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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI050143-11A1
Application #
8628390
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Ferguson, Stacy E
Project Start
2001-07-01
Project End
2018-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
11
Fiscal Year
2014
Total Cost
$426,375
Indirect Cost
$201,375
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Natoni, Alessandro; Macauley, Matthew S; O'Dwyer, Michael E (2016) Targeting Selectins and Their Ligands in Cancer. Front Oncol 6:93
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
Orgel, Kelly A; Duan, Shiteng; Wright, Benjamin L et al. (2016) Exploiting CD22 on antigen-specific B cells to prevent allergy to the major peanut allergen Ara h 2. J Allergy Clin Immunol :
Hiono, Takahiro; Okamatsu, Masatoshi; Igarashi, Manabu et al. (2016) Amino acid residues at positions 222 and 227 of the hemagglutinin together with the neuraminidase determine binding of H5 avian influenza viruses to sialyl Lewis X. Arch Virol 161:307-16
Angata, Takashi; Nycholat, Corwin M; Macauley, Matthew S (2015) Therapeutic Targeting of Siglecs using Antibody- and Glycan-Based Approaches. Trends Pharmacol Sci 36:645-60
Macauley, Matthew S; Kawasaki, Norihito; Peng, Wenjie et al. (2015) Unmasking of CD22 Co-receptor on Germinal Center B-cells Occurs by Alternative Mechanisms in Mouse and Man. J Biol Chem 290:30066-77
Jin, Hyun Yong; Gonzalez-Martin, Alicia; Miletic, Ana V et al. (2015) Transfection of microRNA Mimics Should Be Used with Caution. Front Genet 6:340
Macauley, Matthew S; Arlian, Britni M; Rillahan, Cory D et al. (2014) Systemic blockade of sialylation in mice with a global inhibitor of sialyltransferases. J Biol Chem 289:35149-58
Macauley, Matthew S; Paulson, James C (2014) Immunology: glyco-engineering 'super-self'. Nat Chem Biol 10:7-8
Macauley, Matthew S; Paulson, James C (2014) Siglecs induce tolerance to cell surface antigens by BIM-dependent deletion of the antigen-reactive B cells. J Immunol 193:4312-21

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