| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Short Communications |
From the Department of Epidemiology and Public Health and Section
of Immunobiology*
and the Department of Neurology and
Neuroscience Research Center,
Yale University
School of Medicine, New Haven, Connecticut
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
(LT), a cytokine crucial for
development of lymphoid organs, is important for expression of
SLC and BLC in secondary lymphoid organs during development. Here we
report that transgenic expression of LT induces inflammation and
ectopic expression of SLC and BLC in the adult animal. LTß was not
necessary for induction of BLC and SLC in inflamed tissues,
whereas, in contrast, tumor necrosis factor receptor-1
was found to be important for the LT-mediated induction of these
chemokines. The ectopic expression of LT is associated with a
chronic inflammation that closely resembles organized lymphoid tissue
and this lymphoid neogenesis can also be seen in several chronic
inflammatory diseases, including in the pancreas of the
prediabetic nonobese diabetic (NOD) mouse. Expression of SLC was also
observed in the pancreas of prediabetic NOD mice. This study implicates
BLC and SLC in chronic inflammation and presents further evidence that
LT orchestrates lymphoid organogenesis both during development and
in inflammatory processes.
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
(LT; tumor necrosis factor-ß) plays an
important role in both lymphoid organ development and chronic
inflammation. Mice genetically deficient in LT have profound defects
in lymphoid organ development in that they lack lymph nodes (LNs) and
Peyer’s patches and have a disrupted splenic
organization.1
The inflammation induced by transgenic
expression of LT under the rat insulin promoter (RIPLT mice) in the
pancreas and kidney has several characteristics of lymphoid organs with
regard to cellular composition, including naive and
memory T cells, B cells, dendritic cells, and
follicular dendritic cells. Furthermore, there is T- and B-cell
compartmentalization with formation of B lymphocyte follicles and
germinal center-like structures, a specialized vascular system with
high endothelial venules, and an increased expression of markers
associated with LN endothelium such as mucosal addressin cell adhesion
molecule (MAdCAM) and peripheral lymph node addressin.2,3
This cellular accumulation closely resembles the organized ectopic
lymphoid tissues (tertiary lymphoid organs) seen in a number of human
autoimmune diseases, including type I diabetes, rheumatoid arthritis,
multiple sclerosis, and Hashimoto’s thyroiditis.3
The NOD
mouse spontaneously develops insulitis, which progresses to
islet destruction and diabetes.4
The adhesion molecules
MAdCAM and peripheral lymph node addressin are also expressed in the
prediabetic insulitis of such mice.5
The hypothesis to be
tested here is that the mechanisms by which LT directs lymphoid
organogenesis during embryogenesis and in chronic inflammation are
similar, particularly with regard to chemokine induction.
LT is a member of the immediate tumor necrosis factor (TNF) family
and can be produced either as a secreted LT3 homotrimer or as a
membrane-bound LT1ß2 heterotrimer. The LT3 homotrimer interacts
with the TNFR1 and TNFR2 receptors, whereas the LT1ß2 heterotrimer
binds to the LTß receptor (LTßR). LT is primarily a product of
activated CD4TH1, CD8, and early nonactivated B cells in the adult
animal, and a recent study shows that activated naive T cells also
express high levels of soluble LT3.6
LT has a number
of proinflammatory effects and induces inflammation in vivo
in RIPLT mice at the sites of transgene expression in the pancreas and
kidney.2,3
This occurs even in RIPLT mice genetically
deficient in LTß (RIPLT.LTß -/- mice),7
confirming
earlier in vitro studies indicating that LT3 alone can
induce inflammation.8
The LT3-induced inflammation is
dependent on TNFR1, but not TNFR2, as shown by studies of RIPLT mice
deficient in TNFR1 or TNFR2.7
As noted above, the
LT3-induced inflammation in RIPLT mice exhibits characteristics of
lymphoid organs.
It is likely that LT3 mediates some of its effects through induction
of chemokines, and it has recently been shown that recombinant LT3
induces expression of the chemokines RANTES, IP-10, and MCP-1 in an
endothelial cell line in vitro.9
The same
chemokines are expressed in vivo in the transgene-induced
inflammation in RIPLT mice,5
but as these chemokines do
not preferentially attract naive lymphocytes they are probably not
directly involved in de novo formation of lymphoid tissues.
More likely candidates for the link between lymphoid neogenesis during
development and chronic inflammation are the recently discovered
chemokines BLC (also called BCA-1)10,11
and SLC (also
called 6Ckine, Exodus-2, or TCA-4).12-16
These two
chemokines appear to be important for normal organization of lymphoid
tissue compartments during development. BLC is constitutively expressed
by stromal cells in lymphoid tissues and interacts with the CXCR5
receptor (formerly called Burkitt’s lymphoma receptor 1), which is
primarily expressed on mature B cells. Mice genetically deficient in
CXCR5 lack inguinal LNs, possess few or abnormal Peyer’s patches, and
have a disorganized spleen,17
characteristics similar to
those of LT -/- mice. SLC is expressed by high endothelial venules
in LNs and Peyer’s patches and by stromal cells in the T-cell zone of
secondary lymphoid organs and it has been reported to interact with the
CCR7 and possibly also the CXCR3 receptors expressed primarily on naive
and mature T cells and dendritic cells.18-21
Mice
homozygous for the paucity of lymph node T-cell (plt)
mutation lack expression of SLC and have defects in T-cell homing and
dendritic cell localization in the spleen and LNs.22
A
recent study by Ngo and colleagues23
shows that mice
deficient in any of several members of the LT/TNF ligand and receptor
family indeed have markedly reduced expression of both BLC and SLC in
secondary lymphoid organs. That report suggests that all members of the
family are important for maximal production of these chemokines. The
precise role of secreted LT3 in inducing BLC and SLC expression has
not been defined, nor has the role of the lymphoid trafficking
chemokines in inflammation been previously addressed.
In the present study, we have used the RIPLT transgenic mouse model to
elucidate the mechanisms by which LT induces chronic inflammation in
the kidney and pancreas that is organized into lymphoid tissue. We
report that LT expressed in the kidney induces expression of both
BLC and SLC in chronic inflammation in large part through TNFR1,
although a role for LTßR is confirmed in the spleen. We have tested
the applicability of the conclusions drawn here regarding the parallel
between lymphoid neogenesis and normal development of secondary
lymphoid organs by studying the NOD mouse that spontaneously exhibits
inflammation. We confirm the expression of the SLC in chronic
inflammation by detecting it in the pancreas of prediabetic NOD mice.
Our studies are the first to implicate a role for BLC and SLC in
chronic inflammation, and they present further evidence that chronic
inflammation has characteristics of lymphoid neogenesis and emphasize
the unifying role of LT in the processes.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
The generation and subsequent genotyping of RIPLT.wt, RIPLT.LTß -/-, and RIPLT.TNFR1 -/- mice has been previously described.2,7 Ten-week-old female NOD/Caj mice were kindly provided by Dr. F. Susan Wong from the NOD mouse core colony at Yale University, New Haven, CT. All animals were housed under specific pathogen-free conditions.
In Situ Hybridization
Digoxygenin (DIG)-labeled BLC and SLC antisense and sense probes were prepared by in vitro transcription from I.M.A.G.E. consortium expressed sequence tags 596050 and 389013, obtained from Genome Systems (St. Louis, MO), as previously described.10,16 Transcript yield and integrity of the probes were determined by comparison with control DIG-labeled RNA (Boehringer Mannheim, Mannheim, Germany). Mice were deeply anesthetized and intracardially perfused, first with phosphate-buffered saline and then with 4% paraformaldehyde in 0.14 mol/L Sorenson’s phosphate buffer. Tissues were fixed overnight and snap-frozen in Tissue-Tek OCT compound (VWR Scientific, Bridgeport, NJ) and stored at -70°C. Sections of 5- to 10-µm thickness were cut onto poly-L-lysine-treated glass slides and in situ hybridization was done as previously described.24 In brief, sections were fixed in 4% paraformaldehyde, pretreated with Proteinase K (Boehringer Mannheim) and acetic anhydride, prehybridized, hybridized overnight at 58°C with the DIG-labeled riboprobes, washed at high stringency, incubated with anti-DIG antibody conjugated to alkaline phosphatase (Boehringer Mannheim), and developed with nitro blue tetrazolium/5-bromo-4-chloro-3-indole-phosphate.
Northern Blot Analysis
Twenty micrograms of total RNA from spleens and kidneys of 5-week-old mice was subjected to gel electrophoresis, transferred to positively charged nylon membrane (Boehringer Mannheim), and probed using DIG-labeled BLC- and SLC-specific antisense riboprobes. The hybridization signal was detected by chemiluminescence using disodium -3-(4-methoxyspiro{1,2-dioxetane-3,2'-(5'-chloro) tricyclo [3.3.1.13,7]decan}-4yl)phenyl phosphate (CSPD) as substrate (Boehringer Mannheim). To control for loading and RNA integrity, membranes were reprobed for ß-actin mRNA using a DIG-labeled riboprobe (Boehringer Mannheim) under similar conditions. The gels were scanned and the relative intensity of the different bands were obtained using Scion Image software (Frederick, MD).
Immunohistochemistry
Mice were deeply anesthetized and sacrificed and tissues for immunohistochemistry were either immediately snap-frozen in Tissue-Tek OCT compound (VWR Scientific) or fixed in periodate-lysine-paraformaldehyde, sucrose infused, and then frozen in Tissue-Tek OCT. Sections of 5- to 8-µm thickness were cut onto poly-L-lysine-coated slides, fixed in acetone, and rehydrated in phosphate-buffered saline, pH 7.4, with 0.01% Triton X-100. To prevent background staining and nonspecific binding of antibodies, sections were treated with 0.2 mol/L HCl and blocked with 3% bovine serum albumin/5% normal goat serum/0.01% Triton X-100 in phosphate-buffered saline. Sections were incubated overnight at 4°C with a rabbit anti-murine SLC antibody (Pepro Tech, Rocky Hill, NJ). The control was rabbit IgG control antibodies (I-1000) from Vector Laboratories (Burlingame, CA). After washing, a secondary biotinylated anti-rabbit antibody (Vector Laboratories) was applied, followed by incubation with alkaline-phosphatase-streptavidin (Vector Laboratories). Enzymatic reactivity was visualized with Vector Red (Vector Laboratories) according to the manufacturer’s instructions. Tissues were counterstained in 3% methyl green.
|
Results and Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
Induces mRNA Expression of BLC and SLC
To determine the effect of locally produced LT on mRNA
expression of the homing chemokines BLC and SLC in vivo,
Northern blotting was performed on kidneys from RIPLT.wt mice (Figure 1)
. For these studies we concentrated on
the chronic inflammatory infiltrates seen at the site of LT
expression in the proximal tubules of the kidneys in RIPLT mice rather
than in the pancreas. The kidneys exhibit more inflammation and lack
adjacent lymphoid structures, such as the peripancreatic LNs, that
could have confounded interpretations. Both BLC and SLC mRNA
transcripts were detected in the kidneys of RIPLT.wt mice, but not in
kidneys from control wild-type mice. The increase in staining by
densitometry of SLC mRNA in RIPLT kidney was 41 times that of wild-type
kidney. BLC was increased threefold over wild-type kidney. In
situ hybridization analysis of kidneys from RIPLT.wt mice
confirmed the presence of BLC and SLC mRNA expression (Figure 2, A and B)
. The expression pattern was
similar to that seen in the spleen and LNs of wild-type animals; BLC
appeared to be produced by cells other than mononuclear cells, whereas
nonmononuclear and endothelial cells expressed SLC. In a previous
study, such nonmononuclear cells were identified as stromal cells by
their expression of BP-3.23
This analysis was not carried
out here. Notably, inflammatory infiltrates were always found adjacent
to expression of SLC and BLC, consistent with the chemotactic activity
of these chemokines. Occasionally there was very low level expression
of SLC in wild-type kidneys, consistent with previous reports of SLC
expression in several tissues.
|
|
has recently been shown to induce expression of the chemokines
RANTES, IP-10, and MCP-1 both in an endothelial cell line in
vitro9
and at the sites of transgene expression in
RIPLT.wt mice in vivo.5
These chemokines are
found even in RIPLT.RAG2 -/- mice, which have a reduced inflammatory
infiltrate, suggesting a direct action of LT in their induction. It
is likely that these chemokines contribute to the recruitment of
leukocytes that are distinct from those recruited by BLC and SLC in the
RIPLT kidneys. It is also likely that LT induces expression of
additional lymphoid organizing chemokines, such as Epstein-Barr
virus-induced molecule 1 ligand chemokine/macrophage
inflammatory protein-3ß. Further studies with RIPLT mice deficient
in various chemokine ligands and receptors will determine the role of
the individual chemokines in LT-induced inflammation. LT could
induce expression of BLC and SLC through direct and/or indirect
mechanisms. Indirect mechanisms could, for instance, include production
by infiltrating cells of other factors inducing expression of homing
chemokines. In vitro studies with recombinant LT protein
and in vivo studies with transgenic mice lacking certain
cell types will identify what role, if any, the infiltrating
cells play in the expression of homing chemokines in
LT-induced inflammation.
LT-Induced Expression of BLC and SLC Is Not Dependent on LTß
Expression
It has previously been shown that the presence of
RIPLT-induced inflammation is not dependent on LTß expression,
although its cellular composition with regard to naive and memory cells
is influenced by that cytokine.5,7
Ngo et
al23
have reported that LTß-deficient mice have
diminished expression of BLC and SLC in the spleen, and treatment of
adult mice with LTß antagonists reduces the splenic expression of
these chemokines, suggesting a role for expression of membrane
LT1ß2 in maintaining normal levels of BLC and SLC. To determine
whether LT1ß2 heterotrimer is necessary for BLC and SLC expression
in RIPLT-induced chronic inflammation, kidneys from RIPLT.LTß -/-
mice were analyzed by Northern blotting and in situ
hybridization. As shown in Figure 1
and Figure 2, C and D
, LTß is not
needed for RIPLT-induced BLC and SLC expression in the inflammatory
sites. In fact, SLC mRNA was increased 65-fold in RIPLT.LTß-/-
kidneys compared to wild type, and BLC was increased threefold compared
to wild-type. These levels are comparable or higher than that seen in
RIPLT.wt kidney. Homotrimeric LT3 alone is thus capable of inducing
expression of these chemokines. This is consistent with previous
observations that LTß is not required for LT-induced expression of
the proinflammatory chemokines RANTES, IP-10, and MCP-1 both in
vitro,9
and in vivo.5
Interestingly, in contrast, we can confirm the important role of LTß
for expression of SLC and BLC in secondary lymphoid organs, as the
spleens and mesenteric LN of RIPLT.LTß -/- mice did exhibit reduced
expression of SLC and BLC (data not shown) as has been noted previously
in LTß-/- mice.23
The TNFR1 Receptor Plays an Important Role in
LT3-Induced Expression of BLC and SLC
Mice that expressed the RIPLT transgene in the absence
of TNFR1 were analyzed for BLC and SLC expression in the kidneys.
Expression of BLC and SLC was markedly reduced at the site of transgene
expression as determined by Northern blotting (Figure 1)
and in
situ hybridization (Figure 2, E and F)
, in RIPLT.TNFR1-/- mice,
in agreement with the previous finding that TNFR1 is important for
LT3-induced inflammation and lymphoid neogenesis.7
The
signals for SLC and BLC mRNA were approximately three times less
intense than those seen for RIPLT.wt kidneys. The reduction, but not
complete loss, of BLC and SLC expression induced by locally produced
LT in the absence of TNFR1 is consistent with the finding that TNFR1
deficient mice still have some constitutive expression of these
chemokines in the spleen (23; and our unpublished data), implicating a
role for LTßR during development. In inflammation, there might be a
role for an additional non-LTß, non-TNFR1 receptor.
SLC mRNA Is Detected in the Chronic Pancreatic Inflammation of Prediabetic NOD Mice
We were interested to determine whether the increased expression
of homing chemokines seen in the somewhat artificial situation of
transgene-induced inflammation was also seen in a spontaneous model of
inflammation. We first analyzed expression of SLC mRNA in the pancreas
of the RIPLT mouse and found that it was apparent in and around areas
of inflammation, with particular prominence in the vessel walls (Figure 3A)
. We then analyzed expression of SLC
mRNA in the insulitis seen in the pancreas of prediabetic female NOD
mice. The chronic inflammation in NOD mice has characteristics of
lymphoid neogenesis and is present for several weeks without tissue
destruction before the onset of diabetes.4
We detected SLC
mRNA in the islets of Langerhans in the prediabetic female NOD mouse
(Figure 3B)
. This was apparent in both the infiltrates and in the
vessel walls and connective tissue. It appeared to be limited to the
areas near those islets that contained infiltrates. SLC mRNA was rarely
detected and when present it was at very low levels in the pancreas
from healthy control wild-type mice. SLC protein was also detected in
RIPLT and NOD pancreas (data not shown). These observations in a
spontaneous inflammatory model confirm and extend the observations with
the transgene-induced inflammation. These data indicate that homing
chemokines are not restricted to development, but are also
characteristic of lymphoid neogenesis in inflammation. The role of the
LT/TNF family in NOD diabetes is unclear and complex. Nevertheless,
TNF- and TNF receptors (which can also be used by LT) are
expressed in the pancreas of NOD mice.25,26
Our data
suggest that one role for this family of cytokines in inflammation
could be through induction of homing chemokines.
|
3 alone
is a potent inducer of adhesion molecules normally expressed in
lymphoid tissues, such as MAdCAM-1.5,9
MAdCAM-1 is
expressed on high endothelial venules in the developing mesenteric and
peripheral LN of perinatal animals and the mesenteric LN and Peyer’s
patches of adult animals.27
Induction of MAdCAM-1 by
LT3 may be an early event in the development of LNs. It is
interesting that SLC has been found to stimulate
4ß7 (LPAM-1) mediated
adhesion to MAdCAM-1,28
and the present study thus
indicates that LT3, in addition to regulating expression of
MAdCAM-1, also stimulates MAdCAM-1 mediated homing through induction of
SLC production. Another similarity between sites of inflammation and
lymphoid organs that might be mediated by chemokines induced by LT3
is homing of antigen-presenting dendritic cells. SLC has recently been
found to be an important chemoattractant for dendritic cells both
in vivo and in vitro.22,29-32
Both
interdigitating and follicular dendritic cells are present in the
infiltrate of RIPLT mice,3
and it will be interesting to
see if these cells have been recruited by certain chemokines by
studying RIPLT mice deficient in chemokine ligands and receptors. In
conclusion, our findings support the challenging hypothesis that LT3
is important for local recruitment of both lymphoid and
antigen-presenting cells and orchestrates lymphoid neogenesis during
the immune response through regulation of adhesion molecules and
chemokines normally found in secondary lymphoid organs. Furthermore the
observation in the NOD mouse suggests that this phenomenon has
relevance for understanding the mechanisms of inflammation in
autoimmune diseases. Formation of ectopic lymphoid follicles with
germinal centers occurs in a number of chronic inflammatory diseases
and a detailed understanding of the processes leading to this lymphoid
neogenesis will provide a rationale for development of new
therapeutics.
|
Acknowledgements |
|---|
|
Footnotes |
|---|
Supported by National Cancer Institute grant R01 CA16885 and 5P30 DK45735, a fellowship from the Swedish Foundation for International Cooperation in Research and Higher Education (P. H.), The Blancheflor Boncompagni-Ludovisi née Bildt Foundation (J. F.), the Japan Society of the Promotion of Science (T. N.), the NIH Office of Research on Womens’ Health Re-entry Program (R. S.), and National Institutes of Health grant T32 AI 07019 (C. A. C.).
P. Hjelmström’s present address is Department of Medicine, Rheumatology Research Laboratory, Karolinska Institute, SE-171, 76 Stockholm, Sweden; R. Sacca’s present address is Department of Genetic Technologies, Central Research Division, Pfizer Inc, Groton, CT 06340; C.A. Cuff’s present address is The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104.
Accepted for publication December 22, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
3 and LTß in inflammation elucidates potential mechanisms of mesenteric and peripheral lymph node development. J Immunol 1999, 162:5965-5972. J Immunol 1999, 162:3790-37943 and membrane lymphotoxin-1ß2 in lymphotoxin-induced inflammation: critical role of TNF receptor 1 signaling. J Immunol 1998, 160:485-4913 induces chemokines, and adhesion molecules: insight into the role of LT in inflammation and lymphoid organ development. J Immunol 1998, 161:6853-6860This article has been cited by other articles:
 |
|
 |
|
  V F Panoulas, S N Nikas, J P Smith, K M J Douglas, P Nightingale, H J Milionis, G J Treharne, T E Toms, M D Kita, and G D Kitas Lymphotoxin 252A>G polymorphism is common and associates with myocardial infarction in patients with rheumatoid arthritis Ann Rheum Dis, November 1, 2008; 67(11): 1550 - 1556. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. R. Mullegger, T. K. Means, J. J. Shin, M. Lee, K. L. Jones, L. J. Glickstein, A. D. Luster, and A. C. Steere Chemokine Signatures in the Skin Disorders of Lyme Borreliosis in Europe: Predominance of CXCL9 and CXCL10 in Erythema Migrans and Acrodermatitis and CXCL13 in Lymphocytoma Infect. Immun., September 1, 2007; 75(9): 4621 - 4628. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Rangel-Moreno, J. E. Moyron-Quiroz, L. Hartson, K. Kusser, and T. D. Randall Pulmonary expression of CXC chemokine ligand 13, CC chemokine ligand 19, and CC chemokine ligand 21 is essential for local immunity to influenza PNAS, June 19, 2007; 104(25): 10577 - 10582. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. P. Martin, J. M. Alexander-Brett, C. Canasto-Chibuque, A. Garin, J. S. Bromberg, D. H. Fremont, and S. A. Lira The Chemokine Binding Protein M3 Prevents Diabetes Induced by Multiple Low Doses of Streptozotocin J. Immunol., April 1, 2007; 178(7): 4623 - 4631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. V. Bagaeva, P. Rao, J. M. Powers, and B. M. Segal CXC chemokine ligand 13 plays a role in experimental autoimmune encephalomyelitis. J. Immunol., June 15, 2006; 176(12): 7676 - 7685. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. C. Nacionales, K. M. Kelly, P. Y. Lee, H. Zhuang, Y. Li, J. S. Weinstein, E. Sobel, Y. Kuroda, J. Akaogi, M. Satoh, et al. Type I Interferon Production by Tertiary Lymphoid Tissue Developing in Response to 2,6,10,14-Tetramethyl-Pentadecane (Pristane) Am. J. Pathol., April 1, 2006; 168(4): 1227 - 1240. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Carriere, R. Colisson, C. Jiguet-Jiglaire, E. Bellard, G. Bouche, T. Al Saati, F. Amalric, J.-P. Girard, and C. M'Rini Cancer Cells Regulate Lymphocyte Recruitment and Leukocyte-Endothelium Interactions in the Tumor-Draining Lymph Node Cancer Res., December 15, 2005; 65(24): 11639 - 11648. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. A. Rupprecht, H. W. Pfister, B. Angele, S. Kastenbauer, B. Wilske, and U. Koedel The chemokine CXCL13 (BLC): A putative diagnostic marker for neuroborreliosis Neurology, August 9, 2005; 65(3): 448 - 450. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. G. McDonald, J. S. McDonough, and R. D. Newberry Adaptive Immune Responses Are Dispensable for Isolated Lymphoid Follicle Formation: Antigen-Naive, Lymphotoxin-Sufficient B Lymphocytes Drive the Formation of Mature Isolated Lymphoid Follicles J. Immunol., May 1, 2005; 174(9): 5720 - 5728. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Burman, O. Haworth, D. L. Hardie, E. N. Amft, C. Siewert, D. G. Jackson, M. Salmon, and C. D. Buckley A Chemokine-Dependent Stromal Induction Mechanism for Aberrant Lymphocyte Accumulation and Compromised Lymphatic Return in Rheumatoid Arthritis J. Immunol., February 1, 2005; 174(3): 1693 - 1700. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Cupedo and R. E. Mebius Cellular Interactions in Lymph Node Development J. Immunol., January 1, 2005; 174(1): 21 - 25. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Ying, K. Chan, P. Shenoy, M. Hill, and N. H. Ruddle Lymphotoxin Plays a Crucial Role in the Development and Function of Nasal-Associated Lymphoid Tissue through Regulation of Chemokines and Peripheral Node Addressin Am. J. Pathol., January 1, 2005; 166(1): 135 - 146. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. Martin, E. C. Coronel, G.-i. Sano, S.-C. Chen, G. Vassileva, C. Canasto-Chibuque, J. D. Sedgwick, P. S. Frenette, M. Lipp, G. C. Furtado, et al. A Novel Model for Lymphocytic Infiltration of the Thyroid Gland Generated by Transgenic Expression of the CC Chemokine CCL21 J. Immunol., October 15, 2004; 173(8): 4791 - 4798. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Cupedo, F. E. Lund, V. N. Ngo, T. D. Randall, W. Jansen, M. J. Greuter, R. de Waal-Malefyt, G. Kraal, J. G. Cyster, and R. E. Mebius Initiation of Cellular Organization in Lymph Nodes Is Regulated by Non-B Cell-Derived Signals and Is Not Dependent on CXC Chemokine Ligand 13 J. Immunol., October 15, 2004; 173(8): 4889 - 4896. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Wareing, A. B. Lyon, B. Lu, C. Gerard, and S. R. Sarawar Chemokine expression during the development and resolution of a pulmonary leukocyte response to influenza A virus infection in mice J. Leukoc. Biol., October 1, 2004; 76(4): 886 - 895. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. R. Vuillemenot, J. F. Rodriguez, and G. W. Hoyle Lymphoid Tissue and Emphysema in the Lungs of Transgenic Mice Inducibly Expressing Tumor Necrosis Factor-{alpha} Am. J. Respir. Cell Mol. Biol., April 1, 2004; 30(4): 438 - 448. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. Voon, L. S. Subrata, M. Karimi, D. Ulgiati, and L. J. Abraham TNF and Phorbol Esters Induce Lymphotoxin-{beta} Expression through Distinct Pathways Involving Ets and NF-{kappa}B Family Members J. Immunol., April 1, 2004; 172(7): 4332 - 4341. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Buckley Why do leucocytes accumulate within chronically inflamed joints? Rheumatology, December 1, 2003; 42(12): 1433 - 1444. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Katakai, T. Hara, M. Sugai, H. Gonda, and A. Shimizu Th1-Biased Tertiary Lymphoid Tissue Supported by CXC Chemokine Ligand 13-Producing Stromal Network in Chronic Lesions of Autoimmune Gastritis J. Immunol., October 15, 2003; 171(8): 4359 - 4368. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Schiffer, J. Sinha, X. Wang, W. Huang, G. von Gonsdorff, M. Schiffer, M. P. Madaio, and A. Davidson Short Term Administration of Costimulatory Blockade and Cyclophosphamide Induces Remission of Systemic Lupus Erythematosus Nephritis in NZB/W F1 Mice by a Mechanism Downstream of Renal Immune Complex Deposition J. Immunol., July 1, 2003; 171(1): 489 - 497. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. H. Shomer, J. G. Fox, A. E. Juedes, and N. H. Ruddle Helicobacter-Induced Chronic Active Lymphoid Aggregates Have Characteristics of Tertiary Lymphoid Tissue Infect. Immun., June 1, 2003; 71(6): 3572 - 3577. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Drayton, X. Ying, J. Lee, W. Lesslauer, and N. H. Ruddle Ectopic LT{alpha}{beta} Directs Lymphoid Organ Neogenesis with Concomitant Expression of Peripheral Node Addressin and a HEV-restricted Sulfotransferase J. Exp. Med., May 5, 2003; 197(9): 1153 - 1163. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Weninger, H. S. Carlsen, M. Goodarzi, F. Moazed, M. A. Crowley, E. S. Baekkevold, L. L. Cavanagh, and U. H. von Andrian Naive T Cell Recruitment to Nonlymphoid Tissues: A Role for Endothelium-Expressed CC Chemokine Ligand 21 in Autoimmune Disease and Lymphoid Neogenesis J. Immunol., May 1, 2003; 170(9): 4638 - 4648. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Y. Savinov, F. S. Wong, A. C. Stonebraker, and A. V. Chervonsky Presentation of Antigen by Endothelial Cells and Chemoattraction Are Required for Homing of Insulin-specific CD8+ T Cells J. Exp. Med., March 3, 2003; 197(5): 643 - 656. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Jiang, N. Takahashi, N. Matsui, T. Tetsuka, and T. Okamoto The NF-kappa B Activation in Lymphotoxin beta Receptor Signaling Depends on the Phosphorylation of p65 at Serine 536 J. Biol. Chem., January 3, 2003; 278(2): 919 - 926. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L E Schiffer, N Hussain, X Wang, W Huang, J Sinha, M Ramanujam, and A Davidson Lowering anti-dsDNA antibodies--what's new? Lupus, December 1, 2002; 11(12): 885 - 894. [Abstract] [PDF]
|
|
|
|
 |
|
 H S Carlsen, E S Baekkevold, F-E Johansen, G Haraldsen, and P Brandtzaeg B cell attracting chemokine 1 (CXCL13) and its receptor CXCR5 are expressed in normal and aberrant gut associated lymphoid tissue Gut, September 1, 2002; 51(3): 364 - 371. [Abstract] [Full Text]
|
|
|
|
|
|
S. A. Luther, A. Bidgol, D. C. Hargreaves, A. Schmidt, Y. Xu, J. Paniyadi, M. Matloubian, and J. G. Cyster Differing Activities of Homeostatic Chemokines CCL19, CCL21, and CXCL12 in Lymphocyte and Dendritic Cell Recruitment and Lymphoid Neogenesis J. Immunol., July 1, 2002; 169(1): 424 - 433. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. F. Debes, U. E. Hopken, and A. Hamann In Vivo Differentiated Cytokine-Producing CD4+ T Cells Express Functional CCR7 J. Immunol., June 1, 2002; 168(11): 5441 - 5447. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Browning and L. E. French Visualization of Lymphotoxin-{beta} and Lymphotoxin-{beta} Receptor Expression in Mouse Embryos J. Immunol., May 15, 2002; 168(10): 5079 - 5087. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Grant, S. Goddard, J. Ahmed-Choudhury, G. Reynolds, D. G. Jackson, M. Briskin, L. Wu, S. G. Hubscher, and D. H. Adams Hepatic Expression of Secondary Lymphoid Chemokine (CCL21) Promotes the Development of Portal-Associated Lymphoid Tissue in Chronic Inflammatory Liver Disease Am. J. Pathol., April 1, 2002; 160(4): 1445 - 1455. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Ploix, D. Lo, and M. J. Carson A Ligand for the Chemokine Receptor CCR7 Can Influence the Homeostatic Proliferation of CD4 T Cells and Progression of Autoimmunity J. Immunol., December 15, 2001; 167(12): 6724 - 6730. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Christopherson II and R. Hromas Chemokine Regulation of Normal and Pathologic Immune Responses Stem Cells, September 1, 2001; 19(5): 388 - 396. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Weyand, P. J. Kurtin, and J. J. Goronzy Ectopic Lymphoid Organogenesis : A Fast Track for Autoimmunity Am. J. Pathol., September 1, 2001; 159(3): 787 - 793. [Full Text] [PDF]
|
|
|
|
|
|
S. Takemura, A. Braun, C. Crowson, P. J. Kurtin, R. H. Cofield, W. M. O'Fallon, J. J. Goronzy, and C. M. Weyand Lymphoid Neogenesis in Rheumatoid Synovitis J. Immunol., July 15, 2001; 167(2): 1072 - 1080. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Abe, S. C. Donnelly, T. Peng, R. Bucala, and C. N. Metz Peripheral Blood Fibrocytes: Differentiation Pathway and Migration to Wound Sites J. Immunol., June 15, 2001; 166(12): 7556 - 7562. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Hjelmström Lymphoid neogenesis: de novo formation of lymphoid tissue in chronic inflammation through expression of homing chemokines J. Leukoc. Biol., March 1, 2001; 69(3): 331 - 339. [Abstract] [Full Text]
|
|
|
|
|
|
K. Shi, K. Hayashida, M. Kaneko, J. Hashimoto, T. Tomita, P. E. Lipsky, H. Yoshikawa, and T. Ochi Lymphoid Chemokine B Cell-Attracting Chemokine-1 (CXCL13) Is Expressed in Germinal Center of Ectopic Lymphoid Follicles Within the Synovium of Chronic Arthritis Patients J. Immunol., January 1, 2001; 166(1): 650 - 655. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Serafini, S. Columba-Cabezas, F. Di Rosa, and F. Aloisi Intracerebral Recruitment and Maturation of Dendritic Cells in the Onset and Progression of Experimental Autoimmune Encephalomyelitis Am. J. Pathol., December 1, 2000; 157(6): 1991 - 2002. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
