The dual function of the splenic marginal zone: essential for initiation of anti‐TI‐2 responses but also vital in the general first‐line defense against blood‐borne antigens

Summary The splenic marginal zone (S‐MZ) is especially well equipped for rapid humoral responses and is unique in its ability to initiate an immune response to encapsulated bacteria (T‐cell independent type 2 (TI‐2) antigens). Because of the rapid spreading through the blood, infections with blood‐borne bacteria form a major health risk. To cope with blood‐borne antigens, a system is needed that can respond rapidly to a great diversity of organisms. Because of a number of unique features, S‐MZ B cells can respond rapid and efficient to all sorts of blood‐borne antigens. These unique features include a low blood flow microenvironment, low threshold for activation, high expression of complement receptor 2 (CR2, CD21) and multireactivity. Because of the unique high expression of CD21 in a low flow compartment, S‐MZ B cells can bind and respond to TI‐2 antigens even with relatively low‐avid B cell receptors. Although TI‐2 antigens are in general poorly opsonized by classic opsonins, a particular characteristic of these antigens is their ability to bind very rapidly to complement fragment C3d without the necessity of previous immunoglobulin binding. TI‐2 primed S‐MZ B cells, already by first passage through the germinal centre, will meet antigen‐C3d complexes bound to follicular dendritic cells, allowing unique immediate isotype switching. This explains that the primary humoral response to TI‐2 antigens is unique in its characterization by a rapid increase in IgM concurrent with IgG antibody levels.