Read The Official Patient's Sourcebook on Lupus Online
Authors: MD James N. Parker,PH.D Philip M. Parker
responsible for increasing serum CSF-1 and establish if this production is
constitutive or is dependent on a stimulus. In addition, we will determine
whether a circulating stimulant in the serum of MRL-lpr/lpr mice
induces intrarenal CSF-1 and at what age this begins. Finally, we will test
whether a kidney unable to express CSF-1 transplanted in the MRL-
lpr/lpr mice develops renal injury. Taken together, using several novel
approaches we will be able to clarify the importance of CSF-1 in the
pathogenesis of lupus nephritis.
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Project Title: Cellular and Genetic Basis of Systemic Lupus
Principal Investigator & Institution: Fu, Shu Man M.; Professor; Internal
Medicine; University of Virginia Charlottesville Box 400195
Charlottesville, Va 22904
Timing: Fiscal Year 2001; Project Start 8-SEP-2001; Project End 1-JUL-2005
Summary: (provided by applicant): Systemic lupus erythematosus (SLE)
is an autoimmune disorder affecting multiple organs with considerable
morbidity and mortality. The disorder is characterized by multiple
autoantibody production including antinuclear antibodies (ANA and
anti-dsDNA antibodies with immune complex formation leading to
intense inflammation and end organ damage. Immune complex-
mediated glomerulonephritis (GN) is a major manifestation of this
disorder. Both genetic and environmental factors play important roles in
its pathogenesis. Our laboratory has focused on the origin(s) of the
autoantibodies detected in SLE and the genetic factors important in the
generation of ANA and anti-dsDNA antibodies and lupus nephritis.
Recently, a new model of SLE NZM2328 has been characterized. In this
strain, there is female bias for ANA and chronic GN. In a backcross
(NZM2328 X C57L/J F1) X NZM2328 analysis, a genetic interval has been
identified on chromosome 1 in NZM2328 to control the development of
Studies 59
chronic GN. An interval on chromosome 4 was shown to be linked to the
production of ANA and anti-dsDNA antibodies. By a marker assisted
method, two congenics NZM2328.C57Lc1 and NZM2328.C57L.c4 were
generated by moving the genetic segments of interest from chromosomes
1 and 4 respectively from C57L/J to NZM2328. In NZM2328.C57Lc1 little
ANA, anti-dsDNA or chronic GN were seen. In contrast in
NZM2328.C57Lc4, chronic GN was detected despite marked reductions
in ANA and anti dsDNA, dissociating ANA and anti-dsDNA production
from lupus nephritis. It appeared that the genetic segment on
chromosome 1 controls lupus nephritis and regulates ANA and anti-
dsDNA production. These genetic loci have been named Lnc 1, the lupus
nephritis controlling gene 1 and Adn1, the anti-dsDNA and ANA
production gene 1. For this proposal, Lnc 1 is assumed to be different
from Adn1. This application is focused on the elucidation of the cellular
and immunochemical basis for autoantibody production and the
generation of GN and to identify the genes, Lnc 1 and Adn1. Four specific
aims proposed are (1) to characterize further NZM2328 and its two
congenic lines NZM2328.C57Lc1 an NZM2328.C57Lc4; (2) to determine
the specificities of immunoglobulins eluted from diseased kidneys from
NZM2328.Lc4, clarifying the basis for the dissociation of anti-dsDNA
antibody and ANA production from sever proteinuria and chronic GN;
(3) to determine the cellular basis of severe proteinuria, chronic GN, and
autoantibody production by adoptive cell transfer analysis; and (4) to
generate intra c1 congenic recombinant strains from the parental strain
NZM2328.C57Lc1, which contain smaller genetic intervals of
chromosome 1 derived from C57LIJ to determine the minimal C57L/J
genetic segment(s) to suppress anti-dsDNA antibody and ANA
production, and/or severe proteinuria an chronic GN. Thus, we will
refine the genetics for this interval so that we may identify the genes, Lnc
1 and Adn1, relevant to the phenotypic expression by positional cloning.
The results from these experiments will provide us further
understanding of the pathogenesis of SLE. This information should lead
to orthologous gene(s) identification in the SLE patients and provide us
potential targets for more specific and novel therapeutic interventions.
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Project Title: Characterization of SLE Susceptibility Loci on Mouse
Chromosome 4
Principal Investigator & Institution: Morel, Laurence; University of Texas Sw Med Ctr/Dallas Southwestern Medical Ctr/Dallas Dallas, Tx 75390
Timing: Fiscal Year 2000; Project Start 1-JUN-1996; Project End 1-AUG-
2005
60 Lupus Nephritis
Summary: Sle2 on mouse chromosome 4 is a strong recessive locus
associated with lupus nephritis in the NZM2410 model. Other groups
have identify other SLE-associated loci in the centromeric half of this
chromosome. Congenic analysis has showed that Sle2 is associated with
B cell hyperactivity resulting in producing of polyclonal IgM antibodies,
in vivo and in vitro hyper-responsiveness, increased B7.2 expression, and
enlargement of the Bl1 population. Characterization of polycongenic
strains combining Sle1, -2. and -3 has shown that Sle2 is necessary for full
disease expression, and that, in combination of Sle3, Sle2 results in highly
penetrant non-pathogenic hyaline and mesangial renal lesions that might
constitute an accelerating factor for lupus nephritis. Using the congenic
dissection approach, and following the steps that we are following in the
functional and genetic dissection of the role of telomeric chromosome 4 in
SLE pathogenesis. To achieve this goal, we have produced a series of 10
sub-congenic strains covering the area. We will use these strains in two
specific aims: 1) We will assess whether the various phenotypes
associated with Sle2 result from a single or several loci and generate a
high resolution genetic map of these loci. The immunological defects and
gene expression profile associated with each of these loci will be
established. 2) We will determine the contribution of these loci to SLE
pathogenesis by combining the corresponding sub-intervals to either Sle3
or the Sle1/Sle3 combination to reconstitute the Sle2/Sle3 or
Sle1/Sle2/Sle3 immunopathology, respectively. Preliminary results
indicate that the elevated B7.2 expression, but not increased Bl1
compartment, is associated with increased pathogenicity. These
experiments are a necessary step towards the identification of the SLE-
susceptibility genes on mouse chromosome 4. A high resolution genetic
map that leads to the physical map and ultimate cloning of the gene
cannot be constructed without a solid evaluation of the number of loci
and their associated defects. Finally, the understanding of their relative
contribution to the disease process will establish priorities for gene
identification.
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Project Title: FC Receptor Function in Normals and SLE
Principal Investigator & Institution: Salmon, Jane E.; Professor; Hospital for Special Surgery 535 E 70Th St New York, Ny 10021
Timing: Fiscal Year 2000; Project Start 1-DEC-1992; Project End 1-AUG-
2002
Summary: (Adapted from Investigator's abstract): Human Fc receptors
(FcgR) consist of three families with extensive diversity of structure and
function. Recent advances bring into focus four observations pertinent to
Studies 61
SLE: 1) FcgRIIa is a crucial receptor mediating phagocytic function; 2)
FcgRIIa is unique among FcgR in that it is targeted for oxidant and
protease-induced amplification of effector function as well as avidity
modulation, independent of receptor number; 3) the H131 allele of
FcgRIIa is the only human FcgR which recognizes IgG2 efficiently; 4) the
distribution of FcgRIIa alleles is skewed in SLE patients compared to
normals, with a highly significant decrease in FcgRIIa-H131 in lupus
nephritis. In SLE, FcgR-specific immune complex removal by the
mononuclear phagocytes system is impaired. This defect is related to
renal disease, emphasizing the possible role of FcgR dysfunction in
immune complex deposition and the pathogenesis of SLE. Despite the
decrease in FcgR function in vivo , there is a paradoxical increase in FcgR
binding in vitro. Preliminary data indicate that FcgRIIa is a compelling
candidate for the FcgR dysfunction in SLE. Monocytes in SLE patients
have increased FcgRIIa-mediated binding, but markedly decreased
FcgRIIa phagocytosis, indicating dissociation of receptor-effector
coupling. Disease-induced dysfunction superimposed upon inherited
polymorphisms of FcgRIIa with decreased functional capacity may
provide the milieu for the development of immune complex deposition
and nephritis. Recent evidence for a role of IgG2 autoantibodies in
nephritis underscores the importance of FcgRIIa in disease phenotype.
Based on these observations, the investigators hypothesize that 1)
abnormal FcgRIIa function provides a basis for disease-related defects in
SLE, and 2) that alleles of FcgRIIa which affect ligand binding are
important heritable disease susceptibility factors. Therefore, the specific
aims of this application: 1. to define the mechanism of activation of
FcgRIIa; 2. to define the basis for the defect in phagocytosis by FcgRIIa in
SLE; 3. to define the role of FcgRIIa alleles as risk factors for lupus
nephritis: (a) to establish genetic linkage of lupus and nephritis to
FcgRIIa and (b) to define the relative importance of FcgRIIa alleles among
different ethnic groups; and 4. to define subclasses of IgG deposited
within glomeruli in lupus nephritis and their relationships to FcgRIIa
alleles, autoantibodies, and induction of glomerular injury.
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Project Title: Immunological Mechanisms of Nephritis in Childhood
SLE
Principal Investigator & Institution: Reichlin, Morris; Professor and
Scientific Director; Oklahoma Medical Research Foundation 825 Ne 13Th
St, Ms 31 Oklahoma City, Ok 73104
Timing: Fiscal Year 2000; Project Start 0-SEP-1995; Project End 1-MAR-
2005
62 Lupus Nephritis
Summary: (Adapted from the Investigator's abstract): Childhood
systemic lupus erythematosus (SLE) differs from the disease in adults by
a higher prevalence of nephritis. The investigators hypothesize that this
higher prevalence of nephritis is due to several types of nephritogenic
autoantibodies that occur concurrently in the childhood form of SLE.
Two major candidates for these autoantibodies are those directed against
dsDNA which have long been recognized to play a role in adult lupus
nephritis and autoantibodies to ribosomal "P" protein which have not been reported previously to be associated with either adult or pediatric
lupus nephritis. Aside from recent preliminary clinical and animal data
that support a role for anti-P in lupus nephritis, both anti-dsDNA and
anti-ribosomal "P" antibodies have been found to contain subsets that directly bind and injure cells in culture. According to the investigators,
this antibody-mediated, in vitro cell injury phenomenon could be a
surrogate for their immunopathogenic potential in vivo. The
investigators propose to define the pathogenic potential of the
autoantibodies in individual patients by affinity purifying their
autoantibodies and by studying their interaction with various cell types
in culture and the effects on cell function and viability. In preliminary
studies, they have reproduced previous work by showing that some
human anti-dsDNA antibodies injure cells by a complement dependent
mechanism at the cell surface, and others penetrate the cell, localize in
either the nucleus or the cytoplasm, and like anti-P, inhibit protein
synthesis. The investigators will correlate these immunopathogenetic
properties in vitro with the patients' clinical status. They propose to
expand their studies of the idiotypic regulation of these antibodies in
patients with anti-P antibodies. Parallel studies in adults suggest that,
like children, the presence of both anti-dsDNA and anti-P antibodies
greatly increase the risk of active nephritis. The investigators also have
preliminary data that anti-P may be enriched in human glomerular
eluates and propose to expand these studies. Lastly, they propose to
develop an animal model to assess the nephritogenic potential of induced
anti-P antibodies. They hope that these studies would expand
perspectives on the immunopathogenesis of nephritis in both children
and adults with SLE.
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Project Title: Regulation of TNF-Alpha Production in SLE
Principal Investigator & Institution: Liu, Yi; Medicine; University of
Southern California University Park Los Angeles, Ca 90007
Timing: Fiscal Year 2000; Project Start 1-JUN-2000; Project End 1-JUL-
2000
Studies 63
Summary: It is estimated that 1.4 to 2 million people in the USA suffer