IgE‐mediated enhancement of antibody responses: the beneficial function of IgE?

Antigen in complex with antibodies elicits profoundly different antibody responses than does antigen alone (1). Small amounts of passively administered, as well as actively produced, antibodies can cause complete suppression or more than a 1000-fold enhancement of antibody responses to the antigens to which they bind. An important feature of feedback regulation is that it is antigenbut not epitope-specific. This means that when an animal is immunized with e.g. immunoglobulin (Ig)G anti-TNP (trinitrophenyl) and TNP-BSA (bovine serum albumin) and an unrelated antigen such as ovalbumin (OVA), responses to both TNP and BSA, but not to OVA,will be regulated. Although the antibody feedback regulation was described already over 100 years ago (2), the molecular mechanisms behind the phenomenon remain elusive. An immune complex is composed of antigen, antibody, and, when the antibody is of a complement-activating class, complement factors and can bind to B-cell receptors (BCR) as well as to Fcand complement-receptors. Ligation and coligation of these receptors can affect cell activation, both negatively and positively. Cocrosslinking of BCR and FccRIIB (CD32) leads to inhibition of B-cell activation through an ITIM (immuno-receptor tyrosine-based inhibitory motif) in the cytoplasmic tail of FccRIIB (3). When an ITIM is brought in close contact with other receptors containing ITAMs (immuno-receptor tyrosine-based activation mo-tifs), such as the BCR, T-cell receptor (TCR), FccRI (CD64), FccRIIA (CD32), FccRIII (CD16) and FceRI, it inhibits cell activation through the latter. Other explanations for antibody-mediated suppression may be that immune complexes are eliminated via Fcor complement-receptor-mediated phagocytosis before they are able to elicit an antibody response, or evenmore simple, that antibodies mask antigenic epitopes, thereby preventing B cells from recognizing and responding to the antigen. Feedback enhancement of antibody responses on the other hand, may take place by cocrosslinking BCR and the complement-receptor 2 (CD21)/ CD19-complex, known to lower the threshold for B-cell activation more than 100-fold (4). Immune complexes are also endocytosed efficiently by antigen-presenting cells (APCs) and increased presentation of antigen to Thelper cells may indirectly facilitate antibody production. In addition, follicular dendritic cells (FDCs) can capture immune complexes and present them to B cells. Given this multitude of possibilities for antibodies to interfere with responses to antigen, it is not surprising that identification of the mechanisms involved has proven to be a difficult task. Antibodies play an important role in the modulation of normal antibody responses and in the pathogenesis of allergic and autoimmune disease. In addition, the ability of small doses of syngeneic antibody to specifically upor downregulate immune responses has therapeutic potential. One of the most successful clinical applications of specific immunoregulation utilizes the ability of IgG antibodies to suppress responses to erythrocytes. Rhesus D negative (RhD) mothers may become immunized against transplacentally aquired RhD fetal erythrocytes, resulting in production of IgG anti-RhD which cross the placenta and damage fetal erythrocytes. Since the 1960s, small amounts of IgG anti-RhD are administered to RhD mothers shortly after delivery of their RhD babies (5). This treatment has dramatically decreased the incidence of hemolytic disease of the newborn (6). The mechanism behind the clinical effects of specific immunotherapy in the treatment of allergies may involve negative regulation of B cells via cocrosslinking of BCR and FccRIIB by IgG/allergen complexes, generated after hyperimmunization with allergen *Address until July 2002: Center for Blood Research, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA. Allergy 2002: 57: 577–585 Printed in UK. All rights reserved Copyright # 2002 Blackwell Munksgaard