FG, Kapsenberg ML: IL-12 deficient den-
dritic cells, generated in the presence of prosta-
glandin E2, promote type 2 cytokine produc-
tion in maturing naı̈ve T helper cells. J Immu-
nol 1997;159:28–35.
44 MacLennan IC, Gulbranson-Judge A, Toellner
K-M, Casamayor-Palleja M, Chan E, Sze DM,
Luther SA, Orbea HA: The changing prefer-
ence of T and B cells for partners as T-depen-
dent antibody responses develop. Immunol
Rev 1997;156:53–66.
45 Liu Y-J, Zhang J, Lane PJ, Chan EY, MacLen-
nan IC: Sites of specific B-cell activation in pri-
mary and secondary responses to T-cell depen-
dent and T-cell-independent antigens. Eur J
Immunol 1991;21:2951–2962.
46 Krzysiek R, Lefèvre E, Zou W, Foussat A, Ber-
nard J, Portier A, Galanaud P, Richard Y:
Antigen receptor engagement selectively in-
duces macrophage inflammatory protein-1·
(MIP-1·) and MIP-1ß chemokine production
in human B cells. J Immunol 1999;162:4455–
4463.
47 Clark EA, Ledbetter JA: How B and T cells talk
to each other. Nature 1994;367:425–428.
48 Foy TM, Shepherd DM, Durie FH, Aruffo A,
Ledbetter JA, Noelle RJ: In vivo CD40-gp39
interactions are essential for thymus-depen-
dent humoral immunity. II. Prolonged sup-
pression of the humoral immune response by
an antibody to the ligand for CD40, gp39. J
Exp Med 1993;178:1567–1575.
49 Callard RE, Armitage RJ, Fanslow WC,
Spriggs MK: CD40 ligand and its role in X-
linked hyper IgM syndrome. Immunol Today
1993;14:559–564.
50 Dubois B, Vandervliet B, Fayette J, Massacrier
C, Van Kooten C, Briere F, Banchereau J,
Caux C: Dendritic cells enhance growth and
differentiation of CD40-activated B-lympho-
cytes. J Exp Med 1997;185:941–951.
51 Fayette J, Dubois B, Vandenabeele S, Bridon
JM, Vanbervliet B, Durand I, Banchereau J,
Caux C, Briere F: Human dendritic cells skew
isotype switching of CD40-activated naı̈ve B-
cells towards IgA1 and IgA2. J Exp Med 1997;
185:1909–1918.
52 Ho F, Lortan J, Khan M, MacLennan IC, Khan
M: Distinct short-lived and long-lived anti-
body-producing cell populations. Eur J Immu-
nol 1986;16:1297–1301.
53 Gulbranson-Judge A, MacLennan ICM: Se-
quential antigen-specific growth of T cells in the
T zones and follicles in response to pigeon cyto-
chrome c. Eur J Immunol 1996;26:1830–1837.
54 Van Parijs L, Abbas AK: Homeostasis and self-
tolerance in the immune system: Turning lym-
phocytes off. Science 1998;280:243–248.
55 Liu Y-J, Arpin C: Germinal center develop-
ment Immunol Rev 1997;156:111–126.
56 Grouard G, de Bouteiller O, Barthelemy C:
Regulation of human B cell activation by follic-
ular dendritic cell and T cell signals; in Kosco-
Vilbois MH (ed): Current Topics in Microbiol-
ogy and Immunology. Berlin, Springer, 1995,
vol 201, pp 105–117.
57 Dubois B, Barthélémy C, Durand I, Liu YJ,
Caux C, Briere F: Toward a role of dendritic
cells in the germinal center reaction: Triggering
of B cell proliferation and isotype switching. J
Immunol 1999;162:3428–3436.
58 MacLennan ICM: Germinal centers. Annu
Rev Immunol 1994;12:117–139.
59 Heinen E, Radoux D, Kinet-Denoël C, Moere-
mans M, De Mey J, Simar LJ: Isolation of fol-
licular dendritic cells from human tonsils and
adenoids. III. Analysis of their Fc receptors.
Immunology 1985;54:777–784.
60 Gray D, Kumararatne DS, Lortan JE, Khan M,
MacLennan IC: Relation of intra-splenic mi-
gration of marginal zone B cells to antigen
localization on follicular dendritic cells. Immu-
nology 1984;52:659–669.
61 Szakal AK, Kosco MH, Tew JG: A novel in
vivo follicular dendritic cell-dependent icco-
some-mediated mechanism for delivering of
antigen to antigen-processing cells. J Immunol
1988;140:341–353.
62 Lindhout E, Koopman G, Pals ST, de Groot C:
Triple check for antigen specificity of B-cells
during germinal center reactions. Immunol To-
day 1997;18:573–577.
63 Liu Y-J, Joshua DE, Williams GT, Smith CA,
Gordon J, MacLennan IC: Mechanisms of an-
tigen-driven selection in germinal centers. Na-
ture 1989;342:929–931.
64 Hardie DL, Johnson GD, Khan M, McLennan
IC: Quantitative analysis of molecules, which
distinguish functional compartments within
germinal centers. Eur J Immunol 1993;23:997–
1004.
van Kempen/Rijkers/Van Cauwenberge
65 Koopman G, Keehen RM, Lindhout E, New-
man W, Shimizu Y, van Seventer GA, de
Groot C, Pals ST: Adhesion through the LFA-1
(CD11a/CD18)-ICAM-1 (CD54) and the VLA-
4 (CD49d)-VCAM-1(CD106) pathways pre-
vents apoptosis of germinal center B cells. J
Immunol 1994;152:3760–3767.
66 Kosco MH, Szakal AK, Tew JG: In vivo-
obtained antigen presented by germinal center
B cells to T cells in vitro. J Immunol 1988;140:
354–360.
67 Zheng B, Han SH, Kelsoe G: T helper cells in
murine germinal centers are antigen-specific
emigrants that downregulate Thy-1. J Exp Med
1996;184:1083–1091.
68 Lederman S, Yellin MJ, Inghirami G, Lee JJ,
Knowles DM, Chess L: Molecular interactions
mediating T-B lymphocyte collaboration in hu-
man lymphoid follicles. Roles of T cell-B-cell-
activating molecule (5c8 antigen) and CD40 in
contact-dependent help. J Immunol 1992;149:
3817–3826.
69 Koopman G, Keehnen RM, Lindhout E, Zhou
DF, de Groot C, Pals ST: Germinal center B
cells rescued from apoptosis by CD40 ligation
or attachment to follicular dendritic cells, but
not by engagement of surface immunoglobulin
or adhesion receptors, become resistant to
CD95-induced apoptosis. Eur J Immunol
1997;27:1–7.
The Immune Response in Adenoids and
Tonsils
70 Rousset F, Garcia E, Banchereau J: Cytokine-
induced proliferation and immunoglobulin
production of human B-lymphocytes triggered
through their CD40 antigen. J Exp Med 1991;
173:705–710.
71 Casamayor-Palleja M, Khan M, MacLennan
IC: A subset of CD4+ memory T cells contains
preformed CD40 ligand that is rapidly but
transiently expressed on their surface after acti-
vation through the T cell receptor complex. J
Exp Med 1995;181:1293–1301.
72 Liu Y-J: Tracing antigen-driven B cell develop-
ment in humans; in Ferrarini M, Cakligaris-
Cappio F (eds): Human B cell populations.
Basel, Karger, 1997, vol 67, pp 14–26.
73 Brandzaeg P: Role of J chain and secretory
component in receptor-mediated glandular and
hepatic transport of immunoglobulins in man.
Scand J Immunol 1985;22:111–146.
74 Brandzaeg P, Baekkevold ES, Farstad IN,
Jahnsen FL, Johansen F-E, Nilsen EM, Yama-
naka T: Regional specialization in the mucosal
immune system: What happens in the micro-
compartments? Immunol Today 1999;20:141–
151.
75 Korsrud FR, Brandzaeg P: Influence of tonsil-
lar disease on the expression of J-chain by
immunoglobulin-producing cells in human pal-
atine and nasopharyngeal tonsils. Scand J Im-
munol 1981;13:281–287.
Int Arch Allergy Immunol 2000;122:8–19
76 Liu Y-J, Barthélémy C, de Bouteillier O, Arpin
C, Durand I, Banchereua J: Memory B cells
from human tonsils colonize mucosal epithe-
lium and directly present antigen to T cells by
rapid up-regulation of B7-1 and B7-2. Immuni-
ty 1995;2:239–248.
77 Brandzaeg P: Immunocompetent cells of the
upper airway: Functions in normal and dis-
eased mucosa. Eur Arch Otorhinolaryngol
1995;252(suppl 1):S8–S21.
78 Mackay CR: Immunological memory. Adv Im-
munol 1993;53:217–265.
79 Van Seventer GA, ShimizuY, Shaw S: Roles of
multiple accessory molecules in T cell activa-
tion. Curr Opin Immunol 1991;3:294–303.
80 Robinson AT, Miller N, Alexander DR: CD3
antigen-mediated calcium signals and protein
kinase C activation are higher in CD45RO+
than in CD45RA+ human T lymphocyte sub-
sets. Eur J Immunol 1993;23:61–68.
81 Farstad IN, Halstenen TS, Fausa O, Brandzaeg
P: Heterogeneity of M-cell-associated B and T
cells in human Peyer’s patches. Immunology
1994;83:457–464.
82 Arpin C, Banchereau J, Liu Y-J: Memory B
cells are biased towards terminal differentia-
tion: A strategy that may prevent repertoire
freezing. J Exp Med 1997;186:931–940.
19
Copyright: S. Karger AG, Basel 2000. Reproduced with the permission of S. Karger AG, Basel. Further
reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright
holder.