The Official Patient's Sourcebook on Lupus (12 page)

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