Abstract
Pathogen-specific antibody responses need to be tightly regulated to generate protective but limit self-reactive immune responses. While loss of humoral tolerance has been associated with microbial infections, the pathways involved in balancing protective versus autoreactive antibody responses in humans are incompletely understood. Studies in classical mouse model systems have provided evidence that balancing of immune responses through inhibitory receptors is an important quality control checkpoint. Genetic differences between inbred mouse models and the outbred human population and allelic receptor variants not present in mice; however, argue for caution when directly translating these findings to the human system. By studying Borrelia burgdorferi infection in humanized mice reconstituted with human hematopoietic stem cells from donors homozygous for a functional or a non-functional FcγRIIb allele, we show that the human inhibitory FcγRIIb is a critical checkpoint balancing protective and autoreactive immune responses, linking infection with induction of autoimmunity in the human immune system.
Highlights
B cells are an essential part of the adaptive immune system and antibody responses mounted during microbial infections protect the host from re-infection, ideally inducing sterile immunity
These findings suggest that hematopoietic stem cell (HSC) humanized mice may provide a suitable model system to study whether human FcgRIIb controls pathogen and concomitant self-reactive immune responses during an infection with B. burgdorferi
To test if humanized NOD.Cg-Prkdc Il2rgtm1Wjl/Szj (NSG) mice are able to respond to an infection with B. burgdorferi, humanized and non-humanized NSG mice were infected subcutaneously via needle injection in the right hind foot pad and followed for signs of Lyme disease, which is characterized by an initial unilateral arthritis in the ankle tissue of the infected side followed by systemic pathogen spread through the blood resulting in inflammation of the contralateral joint
Summary
B cells are an essential part of the adaptive immune system and antibody responses mounted during microbial infections protect the host from re-infection, ideally inducing sterile immunity. A variety of well-defined inbred mouse model systems have firmly established that autoantibodies can directly cause tissue inflammation and destruction (Hogarth and Pietersz, 2012; Nimmerjahn and Ravetch, 2008; Takai, 2002). There is a link between infections and the induction of autoimmune diseases, suggesting that during the initiation of pathogen-specific immune responses self-reactive responses may be triggered (Brownlie et al, 2008; Smith and Clatworthy, 2010; Waisberg et al, 2011). One prime example for such a scenario is an infection with Borrelia burgdorferi, which can lead to the development of joint inflammation and induction of autoimmune arthritis (Arvikar et al, 2017; Steere and Glickstein, 2004). Checkpoints must be in place to limit the production of self-reactive immune responses while simultaneously promoting pathogen-specific immune system activation. Studies in inbred mouse model systems have identified the inhibitory Fcg-receptor IIb
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