CD22 and Siglec-G are B lymphocyte specific glycan binding proteins that participate in regulation of B cell receptor signaling. The extracellular domain recognizes sialic acid containing glycans as ligands, which are abundantly expressed as glycan chains all mammalian cells. In this project we have sought to understand how CD22 regulates the activation of B lymphocytes and, in particular, to understand the impact of glycoprotein ligands on CD22 function. Over the last decade, the major focus has been on the roles of cis ligands on the B cell, which mask the ligand-binding site of CD22. However, we now recognize that trans ligands on opposing cells have profound impact on CD22 in the context of B cell receptor recognition of antigens on the same cell. During the past project period we have obtained evidence that a major role of trans ligands of B cell siglecs, CD22 and Siglec-G/10, is to enforce tolerance to membrane antigens in the periphery. Tolerance induction involves recruitment of B cell siglecs to an immunological synapse between the B cell and an opposing cell containing both the antigen and siglec ligands, comprising sialic acid containing glycans present on all mammalian cells. The enforced juxtaposition of siglecs with the B cell receptor (BCR) triggers a siglec-mediated tolerogenic circuit that results in apoptosis of the antigen reactive B cell. Data in support of this mechanism have been obtained using nanoparticle platforms developed for multivalent display of both antigen and synthetic siglec ligands. We now have evidence that antigens displayed on cell membranes with natural sialoside ligands also invoke robust tolerance in a siglec dependent manner. Based on these and related findings, the aims of the next project period are directed towards documenting roles of siglecs and their ligands in B cell tolerance, and defining the major signaling components of the tolerogenic circuit that mediates apoptosis of antigen reactive B cells. In particular, we will: 1) Investigate the roles of CD22 and Siglec-G and their natural ligands in peripheral tolerance;2) Assess the contributions of signaling components that define a tolerogenic circuit induced by B cell siglecs; and 3) Assess the potential for Siglec-G to contribute to central B cell tolerance.
These aims will be pursued using a variety of chemical and genetic tools and approaches that have been developed in the past project period.

Public Health Relevance

This project is directed to developing a deeper understanding of basic processes that regulate an immune response by lymphocytes. We are investigating processes that allow B lymphocytes to recognize self, and prevent an autoimmune response. Such information may aid in the development of novel therapeutic approaches to treat or prevent autoimmune disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Ferguson, Stacy E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
Sun, Yuting; Hong, Senlian; Xie, Ran et al. (2018) Mechanistic Investigation and Multiplexing of Liposome-Assisted Metabolic Glycan Labeling. J Am Chem Soc 140:3592-3602
Edgar, Landon J; Kawasaki, Norihito; Nycholat, Corwin M et al. (2018) Targeted Delivery of Antigen to Activated CD169+ Macrophages Induces Bias for Expansion of CD8+ T Cells. Cell Chem Biol :
Nemanichvili, Nikoloz; Tomris, Ilhan; Turner, Hannah L et al. (2018) Fluorescent Trimeric Hemagglutinins Reveal Multivalent Receptor Binding Properties. J Mol Biol :
Spiller, Fernando; Nycholat, Corwin M; Kikuchi, Chika et al. (2018) Murine Red Blood Cells Lack Ligands for B Cell Siglecs, Allowing Strong Activation by Erythrocyte Surface Antigens. J Immunol 200:949-956
Bednar, Kyle J; Shanina, Elena; Ballet, Romain et al. (2017) Human CD22 Inhibits Murine B Cell Receptor Activation in a Human CD22 Transgenic Mouse Model. J Immunol 199:3116-3128
Peng, Wenjie; Paulson, James C (2017) CD22 Ligands on a Natural N-Glycan Scaffold Efficiently Deliver Toxins to B-Lymphoma Cells. J Am Chem Soc 139:12450-12458
Lopez Aguilar, Aime; Briard, Jennie Grace; Yang, Linette et al. (2017) Tools for Studying Glycans: Recent Advances in Chemoenzymatic Glycan Labeling. ACS Chem Biol 12:611-621
Orgel, Kelly A; Duan, Shiteng; Wright, Benjamin L et al. (2017) Exploiting CD22 on antigen-specific B cells to prevent allergy to the major peanut allergen Ara h 2. J Allergy Clin Immunol 139:366-369.e2
Pang, Lijuan; Macauley, Matthew S; Arlian, Britni M et al. (2017) Encapsulating an Immunosuppressant Enhances Tolerance Induction by Siglec-Engaging Tolerogenic Liposomes. Chembiochem 18:1226-1233
Gicheva, Nadezhda; Macauley, Matthew S; Arlian, Britni M et al. (2016) Siglec-F is a novel intestinal M cell marker. Biochem Biophys Res Commun 479:1-4

Showing the most recent 10 out of 67 publications