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Abstract
CD22 is a cell-surface receptor of resting mature B cells that recognizes sialic acid (Sia) in the natural structure Sia alpha 2-6Gal beta 1-4GlcNAc (Powell, L. D., Jain, R. K., Matta, K. L., Sabesan, S., and Varki, A. (1995) J. Biol. Chem. 270, 7523-7532). Human umbilical vein endothelial cells (HEC) treated with inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) display increases in cell-surface CD22 ligands, caused by increased expression of the enzyme beta-galactoside alpha 2,6-sialyltransferase (Hanasaki, K., Varki, A., Stamenkovic, I., and Bevilacqua, M. P. (1994) J. Biol. Chem. 269, 10637-10643; Hanasaki, K., Varki, A., and Powell, L. D. (1995) J. Biol Chem. 270, 7533-7542). Thus, CD22 could direct potential interactions between mature B cells and endothelial cells during inflammatory states. However, this would have to occur in the presence of blood plasma, which contains many sialoglycoproteins known to carry alpha 2-6-linked sialic acids. We show here that human plasma can indeed inhibit Sia-dependent binding of a recombinant soluble chimeric form of human CD22 (CD22Rg) to TNF-alpha activated HEC. Affinity adsorption of individual human plasma samples with immobilized CD22Rg showed that, of the numerous alpha 2-6-sialic acid containing glycoproteins in plasma, only three polypeptides with apparent molecular mass (under reducing conditions) of 74, 44, and 25 kDa bound, and were specifically eluted with alpha 2-6-sialyllactose. NH2-terminal amino acid sequencing of these high affinity CD22 ligands revealed that they are subunits of immunoglobulin M (IgM) and haptoglobin. Purified human IgM from pooled human plasma can be quantitatively bound by CD22Rg, and binding is blocked by alpha 2-6-sialyllactose, but not by alpha 2-3-sialyllactose. Pretreatment by sialidase or by mild periodate oxidation of sialic acid side chains abolishes these interactions. IgM at physiological concentrations also inhibits CD22Rg binding to TNF-alpha-activated HEC in a manner dependent not only upon its sialylation but also requiring its intact multimeric structure. These data show that CD22 is capable of highly selective recognition of certain multimeric plasma sialoglycoproteins that carry alpha 2-6-linked sialic acids. Notably, the two proteins that are selectively recognized are known to be involved in immune and inflammatory responses. Haptoglobin synthesis by the liver is markedly increased during the "acute phase response" to systemic inflammation, while IgM is the major product resulting from activation of resting CD22-positive B cells.
Highlights
CD22 is a cell-surface phosphoglycoprotein found on the majority of resting mature B cells, and appears to be involved in antigen-induced cell activation [1, 2] and in cell adhesion, mediating interactions with activated blood cells, accessory cells, and endothelial cells [3,4,5,6,7]
We recently found that treatment of human umbilical vein endothelial cells (HEC) with inflammatory cytokines such as tumor necrosis factor-a (TNF-a), causes increased expression of l3-galactoside a2,6-sialyltransferase, and enhanced expression ofCD22 ligands [7]
The preceding paper [9] shows that activated vascular endothelium expresses increased levels of CD22-ligands bearing a2-6-linked sialic acids. Such activated endothelial cells are potentially in a position to bind CD22-positive B lymphocytes present in the bloodstream
Summary
(Received for publication, November 30, 1994, and in revised form, January 13, 1995). IgM at physiological concentrations inhibits CD22Rg binding to TNF-a-activated BEC in a manner dependent upon its sialylation and requiring its intact multimeric structure These data show that CD22 is capable of highly selective recognition of certain multimeric plasma sialoglycoproteins that carry a2-6-linked sialic acids. Soluble chimeric forms of CD22 (CD22Rg)!, containing the three amino-terminal Ig-like domains of human CD22{3fused to the COOH-terminal Fe domains of human IgG or mouse IgG 00, 11) have been previously used to identify sialoglycoprotein ligands on activated T and B cells, which include, among others, CD45, the leukocyte-specific receptorlinked phosphotyrosine-phosphatase [5, 10, 12] These interactions involve recognition of the sialic acid (Sia) containing structural motif Siaa2-6Gal{31-4GlcNAc{31- [8, 11, 13, 14]. We have identified the major high-affinity plasma ligands for CD22, which are dependent upon a2-6-linked sialic acids for recognition
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