(Journal of Leukocyte Biology. 2001;69:331-339.)
© 2001
by Society for Leukocyte Biology
Lymphoid neogenesis: de novo formation of lymphoid tissue in chronic inflammation through expression of homing chemokines
Peter Hjelmström
Department of Medicine, Karolinska Institute, Stockholm, Sweden
Correspondence: Dr. Peter Hjelmström, Karolinska Institutet, Department of Medicine, Rheumatology Unit, Karolinska Hospital CMM L8:04, SE-171 76 Stockholm, Sweden. E-mail:
peter.hjelmstrom{at}medks.ki.se
 |
ABSTRACT
|
|---|
Chronic inflammation is a complex pathophysiological process with
accumulation of mononuclear cells seen in response to invading
pathogens, neoplastic transformation, or autoimmune recognition of
self-antigens. The inflammatory process has evolved to facilitate
effective elimination of pathogens and tumors and it is normally
transient and turned off when the causative stimulus has been
eliminated. Occasionally, however, the process is sustained for a long
time and can lead to severe tissue damage. This is seen in
organ-specific autoimmune diseases such as rheumatoid arthritis,
Sjögren’s syndrome, and Hashimoto’s thyroiditis, but also in
infectious diseases such as Helicobacter pylori-induced
gastritis. Disturbingly, many of these chronic inflammatory diseases
are associated with an increased risk for neoplastic transformation and
development of lymphomas. This review summarizes experimental evidence
suggesting that chronic inflammation involves ectopic de
novo formation of organized lymphoid tissue and that this
lymphoid neogenesis is regulated by expression of homing
chemokines.
Key Words: autoimmune diseases • lymphoma • CXCL13/CXCR5 • CCL21/CCR7 • germinal centers • high endothelial venules
|
INTRODUCTION
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Chronic inflammation is a necessary, albeit often unappreciated,
component of host defense that frequently leads to tissue damage. The
chronic inflammatory response is heterogeneous and generates different
types of cellular infiltrates depending on factors such as antigenic
stimulus and affected tissue. Chronic inflammatory infiltrates that
morphologically resemble the secondary lymphoid organs lymph nodes
(LNs), Peyer’s patches (PPs), and spleen have long been observed and
named tertiary lymphoid organs [1
].
|
TUMOR NECROSIS FACTOR (TNF) PROTEINS WERE THE FIRST DISCOVERED
MEDIATORS OF LYMPHOID NEOGENESIS
|
|---|
The molecular mechanisms behind organization of chronic
inflammatory lesions into lymphoid tissue were not studied until Ruddle
and colleagues showed that it could be induced by the same signals as
those involved in lymphoid organogenesis during development
[2
]. They consequently named the process of de
novo formation of organized lymphoid tissue in chronic
inflammation lymphoid neogenesis. Lymphotoxin-
(LT; TNF-ß), a
member of the TNF family that has been found to be crucial for
development of secondary lymphoid organs during ontogeny, ectopically
expressed in transgenic mice under the rat insulin promoter (RIP),
induced chronic inflammatory infiltrates closely resembling LNs with
respect to both cellular composition and organization
[2
]. RIP-LT infiltrates were furthermore
characterized by presence of activated postcapillary lymphoid blood
vessels; high endothelial venules (HEVs), and an increased expression
of adhesion molecules mediating homing of naive lymphocytes in
secondary lymphoid organs, such as mucosal addressin cell adhesion
molecule (MAdCAM) and peripheral LN addressin (PNAd). These
morphological characteristics strongly suggest that a de
novo formation of lymphoid tissue can be induced by ectopic
expression of LT, but the infiltrates still needs to be evaluated
with regard to functional characteristics such as antigen-presenting
capabilities. LT and other members of the TNF family contribute both
to inflammation and lymphoid organ development through induction of
adhesion molecules, chemokines, and other cytokines in complex
interactions with the TNFR1 (p55), TNFR2 (p75), and LTß receptors
[reviewed in refs. 3
4
]. The role of the individual members of the
TNF family in lymphoid neogenesis is controversial and has been the
focus of a recent review [5
].
|
LYMPHOID NEOGENESIS AND TRANSCRIPTION FACTORS
|
|---|
TNF proteins are not the only mediators of lymphoid neogenesis and
the whole microenvironment of cytokines and chemokines is probably of
importance in development and maintenance of lymphoid tissue in chronic
inflammation. Important mediators of lymphoid neogenesis acting
downstream of TNF proteins are transcription factors, adhesion
molecules, and lymphoid tissue homing chemokines. The transcription
factor NF-
B is induced by TNF proteins and during the last year it
was shown that alymphoplasia (aly) mice, which exhibit
similar developmental defects of lymphoid tissues as LT and LTßR
deficient mice [6
], have a point mutation in the
NF-B-inducing kinase (NIK) [7
]. Impaired signal
transduction downstream of receptors for the homing chemokine CCL21
(formerly called SLC, 6Ckine, TCA-4, or Exodus-2) explains some of the
defects in homing of cells to lymphoid tissues in the aly
mice [8
]. CCL21 has been found to stimulate
4ß7 (LPAM-1) -mediated adhesion to
MadCAM-1 on HEVs [9
], which is interesting because
aly mice show a defect in expression of this adhesion
molecule in the spleen [10
]. Splenectomized
aly mice, which completely lack secondary lymphoid organs,
do not reject vascularized organ transplants, and crossing these mice
to RIP-LT mice might be a valuable model to study functional
capabilities of transgene-induced lymphoid tissue [11
].
Other mouse strains rendered genetically deficient for NF-B subunits
with defects in the microarchitecture of secondary lymphoid organs are
p52- and Bcl-3-deficient mice and it has been shown that these mice
have reduced expression of another homing chemokine, CXCL13 (formerly
called BLC or BCA-1) [12
]. The receptor for CXCL13,
CXCR5 (formerly denoted BLR-1), is a target for both NF-B and the
transcription factors Oct-2 and Bob-1 [13
,
14
]. The most likely targets for NF-B in lymphoid
neogenesis are chemokines, adhesion molecules and members of the TNF
family themselves, but further experiments with NF-B knockout mice
or inhibitors of NF-B proteins are necessary to identify the precise
targets. In addition, there are probably still undiscovered mediators
of lymphoid neogenesis both dependent on and independent of TNF
signaling. It will be of great interest to identify these specific
signals to analyze whether there are several, perhaps redundant,
pathways leading to different types of lymphoid neogenesis in different
tissues through further experiments with crossed genetically
manipulated mice.
|
LYMPHOID NEOGENESIS AND HOMING CHEMOKINES
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|---|
In the last year, substantial advances were made in our
understanding of how the development and organization of lymphoid
follicles depend upon molecular signals from homing chemokines [for
recent reviews see refs. 15
16
17
18
19
]. In particular, the chemokines CXCL13
and CCL21 have been the focus of intense interest. TNF proteins, and in
particular the membrane-bound molecule LT1ß2, a cytokine that
promotes development of follicular dendritic cells (FDCs), are required
for normal expression of both CXCL13 and CCL21 [20
].
Furthermore, gene profiling experiments show that these chemokines are
differentially expressed in mice with deficiencies in TNF proteins
[21
]. Expression of CXCL13 and CCL21 is induced in the
newly formed lymphoid tissue in the pancreas of RIP-LT mice through
interaction between the soluble LT3 homotrimer and the TNFR1
receptor [22
]. The most convincing evidence for direct
roles of CXCL13 and CCL21 in lymphoid neogenesis in vivo
have been shown by studies of transgenic mice expressing these
chemokines under the RIP in the pancreas. Ectopic expression of either
CXCL13 [23
] or CCL21 [24
] triggers
lymphoid neogenesis and leads to a de novo formation of
organized lymphoid tissue in a similar fashion as seen in RIP-LT
mice. It is important to note that the infiltrating lymphocytes in
RIP-CXCL13 and RIP-CCL21 expressed less activation markers than in
RIP-LT mice, indicating that lymphocyte activation is not a
prerequisite for lymphoid neogenesis.
CXCL13 is constitutively produced by stromal cells in lymphoid tissues
and attracts naive B cells and certain activated and memory T cells
in vitro [25
26
27
28
]. The specific receptor for
CXCL13, CXCR5, is primarily expressed on mature B lymphocytes and
Burkitt’s lymphoma cells [29
30
31
32
33
34
]. Mice genetically
deficient in either CXLC13 or CXCR5 lack most inguinal and peripheral
LNs, possess few or abnormal PPs, and have a disorganized spleen
[35
, 36
]. The membrane-bound molecule
LT1ß2 is required for normal expression of CXCL13 in lymphoid
tissues [20
], and a major recent advance is the finding
that CXCL13 induces B cells to up-regulate LT1ß2, thereby
establishing a positive-feedback loop that is important for follicle
development and homeostasis [23
, 35
].
Cyster and colleagues propose a role for CXCL13 in LN and PP
development by recruiting
CXCR5+CD3-IL7R+ cells, which have
been found to accumulate very early during the development of secondary
lymphoid organs [37
38
39
], and inducing them to express
LT1ß2 [35
, 40
]. These cells have been
shown to express the transcriptional repressor Id2 and the orphan
nuclear hormone receptor ROR
, and mice lacking these proteins have
impaired development of secondary lymphoid organs and lack this cell
population [38
, 41
, 42
]. The
presence of CXCR5+CD3-IL7R+ cells,
Id2, and ROR in lymphoid neogenesis has not been studied so far. The
CXCL13-mediated feedback loop appears to be overridden in germinal
centers because these develop after immunization with a T
cell-dependent antigen both in mice deficient in CXCL13
[35
] and CXCR5 [43
]. In germinal centers
of CXCL13-deficient mice, B cells expressing LT1ß2 are found and
this indicates that other signals, which probably are T cell-derived
such as CD40-CD40 ligand interaction, drive development and maintenance
of FDCs in secondary follicles [35
]. It is interesting
that FDCs do not develop in the lymphoid neogenesis seen in the
pancreas of RIP-CXCL13 mice [23
] and the CXCL13 protein
appears, as initially thought, not to be expressed by FDCs
[44
]. Nevertheless, failure to form germinal centers in
mice rendered deficient in CD28 signaling and up-regulation of OX40
after immunization have been associated with a lack of CXCR5 on
CD4+ T cells [45
]. The cellular sources of
CXCL13 and other mediators of lymphoid neogenesis are still unknown,
but likely candidates include B cells [23
], dendritic
cells [46
], and epithelial mesenchymal cells
[47
]. Further research is needed to identify the
mechanisms leading to development of FDCs and secondary follicles.
CCL21 is a unique CC-chemokine containing six cysteines expressed in
HEVs and by cells in the T cell zone of lymphoid tissues
[48
49
50
51
52
]. It is primarily a ligand for the CCR7 receptor
(previously called EBI1) [53
54
55
56
], even though it has
been reported to bind other chemokine receptors [57
,
58
]. CCR7 primarily directs the migration of naive T
cells and dendritic cells [59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
], but it is also
expressed on a subset of memory T cells that home to LNs upon
stimulation [77
, 78
] and on
CD56+CD16- NK cells [79
]. CCR7
sorts TH1 and TH2 cells in lymphoid tissues
[80
], arrests T cells on HEVs in LNs [81
]
and PPs [82
], and may dictate the actions of T cells in
response to agonist MHC-peptide complexes [83
]. High
expression of CCR7 has been found on adult T cell leukemia (ATL) cells
from patients with lymphoid organ involvement of the cancer, indicating
that CCL21 might mediate tumor expansion and vascularization
[84
]. This is interesting because inflammation with a
follicular pattern and HEVs has been observed in some human cancers,
and the presence of CCL21 has not been studied in these diseases
[85
]. In contrast, CCL21 has been found to effectively
mediate T cell-dependent antitumor responses in vivo when
injected into tumors [86
] and the mouse C26 colon
carcinoma tumor cell line showed reduced tumorigenicity through
angiostatic, CD8+ T cell-mediated and NK-mediated tumor
resistance mechanisms when transduced with a cDNA encoding CCL21
[87
]. The bearing of these results for lymphoid
neogenesis is not clear and it will be interesting to study the
susceptibility of CCL21-deficient mice to neoplastic diseases. In
addition, studies of CCR7-deficient mice have shown that the receptor
is required for coordination of the primary adaptive immune response
and delayed-type hypersensitivity (DTH) reactions by bringing together
lymphocytes and dendritic cells to form the characteristic
microarchitecture of secondary lymphoid organs [88
].
Treatment with an anti-CCL21 antibody can inhibit
contact-hypersensitivity T cell-dependent DTH reactions induced by
hapten sensitization in the skin by interfering with dendritic cell
trafficking [89
]. The mouse strain DDD/1 carries an
autosomal recessive mutation designated paucity of lymph node T cells
(plt) and have reduced numbers of T cells in the peripheral
LN, PP, and spleen [90
]. Gunn and co-workers showed that
plt mice lack expression of CCL21 in lymphoid organs and
have defects in both T cell homing and dendritic cell localization
[91
] and the genetic defect in plt mice has
indeed been shown to be a deletion of one of two CCL21 genes in the
mouse genome [92
].
Expression of CXCL13 and CCL21 has been found in some human diseases
and disease models of chronic inflammation characterized by lymphoid
neogenesis. Both CXCL13 and CCL21 are found in the newly formed
lymphoid tissue in the pancreas of RIP-LT mice and in the insulitis
seen in prediabetic non-obese diabetic (NOD) mice [22
].
CXCL13 are found also in the human diseases Helicobacter
pylori-induced chronic gastritis [93
],
Sjögren’s syndrome, and rheumatoid arthritis (Fig. 1
) [unpublished observations]. The expression of these homing
chemokines appears so far to be specific to inflammation characterized
by lymphoid neogenesis, and CCL21 expression has for instance not been
found in human atherosclerotic plaques [94
].
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Figure 1. The homing chemokine CXCL13 is present in lymphoid follicles of
patients with rheumatoid arthritis. (A) Immunohistochemical staining of
CXCL13 protein (arrows) using a purified IgG1 monoclonal mouse antibody
from R & D Systems, in a follicular lymphocytic cell infiltrate (lc) of
a patient with chronic rheumatoid arthritis. (B) Control staining of
the same section with an isotype-matched mouse monoclonal antibody
(Dako). Original magnification x100 in both panels.
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|
LYMPHOID NEOGENESIS IN AUTOIMMUNE DISEASES
|
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Histopathologists have long observed infiltration of target organs
with mononuclear cells and presence of lymphoid follicles in chronic
inflammatory autoimmune diseases. Söderström and colleagues
found in the beginning of the 1970s that the thyroid gland in patients
with Hashimoto’s thyroiditis was organized into a structure that
closely resembled a LN, with the presence of germinal centers, large
number of plasma cells, and HEVs [95
], findings
subsequently confirmed by other groups [96
,
97
]. They could also show the presence of ectopic
lymphoid follicles with HEVs in the thymus of some patients with the
antibody-mediated autoimmune disease myasthenia gravis (MG)
[98
]. It has later been shown that the autoantigen in
MG, the nicotinic acetylcholine receptor, is naturally present in the
thymus and that germinal centers in the thymus of MG patients contain
activated B lymphocytes and plasma cells that produce antibodies
against this autoantigen [99
]. Different mechanism
leading to intrathymic development of autoreactive B cell clones in MG
have been proposed, including high intrathymic expression of CD23
[100
] and failure to down-regulate the Bcl-2 protein in
the thymic germinal centers [101
]. Removal of the
thymus, thymectomy, is a standard treatment of MG and the clinical
signs of muscle weakness ameliorates in many patients after this
treatment, indicating a functional role of the ectopic lymphoid tissue
in the autoimmune reaction [102
].
Lymphoid neogenesis is also a characteristic of a number of other human
autoimmune diseases (see Table 1
). In multiple sclerosis, organized lymphoid tissue has been found
in the lesions of the central nervous system [103
]. The
rheumatoid disease Sjögren’s syndrome has been shown to be
characterized by both morphological and functional features of lymphoid
neogenesis, such as presence of HEVs [104
], dendritic
cells and FDCs [105
, 106
], and
antigen-driven clonal proliferation of B cells and lymphoid follicles
with clonally expanded lymphocytes [107
108
109
]. It is
interesting that a gene-modified mouse strain deficient in the
molecular adaptor Cbl-b spontaneously develops lymphoid structures in
primarily the salivary glands and it will be interesting to determine
whether this mouse strain has other features of lymphoid neogenesis
such as expression of homing chemokines [110
]. In the
salivary gland inflammation of patients with Sjögren’s syndrome
expression of both the homing chemokine CXCL13 and its receptor CXCR5
have been observed [unpublished observations]. Rheumatoid arthritis
is the human disease where lymphoid neogenesis has been most
extensively studied. As early as 1964, Ziff compared the inflamed
rheumatic synovial tissue with a LN where primary immunization occurs
[111
], and extensive morphological evidence for lymphoid
neogenesis in rheumatoid arthritis has since been accumulated
[112
113
114
115
116
117
118
119
120
121
]. In addition, strong functional evidence
suggests that de novo formation of a lymphoid organ occurs
in chronic synovial inflammation in rheumatoid arthritis. B cell
diversification and somatic hypermutation of antibodies occur in
lymphoid follicles in the inflamed joint [118
,
122
] and Berek and colleagues recently showed that plasma
cells develop in synovial germinal centers in rheumatoid arthritis
[123
]. These findings strongly suggest that naive B
cells are activated by antigens directly in germinal center reactions
in ectopic lymphoid tissue in the synovia. Both CD8+ T
cells expressing the CD40 ligand and professional antigen-presenting
cells such as dendritic cells appear to play an important role in the
formation of these germinal centers in synovitis [119
].
Preliminary data indicate that the homing chemokine CXCL13 is present
in synovial follicles of patients with rheumatoid arthritis (Fig. 1)
[unpublished observations]. It is important to note, however, that
rheumatoid arthritis, like the other autoimmune diseases, is
heterogeneous and that not all patients have morphological evidence of
lymphoid neogenesis [124
125
126
]. Clearly, other
mechanisms must lead to sustained arthritis in many patients.
|
LYMPHOID NEOGENESIS IN INFECTIOUS DISEASES
|
|---|
Lymphoid neogenesis has not only been found in autoimmune
diseases, but also in some chronic infectious diseases. Intrahepatic
lymphoid nodules with functional germinal centers can often be seen in
chronic hepatitis C [127
128
129
130
] and chronic Lyme
synovitis has been found to closely resemble LNs with HEVs
[131
]. Gastric infection with Helicobacter
pylori induces formation of lymphoid tissue in the gastric mucosa,
and this lymphoid neogenesis has also been associated with development
of primary gastric mucosa-associated lymphoid tissue (MALT) B cell
lymphomas [93
, 132
133
134
135
136
]. It is interesting
that Mazzuccheli and colleagues link lymphoid neogenesis and
development of MALT lymphomas in Helicobacter pylori
gastritis to expression of CXCL13 [93
].
|
LYMPHOID NEOGENESIS AND DEVELOPMENT OF LYMPHOMAS
|
|---|
Chronic inflammation with lymphoid neogenesis seems to be able to
induce neoplastic transformation of lymphocytes from ectopic germinal
centers leading to, in particular, B cell MALT-lymphomas
[137
]. Autoimmune diseases that have been associated
with a highly increased risk for development of lymphomas include for
instance Hashimoto’s thyroiditis [138
,
139
], rheumatoid arthritis [140
],
Sjögren’s syndrome [109
, 141
,
142
], and celiac disease [143
,
144
]. Chronic inflammatory infectious diseases are also
associated with an increased risk for neoplastic transformation, best
exemplified in Helicobacter pylori-induced gastritis as
mentioned above. Low-grade B cell MALT-lymphomas developed against a
background of chronic inflammation seem to be T cell-dependent because
they respond to autologous T cell help [145
] and express
co-stimulatory molecules [146
]. Continuous antigen
stimulation has been shown to be crucial for these lymphomas as they
regress in their early stages upon eradication of the antigenic
stimulus [147
148
149
150
]. The hypothesis that MALT
lymphomagenesis in its early steps require antigen stimulation is
furthermore supported by findings of a restricted immunoglobulin
VH gene repertoire and ongoing Ig gene hypermutation in
salivary gland MALT lymphomas associated with Sjögren’s syndrome
myoepithelial sialadenitis [151
]. A continuous antigen
drive leading to lymphoid neogenesis and formation of lymphoid tissue
in a microenvironment where normal regulatory mechanisms probably are
absent thus seem to be able to cause both autoimmunity and neoplastic
transformation.
|
THE PHYSIOLOGICAL AND PATHOLOGICAL ROLE OF LYMPHOID NEOGENESIS
|
|---|
A geographical view of immune reactivity, in which an immune
response depends upon antigen reaching and being available in secondary
lymphoid organs in a dose- and time-dependent manner, was recently
proposed by Zinkernagel and co-workers [46
,
152
, 153
]. In some forms of chronic
inflammation, this geographical view is reversed and ectopic lymphoid
tissue is formed close to the antigen in the peripheral solid tissue
where antigens are available in sufficient concentration and during
time enough to promote antigen presentation and immune reactions.
Lymphoid neogenesis might provide a focal region where interactions
between immune cells, antigen-bearing cells, and pathogens can proceed
potentially more efficiently than in normal lymphoid organs. The
physiological role for lymphoid neogenesis is, however, so far unknown
and as the reaction occurs in a microenvironment where normal
mechanisms that should operate to prevent the expansion and maturation
of autoreactive T and B cells probably are absent there is a risk for
autoimmunity and neoplastic transformation. A local infection or
cell-destruction in an adult animal might lead to a burst of previously
ignored self-antigens, which directly triggers lymphoid neogenesis and
autoimmune reactions in tissues where the self-antigen is continuously
expressed. Many autoimmune diseases show a predilection for specific
organs and it is possible that autoimmune reactions can be induced and
sustained only in tissues where self-antigens are continuously
expressed in an appropriate cytokine and chemokine milieu for
differentiation of HEVs and initiation of lymphoid neogenesis. Chronic
inflammation induced by T cell-mediated cytokine signals in transgenic
animals differs in various tissues, and a caveat of the present studies
of lymphoid neogenesis is that most experiments have been done of
pancreatic inflammation that is characterized by infiltration of
mononuclear cells and expression of chemokines specific for Th1
lymphocytes [154
]. Future experiments with other
promoters than the RIP will allow a more precise delineation of tissue
and cell-specific factors in lymphoid neogenesis. Another limitation
with the present studies using genetically manipulated mice is the lack
of experiments using conditionally regulated knockouts and transgenes
that would allow kinetic analysis of lymphoid neogenesis in the adult
animal. Furthermore, an increasing number of other candidate proteins
important for lymphoid organogenesis and differentiation of HEVs during
development wait to be studied in vivo in transgenic and
knockout models of lymphoid neogenesis and chronic inflammation.
|
CONCLUSION
|
|---|
Evidence has accumulated that some forms of chronic inflammation
can be viewed as a form of lymphoid neogenesis and that TNF proteins
and homing chemokines play important roles in this process. Continuous
antigen presentation might be the driving force behind lymphoid
neogenesis and subsequent development of germinal center-derived
lymphomas. From a clinical point of view this emphasizes the need to
detect and suppress the antigenic drive aggressively to prevent
malignant transformation. Removal of the antigen is already a
therapeutic approach in, for instance, celiac disease or
Helicobacter pylori-induced gastritis, whereas the therapy
for most other diseases with lymphoid neogenesis traditionally is based
upon general immunosuppression. In recent years, however, new specific
immunomodulatory therapies have been developed targeting in particular
the TNF family of proteins, and it is still unknown whether these
therapies will inhibit lymphoid neogenesis or development of lymphomas.
Our expanding knowledge about homing chemokines and other molecular
mediators of lymphoid neogenesis give hope for development of new and
more specific therapeutics for chronic inflammatory diseases.
|
ACKNOWLEDGEMENTS
|
|---|
This study was supported by the Jeansson Foundation, the Swedish
Rheumatism Association, the King Gustaf V’s 80-year Foundation and the
Karolinska Institute. The author thanks Helena Hildenwall for technical
assistance and Nancy H. Ruddle and Åke Lernmark for valuable
discussions.
Received August 2, 2000;
revised October 21, 2000;
accepted October 25, 2000.
|
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ABSTRACT
INTRODUCTION
