Role of neutrophil immunoglobulin A Fc receptor (FcaRI) in mucosal homeostasis and inflammation of the gastro-intestinal tract
12 / 2007 - unknown
Immunoglobulin A (IgA) is the principal antibody class in mucosal areas and plays a key role in mucosal defense. Secreted IgA (SIgA) can act as first line of defense, mainly by forming an anti-septic paint covering the mucosa, and hereby passively inhibit adherence of microorganisms. However, serum and dimeric IgA can actively trigger inflammatory functions like phagocytosis, super oxide production and antibody-mediated cellular cytotoxicity via cross-linking of the IgA Fc receptor (FcalphaR, CD89), which is expressed on myeloid immune cells. I now demonstrate that in vitro, FcalphaR is the only Fc receptor that triggers neutrophil migration, through release of chemoattractants like leukotriene B4. Additionally, crosslinking of FcalphaR on neutrophils results in release of inflammatory mediators including interleukin 1beta, interleukin 8 and tumor necrosis factor-alpha, which can attract and activate other immune cells. Pathogens that have breached the epithelial barrier immediately come in contact with dimeric IgA. Since neutrophils are the first cells to arrive at inflammatory sites upon invasion by microorganisms, I hypothesize that neutrophils become activated via FcalphaR, which results in release of chemoattractants and inflammatory cytokines. Subsequently, this may trigger an inflammatory loop, because more neutrophils will be attracted as well as other immune cells like lymphocytes, monocytes and dendritic cells. Thus, via this process neutrophils may help to clear the infection and communicate its presence to other cells, hereby initiating immune responses. However, in the case of aberrant translocation of bacteria (e.g. in ulcerative colitis) a perpetuating inflammatory loop may be initiated, which can seriously aggravate tissue damage. The overall aim of this proposal is therefore to unravel the role of IgA and FcalphaR in homeostasis and inflammation of the intestinal tract. As such, we will investigate FcalphaR-induced signaling pathways and neutrophil migration in more detail. We will determine which inflammatory mediators are released by neutrophils after FcaRI cross-linking as well as their influence on other cells. Additionally, we will study whether direct cell-cell contact after activation of neutrophils via FcalphaR leads to activation of other immune cells like dendritic cells. Up till now it has not been possible to address the in vivo function of FcalphaR, mainly due to lack of suitable animal models. Importantly, we are now able to address the in vivo role of FcalphaR-IgA interactions by crossing human FcalphaR transgenic mice with human IgA transgenic mice, hereby creating human FcalphaRxIgA double transgenic mice. Infection models with Salmonella bacteria and ulcerative colitis models will be used to investigate homeostasis and inflammation of the intestinal mucosa.
Onze darmflora helpt met het verteren van voedsel, maar het zou zeer schadelijk zijn als darmbacteriën ons lichaam binnendringen. Het antilichaam IgA vormt een passieve antibacteriële laag om dit te verhinderen. Ons onderzoek richt zich echter op de actieve functie van IgA om afweerreacties op te wekken tegen binnengekomen bacteriën, zodat infecties worden voorkomen.