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Department of Orthopedic Surgery, Osaka University Medical School, Suita, Osaka, Japan; and
National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. Within the inflamed synovium, there is an accumulation of lymphoid and myeloid cells, including T cells, B cells, and monocytes. The local activation of these cells is thought essential in perpetuating chronic inflammation and accelerating joint damage (6, 7). T cells and B cells in RA synovium frequently accumulate underneath the synovial surface and organize into lymphocyte aggregates with certain features of GC (8, 9), including the local differentiation of FDC and plasma cells (PC) and the production of large amounts of Ab (10, 11). The development of these structures appears to contribute to the pathogenesis of the disease by leading to the local production of the autoantibody, rheumatoid factor.
The mechanism underlying the formation of lymphocyte aggregates and GC-like structures in RA synovium has not been elucidated. In the present study, we explored the hypothesis that local expression of BCA-1 might play a role. BCA-1 expression in synovia of RA and osteoarthritis (OA) was assessed, and its distribution and relationship to the location of T cells, B cells, macrophages, and FDC were examined. BCA-1 was expressed by FDC in GC of RA and OA synovia and was found in regions of B cell aggregation. Therefore, BCA-1 may play a central role in attracting B cells to form GC in the synovium of patients with chronic arthritis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Tissue samples were obtained from seven patients with RA (mean age, 54.4 years; range, 29–71 years) and eight patients with knee OA (mean age, 74.1 years; range, 65–86 years) during surgeries. RA was diagnosed according to the American College of Rheumatology (ACR) criteria for the classification of RA (12), and OA was diagnosed according to ACR criteria for the classification of OA of the knee (13). Tissue samples of normal inguinal lymph nodes were obtained from nonarthritic patients during other surgeries.
Primary Abs
Goat anti-human BCA-1 (R&D Systems, Minneapolis, MN) was used to detect BCA-1. For detection of FDC, Abs for CD21 (clone 1F8; Dako, Glostrup, Denmark) and for dendritic reticulum cells (DRC) (clone R4/23; Dako) were used. mAbs directed against CD3-positive T cells (clone PS1; Medac, Hamburg, Germany), CD20-positive B cells (clone L26; Dako), and CD68-positive macrophages (clone KP1; Dako) were also used.
Primary Abs against another lymphoid chemokine, secondary lymphoid tissue chemokine (SLC) (CCL21; R&D Systems), were also used for immunohistochemistry in RA synovium as well as in normal inguinal lymph nodes as a control.
RNA isolation and RT-PCR
RA and OA tissues obtained at surgery were minced and weighed.
One milligram of the tissue was dissolved with 1 ml of Isogen
(Nippongene, Tokyo, Japan) and sonicated. RNA was extracted in
accordance with the company’s directions. Two micrograms of the
extracted RNA was treated with DNase I (Life Technologies, Rockville,
MD) to eliminate DNA and reverse-transcribed by SuperScript II
reverse-transcriptase (Life Technologies) at 42°C for 70 min using
oligo (dT) as a primer (Amersham Pharmacia Biotech, Piscataway, NJ).
PCR was conducted with Taq DNA polymerase (AmpliTaq Gold;
Perkin-Elmer Applied Biosystems, Foster City, CA) using 1–3 µl of
cDNA (1.5 mM of MgCl2) on a PCR thermal cycler
(PC-700; Astec, Fukuoka, Japan). The primer pair for BCA-1 was CAG AAT
CCT CTG GAA CTT GAG G (5') and CTT CCA GAC ATT CGG AGA CC (3'), and
that of 
-actin was GTC CTC TCC CAA GTC CAC ACA (5') and CTG GTC TCA
AGT CAG TGT ACA GGT AA (3'). Annealing temperatures used for the
amplifications were 56°C for -actin and 58°C for BCA-1. PCR
products were resolved by electrophoresis on 1.5% agarose gels and
identified with ethidium bromide staining. To adjust the amount of cDNA
of each sample precisely, -actin expression was examined first using
26–30 cycles of RT-PCR to amplify 0.1, 0.2, and 0.3 µl of cDNA.
After resolving the PCR products on agarose gels and identifying the
relevant bands with ethidium bromide, the optimal amounts of cDNA for
analysis were determined. Chemokine expression in this amount of cDNA
was examined using 35, 38, and 40 cycles of PCR amplification, and the
results in the linear part of the amplification curve are indicated in
Fig. 1
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Tissues from RA and OA patients were embedded in Tissue Tek (Sakura, Tokyo, Japan), and stored at -80°C until use. The tissue was cut into 4- to 7-µm sections with a cryostat, dried at room temperature for 1 h, and fixed in 2% paraformaldehyde at 4°C for 8 min. Normal inguinal lymph nodes were treated in the same manner.
For detection of CD3 and CD20, tissue sections were boiled in 10 mM sodium citrate buffer (pH 6.0) in a 90°C water bath for 90 min to unmask the Ags.
After blocking endogenous peroxidase and nonspecific Ags, primary Abs were applied onto tissue sections. Tissues were incubated for 2 h at room temperature for detection of CD3, CD20, CD21, DRC, and CD68 and for 24 h at 4°C for detection of BCA-1 and SLC. Isotype-matched Abs were used for control staining.
Thereafter, detection using the streptavidin biotin-peroxidase complex technique (Histofine SAB-PO Kit; Nichirei, Tokyo, Japan) was conducted. Finally, the sections were developed in 3,3'-diaminobenzidine tetrahydrochloride (Dojindo Laboratories, Kumamoto, Japan) and counterstained with hematoxylin.
Two-color immunofluorescence staining
To determine the expression of BCA-1 by FDC, two-color immunofluorescence staining was performed with CD21 and with DRC, respectively. Two primary Abs raised in different species (BCA-1, goat; CD21 and DRC, mouse) were diluted together and applied onto tissue sections for 24 h at 4°C. Isotype-matched Abs were used for negative control.
FITC-conjugated rabbit anti-goat IgG (Wako, Osaka, Japan) was used as the secondary Ab for BCA-1, and rhodamine-conjugated rabbit anti-mouse Igs (Dako) for CD21 or DRC. Secondary Abs were diluted together and applied onto each tissue section for 30 min at room temperature. Finally, slides were coverslipped with PBS-glycerol with antifading agents (p-phenylenediamine dihydrochloride; Sigma, St. Louis, MO) and observed under a fluorescence microscope (E800; Nikon, Tokyo, Japan) equipped with a standard mercury lamp power supply.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Expression of BCA-1 mRNA was assessed by RT-PCR using mRNA
directly extracted from RA and OA tissues (Fig. 1
). All samples from RA
patients expressed BCA-1, whereas only one of five samples from OA
patients expressed BCA-1.
BCA-1 is expressed in lymphoid follicles of RA and OA synovium
The location of BCA-1 protein expression was determined by
immunohistochemistry (Fig. 2). BCA-1 was
mostly expressed in lymphoid follicles in RA synovium, but no
expression of BCA-1 was recognized in areas of diffuse lymphoid cell
infiltration. Notably, BCA-1 was also detected in a few OA synovia with
follicular lymphocytic infiltrates, but not so obviously as was
observed in RA. No expression of BCA-1 was detected in OA synovia
without lymphoid follicle formation.
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Histological characteristics of each sample were assessed to
determine whether it contained a follicular and/or diffuse lymphocyte
infiltrate (Table I). Of seven RA
samples, four contained follicular and five diffuse infiltrates. Three
of the samples contained both, and one contained no lymphocyte
infiltrates. Of eight OA samples, two contained follicular, one
diffuse, and five no lymphocytic infiltration.
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BCA-1 is expressed in the area of B cell accumulation in lymphoid follicles
Immunohistohemistry for CD3, CD20, or CD68 demonstrated an
accumulation of CD20-positive B cells in the central area of almost all
lymphoid follicles. CD3-positive T cells were aggregated at the
boundary of lymphoid follicles, and CD68-positive macrophages did not
present remarkable expression within lymphoid follicles (Fig. 3). BCA-1 expression was almost
compatible with the accumulation of B cells, and the positivity, which
was expressed as the ratio of the number of BCA-1-positive follicles to
the number of follicles with B cell accumulation, was 100% in RA and
60% in OA (Table I). Notably, aggregations of CD20-positive cells were
not found in regions that did not express BCA-1 in RA.
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BCA-1-positive cells were usually found in the central area of
lymphoid follicles, which could be regarded as GC due to the
accumulation of B cells. CD21-positive cells and DRC-positive cells
were also enriched in those regions (Fig. 4). Furthermore, two-color
immunofluorescence staining demonstrated that BCA-1-positive cells were
observed in the center of lymphoid follicles and colocalized with the
expression of CD21 and DRC, respectively (Fig. 5). These findings demonstrated that
BCA-1 is expressed by FDC in GC, the B cell-rich area of lymphoid
follicles.
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Immunohistochemistry for another lymphoid chemokine, SLC, showed
no notable expression in RA synovium. SLC was not detected even in the
area that was rich in CD3-positive T cells in RA synovium, although it
was observed to express in T cell-rich areas of normal inguinal lymph
nodes that we examined as a positive control (Fig. 6).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Lymphoid follicles are usually observed in secondary lymphoid tissues and organs, such as spleen, tonsils, lymph nodes, and mucosa-associated lymphoid tissues, and are thought to be essential structures for the normal immune response in which Ag-specific B and T cells are expanded against Ags. Lymphoid follicle formation is also observed ectopically in chronic inflammatory sites. Although there is no knowledge of the true role of an ectopic lymphoid follicle in chronic inflammation, it could contribute to Ag presentation in situ, to clonal expansion of Ag-specific B and T cells, and to rendering an acute inflammation into a chronic one (10, 11, 14).
RA is a representative chronic inflammatory arthritis, the pathological mechanism of which could be thought of as being an acute inflammation at the onset, followed by progression of the chronic process (6). Although the mechanism underlying the change of the inflammatory course from acute to chronic has not been elucidated, an immune response to Ag proteins derived from joint structures might be one of the causes of prolonged inflammation. From this point of view, the formation of lymphoid follicles, especially those with GC, which is a typical histological feature of RA synovium, seems an important process in the development of chronic arthritis.
The literature illustrates that lymphoid follicles with GC consist of naive B cells in the central zone surrounded by mature B cells, PCs, and CD4-positive T cells in RA synovium, and there, naive B cells are specifically selected, activated, and clonally expanded, exhibiting isotype switching and somatic hypermutation (8, 9, 10, 11). PCs in RA synovium have been reported to synthesize high amounts of Igs, including rheumatoid factor, which is thought to participate in the pathogenesis of tissue damage (6, 15, 16, 17). Moreover, rheumatoid synoviocytes are reported to support the terminal differentiation of B cells into mature PCs in vitro (18). Based on this knowledge, B cell development in GC might be one of the essential courses in the pathogenesis of RA.
In the formation of GC as well as in the events necessary for B cell
development, FDCs are supposed to be involved (19). It is
also reported that FDC contribute to the apoptosis of B cells in GC via
Fas-Fas ligand (20). As shown in Fig. 3, B cells are
localized around BCA-1 expression in the central area of lymphoid
follicles in RA synovium. Moreover, FDC characterized by CD21 and DRCs
has been observed to express BCA-1 in GC of the follicles (Figs. 4 and 5). These results indicate that FDC might play crucial roles in
constructing GC in RA synovium and that BCA-1 produced by FDC might act
as a potent chemoattractant of naive B cells into the synovium.
In this study, BCA-1 expression was recognized in all RA samples, although the formation of lymphoid follicles was observed histologically in four of seven RA patients. The most explanatory reason for this discrepancy could be the sampling issue; the part without lymphoid follicles might be used for histological analysis, whereas another part of such tissues might include lymphoid follicles. A divergence in transcription and translation might also be present.
Recently, several lymphoid chemokines, which are mainly expressed in secondary lymphoid tissues and organs, have been found, and their role in the organization of secondary lymphoid tissue has been elucidated (4, 5). Their potent chemotaxis and constitutive expression in lymphoid organs suggest that lymphoid chemokines may play important roles in the generation and maintenance of the architecture of the immune system.
BCA-1 was first reported in 1998 with its specific expression in
lymphoid organs, especially in GC in secondary lymphoid tissues and
organs (2, 4). BCA-1 is a potent chemoattractant of B
cells and is produced by FDC in lymphoid organs. Because CXCR5, the
specific receptor of BCA-1, is mostly expressed by B cells, FDC may
produce BCA-1 to attract B cells and initiate the formation of GC in
lymphoid organs. Recently, BCA-1 expression was recognized in
mucosa-associated lymphoid tissues with Helicobacter pylori
infection (21). In addition, BCA-1 was detected in chronic
inflammation induced by lymphotoxin-
in a transgenic mouse model
(22). These reports suggest that BCA-1 may contribute to
the development of chronic inflammation.
The origin of FDC is controversial. Kapasi et al. (23)
reported that precursors of FDC exist in bone marrow, move into target
organs, and differentiate into FDC, while Humphery et al.
(24) and Yamakawa et al. (25) did not support
the idea that FDC originate from bone marrow. According to previous
reports using knockout mice, lymphotoxin- and TNFRI play a crucial
role in establishing FDC in vivo (26, 27, 28, 29, 30).
RA fibroblast-like synoviocytes are known to produce pro-inflammatory
chemokines such as IL-8, monocyte chemoattractant protein-1, epithelial
neutrophil activating peptide-78, macrophage inflammatory protein-1,
and RANTES (31, 32, 33, 34, 35). Furthermore, Lindhout et al.
(36) reported that RA fibroblast-like synoviocytes
stimulated with TNF- and IL-1 had intrinsic properties of FDC.
However, in this study, BCA-1 was not expressed in fibroblast-like
cells in synovium. Moreover, RA fibroblast-like synoviocytes stimulated
with pro-inflammatory cytokines including IL-1, TNF-, and
lymphotoxin- did not show BCA-1 expression (data not shown). Further
investigation is necessary to address the problem of which cell in RA
synovium is the precursor of FDC.
Recently, several investigators have reported inflammatory features of
OA. Krenn et al. (37) demonstrated highly mutated
VH genes in B cells, with a characteristic
arrangement of B cells and PCs. Nakamura et al. (38)
reported the infiltration of T cells in the synovium of OA in the early
stage as well as the restricted TCR usage of V-chain among those T
cells. These findings suggest that OA can be regarded as one of the
chronic inflammatory diseases with a certain immune response resembling
autoimmune diseases like RA, although the clinical feature of
inflammation is not so severe.
In this study, formation of a few lymphoid follicles with BCA-1 expression was recognized in two of eight OA synovia. The aggregation of CD20-positive B cells was also observed in those lymphoid follicles. The synovium of these patients apparently showed inflammatory changes including villous formation and looked like RA synovium. Although we diagnosed these patients as OA simply by their clinical features and by ACR criteria for the classification of OA, they might have possessed inflammatory properties similar to those in RA in their pathological process. Further follow-up will be necessary to diagnose these patients precisely.
In this study, we examined the expression of lymphoid chemokines other than BCA-1 in RA synovium. Because the expression of SLC was detected by immunohistochemistry in T cell-rich areas of normal lymph nodes but not in RA synovium, even in the area with abundant T cells, SLC might not contribute to T cell accumulation in RA synovium.
Many chemokines have been reported and they are classified into two groups as pro-inflammatory chemokines and lymphoid chemokines. BCA-1 has been classified as a lymphoid chemokine so far, but the results of this study showed its marked expression in chronic inflammatory sites. BCA-1 may play an important role in the induction of immune response in chronic inflammatory diseases, especially in autoimmune diseases such as RA. Further investigation of lymphoid chemokines in inflammatory conditions will be necessary to better understand the immunological pathogenesis in such diseases.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Kenji Hayashida, Department of Orthopedic Surgery, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
3 Abbreviations used in this paper: BCA-1, B cell attracting chemokine-1; ACR, American College of Rheumatology; DRC, dendritic reticulum cell; FDC, follicular dendritic cell; GC, germinal center; OA, osteoarthritis; PC, plasma cell; RA, rheumatoid arthritis; SLC, secondary lymphoid tissue chemokine.
Received for publication July 10, 2000. Accepted for publication October 9, 2000.
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References |
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and the type I tumor necrosis factor (TNF) receptor in the establishment of follicular dendritic cells from non-bone marrow-derived cells. J. Exp. Med. 186:1997./ and tumor necrosis factor are required for stromal cell expression of homing chemokines in B and T cell areas of the spleen. J. Exp. Med. 189:403.-dependent fashion. J. Exp. Med. 187:1009.: a C-C chemokine in osteoarthritis. Clin. Immunol. Immunopathol. 77:307.[Medline]
production by synovial T cells. Clin. Exp. Immunol. 101:398.[Medline]
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