| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
2-Microglobulin, But Not CD1, Accelerates Spontaneous Lupus Skin Disease While Inhibiting Nephritis in MRL-Faslpr Mice: An Example of Disease Regulation at the Organ Level1
*
Section of Immunobiology, Departments of
Laboratory Medicine and
Dermatology and Pathology, Yale University School of Medicine, New Haven, CT 06520; and
Department of Molecular Biology, Princeton University, Princeton, NJ 08544
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
2-microglobulin
(2m)-deficient
MRL-Faslpr (MRL/lpr)
mice: lupus skin lesions are accelerated, whereas nephritis is
ameliorated. 2m deficiency affects the expression of
classical and nonclassical MHC molecules and thus prevents the normal
development of CD8- as well as CD1-dependent NK1+ T cells.
To further define the mechanism by which 2m deficiency
accelerates skin disease, we studied CD1-deficient
MRL/lpr mice. These mice do not have accelerated skin
disease, excluding a CD1 or NK1+ T cell-dependent mechanism
of 2m deficiency. The data indicate that the regulation
of systemic disease is not solely governed by regulation of initial
activation of autoreactive lymphocytes in secondary lymphoid tissue, as
this is equally relevant to renal and skin diseases. Rather, regulation
of autoimmunity can also occur at the target organ level, explaining
the divergence of disease in skin and kidney in
2m-deficient mice. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Various lupus-prone mouse strains bearing targeted mutations of genes
important to immune function have generally demonstrated a uniform
amelioration or exacerbation of autoimmune disease among the target
organs studied (11). An example of uniform disease
down-regulation is the 
T cell-deficient MRL/lpr
strain, which has milder renal disease, delayed skin
lesions, reduced lymphoaccumulation, and reduced Ig production
(12, 13). Similarly, IFN-
-knockout MRL/lpr
mice have ameliorated renal and salivary gland disease in addition to
decreased lymphoaccumulation and autoantibody production
(14). Examples of uniform disease up-regulation include
MRL/lpr mice deficient in perforin, which have increased
kidney, liver, and salivary gland infiltrates (15), and
TNF receptor type I-deficient
C57BL/6-Faslpr mice, which develop
increased cellular infiltration in the kidney, liver, lung, and knee
joints (16).
These previous studies suggest that end-organ disease is an inevitable
consequence of initial autoreactive cell activation and loss of
tolerance in secondary lymphoid tissues. Under this hypothesis, for
example, B cell autoantibody secretion would lead to deposition and
damage in multiple target organs (i.e., kidney and skin), after which a
program of end-organ disease ensues in proportion to Ig deposition.
Observations we report here regarding
2-microglobulin
(2m)-deficient MRL/lpr mice
(2m-/-/lpr)
differ from the findings in these other knockout strains and suggest a
model in which local conditions in target organs can control disease
manifestations.
Christianson et al. (17) reported that certain aspects of
autoimmunity were ameliorated in MRL/lpr mice deficient in
2m. They noted that
2m-/-/lpr
mice have only mild glomerulonephritis and reduced numbers of
CD3+CD4-CD8-B220+
lymph node T cells.
2m-/-/lpr
mice also have reduced total IgG1, rheumatoid factor, anti-dsDNA,
and anti-Smith. However, total IgM, IgG2a, and IgG3 levels
remained comparable to those of age-matched MRL/lpr mice.
Although renal disease was assessed in these mice, no spontaneous skin
disease was described.
Here we analyze skin disease in
2m-/-/lpr
mice and report an interesting dissociation in end-organ disease.
2m deficiency reduces kidney disease; however,
the deficiency accelerates, rather than suppresses, the onset of skin
lesions. Thus,
2m-/-/lpr
mice, in having divergent disease in the kidney and skin, differ from
other knockout lupus models. 2m noncovalently
associates with classical and nonclassical MHC class I proteins and is
required for optimal expression of the protein complex
(18). 2m deficiency can affect
several molecules and cellular compartments, prominently including CD8
T cells and CD1-dependent NK1+ T cells.
Therefore, we further investigated how 2m
deficiency leads to accelerated skin disease by studying
CD1-/- mice, which we crossed onto the
MRL/lpr background. These mice do not have accelerated skin
disease, indicating that 2m deficiency is not
working via regulatory NK T cells that depend on CD1 or on CD1
expression itself as on Langerhans or B cells. We discuss the
implications of these findings for the pathogenesis of disease in
target organs.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Mice used in the study were progeny of brother-sister
matings of homozygous 2m-deficient
MRL/lpr mice obtained from The Jackson Laboratory
(http://jaxmice.jax.org/jaxmice-cgi/jaxmicedb.cgi?objtype =
framedetail&stock = 002453). The strain was derived from N10 crossed to
MRL/lpr and thus has 99.9% MRL background genes.
2m-intact (i.e., wild-type) MRL/lpr
mice were obtained from The Jackson Laboratory (Bar Harbor, ME) or were
B cell-sufficient progeny derived during backcrossing of the hemizygous
JHD allele to
MRL/lpr. These latter mice were from the N7 to N13
generation and thus also had 99% MRL background genes. These mice
were bred in our specific pathogen-free animal colony at Yale
University School of Medicine (New Haven, CT).
MRL/lpr.CD1-/- mice were derived by crossing the CD1-targeted allele (19) onto the MRL/lpr background. Homozygosity for lpr was fixed at the first BC generation. To obtain homozygotes, mice were intercrossed at either N6 (98.5% MRL genes) or N10 (99.9% MRL genes) and were typed by PCR. Data obtained both cohorts of mice were pooled, as there were no differences between them. These mice were bred initially at Princeton University, but were observed for skin disease as adults at Yale University, housed under the same conditions as other mice in this study. Thus, all mice were aged and followed for disease in the same animal housing room at Yale.
Photography
Clinical observations were recorded using an EOS Rebel G camera (Canon, Tokyo, Japan) with a 90-mm F2.8 macro lens (Sigma, Tokyo, Japan). The camera and lens were mounted on a copy stand (model CS-2; Testrite, Newark, NJ), while the subject lay below on the base. Photographs were taken with Kodak Gold ASA 100 film (Eastman Kodak, Rochester, NY).
Renal disease grading
H&E-stained, formalin-fixed sections were graded as we have previously described (20).
Skin disease grading
Skin samples from the shaved dorsal neck region were fixed in 10% buffered formalin and embedded in paraffin. Sections were stained with hematoxylin and eosin.
The severity of skin disease was graded based on a semiquantitative scale using the following parameters: acanthosis: 1) mildly, 2) markedly, or 3) very markedly thickened dermis; hyperkeratosis: 1) mildly or 2) markedly increased amount of keratin; interface (liquefaction): 1) focal or 2) extensive damage to basal cell layer; inflammation: 1) sparse or 2) heavy infiltrates of dermal cells resembling lymphocytes; mast cells: numbers of dermal mast cells counted at x20 (0.5 mm) in five fields and averaged for number of mast cells per 0.5 mm, measurements made sequentially in areas of greatest histologic change; fibrosis: increased dermal cellularity with 1) slight or 2) markedly thickened dermis; vessels: presence of dilated vessels with hemorrhage, 1) focal or 2) diffuse; and ulcer: epidermal erosion or ulcer recorded when present (0 or 1). The averages plus 1 SD were generated. For comparative purposes, all tissue sections were scored by one observer (J.M.M.), who was blinded to their origin. Scores for MRL/lpr mice lacking B cells (no disease control) were 0 for all parameters except mast cells (4/0.5 mm; our unpublished observations, and O. T. M. Chan, J. M. McNiff, and M. J. Shlomchik, manuscript in preparation). Similarly, clinically unaffected skin from several mice was observed to be essentially normal (data not shown).
Skin disease incidence and statistical analysis
Cohorts of 2m-deficient or
CD1-deficient MRL/lpr mice and wild-type MRL/lpr
mice were followed in time, and the onset of macroscopic skin disease
was recorded along with the ages of the animals. Mice were considered
affected when an area 
0.5 cm of hair loss, ulceration, and induration
typical of MRL/lpr skin disease (our unpublished
observations) was noted. All data was recorded in Microsoft Excel 98
(Microsoft, Redmond, WA) for the Macintosh.
Survival-type curves of the mouse strains were plotted using the Kaplan-Meier method and were examined for significance with the Mantel-Cox log-rank test using StatView 4.5 (Abacus Software, Berkeley, CA) for the Macintosh. Values of p < 0.05 were considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
2m deficiency in MRL/lpr mice
suppresses spontaneous lupus nephritis
Glomerulonephritis was previously shown to be reduced in
2m-/-/lpr
mice as expected (17). We confirmed that a similar
phenomenon was occurring in our mice, as expected, by formal scoring of
a small cohort;
2m-/-/lpr
mice had lower scores for glomerulonephritis (p
= 0.049; Fig. 1
, A and
B) (17). In addition, interstitial nephritis
and vasculitis (17), which had not been previously
evaluated, were reduced (Fig. 1, C and D).
Inflammatory cellular infiltrates were noticeably decreased compared
with those in age-matched, diseased MRL/lpr controls. These
data are summarized in Fig. 1E. Thus, both Ab-mediated and
cell-mediated diseases were ameliorated. However, it should be noted
that 2m-deficiency did not completely abrogate
disease, because mild glomerulonephritis and cellular infiltrates were
still present.
|
2m deficiency in MRL/lpr mice
accelerates spontaneous lupus skin disease
In contrast to the reduced renal disease, the kinetics of skin
disease onset as well as the penetrance of skin disease were
dramatically accelerated by 2m deficiency
(p < 0.0001; Fig. 2). A significant difference emerged at
12–14 wk, when none of the 2m-intact mice had
skin disease, but one-third of
2m-/-/lpr
mice already had clinical disease. There was very little mortality in
either cohort at this age (data not shown), thus ruling out selective
survival as a reason for differences in skin disease incidence. The
50% incidence of disease was 15 wk of age for
2m-deficient mice and 31 wk for
2m-intact mice. By 28 wk of age, all
2m-/-/lpr
mice were affected, whereas, one-fourth of the original
2m-intact cohort remained unaffected at 44 wk,
an age when most mice in the 2m-intact cohort
had already succumbed to disease in other organs (data not shown).
There was no significant difference between males and females in either
the 2m-intact (p =
0.55) or 2m-deficient
(p = 0.55) cohorts.
|
2m-/-/lpr
mice. Lesions were never observed in our other nonautoimmunity-prone
strains housed in the same room. Furthermore, all the mice were raised
under specific pathogen-free conditions. It was also unlikely that
disease was caused by fighting, as we had numerous examples of affected
mice that were singly housed, and disease was similar in males and
females, whereas females are rarely observed to fight. Finally, neither
T nor B cell-deficient MRL/lpr mice, which are more
immunocompromised than
2m-/-/lpr
mice, develop skin disease despite being housed in the same colony,
again strongly arguing against a role for pathogen-induced lesions.
As the 2m-intact control group included mice
derived during backcross of a JHD allele
(although with 99% MRL background genes), we considered that the
incidence of skin disease may have been affected in some unexpected way
and that this could have affected our conclusions. However, in our
colony, the times to 50% incidence of skin disease in
MRL/lpr mice acquired from The Jackson Laboratory (32 wk)
and bred in our facility (27 wk) were similar, with overall curves
being statistically indistinguishable (p =
0.40; data not shown). If anything, disease may have occurred faster in
our BC mice than in mice acquired from Jackson, but certainly not the
reverse. These incidence rates are somewhat slower than those reported
by Furukawa and colleagues, most likely due to different husbandry
conditions, a factor thought to affect the incidence of autoimmunity in
MRL/lpr mice, as suggested by Furukawa and colleagues
(21).
Pathological characteristics of lupus skin disease of
2m-/-/lpr mice are similar
to those of MRL/lpr mice
Clinically, the skin lesions in
2m-deficient and
2m-intact mice were similar (Fig. 3). Lesions were localized to the
dorsal neck region and ears and typically were not observed elsewhere.
However, disease was usually more aggressive in the
2m-deficient mice, which had more total skin
area affected than the MRL/lpr controls (Fig. 3).
Histologically, lesions in the two types of mice were
indistinguishable. This was evaluated formally by the reading of coded
slides (see Materials and Methods). The data are summarized
in Table I. Overall, disease most resembled
discoid lupus erythematosus lesions (22), with prominent
acanthosis, hyperkeratosis, and interface change. This is consistent
with previous reports (7); our data add to those from
previous studies of MRL/lpr skin disease by using a more
systematic classification according to criteria used to evaluate human
discoid lupus erythematosus lesions. In addition, Ig was deposited in
the dermis and along the dermal-epidermal junction of both strains, as
assayed by immunofluorescence (data not shown).
|
|
The expression of both classical MHC class I and CD1 molecules is
absent or markedly reduced in the absence of
2m; 2m-deficient mice
are also deficient in CD8 and NK1+ T cells that
depend on these class I molecules (23, 24, 25, 26, 27). To distinguish
whether 2m deficiency mediated its effects on
skin disease through lack of CD1 and/or CD1-dependent
NK1+ T cells, we studied cohorts of CD1-deficient
mice. CD1-deficient MRL/lpr mice did not demonstrate
accelerated skin disease (Fig. 4;
p = 0.246), as disease incidence was equivalent to that
in CD1-sufficient mice derived as littermates of heterozygote
intercrosses. Incidence in both CD1-sufficient and -deficient mice was
somewhat more accelerated than that in the MRL/lpr control
cohorts used to compare with the 2m-deficient
mice (see above). This could be due to the less backcrossed nature of
the CD1 cohorts. As these data were acquired after the
2m-intact data, we cannot formally rule out a
change in the overall rate within the colony, although there were no
specific changes made in husbandry conditions during this time.
Regardless, the internal comparison between CD1-deficient and
-sufficient mice was conducted in concert and showed no difference.
Most importantly, disease occurred more slowly in the CD1 cohort than
in the 2m-deficient mice
(p = 0.0001), thus ruling out that CD1 plays a
major role in the 2m-deficient phenotype.
|
2m-deficient mice, in which nephritis and
vasculitis were markedly reduced (17). Thus, CD1 and
NK1+ T cells do not play a role in the
amelioration of kidney disease observed in
2m-deficient mice. |
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
2m-/-/lpr
mice, whereas cutaneous disease is accelerated, rather than suppressed.
The
2m-/-/lpr
strain is the first reported lupus model with exacerbated skin disease
coupled with diminished renal disease. Nearly all published knockout
autoimmunity-prone strains demonstrated either a uniform up-regulation
or down-regulation of end-organ pathology (11).
CD40L-/- MRL/lpr mice have reduced
kidney disease (nephritis, vasculitis, and renal Ig deposition), like
2m-/-/lpr
mice (13). Cutaneous lesions in CD40 ligand-deficient mice
are not inhibited and are comparable to those in MRL/lpr
controls. However, as far as can be discerned, skin disease is not
accelerated as it is in the
2m-/-/lpr
strain. The phenotypes of both the
2m-/-/lpr
and CD40 ligand-/- MRL/lpr strains
support the hypothesis that regulation of autoimmune pathogenesis,
presumably at the level of the effector cell, occurs in individual
target organs.
A number of mechanisms exist that could potentially explain the
up-regulation of skin disease in the
2m-/-/lpr
strain. For example, the presence of
2m-dependent molecules on the target tissue
might have suppressive effects on pathogenic effector cells
(28). The absence of these
2m-dependent proteins in
2m-/-/lpr
mice would prevent any such inhibition. Indeed, target cell lysis by NK
cells is inhibited upon interaction with classical MHC class I
molecules (29, 30, 31, 32, 33). However, this mechanism does not
readily explain why skin vs kidney would be more susceptible to immune
cell attack.
The MHC class I-related receptor, FcRB, plays a role in the regulation
of serum Ig levels, possibly by preventing the catabolism of IgG
(34). Indeed, serum IgG has a short half-life in
2m-deficient mice (35, 36, 37).
2m-/-/lpr
mice have a decrease in total IgG1 (17), which could
explain the ameliorated renal disease (Fig. 1
) (17).
However, this observation would not account for their exacerbated skin
disease (Fig. 2).
Another possibility is that the absence of 2m
prevents the maturation of suppressive, regulatory cells. One candidate
is the NK1+ T cell, the development of which is
dependent on the expression of CD1 (23, 24, 25, 26, 27), a
2m-associated molecule.
NK1+ T cells are important for the early
production of IL-4, a Th2 cytokine capable of down-regulating Th1
cytokines (25, 38, 39, 40), and lupus pathogenesis has been
argued to be augmented by Th1 cytokines (41, 42, 43, 44, 45). We
constructed CD1-deficient MRL/lpr mice to directly test this
idea. However, we found that CD1 deficiency does not contribute to the
2m-deficient phenotype of accelerated skin
disease, excluding a role for NK1+ T cells and
CD1 expression on APCs and target tissue.
+ T cells also have the potential to
suppress or regulate lupus. Peng et al. (46) demonstrated
that + T cell-deficient MRL/lpr
mice developed exacerbated autoimmune renal disease, suggesting that
such T cells play a regulatory role. Evidence that a subset of
+ T cells may be positively selected in
development by MHC class I molecules comes from transgenic mice bearing
TCR transgenes specific for MHC class I (47, 48).
However, it should be noted that + T cells
do not generally require positive selection via MHC class I, as shown
by the detection of + T cells in the
thymus, secondary lymphoid organs, and epithelia of
2m-deficient mice (49, 50, 51). Thus,
the potential role of + T cells in
modulating lupus skin disease requires further investigation.
Finally, CD8+ T cells, whose maturation is
dependent on MHC class I in the thymus (50, 51), may also
negatively regulate immune responses, for example by acting on T cells
(52, 53), dendritic cells (54), B cells
(55), or CD11b+
monocytes/macrophages (56). In addition,
CD8+ T cells regulate T cell responses through
nonclassical MHC class I molecules, such as Qa-1, which depend on
2m for proper expression.
CD8+ T cells are induced by recognition of
Qa-1-Ag complexes (57, 58) and delete
Qa-1+, CD4+ T cells in an
Ag-restricted manner after superantigen administration. Interestingly,
stimulation of CD8+ T cells via Qa-1 on activated
B cells induced the production of IFN- (52), which
could suppress Th2 cells (59) and IgM and IgG1 Ab
responses (60, 61). Given these defined regulatory roles
of CD8+ T cells along with the clear dependence
of CD8+ T cell development on
2m, CD8+ T cells are
strong candidates for regulating skin disease in our model.
Although we were able to use CD1 knockout mice to rule out a role for
NK1+ T cells and CD1, maturation of a subset of
+ T cells and CD8+ T
cells is also affected by 2m deficiency. To
investigate the regulatory role of each cell type will require analysis
of disease in each of the respective knockout mice.
CD8-/- MRL/lpr mice were reported to
develop skin vasculitis (62). Unfortunately, the study did
not characterize the kinetics of the cutaneous disease; whether skin
lesion onset was accelerated is unknown. We were unable to establish
successful breeding of CD8-/-
MRL/lpr mice. This strain may be extinct and will need
to be remade. Characterization of spontaneous skin disease
hasnot been conducted in + T
cell-deficient MRL/lpr mice. Qa-1 knockout mice,
which would also be of interest, do not yet exist as far as we are
aware.
A key question raised by our findings in the
2m-/-/lpr
mice is why there is differential immunoregulation in skin and kidneys.
The most obvious answer is that skin is a barrier organ, whereas kidney
is not. Barrier sites, such as skin, gut, and respiratory tract, have
specialized immune systems (63, 64, 65). These systems are
designed to respond efficiently to breach of the barrier, but are also
prone to inflammatory diseases, such as asthma, inflammatory bowel
diseases, lupus, and graft-vs-host disease. Perhaps to prevent overly
exuberant responses, these local immune systems have a variety of
embedded, regulatory mechanisms as well. For example, immune responses
in the lung may be preferentially deviated toward Th2-type responses
(66, 67, 68). In the skin and gut,
+ T cells may play a regulatory role
(69, 70). A similar role is possible for other
lymphocytes, as discussed above. The most likely interpretation of our
data is that a 2m-dependent, regulatory cell
operates in skin, but not in the kidney. Thus, in skin the natural
proinflammatory tendency, presumably not found in the nonbarrier organs
(i.e., kidney), may be unopposed in the absence of
2m.
If this concept is correct, it would fit with a modified view of
pathogenesis for systemic autoimmunity. In this view, regulation of
autoreactive cells can occur both at the stage of initial activation
that presumably occurs in secondary lymphoid tissues and in the target
tissues themselves, when autoreactive lymphocytes have become or are
differentiating into effector cells. Our results showing divergent
effects on disease in kidney and skin are best accounted for by this
model. In nearly all other cases, mutations inactivating molecules or
cells in the immune system have had concordant effects, either
ameliorating or exacerbating disease in all target organs
(11). These studies had led to the concept that loss of
tolerance resulted in an inevitable program of target organ pathology
(71). It is interesting to speculate that the spectrum of
affected organs, which differs among lupus patients, is in part due to
genetically based variation in defects in organ-level immune
regulation, such as manifested in the
2m-deficient model studied here. Gene-mapping
studies (72, 73, 74) should consider this possibility, as it
may be that distinct loci control disease in particular target
organs.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Mark J. Shlomchik, Department of Laboratory Medicine, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208035, New Haven, CT 06520-8035. E-mail address: mark.shlomchik{at}yale.edu
3 Abbreviations used in this paper: MRL/lpr, MRL-Faslpr; 2m, 2-microglobulin; 2m-/-/lpr, 2m-deficient MRL/lpr mice.
Received for publication January 4, 2001. Accepted for publication June 26, 2001.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
T cells. J. Immunol. 156:4041.[Abstract]
T cell regulation and CD40 ligand dependence in murine systemic autoimmunity. J. Immunol. 158:2464.[Abstract]
and interleukin-4 in murine lupus. J. Clin. Invest. 99:1936.[Medline]
2-microglobulin dependence of the lupus-like autoimmune syndrome of MRL-lpr mice. J. Immunol. 156:4932.[Abstract]
/(1) T cell receptor /(1) intestinal intraepithelial lymphocytes in the absence of both classical major histocompatibility complex class I and nonclassical CD1 molecules. J. Exp. Med. 190:885.8+CD4-8- thymocytes by class I molecules expressed by hematopoietic cells. J. Exp. Med. 178:901.2-microglobulin-deficient mice are resistant to bullous pemphigoid. J. Exp. Med. 186:777.2-microglobulin-transfected Daudi cells. J. Immunol. 141:17.[Abstract]
-globulin catabolism. Nature 203:1352.[Medline]
2-microglobulin-deficient mice. Eur. J. Immunol. 26:690.[Medline]
2-microglobulin: possible protective role of FcRn. Immunology 89:573.[Medline]
2-microglobulin-containing neonatal intestinal transport receptor. Proc. Natl. Acad. Sci. USA 93:5512. T-cell-receptor transgenic system. Proc. Natl. Acad. Sci. USA 89:6065. T cells. J. Immunol. 157:5689.[Abstract]
T cell development in 2-microglobulin deficient mice. EMBO J. 11:25.[Medline]
receptor-bearing T cells. Science 253:903. T cells develop normally in 2-microglobulin-deficient mice. Proc. Natl. Acad. Sci. USA 89:653.2-microglobulin deficient mice lack CD4-8+ cytolytic T cells. Nature 344:742.[Medline]
2M, MHC class I proteins, and CD8+ T cells. Science 248:1227.-specific Qa-1-restricted regulatory CD8+ T cells. Proc. Natl. Acad. Sci. USA 95:4533.8 TCR: a role of the Qa-1 molecule. Immunity 2:185.[Medline]
modulates the early development of Th1 and Th2 responses in a murine model of cutaneous leishmaniasis. J. Immunol. 147:3149.[Abstract]
-induced nitric oxide production and nitric oxide synthase expression in murine peritoneal macrophages. J. Interferon Cytokine Res. 15:977.[Medline]
This article has been cited by other articles:
|
|
 |
|
  C. Hong, H. Lee, Y.-K. Park, J. Shin, S. Jung, H. Kim, S. Hong, and S.-H. Park Regulation of Secondary Antigen-Specific CD8+ T-Cell Responses by Natural Killer T Cells Cancer Res., May 15, 2009; 69(10): 4301 - 4308. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Menke, M.-Y. Hsu, K. T. Byrne, J. A. Lucas, W. A. Rabacal, B. P. Croker, X.-H. Zong, E. R. Stanley, and V. R. Kelley Sunlight Triggers Cutaneous Lupus through a CSF-1-Dependent Mechanism in MRL-Faslpr Mice J. Immunol., November 15, 2008; 181(10): 7367 - 7379. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Benoit and R. Tan Xenogeneic beta2-Microglobulin Substitution Alters NK Cell Function J. Immunol., August 1, 2007; 179(3): 1466 - 1474. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Blossom, J. C. Doss, and K. M. Gilbert Chronic Exposure to a Trichloroethylene Metabolite in Autoimmune-Prone MRL+/+ Mice Promotes Immune Modulation and Alopecia Toxicol. Sci., February 1, 2007; 95(2): 401 - 411. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C G Katsiari and G C Tsokos Re-establishment of tolerance: the prospect of developing specific treatment for human lupus Lupus, July 1, 2004; 13(7): 485 - 488. [PDF]
|
|
|
|
|
|
J.-Q. Yang, V. Saxena, H. Xu, L. Van Kaer, C.-R. Wang, and R. R. Singh Repeated {alpha}-Galactosylceramide Administration Results in Expansion of NK T Cells and Alleviates Inflammatory Dermatitis in MRL-lpr/lpr Mice J. Immunol., October 15, 2003; 171(8): 4439 - 4446. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Q. Yang, A. K. Singh, M. T. Wilson, M. Satoh, A. K. Stanic, J.-J. Park, S. Hong, S. D. Gadola, A. Mizutani, S. R. Kakumanu, et al. Immunoregulatory Role of CD1d in the Hydrocarbon Oil-Induced Model of Lupus Nephritis J. Immunol., August 15, 2003; 171(4): 2142 - 2153. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. Roopenian, G. J. Christianson, T. J. Sproule, A. C. Brown, S. Akilesh, N. Jung, S. Petkova, L. Avanessian, E. Y. Choi, D. J. Shaffer, et al. The MHC Class I-Like IgG Receptor Controls Perinatal IgG Transport, IgG Homeostasis, and Fate of IgG-Fc-Coupled Drugs J. Immunol., April 1, 2003; 170(7): 3528 - 3533. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Kikawada, D. M. Lenda, and V. R. Kelley IL-12 Deficiency in MRL-Faslpr Mice Delays Nephritis and Intrarenal IFN-{gamma} Expression, and Diminishes Systemic Pathology J. Immunol., April 1, 2003; 170(7): 3915 - 3925. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Miwa, M. A. Maldonado, L. Zhou, X. Sun, H. Y. Luo, D. Cai, V. P. Werth, M. P. Madaio, R. A. Eisenberg, and W.-C. Song Deletion of Decay-Accelerating Factor (CD55) Exacerbates Autoimmune Disease Development in MRL/lpr Mice Am. J. Pathol., September 1, 2002; 161(3): 1077 - 1086. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Yin, G. Bahtiyar, N. Zhang, L. Liu, P. Zhu, M. E. Robert, J. McNiff, M. P. Madaio, and J. Craft IL-10 Regulates Murine Lupus J. Immunol., August 15, 2002; 169(4): 2148 - 2155. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
,
, control
