The Official Patient's Sourcebook on Lupus (13 page)

from Systemic lupus erythematosis (SLE). At present, there is no cure for

SLE. The pathogenesis of SLE is still unknown. Studies have suggested

that cytokines may play an important role in its pathogenesis. Tumor

necrosis factor alpha (TNFalpha) is a cytokine with very diverse

physiological and pathological activities. Several lines of evidence have

suggested that TNFalpha play an essential role in the development and

progression of SLE. First, it has been reported that TNFalpha production

in activated monocytes from SLE patients is significantly decreased.

Second, it has also been shown that lupus patients with low TNFalpha

production have an increased incidence of lupus nephritis. Lastly, in a

SLE murine model, the levels of TNFalpha production by activated

macrophages are significantly lower in NZW lupus prone mice.

Treatment with recombinant TNFalpha significantly reduces the

incidence of lupus nephritis in these mice. Recent studies have

demonstrated that reduced production of TNFalpha in NZW lupus-

prone mice is mainly regulated at the translational level, mediated by the

3' untranslated region (3'UTR) of the TNFalpha gene. In this project, I will

dissect the 3'UTR of the TNFalpha gene and characterize its role in the

regulation of TNFalpha production. My specific aims are: 1. To delineate

the translational regulatory cis-acting elements in the TNFalpha 3'UTR of

NZW lupus-prone mice through deletion and site- directed mutagenesis

using transient transfection assays with the luciferase reporter system. 2.

To test whether the RNA-protein binding profile is different between the

mutated 3'UTR of the lupus-prone NZW mouse and the non-mutated

3'UTR of the non-lupus-prone mouse and to further characterize the

trans- acting factors involved in regulating the T'NFalpha gene. The

elucidation of the mechanism of regulation of TNFalpha production is

fundamental in understanding the pathogenesis of SLE, with possible

implications in SLE treatment through manipulation of TNFalpha

production. Accomplishment of the proposed project also has the

potential to enhance our understanding of post-transcriptional gene

regulation in general.

Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket

·
Project Title: Role of Complement Factor B in the Pathogenesis of SLE

Principal Investigator & Institution: Gilkeson, Gary S.; Professor;

Medicine; Medical University of South Carolina 171 Ashley Ave

Charleston, Sc 29403

Timing: Fiscal Year 2000; Project Start 1-APR-2000; Project End 1-MAR-

2005

64 Lupus Nephritis

Summary: (Adapted from the Investigator's abstract): The complement

cascade plays an important role in the pathogenesis of immune complex

mediated diseases, including lupus nephritis. The alternative

complement pathway is activated in lupus nephritis, though its role in

the pathogenesis of disease is unclear. To provide insight into the role of

the alternative pathway, and specifically the role of Factor B (Bf), in

disease, mice deficient in Bf were derived. Bf deficient mice were found

to have normal immune function despite being unable to activate the

alternative pathway. To determine what role Bf and the alternative

pathway play in autoimmune disease, we bred the Bf knockout genotype

to the lupus prone MRL/lpr background. Compared to Bf expressing

litter mates, the Bf deficient MRL/lpr mice developed significantly less

proteinuria, pathologic renal disease, glomerular IgG immune deposits

and vasculitis. Surprisingly, C3 levels were normal in the MRL/lpr Bf

deficient mice in contrast to significantly, depressed levels in the Bf

producing litter mates, typical of disease in MRL/lpr mice. These

findings suggest Bf has a key pathogenic role in lupus nephritis in

MRL/lpr mice and that the alternative pathway is an important

mechanism for C3 activation and consumption in MRL/lpr disease. Our

central hypothesis is that Factor B and the alternative pathway are pro-

inflammatory in lupus and that blocking Factor B activity provides a

novel approach to treating this disease. To further define the role of

Factor B in immune complex mediated diseases and activation of C3, the

following specific aims are proposed: Aim 1- Determine the mechanisms

by which renal damage is diminished in Bf deficient MRL/lpr mice. Aim

2 - Determine the mechanism for the maintenance of normal serum C3

levels in MRL/lpr Bf-/- mice . Aim 3 - Identify the effects of Bf deficiency

on autoimmune B cell function including isotype switching and tolerance

as well as macrophage/mesangial cell function. Aim 4 - Determine the

potential for disease modification by inhibition of Bf activation using

additional therapeutic strategies and models of glomerular injury. These

studies will provide new insight into the role of the alternative pathway

in disease and potentially provide a new therapeutic target (Factor B) in

immune complex mediated diseases.

Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket

·
Project Title: SLE Triggered Disease Pathways

Principal Investigator & Institution: Mohan, Chandra; 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

Studies 65

Summary: Functional dissection of lupus pathogenesis using B6 congenic

strains, bearing NZM2410-derived lupus susceptibility intervals (Sle1,

Sle2 and Sle3) have collectively added fresh insights to our

understanding of this disease, In effect these efforts have collapsed the

problem of understanding a polygenic (and hence, multi-factorial)

disease into a series of monogenic (and hopefully, unifactorial models)

These studies allude to the existence of 3 distinct genetically-

programmed pathogenic steps: Initial breach in tolerance to chromatin,

"pathogenic maturation" of the initial response., and finally, end-organ damage. Sle1 appears to trigger the first process, since it apparently leads

to anti-chromatin autoimmunity, in a surprisingly, antigen-specific

manner. In contrast, Sl32 and Sl32 appear to impact the immune system

in a generalized fashion (leading to B-cell hyperactivity, and -cell

aberrations, respectively), in effect, promoting the "pathogenic

maturation" of anti- nuclear autoantibodies. Finally, how the Sle loci

might facilitate end- organ damage remains unknown. In addition, what

role(s) T-cells play in these 3 events is also not clear. This proposal aims

to address these knowledge gaps, with the following specific aims. (1) To

determine the role of T-cells in mediating the genetically dictated

pathogenic processes leading to lupus nephritis. We will test this

hypothesis by breeding the TCR -/- mutation onto selected B6.SLE

congenics. (2) To gauge the complexity versus clonality of the T-cell

repertoire mediating the genetically dictated pathogenic processes

leading to lupus nephritis. This will be tested by analyzing the TCR

repertoire by FACS analysis and TCR V CDR3 spectratyping in lymphoid

and intrarenal T- cells isolated from selected B6. Sle congenics. (3) To

define the role of B-cells and autoantibodies in mediating renal pathology

in the B6.Sle polycongenic model. This will be verified by breeding either

the Igh-/- (lacking B-cells and Ig), or the slgM-/- (lacking Ig but not B-

cells) onto selected B6.Sle congenics. (4) To determine if the Sle loci confer intrinsic renal susceptibility to nephrophilic autoantibody-mediated

damage. This will be tested by exposing and studying kidneys bearing

different genotypes to potentially pathogenic autoantibodies.

Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket

E-Journals: PubMed Central
21

PubMed Central (PMC) is a digital archive of life sciences journal literature

developed and managed by the National Center for Biotechnology

21 Adapted from the National Library of Medicine:

http://www.pubmedcentral.nih.gov/about/intro.html
.

66 Lupus Nephritis

Information (NCBI) at the U.S. National Librar
y of Medicine (NLM).22 A
ccess to this growing archive of e-journals is free and unrestr
icted.23 To search, go

to
http://www.pubmedcentral.nih.gov/index.html#search
, and type “lupus

nephritis” (or synonyms) into the search box. This search gives you access to

full-text articles. The following is a sample of items found for lupus nephritis in the PubMed Central database:

·
Effect of genetic background on the contribution of New Zealand Black

loci to autoimmune lupus nephritis
by Stephen J. Rozzo, Timothy J.

Vyse, Charles G. Drake, and Brian L. Kotzin; 1996 December 24

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=26374

·
Immunophilins, Refsum disease, and lupus nephritis: The peroxisomal

enzyme phytanoyl-COA [alpha]-hydroxylase is a new FKBP-associated

protein
by Beatrice Chambraud, Christine Radanyi, Jacques H. Camonis,

Krzysztof Rajkowski, Michael Schumacher, and Etienne-Emile Baulieu;

1999 March 2

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=26744

·
Pathogenic Anti-DNA Autoantibody-Inducing T Helper Cell Lines

from Patients with Active Lupus Nephritis: Isolation of CD4-8- T

Helper Cell Lines That Express the [gamma][delta] T-Cell Antigen

Receptor
by S Rajagopalan, T Zordan, GC Tsokos, and SK Datta; 1990

September 15

http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst

ract&artid=54674

The National Library of Medicine: PubMed

One of the quickest and most comprehensive ways to find academic studies

in both English and other languages is to use PubMed, maintained by the

National Library of Medicine. The advantage of PubMed over previously

mentioned sources is that it covers a greater number of domestic and foreign

references. It is also
free to the public.24 If the publisher has a Web site that

22 With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age.

23 The value of PubMed Central, in addition to its role as an archive, lies the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.

24 PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web Studies 67

offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in

some journals.

To generate your own bibliography of studies dealing with lupus nephritis,

simply go to the PubMed Web site at
www.ncbi.nlm.nih.gov/pubmed
. Type

“lupus nephritis” (or synonyms) into the search box, and click “Go.” The

following is the type of output you can expect from PubMed for “lupus

nephritis” (hyperlinks lead to article summaries):

·
Clinical trials in lupus nephritis.

Author(s): Ginzler EM.

Source: Curr Rheumatol Rep. 2001 June; 3(3): 199-204. Review.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=Pu

bMed&list_uids=11352788&dopt=Abstract

·
Improvement in lupus nephritis following treatment with a Chinese

herbal preparation.

Author(s): Yap HK, Ang SG, Lai YH, Ramgolam V, Jordan SC.

Source: Archives of Pediatrics & Adolescent Medicine. 1999 August;

153(8): 850-2.

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=

PubMed&list_uids=10437759&dopt=Abstract

Vocabulary Builder

Alkalosis:
A pathologic condition resulting from accumulation of base, or from loss of acid without comparable loss of base in the body fluids, and

characterized by decrease in hydrogen ion concentration (increase in pH).

[EU]

Alleles:
Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical

and developmental process. [NIH]

Amenorrhea:
Absence or abnormal stoppage of the menses; called also

amenia. [EU]

Angiitis:
Inflammation of a vessel, chiefly of a blood or a lymph vessel; called also vasculitis. [EU]

Antibody:
An immunoglobulin molecule that has a specific amino acid

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68 Lupus Nephritis

sequence by virtue of which it interacts only with the antigen that induced