Sialic acid acetyl esterase (SIAE) is an enzyme that removes acetyl moieties from the 9-OH position of sialic acid on N-glycans, making available ligands for some inhibitory Siglecs, the best studied member of this family being Siglec-2/CD22. The loss of SIAE results in enhanced B cell receptor signaling and a break in tolerance. Defective rare variants of SIAE have been discovered in human autoimmune subjects. SIAE appears to be an important regulator of a pathway of clonal ignorance in B cells, and the mechanism by which this clonal ignorance is maintained will be studied using B cell receptor knockin and transgenic models. Studies are also proposed to examine why the absence of SIAE results in an increase in CD4+ effector memory phenotype T cells. This phenotype might be mediated by a defect in B cells or a defect in dendritic cells or both. Studies will be performed to determine the mechanism that leads to this enhanced accumulation of effector memory phenotype CD4+ T cells. The potential for the functional categorization of conventional and plasmacytoid dendritic cells based on the level of 9-O-acetylation of sialic acid will be explored and the phenotype of a mutant mouse lacking a putative 9-O-acetyl transferase will be examined. Studies are also proposed to examine whether disease-related heterozygous catalytically defective variants of SIAE are misfolded proteins and a knockin approach will be used to ask if one of these variants functions in a dominant negative fashion in vivo.

Public Health Relevance

Rare variants of the Sialic acid acetyl esterase gene have been discovered in autoimmune subjects and one function of this gene appears to be to prevent autoimmunity in mice and humans. The study of this enzyme and the pathway it regulates may provide both mechanistic insights about immunological tolerance and new therapeutic targets for autoimmune disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI064930-05A1
Application #
8257194
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Ferguson, Stacy E
Project Start
2005-04-01
Project End
2016-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
5
Fiscal Year
2012
Total Cost
$428,640
Indirect Cost
$178,640
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Della Torre, E; Mattoo, H; Mahajan, V S et al. (2014) Prevalence of atopy, eosinophilia, and IgE elevation in IgG4-related disease. Allergy 69:269-72
Della-Torre, Emanuel; Mattoo, Hamid; Mahajan, Vinay S et al. (2014) IgG4-related midline destructive lesion. Ann Rheum Dis 73:1434-6
Mattoo, Hamid; Mahajan, Vinay S; Della-Torre, Emanuel et al. (2014) De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease. J Allergy Clin Immunol 134:679-87
Ahmad, Maimuna; Mahajan, Vinay S; Mattoo, Hamid et al. (2014) Individuals with IgG4-related disease do not have an increased frequency of the K409 variant of IgG4 that compromises Fab-arm exchange. J Rheumatol 41:185-7
Mattoo, H; Della-Torre, E; Mahajan, V S et al. (2014) Circulating Th2 memory cells in IgG4-related disease are restricted to a defined subset of subjects with atopy. Allergy 69:399-402
Kai, Xin; Chellappa, Vasant; Donado, Carlos et al. (2014) I?B kinase ? (IKBKB) mutations in lymphomas that constitutively activate canonical nuclear factor ?B (NF?B) signaling. J Biol Chem 289:26960-72
Chellappa, Vasant; Taylor, Kendra N; Pedrick, Kathryn et al. (2013) M89V Sialic acid Acetyl Esterase (SIAE) and all other non-synonymous common variants of this gene are catalytically normal. PLoS One 8:e53453
Hirschfield, G M; Xie, G; Lu, E et al. (2012) Association of primary biliary cirrhosis with variants in the CLEC16A, SOCS1, SPIB and SIAE immunomodulatory genes. Genes Immun 13:328-35
Pillai, Shiv; Netravali, Ilka Arun; Cariappa, Annaiah et al. (2012) Siglecs and immune regulation. Annu Rev Immunol 30:357-92
Pillai, Shiv; Mattoo, Hamid; Cariappa, Annaiah (2011) B cells and autoimmunity. Curr Opin Immunol 23:721-31

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