Negative feedback regulation of IgE synthesis by murine CD23

Abstract

Immunoglobulin E is found in nanogram amounts in normal human and mouse serum. It is increased during parasitic infestations and mediates allergy. CD23, the low-affinity receptor for IgE (Fc epsilon RII), has been proposed as an important regulator of IgE synthesis. The type-II transmembrane lectin CD23 is expressed in the mouse on B cells and follicular dendritic cells. In humans there are two forms of CD23 which differ in their intracellular amino-terminal 6/7 amino acids; expression of the A-form corresponds to that of murine CD23, whereas the B-form is also found on T and other haematopoietic cells. CD23 has been implicated in cellular adhesion, antigen presentation, as a growth and differentiation factor for human B, T and plasma cells, and as a signal transduction molecule (reviewed in refs 3, 8). Here we disrupt the gene coding for murine CD23 (ref. 9) to clarify the role of CD23 in vivo and find that B- and T-cell development is normal in these CD23-deficient mice. Immune responses to the helminth Nippostrongylus brasiliensis are unaffected. In contrast, immunization with thymus-dependent antigens leads to increased and sustained specific IgE antibody titres compared with controls. Formation of germinal centres is normal. These results suggest that murine CD23 acts as a negative feedback component of IgE regulation.

Inefficient processing of mRNA for the membraneform of IgE is a genetic mechanism to limit recruitment of IgE‐secreting cells

“…One interpretation of these data is that control mechanisms that were adequate in the past and honed in evolution are failing. In the recent past, we and others have described several B cell-specific control mechanisms that indicate a tight control of the IgE response, in agreement with the above arguments, and that are different from the opsonic type of response: (1) short half-life time of free IgE in serum, limiting the danger of a systemic anaphylactic reaction [7]; (2) negative feedback function of CD23, the "low"-affinity receptor for IgE, resulting in a response that is restricted in time and quantity [7]; (3) limited expression of IgE as a membrane-bound, antigen receptor-type molecule, restricting the recruitment of IgE-producing cells in the immune response [8].…”

“…The mechanism described here, together with a negative feedback regulatory mechanism [7], the low half-life of sIgE [7] and the low frequency of switch recombination [23,24], leads to a more than 1000-fold lower IgE than IgG 1 serum level in the mouse. This is in agreement with the notion that IgE is needed for immune defense, but only localized and at a low level.…”

“…CD23-deficient mice were used to avoid binding of sIgE to the low-affinity receptor for IgE, i.e. CD23, on B lymphocytes [7]. After stimulation, B220 + IgE + cells and B220 + IgG 1 + cells were isolated by fluorescence-activated cell sorting.…”

The pathogen receptor liver and lymph node sinusoidal endotelial cell C-type lectin is expressed in human Kupffer cells and regulated by PU.1

“…5,6 CD23 is expressed on myeloid cells and activated B lymphocytes, where it functions as a low affinity receptor for immunoglobulin E and plays a role in limiting the extent of immunoglobulin E-mediated pathologies. 7,8 DC-SIGN is expressed on myeloid dendritic cells (DCs), 1,9 alternatively activated in vitro macrophages, 10 interstitial DCs, 11 a subset of CD14ϩ peripheral blood DCs, 12 and macrophages from various tissues, [13][14][15] whereas L-SIGN is exclusively expressed on endothelial cells of the liver, lymph nodes, and placenta. 16,17 Although reported to be exclusively expressed on liver and lymph node sinusoidal endothelial cells, 4 LSECtin has been later found to be expressed in ex vivo isolated human peripheral blood and thymic DCs, as well as in DCs and alternatively activated macrophages generated in vitro.…”

Soluble CD23 Monomers Inhibit and Oligomers Stimulate IGE Synthesis in Human B Cells

“…Membrane CD23 performs a variety of functions, including IgE antibody-dependent presentation of antigens in murine (24) and human (25) B cells, feedback inhibition of IgE synthesis in murine B cells (26), and IgE antibody-dependent killing of tumor cells by human monocytes (27). Soluble fragments of CD23 both positively and negatively regulate IgE synthesis in human B cells (reviewed in Refs.…”