The major focus of SADRC-WNY is clinical and transitional
research of human SLE. At the present time, 6 projects are
underway, with many more planned:
- The lupus database is hoping to follow all the lupus
patients in Western New York prospectively, over the
period of their lifetimes. To participate, a patient must
sign the appropriate consents, and then fill out a from
asking various questions about their disease and its
management every 6 months. Rheumatologists seeing
enrolled patients fill out a SLAM
(Systemic Lupus Activity Measure) form at each visit,
giving their assessment of disease activity. If
permission is granted, sera and plasma are collected and
banked at each doctor's visit for future analysis. The
database hopes at the very least to identify different
subsets of patients with SLE, and to learn about the
course of their diseases. Patients from the database can
participate, if they are interested and grant permission,
in various clinical and basic science/ transitional
studies.
- The diagnosis and treatment of brain and other central
nervous system (CNS) problems in patients with SLE is one
of the most poorly understood clinical issues in SLE. To
develop more sensitive techniques for detecting CNS
disease in SLE, SADRC-WNY has devised a battery of
testing that includes questionaires, skilled tasks and
EEG to assess CNS function. Fast MRI will be added to the
battery of tests in the near future. All SLE patients
willing to participate are tested every 6 months ( and
receive $100/session). These data are correlated with the
clinical and laboratory data acquired in other arms of
these studies.
- Predisposition to developing SLE involves a complex array
of multiple genetic and environmental factors . SADRC-WNY
has initiated studies using functional genomics to
characterize different forms of SLE at a genetic and
molecular level, to ultimately allow the development of
specific therapeutic agents. The first technique to be
applied towards this goal is representational
differential analysis (RDA). RDA is a very sensitive PCR
based technique that allows the identification of genes
selectively expressed in one population of RNA, but not
in another. It allows SADRC - WNY to ask the question:
what genes are selectively expressed, or not expressed,
in particular forms and stages of SLE. This has the
potential to identify not only genes dysregulated in SLE,
but also infectious agents that may be critical for the
expression and/or severity of SLE in particular patients.
We hope to include in the near future studies utilizing
chip technology. This technique allows evaluation of as
many as 50,000 genes simultaneously to determine which
genes are up or down regulated in different forms of SLE,
compared to normals and patients with various other
diseases. These studies will provide an overall picture
of immune dysregulation in SLE, and may suggest distinct
therapeutic targets in each type of disease.
- Interleukin 14, formerly known as High Molecular Weight B
Cell Growth Factor (HMW-BCGF), is a cytokine that has
been shown to participate in the formation and
maintenance of normal B cell memory . It was shown to act
as an autoregulatory growth factor for high-grade tumors
derived from memory B cells . We observedthat a large
percentage of peripheral B cells from patients with SLE
express normally functioning IL-14 receptors (45
–95%), compared to normal donors (5 – 15%) .
Freshly isolated peripheral B and T cells from patients
with SLE expressed mRNA for IL-14, while T cells, not B
cells, from normal donors expressed mRNA for IL-14 only
after in vitro stimulation with PHA. Thus, IL-14 might
have an auto-regulatory role for abnormal memory B cells
in SLE, and contribute to disease pathogenesis. In the
last several months, mapping studies for susceptibility
genes for murine (NZB/NZW mice) have identified the locus
containing the IL-14 gene (chromosome 4, near lck
) as a potential major susceptibility locus. We are
pursuing these preliminary studies by evaluating
overproduction and deletion of IL-14 in various murine
models for SLE. We are evaluating the IL-14 gene, and the
various transcripts derived from it, in patients with
SLE.
- In order to find clues regarding the nature of the
inflammation, serum proteins from 6 patients with SLE
vasculitis (a clinically homogeneous group of SLE
patients treated with corticosteroids and
cyclophosphamide), 6 patients with Wegener granulomatosis
(a systemic vasculitis; patients treated with
corticosteroids and cyclophosphamide), and 6 normal
controls were separated on large two-dimensional gels
(isoelectric focusing and SDS-PAGE) that could delineate
greater than 6000 individual spots . Two spots were found
exclusively in the sera of all the SLE patients and
reliable N-terminal amino acid sequence obtained from
one. In checking the sequence against proteins in the
Swiss Data Bank, three homologous protein sequences were
found: 1) GP57 secretory glycoprotein of Marek's disease
virus, 2) L1 protein of Vaccinia virus, and 3) the beta
chain of apolipoprotein J. While tantalizing, because
Marek's disease virus causes autoimmune disease in
chickens, the degree of sequence homology is not
sufficient to suggest that any of these proteins are
necessarily involved with SLE. A monoclonal antibody was
produced to the N-terminal sequence of this SLE protein
and shown to recognize a protein in the sera of SLE
patients, but not in the sera of patients with Wegener
granulomatosis, other vasculitides, or normal controls.
Further analysis of this protein is in progress.
- SADRC-WNY was recently invited to join the Immune
Tolerance Network, established by Dr. Jeffrey Bluestone
at the University of Chicago, and funded by PHS/NIH. The
Immune Tolerance Network involves various SLE centers
throughout the United States.Its first study, which
should start in the summer of 2000, will examine CTLA-4
Ig in the treatment of human lupus nephritis. CTLA-4 Ig
has been used successfuly in animal models of lupus
nephritis and in human transplant rejection.