Person: Pillai, Shiv
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Pillai
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Shiv
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Pillai, Shiv
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Publication Enhanced binding of antibodies generated during chronic HIV infection to mucus component MUC16(2016) Gunn, Bronwyn; Schneider, Jeffrey; Shansab, Maryam; Bastian, Arangassery Rosemary; Fahrbach, Kelly; Smith, Archer; Mahan, Alison; Karim, Marcus; Licht, Anna; Zvonar, Ivan; Tedesco, Jacquelynn; Anderson, Meegan; Chapel, Anais; Suscovich, Todd; Malaspina, David; Streeck, Hendrik; Walker, Bruce; Kim, Arthur; Lauer, Georg; Altfeld, Marcus; Pillai, Shiv; Szleifer, Igal; Kelleher, Neil L.; Kiser, Patrick F.; Hope, Thomas J.; Alter, GalitTransmission of HIV across mucosal barriers accounts for the majority of HIV infections worldwide. Thus, efforts aimed at enhancing protective immunity at these sites are a top priority, including increasing virus-specific antibodies (Abs) and antiviral activity at mucosal sites. Mucin proteins, including the largest cell-associated mucin, MUC16, help form mucus to provide a physical barrier to incoming pathogens. Here we describe a natural interaction between Abs and MUC16 that is enhanced in specific disease settings such as chronic HIV infection. Binding to MUC16 was independent of IgG subclass, but strongly associated with shorter Ab glycan profiles, with agalactosylated (G0) Abs demonstrating the highest binding to MUC16. Binding of Abs to epithelial cells was diminished following MUC16-knockdown, and the MUC16 N-linked glycans were critical for binding. Further, agalactosylated VRC01 captured HIV more efficiently in MUC16. These data point to a novel opportunity to enrich Abs at mucosal sites by targeting Abs to MUC16 through changes in Fc-glycosylation, potentially blocking viral movement and sequestering the virus far from the epithelial border. Thus, next-generation vaccines or monoclonal therapeutics may enhance protective immunity by tuning Ab glycosylation to promote the enrichment of Abs at mucosal barriers.Publication M89V Sialic Acid Acetyl Esterase (SIAE) and All Other Non-Synonymous Common Variants of This Gene Are Catalytically Normal(Public Library of Science, 2013) Chellappa, Vasant; Taylor, Kendra N; Pedrick, Kathryn; Donado, Carlos; Netravali, Ilka; Haider, Khaleda; Cariappa, Annaiah; Dalomba, Natasha F.; Pillai, ShivCatalytically defective rare variants of Sialic acid Acetyl Esterase (SIAE) have previously been linked to autoimmunity. Studies presented here confirm that the M89V SIAE protein and all other products of common variant alleles of SIAE are catalytically normal. Although overexpressing transfected non-lymphoid cells secrete small amounts of SIAE that can associate with the cell surface, normal human lymphocytes do not exhibit cell surface SIAE, supporting genetic evidence in mice that indicates that this protein functions in a lymphocyte intrinsic manner. Analyses of the plasma proteome also indicate that SIAE is not secreted in vivo. A re-analysis exclusively of catalytically defective rare variant alleles of SIAE in subjects in which this gene was completely sequenced confirmed an association of SIAE with autoimmunity. A subset of catalytically defective rare variant SIAE alleles has previously been typed in a large genotyping study comparing a diverse group of disease subjects and controls; our re-analysis of this data shows that catalytically defective alleles are enriched in disease subjects. These data suggest that SIAE may be associated with autoimmunity and that further study of catalytically defective rare variant SIAE alleles in terms of autoimmune disease susceptibility is strongly warranted.Publication Neutralizing Anti-HIV Antibodies Develop in a Humanized Mouse Model of HIV-1 Infection(BioMed Central, 2012) Vrbanac, Vladimir; Tivey, T; Cariappa, A; Seung, Edward N.; Dugast, Anne-Sophie; Dudek, Timothy E; Mattoo, Hamid; Murooka, Thomas; Pillai, Shiv; Tager, Andrew Martin; Luster, AndrewPublication A unique B2 B cell subset in the intestine(The Rockefeller University Press, 2008) Shimomura, Yasuyo; Ogawa, Atsuhiro; Kawada, Mayumi; Sugimoto, Ken; Mizoguchi, Atsushi; Shi, Hai-Ning; Pillai, Shiv; Bhan, AtulOver 80% of the body's activated B cells are located in mucosal sites, including the intestine. The intestine contains IgM[super]+ B cells, but these cells have not been characterized phenotypically or in terms of their developmental origins. We describe a previously unidentified and unique subset of immunoglobulin M[super]+ B cells that present with an AA4.1[super]−CD21[super]−CD23[super]− major histocompatibility complex class II[super]bright surface phenotype and are characterized by a low frequency of somatic hypermutation and the potential ability to produce interleukin-12p70. This B cell subset resides within the normal mucosa of the large intestine and expands in response to inflammation. Some of these intestinal B cells originate from the AA4.1[super]+ immature B2 cell pool in the steady state and are also recruited from the recirculating naive B cell pool in the context of intestinal inflammation. They develop in an antigen-independent and BAFF-dependent manner in the absence of T cell help. Expansion of these cells can be induced in the absence of the spleen and gut-associated lymphoid tissues. These results describe the existence of an alternative pathway of B cell maturation in the periphery that gives rise to a tissue-specific B cell subset.Publication B Cell Antigen Receptor Signal Strength and Peripheral B Cell Development are Regulated by a 9-O-Acetyl Sialic Acid Esterase(Rockefeller University Press, 2009) Cariappa, Annaiah; Takematsu, Hiromu; Liu, Haoyuan; Diaz, Sandra; Haider, Khaleda; Kalloo, Geetika; Varki, Nissi; Varki, Ajit; Boboila, Cristian; Connole, Michelle; Shi, Hai; Pillai, ShivWe show that the enzymatic acetylation and deacetylation of a cell surface carbohydrate controls B cell development, signaling, and immunological tolerance. Mice with a mutation in sialate:O-acetyl esterase, an enzyme that specifically removes acetyl moieties from the 9-OH position of α2–6-linked sialic acid, exhibit enhanced B cell receptor (BCR) activation, defects in peripheral B cell development, and spontaneously develop antichromatin autoantibodies and glomerular immune complex deposits. The 9-O-acetylation state of sialic acid regulates the function of CD22, a Siglec that functions in vivo as an inhibitor of BCR signaling. These results describe a novel catalytic regulator of B cell signaling and underscore the crucial role of inhibitory signaling in the maintenance of immunological tolerance in the B lineage.Publication Editorial: Cytotoxic CD4+ T Cells in Viral Infections(Frontiers Media S.A., 2017) Phetsouphanh, Chansavath; Pillai, Shiv; Zaunders, John J.