New Functions for the Sialic Acid‐Binding Adhesion Molecule CD22, a Member of the Growing Family of Siglecs

CD22, a B-cell specific transmembrane protein, is a member of the family of Siglecs (sialic acid-binding immunoglobulin(Ig)like lectins). The Siglecs are adhesion receptors that interact specifically with sialic acids. Sialic acids are abundantly expressed on cell surfaces and on secreted glycoproteins. More than 40 natural forms exist in nature and they can be attached in a variety of linkages to other sugars, thereby generating a considerable degree of molecular diversity and specificity [1]. On the cellular surface, sialic acids are a major carrier of negative charge and can reduce nonspecific cell adhesion through a charge repulsion effect. Although a range of pathogenic viruses, bacteria and protozoa use sialic acids on the cell surface for recognition, it is only recently that mammalian lectins have been shown to specifically bind sialic acids. The characterization of Siglecs as sialic acid-binding proteins began with independent studies on sialoadhesin (Sn), a receptor on macrophages [2] and CD22 on B cells [3]. When both cDNAs were cloned, a significant degree of sequence similarity of these two members of the Ig superfamily was observed [4]. Two other known mammalian members of the Ig superfamily, namely myelin-associated glycoprotein (MAG) and CD33, were found to share sequence similarity with Sn and were subsequently shown to be sialic acid-binding proteins [5, 6]. Most recently, several new members of the Siglec family have been discovered, most of them by sequencing of randomly selected human cDNAs. Apart from MAG (Siglec-4a), which is found exclusively in the nervous system, all Siglecs are expressed within the haemopoietic and the immune systems. These new members illustrate a common theme for the Siglecs: all are expressed in a highly tissue-specific manner, have a specificity for certain types of sialic acid in particular linkages and often carry one or several tyrosine-based inhibitory motifs (ITIMs) in their intracellular tails [7±14] (Fig. 1). The ITIM motifs are known to be involved in the negative regulation of the cellular signalling. These properties suggest that most Siglec family members may be involved in cell to cell interactions that result in intracellular inhibitory signals. Sialoadhesin (Sn, Siglec-1, CD169) is expressed on macrophages in a regulated fashion, with high levels on distinct sets of macrophages, for example those present in the perifollicular zones of lymphoid tissues [15]. The Sn expression can be induced by soluble factors or under pathological conditions [16±19]. Sn has a specificity for sialic acids (Sia) in a2,3 linkage (e.g. NeuNAc-a2,3-Gal-b1,3GalNAc) which are expressed for example on the surface of myeloid cells and in the extracellular matrix. Certain pathogenic micro-organisms also express sialylated glycoconjugates on their surface. Therefore, it is thought that the Sn may function in host defence as well as acting as an accessory molecule to promote interactions of macrophages with the host microenvironment. CD22 (Siglec-2) is expressed in a B-cell specific fashion. It has a high specificity for a2,6 Sia (human CD22 the NeuNAc, mouse CD22 the NeuNGc-form) and carries three ITIM motifs on its intracellular tail. Potentially, CD22 can bind to target cells such as lymphocytes or cytokine-activated endothelial cells that express high levels of a2,6 Sia on the surface [5, 20, 21]. The role of CD22 in modulating B-cell signalling is quite well understood, owing to the characterization of CD22-deficient mice, as will be discussed below. CD33 (Siglec-3) was originally shown to have specificity for a2,3-linked Sia [6], although recent observations suggest that CD33 may prefer the a2,6 linkage [22]. CD33 has been extensively used as a marker of myeloid cell progenitors that is absent from pluripotential haemopoeitic stem cells. During myelopoiesis, CD33 is lost from neutrophils but retained on monocytes and some tissue macrophages [6]. MAG (Siglec 4a) and its close homologue SMP (Siglec 4b), which has only been identified in birds, are expressed on glial cells. MAG had been postulated as being important for the process of myelin