TY  - GEN
CY  - Heidelberg
KW  - Nicht-klassische Monozyten
KW  -  Immunkomplexe
KW  -  systemischer Lupus erythematodes
N2  - Immune complexes (ICs) are antibody-antigen complexes, which are constantly formed as part of the humoral immune response against pathogens, facilitating their recognition and clearance. However, when ICs are formed in large excess they can accumulate in the vasculature, tissues and organs and lead to severe pathology including inflammation, tissue damage and organ failure. The formation of ICs is a hallmark of the autoimmune disease systemic lupus erythematosus (SLE), in which the persistent formation of ICs from autoantibodies binding to self-antigen leads to severe chronic inflammation and organ dysfunction. The inflammatory cascade is initiated by immune cells recognizing the deposited ICs via Fcy-receptors, triggering additional immune cell recruitment, cellular activation and pro-inflammatory cytokine release, whereby the mechanisms leading to initial IC recognition and the involved cell types remain unclear.

This dissertation examines the mechanisms underlying the process of IC-induced migration of slan+ non-classical monocytes (SlanMo). SlanMo, a subset of non-classical monocytes, are known as intravascular, patrolling cells, which protect blood vessels. They exhibit a high Fc? receptor diversity and expression, enabling them to uniquely respond to IC-mediated activation. The results in this work demonstrate that SlanMo show strong, FcyRIII-dependent
binding affinity toward ICs and migrate in a very distinct migration pattern on immobilized ICs. During this unique process, SlanMo internalize and digest ICs. Additionally, SlanMo are attracted by and migrate toward ICs in a concentration-dependent and gradient-dependent manner, resembling chemotaxis. This finding is G protein-coupled receptor independent and solely observed in SlanMo, but not in other FcyR-expressing immune cells. It represents a
novel mechanism of immune cell recruitment and enables SlanMo to potentially act as first responders in IC-mediated disease, such as SLE.

Transcriptomic profiling of SlanMo revealed that migration on immobilized ICs triggers a distinct gene expression program in SlanMo, characterized by the upregulation of gene sets associated with SLE and protein digestion. These results suggest an important role in immune responses, with a focus on SLE and the clearance of ICs.

This work integrates into the broader understanding of non-classical monocyte biology by highlighting their unique capability and response to ICs. Previous studies have identified mostly anti-inflammatory functions of NCMs, and this work emphasizes their potential role as early responders to ICs and potential scavengers who remove deposited ICs. The notion of IC-induced chemotaxis resembles a completely new principle in cell recruitment to inflammatory
sites, bridging gaps in the current literature. By linking SlanMo behavior to SLE pathogenesis, this dissertation provides new insights into potential therapeutic strategies targeting Fc? receptors to modulate NCM activity in IC-mediated diseases.
Y1  - 2025///
TI  - Immune Complex-Induced Migration of Slan+ Non-Classical Monocytes
ID  - heidok36839
AV  - public
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/36839/
A1  - Hertwig, Michael
ER  -