group leader

Ibrahim
Dr. Saleh M. Ibrahim
Tel.: +49 +381 494 5872

staff

Gabriel
Jana Gabriel
(project assistant)
Tel.: +49 +381 494 5880

Allenberg
Angelika Allenberg
(computer scientist)

Wernhoff
Dr. Patrik Wernhoff
(Post doc)

Moeller
Dr. Steffen Möller
(Post doc)

Vasilios Kotsikoris
(Post doc)

Tu-Rapp
Hoang Tu-Rapp
(PhD student)

Vogler
Susanne Vogler
(PhD student)

Mazon
Ignacio Mazón Peláez
(PhD student)

Yu
Xinhua Yu
(PhD student)

Bauer
Kristin Bauer
(PhD student)

Ilona Klamfuß
(technical assistant)

Lorbeer
Eva Lorbeer
(technical assistant)

Ernst
Mathias Ernst
(Diploma student)

Andrea Kotitschke
(Diploma student)


Research group "Immunogenetics"

The group is studying the genetic basis of autoimmunity.
The group is also responsible for the transgenic animal unit at the medical faculty.

Projects:

"Functional Genomic Approaches Targeting Arthritis"
"EURO-RA"

The research Network, EURO-RA, brings together leading groups in the field of Arthritis research in Europe. The main scientific goal is to capitulize the modern postgenome methodologies such as genome wide expression profiling (microarrays), proteom analysis, comparative genomics , and genome wide mutagenesis to study Rheumatoid Arthritis (RA), the most common chronic inflammatory autoimmune disease affecting the European population. RA is a systemic, inflammatory, progresseive, chronic and destructive disease affecting primarily periphal joints, and it is associated with pain, disfigurement,and varoius extraarticular manifestations (organ failures). This combined effort of 12 research groups from 9 European countries aims to identify susceptibility genes that determine the onset, progression and chronicity of autoimmune arthritis. This in turn will provide an excellent opportunity to improve our knowledge on in vivo disease mechanism and, hence, to develop more rational forms of therapy.

Funding: EU

Junior Research group 1

Identification of susceptibility genes contributing to the pathogenesis of experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is a mouse model that serves as an experimental tool for studying the etiology, pathogenesis as well as new therapeutic approaches of multiple sclerosis (MS). EAE is a polygenic chronic inflammatory demyelinating disease of the nervous system that involves the interaction between genetic and environmental factors. Previous studies have identified multiple quantitative trait loci (QTL) controlling different aspects of disease pathogenesis. However, progress in identifying new susceptibility genes outside the MHC locus has been slow. With the advent of new global methods for genetic analysis such as large scale sequencing, gene expression profiling combined with classical linkage analysis, congenic and physical mapping progress is considerably accelerating. Our group is using gene expression mapping to identify new putative genetic pathways contributing to the pathogenesis of EAE. Two approaches are being taken, first additional genome scans to identify new QTL linked to disease subtraits in crosses between B10.s and SJL strains. These experiments are underway. Additionally gene expression profiling in target tissues and immune cells in PLP-induced EAE in the B10.s /SJL strains and the MOG-induced EAE in C57bl/6 strains are being conduced. In the first series of experiments using Affymetrix oligonucleotide microarrays representing ~11000 genes to determine the gene expression profiles of the inflamed spinal cords of MOG-induced EAE mice at onset and peak of disease. Inflammation resulted in a profile of increased gene expression of immune-related molecules, extra-cellular matrix and cell adhesion molecules, molecules involved in cell division and transcription; differential regulation of molecules involved in signal transduction, protein synthesis and metabolism. Interestingly, all nervous system-related genes observed were downregulated. 213 genes were differentially regulated and 100 showed consistent differential regulation throughout disease. Of the 91 genes with known chromosomal locations 40 genes mapped to non-MHC EAE-linked QTLs and as such could be considered as putative candidate genes for susceptibility to EAE. We are currently analysing some of those genes for sequence polymorphism. Additionally their influence on disease is being tested in mutant mice.

Funding: BMBF

GENE EXPRESSION MAPPING AS A TOOL TO IDENTIFY NEW GENETIC PATHWAYS CONTRIBUTING TO THE PATHOGENESIS OF COLLAGEN-INDUCED ARTHRITIS
"EUROME"

Collagen-induced arthritis (CIA) is a chronic inflammatory disease bearing all the hallmarks of rheumatoid arthritis (RA). As a widely used animal model, CIA is an experimental tool for studying the etiology, pathogenesis as well as new therapeutic approaches of RA. We use gene expression mapping to identify new putative genetic pathways contributing to the pathogenesis of CIA. Two approaches are being taken, first additional genome scans to identify new QTL linked to disease subtraits in crosses between DBA1/J and FVB/NJ strains, these experiments are underway; additionally gene expression profiling in target tissues and immune cells in CIA in the DBA1/J and FVB/NJ strains are being conducted.

Funding: EU

The role of Fas in the pathogenesis of collagen induced arthritis

How autoimmune dysregulation leads to tissue destruction in collagen induced arthritis (CIA) remains unresolved, inspite of significant work. An impediment to progress is the complexity of the autoimmune processes, which involves multiple immune cell types, target tissues and pathologies. As in rheumatoid arthritis (RA), infiltrating T cells , macrophages, and plasma cells are thought to initiate and contribute to an inflammatory cascade leading to progressive destruction of cartilage and bone, a process that is partially mediated by cytokine induction of destructive enzymes such as matrix metalloproteinases.
Dysregulation of apoptosis is a process that has been implicated in the pathogenesis of autoimmune disease, however, its contribution to the pathogenesis of CIA and RA is not known. Apoptosis defects are thought to contribute to the autoimmune process by failing to establish self tolerance, failure to down regulate the immune response and finally by direct tissue damage. This proposed project attempts to delineate the role of the main apoptotic pathway, Fas (CD95 or APO-1)/FasL in the pathogenesis of CIA. Two aspects will be studied, one is the role of the Fas pathway in regulating the autoimmune process by controlling the generation of autoreactive joint-specific lymphocytes. The second is the contribution of FasL to mediating the effector functions of T cells and other cells involved in joint destruction. We will achieve this by using Fas and Fas ligand mutant mice as well as transgenic mice expressing T-cell specific soluble Fas. These newly generated transgenic mice will also help to clarify the role of sFas, an alternative splice form of the Fas molecule, in autoimmunity.

Funding: DFG

B cell tolerance in normal and autoimmune site-specific transgenic mice expressing arthritis-associated autoantibodies

We plan to delineate the role of B cells, one of the primary mediators in autoimmune arthritis, in disease by generating transgenic mice engineered to produce high levels of joint-specific autoantibodies. These site-directed transgenic mice (Knock-in) will be generated by replacing the germline heavy chain joining region (JH) with rearranged Immunoglobulin (Ig) heavy chain variable region gene of an anti-collagen II-specific monoclonal antibody. The transgenic mouse will be mated to mutant strains of genes involved in immune tolerance with the aim of identifying the mode of regulation of anti-collagen antibodies producing B cells as well as their contribution to early and late stages of disease. We will determine the stage of B cell development at which regulation takes place and the mechanisms by which regulation is carried out.

Funding: EU

Transgenic Animal Facility

To make the technology available to all research groups at the medical faculty we established a unit for the generation of transgenic, Knock-in, Knock-out and conditional mutant mice. This was done in close collaboration with colleagues at the animal facility.
The unit is equiped by a micromanipulator, small animal isolator, Microscope, Tissue culture incubator, and all small equipments needed for animal surgery and cell culture. A permission “Tierversuchsgenehmigung” to produce transgenic/Knock-out mice has been obtained as well as a S1 licence covering the lab space and animal rooms.

The following tasks are being routinely performed at the unit:
- Cloning of targeting vectors
- Culture and maintenance of embryonic stem cells
- Animal surgery, embryo transfer, preparation of blastocysts and embryonic fibroblsts.
- Microinjection of DNA and ES cell transfer into blastocysts
- PCR and southern blotting for the identification of gene modified animals
- Maintenance and analysis of transgenic animals.
- Functional analysis of transgenic/knock-out mice

Funding: BMBF, Medical Faculty