A MUC16 IgG Binding Activity Selects for a Restricted Subset of IgG Enriched for Certain Simian Immunodeficiency Virus Epitope Specificities

Abstract

We have recently shown that MUC16, a component of the glycocalyx of some mucosal barriers, has elevated binding to the G0 glycoform of the Fc portion of IgG. Therefore, IgG from patients chronically infected with human immunodeficiency virus (HIV), who typically exhibit increased amounts of G0 glycoforms, showed increased MUC16 binding compared to uninfected controls. Using the rhesus macaque simian immunodeficiency virus SIVmac251 model, we can compare plasma antibodies before and after chronic infection. We find increased binding of IgG to MUC16 after chronic SIV infection. Antibodies isolated for tight association with MUC16 (MUC16-eluted antibodies) show reduced FcγR engagement and antibody-dependent cellular cytotoxicity (ADCC) activity. The glycosylation profile of these IgGs was consistent with a decrease in FcγR engagement and subsequent ADCC effector function, as they contain a decrease in afucosylated bisecting glycoforms that preferentially bind FcγRs. Testing of the SIV antigen specificity of IgG from SIV-infected macaques revealed that the MUC16-eluted antibodies were enriched for certain specific epitopes, including regions of gp41 and gp120. This enrichment of specific antigen responses for fucosylated bisecting glycoforms and the subsequent association with MUC16 suggests that the immune response has the potential to direct specific epitope responses to localize to the glycocalyx through interaction with this specific mucin. IMPORTANCE Understanding how antibodies are distributed in the mucosal environment is valuable for developing a vaccine to block HIV infection. Here, we study an IgG binding activity in MUC16, potentially representing a new IgG effector function that would concentrate certain antibodies within the glycocalyx to trap pathogens before they can reach the underlying columnar epithelial barriers. These studies reveal that rhesus macaque IgG responses during chronic SIV infection generate increased antibodies that bind MUC16, and interestingly, these MUC16-tethered antibodies are enriched for binding to certain antigens. Therefore, it may be possible to direct HIV vaccine-generated responses to associate with MUC16 and enhance the antibody’s ability to mediate immune exclusion by trapping virions within the glycocalyx and preventing the virus from reaching immune target cells within the mucosa. This concept will ultimately have to be tested in the rhesus macaque model, which is shown here to have MUC16-targeted antigen responses.

Integrative Transcriptomic Analysis Reveals the Immune Mechanism for a CyHV-3-Resistant Common Carp Strain

“…Moreover, as the head kidney is one of the major reticuloendothelial systems in fish ( 49 ), mucin was also found to be upregulated as the anti-virus barrier. This was shown in the comparison group SvC-N as the gel-forming mucin 5B (MUC5B) ( 50 ) was upregulated in the survivors of the non-breeding strain. However, higher expression levels of membrane-bound MUC3 ( 51 ) were found in survivors of the breeding strain versus the non-breeding strain.…”

Integrative Transcriptomic Analysis Reveals the Immune Mechanism for A CyHV-3-Resistant Common Carp Strain

“…Moreover, as the head kidney is one of the major reticuloendothelial systems in fish (33), mucin was also found to be upregulated as the anti-virus barrier. This was shown in group B as the gel-forming mucin 5B (MUC5B) (34) was upregulated in the survivors of the normal strain. However, higher expression levels of membrane-bound MUC3 (35) were found in survivors of the resistant strain versus the normal strain.…”

Gene mutation analysis using next‐generation sequencing and its clinical significance in patients with myeloid neoplasm: A multi‐center study from China

“…MUC16 (also known as CA‐125) plays an important role in tumorigenesis, proliferation, migration, and invasion and is an important target for the diagnosis and treatment of gynecological tumors. 48 , 49 Both in vitro and in vivo studies have proven that this marker may be a potential approach for treating hard‐to‐cure AML. 49 It was interesting to find concurrent mutations KDM5A and MUC16 in s‐AML; however, all MUC16 mutations co‐occurred with CEBPA in AML.…”

“… 48 , 49 Both in vitro and in vivo studies have proven that this marker may be a potential approach for treating hard‐to‐cure AML. 49 It was interesting to find concurrent mutations KDM5A and MUC16 in s‐AML; however, all MUC16 mutations co‐occurred with CEBPA in AML. The prominent concurrent mutation differences between diseases may be related to different pathogeneses, and future studies are needed to confirm this hypothesis.…”

“…However, the clinical value of s‐AML has rarely been reported. MUC16 (also known as CA‐125) plays an important role in tumorigenesis, proliferation, migration, and invasion and is an important target for the diagnosis and treatment of gynecological tumors 48,49 . Both in vitro and in vivo studies have proven that this marker may be a potential approach for treating hard‐to‐cure AML 49 .…”