Research Report - Nikolaus-Fiebiger-Zentrum für Molekulare Medizin

Foxo1 activity in early B cells in the context of IL-7 and pre-BCR signaling. Loss of
EFhd1 should induce loss of function of Foxo1, thereby, reducing rag expression and
slowing down early B cell development. Both gain and loss of function of EFhd1 may
only be revealed under competitive conditions. Thus, we will create mixed bone
marrow chimeras of wt and EFhd1tg bone marrow as well as wt and EFhd1 K.O.
bone marrow and analyze the putative contribution of EFhd1 to early B cell
development
Since there was evidence that EFhd2 might be involved in neurodegeneration
mediated by the microtubule-stabilizing protein tau we tested whether EFhd2
modulates tau function. Surprisingly, we observed that co-expression of EFhd2 with
mutant tau proteins (tau P301S and tau �K280), that cause frontotemporal dementia
associated with parkinsonism (FTDP), but not with wildtype tau, caused degradation
of EFhd2, but not of the co-expressed GFP. We are currently elucidating the
proteolytic pathway underlying this degradation process. In line with a putative
interaction of tau and EFhd2, we detected EFhd2 with newly generated monoclonal
antibodies in ordered presynaptic complexes in murine as well as human brain
sections. Interestingly, the presynaptic, ordered expression of EFhd2 was completely
abolished in barins of Alzheimer’s patients. Likewise, EFhd2 co-localized with tau and
with tau tangles in brains of Alzheimer’s patients. Finally we observed that the
presynaptic marker Bassoon was largely absent from synaptic structures in brains of
EFhd2 K.O. mice whereas tau expression was stronger and more confined to
presynaptic complexes than in wildtype mice. Taken together we hypothesize that
EFhd2 modulates tau function to control the composition of pre-synaptic complexes.
This might be important during onset and progression of tau-mediated
neurodegenerative diseases and for learning or rewarding processes.
Genetic and functional analysis of Lupus-associated risk alleles
Katrin Weiß and Barbara Fürnrohr
Systemic Lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease
involving multiple organs including skin, joints, kidneys, brains, the cardiovascular
system and serosal membranes. Immunologically, SLE is characterised by the
presence of antinuclear autoantibodies, especially against double stranded (ds) DNA
and nucleosomes, activation of the complement system during flares and type I
interferon secretion. The etiology of SLE remains elusive, however, an interplay of
genetic and environmental factors is considered to ultimately cause immune
dysregulation, resulting in clinical symptoms. Twin studies have reported a
concordance of 24-57% and 2-5% in monozygotic and dizygotic twins, respectively,
therefore SLE has an estimated heritability of 66%. Recent genome-wide association
studies together with candidate gene studies have uncovered four major candidate
gene loci, namely the MHC class II locus IKZF1, STAT4 and ITGAM which are most
probably of functional relevance in SLE.
Genetic variation at the ITGAM gene has been identified as a key genetic
susceptibility effect in human systemic lupus erythematosus (SLE). It is one of the
strongest known genetic risk factors in SLE, and is common (minor allele frequency
approximately 10%) in all except East Asian populations. Interest has specifically
focussed on the rs1143679 variant, which encodes an arginine to histidine amino
acid change at position 77 in the �-propeller of the extracellular domain in CD11b
which is encoded by ITGAM. As part of the complement receptor CR3, CD11b is
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