| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Department of Internal Medicine, Section of Rheumatology, and
Department of Pathology and Biology, Yale University School of Medicine, New Haven, CT 06510; and
Immunology Research Division, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
A large number of investigations have established that CD4+ T cells are required for the development of autoantibodies and end organ disease in MRL lupus. Such studies have included treatment by neonatal thymectomy, anti-Thy-1.2 Ab, anti-CD4 Ab, anti-CD3 Ab, FK506, and cyclosporin A, as well as the genetic elimination of CD4+ T cells via MHC class II deficiency and CD4 deficiency: all have shown an abrogation of autoantibody production and glomerulonephritis (5, 6, 7, 8, 9, 10, 11).
Activation of CD4+ T cells requires two signals, an Ag-specific signal through the TCR and a second costimulatory signal between the T cell and APC. TCR ligation in the absence of a costimulatory signal can result in anergy or cell death (12). The major costimulatory molecules expressed by APCs are B7-1 and B7-2, which bind to CD28 and/or CTLA-4 expressed on T cells (12). A requirement for T cell costimulation in the development of autoimmunity has been observed in several animal models. For example, treatment with CTLA-4-Ig, a fusion protein which blocks both B7-1 and B7-2, suppresses the development of spontaneous lupus autoimmunity in NZB/NZW F1 mice, nonobese diabetic (NOD) mice, as well as experimentally induced autoimmune encephalomyelitis (EAE) (13, 14, 15).
However, the role of B7-1 or B7-2 as individual costimulatory ligands in the development of autoimmunity is not as clear. For example, the treatment of animals with anti-B7-1 inhibited the development of EAE, whereas anti-B7-2 exacerbated the severity of disease (16). In contrast, anti-B7-2 suppressed and anti-B7-1 accelerated the development of diabetes in NOD mice (14). Autoimmunity in the NZB/NZW mouse in unaffected by inhibitors of either B7-1 or B7-2 individually (17).
The current studies were designed to investigate the role of B7 costimulation in a murine model of human systemic lupus erythematosus (SLE). We used two approaches to interfere with the biological functions of the B7 molecule in MRL-lpr/lpr mice. First, mice were treated with anti-B7-1 and/or anti-B7-2 blocking Abs throughout the development of disease. Second, parallel studies were performed with B7-1- or B7-2-deficient mice backcrossed into the MRL-lpr/lpr background. Mice were examined for the presence of autoantibody specificity, titers, and isotypes as well as T cell activation status.
Our previous data demonstrated that the blocking of B7-1 alone by Ab treatment or the genetic deletion of either B7-1 or B7-2 did not significantly ameliorate the course of spontaneous lupus autoimmunity, however, blocking B7-1 alone significantly inhibited anti-dsDNA autoantibody while having no effect on anti-snRNP production (18). Moreover, blocking both B7-1 and B7-2 at the same time by Ab treatment significantly suppressed anti-snRNP and anti-dsDNA autoantibody production but it did not completely eliminate autoantibodies (18). In the present studies, we have demonstrated that Ig isotype switching occurs in anti-B7-1/B7-2-treated and in B7-1- or B7-2-deficient mice. However, significantly different immunologic and pathologic outcomes were observed between anti-B7-1/B7-2-treated and between B7-1 and B7-2 genetic-deficient mice. Combined Ab treatment reduced but did not eliminate the production of anti-dsDNA IgG1, IgG2a, and IgG3 isotypes. In contrast, B7-1- or B7-2-deficient mice made anti-dsDNA autoantibodies with isotypes similar to wild-type animals. Furthermore, our observations suggest that B7-1 and B7-2 have unique roles relative to the autoimmune pathology observed in MRL-lpr/lpr mice. An understanding of the inductive phase of autoimmunity and the breakdown of immunologic tolerance will be crucial for understanding both the genesis and the therapeutic intervention of autoimmune diseases such as SLE.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Anti-B7-1/B7-2 Ab treatment protocols for MRL-lpr/lpr mice were based on previous studies for which efficacy in the treatment of EAE and diabetes was observed (13, 14, 16). The duration of Ab treatment lasted from 10–20 wk, with a minimum of 10 mice in each treatment group. MRL-lpr/lpr mice (5–8 wk old; The Jackson Laboratory, Bar Harbor, ME) were injected with: 1) control mAb (2–4A1), 2) rat anti-B7-1 (1G10; IgG2a), 3) rat anti-B7-2 (2D10, IgG1), and 4) anti-B7-1 together with anti-B7-2 mAbs three times a week at the dose of 100 µg/mouse, i.p., over the entire course of the study. Serum samples were collected every 2–3 wk, and examined for the presence of antinuclear autoantibodies by indirect immunofluorescence (ANA) and by ELISA for anti-dsDNA and anti-snRNP as described below.
Genetic deficient mice
B7-1- and B7-2-deficient mice on a 129 and BALB/c background, respectively, were derived as previously reported (19) and backcrossed to the third generation with MRL-lpr/lpr mice (The Jackson Laboratory, Bar Harbor, ME). The intercrossed F3 generation was used in the present experiments. PCR analysis was performed to confirm B7-1-deficient, B7-2-deficient, and lpr/lpr genotypes. As controls, heterozygous B7-1-deficient or B7-2-deficient, MRL-lpr/lpr F3 mice, and wild-type MRL-lpr/lpr mice were examined in parallel studies. Serum samples were collected every 2 wk starting from week 5 to 6, and analyzed for the presence of anti-snRNP and anti-dsDNA autoantibodies. Individual Ig isotype analysis of anti-snRNP and anti-DNA was additionally performed on the samples as described in detail below. Kidney pathology was also examined at the indicated time points as detailed below.
Indirect immunofluorescence (ANA)
Indirect immunofluorescence assays were performed using commercially available cell substrates (Quidel, San Diego, CA). In brief, 30 µl of a 1:40 dilution of serum were placed on slides coated with human epithelial cells (HEp-2) and incubated at room temperature for 1 h. After a 5-min wash in PBS-Tween (0.1%), FITC-conjugated anti-mouse IgG (Sigma) was applied to individual wells and incubated in the dark at room temperature for 1 h. After another 5-min wash, wells were examined by UV-fluorescence microscopy.
Anti-snRNP and anti-dsDNA Ig isotype analysis
The spontaneous production of autoantibodies may reflect the abnormal function of B cells in MRL-lpr/lpr mice. These specific autoantibodies are accompanied by a polyclonal increase in serum Ig, particularly of the IgG2a isotype. To determine the dominant subclass of autoantibody in MRL-lpr/lpr mice, anti-snRNP and anti-dsDNA IgM and four anti-snRNP and anti-dsDNA IgG isotypes, IgG1, IgG2a, IgG2b, and IgG3, were measured by ELISA (using the commercially available ImmunoPure Monoclonal Ab Isotyping Kit; Pierce, Rockford, IL). In brief, native snRNP Ag was coated on U-shape vinyl plate (Costar, Cambridge, MA) overnight at 4°C. Plates were incubated with 3% BSA/PBS followed by a 10-2 dilution of serum samples incubated at room temperature for 2 h. Rabbit anti-mouse IgM, IgG1, IgG2a, IgG2b, and IgG3 Abs were then added to the plate followed by alkaline phosphatase conjugated goat anti-rabbit Ab. Plates were finally incubated with pNPP substrate (Sigma, St. Louis, MO), and OD (405 nm) was measured at various time points (Titertek Multiskan, Titertek, Finland). Experimental values from separate experiments were normalized to a single MRL lpr/lpr positive control serum used in every assay (arbitrarily defined as 100 U).
Anti-dsDNA autoantibody isotypes were examined by modification of a commercially available ELISA (Sanofi Diagnostics Pasteur, Chaska, MN) and ImmunoPure Monoclonal Ab Isotyping Kit (Pierce). In brief, 10-2 serum dilution were incubated at room temperature for 2 h on plates coated with recombinant plasmid dsDNA. Thereafter, rabbit anti-mouse IgM, IgG1, IgG2a, IgG2b, and IgG3 Abs were then added to the plate followed by alkaline phosphatase-conjugated goat anti-rabbit Ab. Plates were finally incubated with pNPP substrate (Sigma), and OD (405 nm) was measured at various time points (Titertek Multiskan). Experimental values from separate experiments were normalized to a single MRL-lpr/lpr-positive control serum used in every assay (arbitrarily defined as 100 U).
Flow cytometry analysis of T cell activation status
Mice were sacrificed at indicated time points (see figure legends) and spleens were removed to cold Click’s medium supplemented with 5% FBS (Gemini Bio-Products, Calabasas, CA), 10 mg/ml gentamicin, 2 mM L-glutamine, 0.1 mM 2-ME. RBCs were lysed in buffer (Sigma) on ice for 5 min. Splenocytes were stained with optimal concentrations of fluorochrome-conjugated mAbs (2 x 106 cells in 200 µl of PBS, 1% BSA, and 0.1% sodium azide in U-shaped microtiter plates at 4°C for 30 min), and fixed with 1% paraformaldehyde. Samples were analyzed on a FACScalibur instrument (Becton Dickinson, Mountain View, CA). The following commercially available mAbs were used for analysis of T cell activation markers: anti-CD62L PE, anti-CD44 Cy-Chrome, anti-CD4 FITC, and anti-CD8 FITC (PharMingen, San Diego, CA).
Immunofluorescent evaluation of IgG, IgM, and C3 depositions in kidney
Kidney halves were fixed in a 0.7% paraformaldehyde-lysine-periodate (PLP) solution overnight at 4°C. Then, each sample was incubated in a 30% sucrose phosphate buffer at room temperature for >2 h and frozen in OCT compound (Sakura Finetek USA, Torrance, CA). Then, 7-µm sections were cut using a Cryocut 1800 cryostat (Reichert-Jung, Deerfield, IL) and blocked with 3% BSA PBS for 2 h. After rinsing in TN buffer for 20 min, the samples were stained with FITC-labeled anti-mouse IgG, IgM, IgG1, IgG2a, IgG2b, IgG3 Abs (Southern Biotechnology Associates, Birmingham, AL) and anti-mouse C3 Ab (ICN/Cappel, Aurora, OH). Fluorescence was examined by UV-fluorescence microscopy.
Statistical analysis
Student’s t test was performed using statistic analysis tools in MS EXCEL program to compare the significant difference between two groups. p < 0.05 is considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
After 5–14 wk of anti-B7-1, anti-B7-2, or both
anti-B7-1/B7-2 treatment (three treatments a week; minimum 10 mice
in each treatment group), all of the control Ab-treated and
anti-B7-1- and/or anti-B7-2 Ab-treated mice showed positive
antinuclear Ab (ANA) responses by immunofluorescence (Table I
). The mice treated with both
anti-B7-1 and anti-B7-2 Abs also showed positive ANA responses,
suggesting that Ab treatment did not completely eliminate autoantibody
production (Table I). The spectrum of ANA patterns were primarily of a
homogeneous nuclear pattern, consistent with anti-DNA
autoantibodies, and a speckled nuclear pattern, typically associated
with autoantibodies to the snRNP complex. A smaller frequency of sera
revealed a nucleolar-staining pattern although all three patterns were
observed in anti-B7-1/B7-2-treated mice or in wild-type
MRL-lpr/lpr mice (18).
|
). There was no significant difference in the onset or
development of ANA between the homozygous and heterozygous B7-1- or
B7-2-deficient MRL-lpr/lpr mice. These results indicate that
blocking both B7-1 and B7-2 molecules with specific Ab or completely
eliminating either B7 molecule did not significantly alter the overall
titers of autoantibodies in MRL-lpr/lpr mice although the
resulting pathologies were significantly different as described
below. Anti-snRNP and anti-dsDNA Ig isotypes
An extensive analysis of anti-snRNP and anti-dsDNA autoantibody isotypes in anti-B7-1/B7-2-treated mice and B7-1/B7-2-deficient mice was performed since studies in nonautoimmune mice have demonstrated that the absence of B7 molecules greatly affects the formation of germinal centers and Ab class switching (20).
Our first Ab experiment showed that IgG1, IgG2a, IgG2b, IgG3, and IgM
autoantibodies specific for snRNPs were significantly elevated over
time by anti-B7-1 treatment (Fig. 1A). Simultaneous
anti-B7-1 and anti-B7-2 Ab treatment significantly suppressed
the production of IgG1, IgG2a, and IgG2b autoantibodies specific for
dsDNA, and IgG2b autoantibody specific for snRNP as compared with
control Ab treatment (Fig. 1, B and C).
Coadministration of anti-B7-1/B7-2 Abs also significantly lowered
the production of IgG1 and IgG2b autoantibodies specific for snRNP as
compared with anti-B7-2 Ab treatment alone (Fig. 1C).
However coadministered Abs did not alter the production of IgG3
specific for dsDNA and IgG1, IgG2a, IgG3, and IgM specific for snRNP as
compared with control Ab treatment (Fig. 1, B and
C). Anti-B7-2 Ab treatment significantly lowered the levels
of IgG2a, IgG3, and IgM autoantibodies specific for snRNP as compared
with anti-B7-1 Ab treatment (Fig. 1C).
|
A).
Anti-dsDNA IgG2a, IgG2b, and IgG3 autoantibodies in B7-2-deficient mice
were surprisingly higher than that in B7-1-deficient mice, despite the
fact that the B7-2-deficient mice had much milder kidney pathology
(Fig. 2B). These observations imply that pathogenic
anti-dsDNA specificities may differ between the groups (i.e.,
B7-2-deficient vs wild-type mice) although the overall titers of
anti-dsDNA Abs may be similar.
|
Surface expression of CD62L, CD44 on CD4 and CD8 T cells were
examined by flow cytometry to determine the T cell activation status in
B7-1- or B7-2-deficient mice. We examined the mice during 8–16 wk old,
MRL-lpr/lpr wild-type mice possess large population of
splenic T lymphocytes of an activated (CD44high,
L-selectinhigh) and memory
(CD44highCD62low)
phenotype, although the role of the B7 costimulatory molecules in this
phenotype is not known. CD4 and CD8 T cells from B7-1-deficient mice
demonstrated similar populations of activation markers as compared with
that of the wild-type mice at all ages (data not shown). However,
B7-2-deficient mice expressed significantly lesser populations of
activated T cells (13% and 17% in CD4 and CD8 T cells, respectively)
and of memory T cells (2% in both CD4 and CD8 T cells) as compared
with that of the wild-type mice (23% and 29% activated T cells and
76% and 69% memory T cells in CD4 and CD8 T cells, respectively)
(Fig. 3). B7-2-deficient mice showed
fewer cells counted due to the tremendous amount of
CD4-CD8- cell population
(data not shown). Furthermore, surface expression of the B7 molecules
was also examined to investigate whether the expression of B7-2 is
altered in the absence of the B7-1 molecules, (or, conversely, if B7-1
levels are altered in the absence of B7-2). The data indicated that
splenocytes of some homozygous B7-1-deficient mice may express B7-2 at
a higher level as compared with heterozygous mice (Fig. 4). Conversely, splenocytes from some
homozygous B7-2-deficient mice also expressed higher level of B7-1 as
compared with heterozygous mice (Fig. 5).
This difference may indicate that there is alternative compensatory
mechanisms for B7-1 and B7-2 expression at the cell surface. B7
expression was not examined on T cell populations although some
possibility exists for their role in regulating immune responses.
|
|
|
As the kidney pathology in B7-1 and B7-2 single-deficient mice was
so distinctively different despite of their similar levels of
anti-snRNP and anti-dsDNA autoantibodies (18), we
next examined specific Ab deposition in the kidneys. Immunofluorescence
staining revealed that MRL-lpr/lpr wild-type mice had
significant granular peritubular, peripheral capillary wall, and
mesangial IgG and IgM deposition in the kidney (Fig. 6, Table II). B7-1-deficient mice also had
granular mesangial and peripheral capillary wall IgG and IgM
deposition. The B7-2-deficient mice only had short linear mesangial IgG
and IgM deposition and lacked peritubular and peripheral capillary wall
deposition with less severe Ab deposition than the B7-1-deficient mice.
We also stained the kidneys for IgG1, IgG2a, IgG2b, IgG3, and
complement C3 deposition. Mesangial and peripheral capillary wall
deposition of IgG1, IgG2a, IgG2b, and IgG3 were found in wild-type
MRL-lpr/lpr mice, whereas only peripheral capillary
wall and mesangial IgG1 and IgG2a deposition in B7-1-deficient mice and
mesangial IgG2a and IgG3 deposition were found in B7-2-deficient mice.
Complement C3 was found in wild-type, B7-1-deficient, and
B7-2-deficient MRL-lpr/lpr mice, however, the wild-type and
B7-1-deficient mice had similar peripheral capillary wall and mesangial
patterns and more severe deposition of IgG2a and C3 as compared with
the B7-2-deficient mice (Fig. 6, Table II). These observations are
consistent with the more severe glomerulonephritis found in
B7-1-deficient mice.
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The results from this study are in contrast to those from a previous study in lupus-prone NZB/NZW F1 mice in which both anti-B7-1 and anti-B7-2 mAbs were able to prevent the development and progression of lupus (17). B7-2 was hypothesized to provide a more critical role in Th2-mediated cytokine production (17). In another study, CTLA-4-Ig suppressed the lupus-like illness in the NZB/NZW F1 mouse model and prolonged life even when the treatment was administered late in disease (13). Mice treated with CTLA-4-Ig did not make Abs to dsDNA at any time during the course of treatment, including the 3 mo of observation after treatment was stopped. Suppression of autoantibody production was accompanied by a significant reduction in the severity of lupus nephritis. The distinct difference among these studies and our current studies suggests that B7 costimulatory signals (or the absence thereof) are unique in MRL-lpr/lpr spontaneous lupus. Furthermore, B7-1 and B7-2 probably play distinct roles in autoantibody specificity and severity of kidney pathology. Clearly, the generation of autoantibodies in MRL-lpr/lpr mice is unaffected by the absence of either B7-1 or B7-2.
Non-autoimmune mice deficient in both B7-1 and B7-2 fail to generate Ag-specific IgG1 and IgG2a responses and lack germinal centers under all conditions of immunization, including immunization in CFA (20). In addition, nonautoimmune B7-2-deficient mice immunized intraperitoneally without adjuvant showed a delay in the kinetics of IgG responses. When immunized i.v. without adjuvant, there was a complete failure to switch Ab isotypes, a 90% reduction in the number of Ab producing cells, and no germinal center formation. In our studies with MRL-lpr/lpr mice, treatment with anti-B7-1 or anti-B7-1 alone or together did not prohibit Ig class switching. However, anti-B7-2 treatment did suppress the levels of IgG1, IgG2b, and IgG3 specific for snRNP while having no effect on the production of IgG2a and IgM specific for the snRNP autoantigen. Anti-B7-1 plus anti-B7-2 treatment significantly suppressed IgG1, IgG2a, and IgG2b specific for dsDNA whereas not affecting the production of IgG3 specific for dsDNA. These data suggest that Th1 mediated IgG2a responses may be inhibited only if both B7-1 and B7-2 are blocked. Recall that IgG2a isotypes of anti-DNA autoantibodies have previously been shown to elicit pathology in MRL-lpr/lpr models of SLE (4).
The different outcomes observed between nonautoimmune and MRL-lpr/lpr mice indicate that there must be fundamental differences in the immune responses or regulation in the MRL-lpr/lpr strain. One possible explanation could be that the autoreactive T and B cells in MRL-lpr/lpr mice have a lower threshold for activation and therefore could be stimulated by weaker or delayed alternative costimulatory signals in the presence of autoantigen. Historically, B7-CD28 costimulation has been considered an essential component of the signaling process required for T cell proliferation and IL-2 production. Subsequently, evidence has emerged which suggests that the requirement for B7-CD28 costimulation may not be absolute in all immune responses. Ags with high affinity for TCR or in high concentration on the surface of APCs may require little or no costimulation. For example, TCR transgenic CD4+ T cells from CD28-deficient mice are able to proliferate and produce IL-2 at high concentrations of antigenic peptide (21). Furthermore, one study demonstrated that the number of IL-2-producing cells increased as the concentration of stimulatory peptide increased within a clonal Th1 population (22). These results demonstrated a quantitative requirement of B7-mediated costimulation on a T cell clone (12). A less number of TCRs had to be triggered for a response to be generated by a given concentration of Ag (12).
The fact that anti-snRNP and anti-dsDNA autoantibodies were significantly inhibited in the anti-B7-1- and anti-B7-2-treated mice but not in B7-1- or B7-2-deficient mice may indicate that B7-1 or B7-2 has the ability of compensate for each other in the absence of the other B7 molecule. Previous studies showed that optimal concentrations of either B7-1- or B7-2-deficient APCs stimulated OVA-transgenic T cells to proliferate and produce cytokines (23). Our studies also showed an elevation of B7-2 and B7-1 in the B7-1- and B7-2-deficient mice, respectively, as compared with control mice.
In addition, there may be other alternative costimulation pathways for T cell activation in the MRL mouse model. One possible pathway that may bypass or compensate for the B7-1/7-2-CD28/CTLA-4 pathway is CD40-CD40L pathway. Mice deficient in CD40L fail to develop normal T cell-dependent humoral immune responses, Ig isotype switching, and germinal center formation. In murine lupus and autoimmune oophoritis, complete long-term suppression of disease was only observed with the inhibition of both the CD28-B7 and CD40-CD40L pathways (24). However, in experimental autoimmune thyroiditis, treatment of recipients with a combination of anti-B7-1, anti-B7-2, and anti-CD40L did not further suppress disease development as compared with the treatment of anti-B7-1 and anti-B7-2 without anti-CD40L (25). This indicates that there may be an alternative pathway that could compensate for the lack of B7-CD28 or CD40-CD40L costimulation.
Two recent studies identified new members of the costimulatory molecule
family, inducible costimulator (ICOS), which resembles CD28 in potency,
and B7 h, which is a close homologue of B7-1 and B7-2 (26, 27). ICOS enhances all basic T cell responses to a foreign Ag,
namely proliferation, secretion of lymphokines,
up-regulation of molecules that mediate cell-cell
interaction, and effective help for Ab secretion by B cells. Unlike the
constitutively expressed CD28, ICOS has to be de novo induced on the T
cell surface, does not up-regulate the production of IL-2, but
superinduces the synthesis of IL-10, a B cell differentiation factor.
B7 h shares only 20% amino acid identity with B7-1 and B7-2. It is a
transmembrane molecule highly expressed in B cells, peripheral lymphoid
and nonlymphoid tissues but not in T cells. This molecule costimulates
T cell proliferation via a CD28-independent mechanism and it can be
rapidly induced and up-regulated by TNF-
through activation of
proinflammatory NF-
B/Rel transcription factors. It is plausible that
ICOS and B7 h may be major regulators of the adaptive immune response
and might contribute to the autoantibody production in
MRL-lpr/lpr mice.
Based on prior studies, we anticipated that interfering with the biological function of B7-2 should impede isotype switching of autoantibodies in spontaneous disease (20). This notion is based on the absence of isotype switching or germinal center formation after i.v. immunization of B7-2-deficient mice or in mice treated with anti-B7-2 blocking Abs (20, 23). We have found that isotype switching of anti-DNA and anti-snRNP indeed occurred in both B7-1-deficient and B7-2-deficient MRL-lpr/lpr mice. The ability to develop mature autoantibody subsets in these mice may be due to the strength of TCR signaling although the source of endogenous autoantigen and its avidity for TCR in MRL-lpr/lpr mice is not known.
Although titers and isotypes of autoantibodies from B7-2-deficient mice resembled those of wild-type mice, overall kidney pathology, IgG and IgM deposition were generally less severe in the absence of B7-2. Studies are underway to examine the fine-specificity (via sequencing of variable regions) of anti-dsDNA Abs from wild-type and B7-deficient mice. Cationic, complement fixing anti-DNA isotypes may be essential for tissue damage (4, 29, 30).
Autoreactive CD4+ T cells can execute a number of direct effector functions to promote pathology such as mediating direct cytotoxicity to target organs (31), secreting inflammatory cytokines (33, 34), and forming memory T cells (35). Activated CD4+ T cells can be cytotoxic both via perforin and granzyme release (36, 37) and through Fas ligand expression (38). Inflammatory cytokine production by the activated T cells can also induce tissue damage directly (39). In addition, this cytokine and subsequent chemokine production (40, 41) also recruits secondary inflammatory cells (42), composed of CTL, dendritic cells, granulocytes, macrophages, and NK cells, which all are observed in the inflammatory infiltrate of diseased MRL kidneys (43). Indeed, T cells can initiate some forms of kidney pathology in B cell deficient MRL-lpr/lpr mice (43).
Whether B7-1 and B7-2 have identical, overlapping, or distinct functions still needs to be further investigated. Some investigators have reported differences in CD4+ T cell cytokine profiles in the selective presence of one B7 molecule vs the other, whereas other investigators find no differences (12). Putative differences in function between B7-1 and B7-2 could potentially be due to differences in the timing and level of expression as well as differences in the strength or quality of the signal delivered upon binding to CD28 and CTLA-4. It is clear from our studies that a greater understanding of the role of B7-mediated costimulation in lupus autoimmunity may be required to fully appreciate the potential therapeutic benefits of manipulating costimulatory pathways.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Mark J. Mamula, Yale University School of Medicine, 333 Cedar Street, LCI 609, New Haven, CT 06510.
3 Abbreviations used in this paper: snRNP, small nuclear ribonucleoprotein; SLE, systemic lupus erythematosus; ANA, antinuclear autoantibodies; EAE, experimentally induced autoimmune encephalomyelitis.
Received for publication January 4, 2000. Accepted for publication June 29, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
. Immunity 11:423.[Medline]
, TNF-, and TNF-ß secretion in IL-2-activated T cells: costimulatory roles for LFA-1, LFA-2, CD44, and CD45 molecules. Cell Immunol. 144:69.[Medline]
This article has been cited by other articles:
|
|
 |
|
  S Dolff, W. Abdulahad, M Bijl, and C. Kallenberg Regulators of B-cell activity in SLE: a better target for treatment than B-cell depletion? Lupus, June 1, 2009; 18(7): 575 - 580. [Abstract] [PDF]
|
|
|
|
|
|
M Her, D Kim, M Oh, H Jeong, and I Choi Increased expression of soluble inducible costimulator ligand (ICOSL) in patients with systemic lupus erythematosus Lupus, May 1, 2009; 18(6): 501 - 507. [Abstract] [PDF]
|
|
|
|
 |
|
 D. A. Jabs, R. A. Prendergast, A. L. Campbell, B. Lee, E. K. Akpek, H. C. Gerard, A. P. Hudson, and J. A. Whittum-Hudson Autoimmune Th2-Mediated Dacryoadenitis in MRL/MpJ Mice Becomes Th1-Mediated in IL-4 Deficient MRL/MpJ Mice Invest. Ophthalmol. Vis. Sci., December 1, 2007; 48(12): 5624 - 5629. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Odobasic, A. R. Kitching, T. J. Semple, J. R. Timoshanko, P. G. Tipping, and S. R. Holdsworth Glomerular Expression of CD80 and CD86 Is Required for Leukocyte Accumulation and Injury in Crescentic Glomerulonephritis J. Am. Soc. Nephrol., July 1, 2005; 16(7): 2012 - 2022. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A Davidson, B Diamond, D Wofsy, and D Daikh Block and tackle: CTLA4Ig takes on lupus Lupus, March 1, 2005; 14(3): 197 - 203. [Abstract] [PDF]
|
|
|
|
 |
|
 K. M. Pollard, M. Arnush, P. Hultman, and D. H. Kono Costimulation Requirements of Induced Murine Systemic Autoimmune Disease J. Immunol., November 1, 2004; 173(9): 5880 - 5887. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Yadav, V. Judkowski, M. Flodstrom-Tullberg, L. Sterling, W. L. Redmond, L. Sherman, and N. Sarvetnick B7-2 (CD86) Controls the Priming of Autoreactive CD4 T Cell Response against Pancreatic Islets J. Immunol., September 15, 2004; 173(6): 3631 - 3639. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. G. Kevil, M. J. Hicks, X. He, J. Zhang, C. M. Ballantyne, C. Raman, T. R. Schoeb, and D. C. Bullard Loss of LFA-1, but not Mac-1, Protects MRL/MpJ-Faslpr Mice from Autoimmune Disease Am. J. Pathol., August 1, 2004; 165(2): 609 - 616. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Catterall, D. Stockwell, V. Marshall, A. Strasser, and J. Allison Autoimmune kidney disease and lymphadenopathy in NODlpr mice are not modified by deficiency in tumor necrosis factor receptor 1 or {beta}2-microglobulin Int. Immunol., June 1, 2003; 15(6): 679 - 690. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Yan and M. J. Mamula B and T cell tolerance and autoimmunity in autoantibody transgenic mice Int. Immunol., August 1, 2002; 14(8): 963 - 971. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Yamada, A. D. Salama, and M. H. Sayegh The Role of Novel T Cell Costimulatory Pathways in Autoimmunity and Transplantation J. Am. Soc. Nephrol., February 1, 2002; 13(2): 559 - 575. [Full Text] [PDF]
|
|
|
|
|
|
D. A. Jabs, R. A. Prendergast, E. M. Rorer, A. P. Hudson, and J. A. Whittum-Hudson Cytokines in Autoimmune Lacrimal Gland Disease in MRL/MpJ Mice Invest. Ophthalmol. Vis. Sci., October 1, 2001; 42(11): 2567 - 2571. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
