Naturally occurring autoantibodies in mediating clearance of senescent red blood cells.
Germline-encoded naturally occurring autoantibodies (NAbs) developed about 400 to 450 million years ago to provide specificity for clearance ofbody waste in animals with 3 germ layers. Such NAbs became a necessity to selectively clear aged red blood cells (RBC) surviving 60 to 120 d in higher vertebrates. IgG NAbs to senescent RBC are directed to the most abundant integral membrane protein, the anion-transport protein or band 3 protein, but only bind firmly upon its oligomerization, which facilitates bivalent binding. The main constituent of RBC, the oxygen-carrying hemoglobin, is susceptible to oxidative damage. Oxidized hemoglobin forms hemichromes (a form of aggregates) that bind to the cytoplasmic portion of band 3 protein, induces their clustering on the cytoplasmic, as well as the exoplasmic side and thereby provides the prerequisites for the low affinity IgG anti-band 3 NAbs to bind bivalently. Bound anti-band 3 NAbs overcome their low numbers per RBC by stimulating complement amplification. An affinity for C3 outside the antigen binding region is responsible for a preferential formation of C3b(2)-IgG complexes from anti-band 3 NAbs. These complexes first bind oligomeric properdin, which enhances their affinity for factor B in assembling an alternative C3 convertase.
Institute of Biochemistry, Swiss Federal Institute of Technology, ETH Hönggerberg, Zurich, Switzerland. hans.lutz@bc.biol.ethz.ch
Hans U
HU
Lutz
D001457:Anion Exchange Protein 1, Erythrocyte / Q000276:immunology* / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology*; D005075:Biological Evolution; D016922:Cellular Senescence / Q000276:immunology*; D003176:Complement C3 / Q000276:immunology; D051561:Complement C3 Convertase, Alternative Pathway / Q000276:immunology; D004912:Erythrocytes / Q000166:cytology / Q000276:immunology*; D006454:Hemoglobins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D007074:Immunoglobulin G / Q000276:immunology*; D010084:Oxidation-Reduction; D011485:Protein Binding
D001457:Anion Exchange Protein 1, Erythrocyte; D001323:Autoantibodies; D003176:Complement C3; D006454:Hemoglobins; D007074:Immunoglobulin G; D051561:Complement C3 Convertase, Alternative Pathway