Zeitschrift für Rheumatologie – Supplement 1 - Deutsche ...

S76
Abstracts
POFER-5
Cathepsin L is an important protease in two diff erent models for
Rheumatoid Arthritis experimental arthritis
Schurigt U. 1 *, Rajasekaran N. 2 *, Eilenstein R. 1 , Mieczyslaw G. 1 , Sevenich L. 3 ,
Reinheckel T. 3 , Peters C. 3 , Illges H. 2 , Bräuer R. 1 **, Wiederanders B 4 **
1 Institute of Pathology, Friedrich-Schiller-Universität Jena, 2 University of
Applied Scieneces, Bonn, 3 Albert Ludwigs Universität Freiburg, 4 Institute
of Biochemistry, Friedrich-Schiller-Universität Jena
* these two authors contributes equally to this abstract
** project leaders
Cathepsin L is a potent matrix-degrading lysosomal cysteine protease
which cleaves collagen and can modulates the antigen presentation. We
investigated cathepsin L-defi cient (ctsl-/-) mice in two diff erent murine
models for rheumatoid arthritis (RA). Th e antigen-induced arthritis
(AIA) was the fi rst model we investigated. Th e knee joint swelling
and the histological arthritic scores were decreased for ctsl-/- mice in
comparison to wild-type animals. Because cathepsin L plays a critical
role in CD4+ T cell selection in the thymus, the absolute number of
CD4+ T helper (Th ) cells is decreased in cathepsin L-defi cient mice.
We determined the CD4+/CD8+ and the FOXP3+/CD4+ ratio in ctsl-
/- mice in comparison to wild-type mice. How expected the absolute
CD4+ Th cell number was reduced in knockout mice. Nevertheless we
found an increase of the protective regulatory FOXP3+ Th cells in the
CD4+ Th cell compartment. To test the hypothesis that the dysbalance
of regulatory versus pathogenic CD4+ Th cells protects ctsl-/- mice we
performed the AIA in transgenic mice, expressing the recently identifi
ed human cathepsin L-like enzyme cathepsin V under the control of
the human keratin 14 promoter (TG [K14-CTSV/ctsl-/-]). Th ese animals
have a normalized CD4+/CD8+ T cell ratio. Th e severity of AIA
in the TG [K14-CTSV/ctsl-/-] mice was not signifi cant diff erent from
the severity in wild-type mice. Th is result showed clearly that cathepsin
L is not important for the joint destruction in AIA in respect to the
antigen presentation and the digestion of collagen but has a role for
the onset of the arthritis. Finally the K/BxN model for RA was used
to investigate macrophage-mediated functions of cathepsin L. Cathepsin
L-expressing cells in the synovial membrane of patient at the sites
of bone and cartilage destruction are oft en described as macrophage-like.
Recently the crucial role of macrophages in the pathology of
K/BxN serum-induced arthritis was shown (1). Interestingly we found
a signifi cant reduction of the arthritis severity on days 9 and 12 aft er the
serum injection, the time points when strong joint destruction takes
place in this model.
Uta Schurigt & Narendiran Rajasekaran equally contributed to this
work
1. Solomon, S., N. Rajasekaran, E. Jeisy-Walder, S.B. Snapper, and H.
Illges. 2005. A crucial role for macrophages in the pathology of K/B x
N serum-induced arthritis. Eur J Immunol 35:3064-3073.
POFER-6
Cardiovascular and pupillary autonomic nervous dysfunction and
mortality in patients with rheumatoid arthritis
Schwemmer S., Härle P., Beer P., Schölmerich J., Straub RH.
Department of Internal Medicine I, University Hospital of Regensburg,
D-93042 Regensburg
Autonomic nervous dysfunction carries an increased risk of mortality
in diabetes mellitus. In rheumatoid arthritis (RA) patients, the association
between cardiovascular (CAD) or pupillary autonomic dysfunction
(PAD) and mortality has never been investigated. Between 1997
and 1998, 33 RA patients were examined for baseline characteristics,
and parameters of CAD and PAD. Th irty patients have been reevaluated
8.3 ± 0.1 yr later using a telephone questionnaire (response rate =
91%). During the 8-year observation period, 4 / 30 RA patients died
(13%) due to heart failure (n=1), immunodefi ciency / infection (n=1),
and sudden deaths (n = 2). Non-survivors as compared to survivors
| Zeitschrift für Rheumatologie · Supplement 1 · 2006
had increased heart rate variation in the respiratory arrhythmia test
(p=0.038, hyperrefl exia) but largely decreased heart rate variation in
the lying-to-standing test (p=0.009). Non-survivors as compared to
survivors demonstrated more frequent pupillary autonomic dysfunction
(100% vs. 42%, p=0.035). Fift een patients were diagnosed with
PAD, and mortality was signifi cantly higher in patients with PAD than
without PAD (27% vs. 0%, p=0.035). Six patients were diagnosed with
CAD (20%), and mortality tended to be higher as compared to patients
without CAD (33% vs. 8%, p=0.113). Th is study demonstrates that
diagnosis of PAD was associated with an increased mortality risk in
patients with RA. Patients with a poor test result in the lying-to-standing
test are also at increased risk of death. Th is study in RA patients
demonstrates similar results as in patients with diabetes mellitus.
POFER-7
The molecular basis of functional stability of regulatory T cells: The
memory of Th cells for IL-10 expression is conditional unless the gene
is imprinted by GATA-3
Radbruch A., Chang H-D., Dong J., Thiel A.
Deutsches Rheuma-Forschungszentrum Berlin
Regulatory T lymphocytes appear to be potent tools for the targeted
therapy of infl ammatory rheumatic diseases. Th eir regeneration in vivo
or their adoptive transfer into rheumatic patients are currently discussed
as therapeutic options. Th erapeutical success will critically depend
on the stability of their regulatory phenotype at the site of interaction
with the proinfl ammatory immune reaction. Here we analyse the memory
of Th memory lymphocytes for the reexpression of the cytokine
Interleukin-10 (IL-10), which is a critical function of regulatory T lymphocytes.
Th e memory of Th lymphocytes for expression of the cytokines
IL-4 and IFN-γ is established already aft er the primary activation
with costimulation by IL-4 and IL-12, respectively, i.e. in later reactivations
of the Th cells, expression of IL-4 or IFN-γ is maintained independently
of the original costimuli. Here we show that the expression
of IL-10 is induced by either IL-4 or IL-12 costimulation, and remains
dependent on these costimulations in reactivated Th cells, i.e. the memory
for IL-10 is not stable and reexpression of IL-10 remains conditional.
When isolated ex vivo by the cytometric cytokine secretion assay,
IL-10 expressing Th lymphocytes lack epigenetic imprinting of the IL-
10 gene and, subsequently, a stable memory for IL-10. Such cells would
be useless for therapeutic applications, unless instructive conditions for
IL-10 expression could be achieved at the presumptive site of action
simultaneously. Alternatively, a stable memory for IL-10 expression under
any, even adverse conditions, can be established in Th lymphocytes
by repeated stimulation with antigen and the instructive signal IL-4.
We show here, that this is due to the IL-4 induced transcription factor
GATA-3. GATA-3 directly addresses the IL-10 promoter in IL-10 expressing
Th cells and induces epigenetic remodelling of the IL-10 gene,
which might be prerequisite for a stable IL-10 memory.
POFER-8
Antibody against mutated citrullinated Vimentin (anti – MCV):
A new sensitive marker in the diagnosis of rheumatoid arthritis
Skoumal M. 1 , Wagner E. 2
1 Ludwig Boltzmann Institute of Osteology at the Hanusch -Hospital of
WGKK and AUVA Trauma Centre Meidling,4 th Medical Dpt., 2 Institute for
Rheumatology of the Kurstadt Baden in Cooperation with the Danube-University
Krems, Austria,
Background: Vimentin is a protein found in mesenchymal cells like
fi broblasts, chondrocytes, osteocytes, leukocytes and endothelial cells,
but also in monocytes and activated macrophages. Th e enzyme peptidyl-Arginin-Deiminase
(PAD) leads to a citrullination of synovial
proteins like vimentin, In rheumatoid arthritis (RA) these citrullinated
peptides activate T-lymphocytes by binding on HLA-DR4 on the sur-