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1.
Glycobiology ; 32(9): 803-813, 2022 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-35746897

RESUMEN

The glycosylation of immunoglobulin G (IgG) has attracted increased attention due to the impact of N-glycan modifications at N297 on IgG function, acting primarily through modulation of Fc domain conformation and Fcγ receptor-binding affinities and signaling. However, the mechanisms regulating IgG glycosylation and especially α2,6-sialylation of its N-glycan remain poorly understood. We observed previously that IgG is normally sialylated in mice with B cells lacking the sialyltransferase ST6Gal1. This supported the hypothesis that IgG may be sialylated outside of B cells, perhaps through the action of hepatocyte-released plasma ST6Gal1. Here, we demonstrate that this model is incorrect. Animals lacking hepatocyte expressed ST6Gal1 retain normal IgG α2,6-sialylation despite the lack of detectable ST6Gal1 in plasma. Moreover, we confirmed that B cells were not a redundant source of IgG sialylation. Thus, while α2,6-sialylation is lacking in IgG from mice with germline ablation of ST6Gal1, IgG α2,6-sialylation is normal in mice lacking ST6Gal1 in either hepatocytes or B cells. These results indicate that IgG α2,6-sialylation arises after release from a B cell but is not dependent on plasma-localized ST6Gal1 activity.


Asunto(s)
Inmunoglobulina G , Sialiltransferasas , Animales , Glicosilación , Inmunoglobulina G/genética , Inmunoglobulina G/metabolismo , Ratones , Polisacáridos/química , Receptores de IgG , Sialiltransferasas/genética , Sialiltransferasas/metabolismo
2.
Glycoconj J ; 37(3): 395-407, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32222873

RESUMEN

Through the catalysis of α2,6-linked sialylation, the enzyme ST6Gal1 is thought to play key roles in immune cell communication and homeostasis. Of particular importance, glycans with terminal α2,6-sialic acids are known to negatively regulate B cell receptor signaling and are associated with an immunosuppressive tumor microenvironment that promotes T cell anergy, suggesting that α2,6-sialic acids are a key immune inhibitory signal. Consistent with this model, mice harboring a hepatocyte-specific ablation of ST6Gal1 (H-cKO) develop a progressive and severe non-alcoholic fatty liver disease characterized by steatohepatitis. Using this H-cKO mouse, we have further discovered that loss of hepatocyte α2,6-sialylation not only increases the inflammatory state of the local tissue microenvironment, but also systemic T cell-dependent immune responses. H-cKO mice responded normally to innate and passively induced inflammation, but showed significantly increased morbidity in T cell-dependent house dust mite-antigen (HDM)-induced asthma and myelin oligodendrocyte glycoprotein (MOG) peptide-induced experimental autoimmune encephalomyelitis (EAE). We further discovered that H-cKO mice have a profound shift toward effector/memory T cells even among unchallenged mice, and that macrophages from both the liver and spleen expressed the inhibitory and α2,6-sialic acid-specific glycan binding molecule CD22. These findings align with previously reported pro-inflammatory changes in liver macrophages, and support a model in which the liver microenvironment sets a systemic immune tone that is regulated by tissue α2,6-sialylation and mediated by liver macrophages and systemic T cells.


Asunto(s)
Hepatocitos/metabolismo , Inmunidad Innata/fisiología , Sialiltransferasas/metabolismo , Linfocitos T/inmunología , Animales , Asma/etiología , Asma/inmunología , Colitis/inducido químicamente , Colitis/inmunología , Modelos Animales de Enfermedad , Hepatocitos/inmunología , Lipopolisacáridos/administración & dosificación , Lipopolisacáridos/toxicidad , Hígado/inmunología , Pulmón/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones Noqueados , Peritonitis/inducido químicamente , Peritonitis/inmunología , Lectina 2 Similar a Ig de Unión al Ácido Siálico/metabolismo , Sialiltransferasas/genética , Tioglicolatos/toxicidad
3.
Glycobiology ; 30(5): 346-359, 2020 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-31742330

RESUMEN

Circulatory protein glycosylation is a biomarker of multiple disease and inflammatory states and has been applied in the clinic for liver dysfunction, heart disease and diabetes. With the notable exception of antibodies, the liver produces most of the circulatory glycoproteins, including the acute phase proteins released as a function of the inflammatory response. Among these proteins is ß-galactoside α2,6-sialyltransferase (ST6Gal1), an enzyme required for α2,6-linked sialylation of glycoproteins. Here, we describe a hepatocyte-specific conditional knockout of ST6Gal1 (H-cKO) using albumin promoter-driven Cre-lox recombination. We confirm the loss of circulatory glycoprotein α2,6 sialylation and note no obvious dysfunction or pathology in young H-cKO mice, yet these mice show robust changes in plasma glycoprotein fucosylation, branching and the abundance of bisecting GlcNAc and marked changes in a number of metabolic pathways. As H-cKO mice aged, they spontaneously developed fatty liver disease characterized by the buildup of fat droplets in the liver, inflammatory cytokine production and a shift in liver leukocyte phenotype away from anti-inflammatory Kupffer cells and towards proinflammatory M1 macrophages. These findings connect hepatocyte and circulatory glycoprotein sialylation to the regulation of metabolism and inflammation, potentially identifying the glycome as a new target for liver-driven disease.


Asunto(s)
Hepatocitos/metabolismo , Inflamación/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Animales , Glicoproteínas/metabolismo , Glicosilación , Hepatocitos/patología , Inflamación/patología , Ratones , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/patología
4.
FASEB J ; 33(2): 1852-1859, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30183373

RESUMEN

Despite effective control of HIV infection with antiretroviral drugs, individuals with HIV have high incidences of secondary diseases. These sequelae, such as cardiovascular disease (CVD), are poorly understood and represent a major health burden. To date, predictive biomarkers of HIV-associated secondary disease have been elusive, making preventative clinical management essentially impossible. Here, we applied a newly developed and easy to deploy, multitarget, and high-throughput glycomic analysis to banked HIV+ human plasma samples to determine whether the glycome may include biomarkers that predict future HIV-associated cardiovascular events or CVD diagnoses. Using 324 patient samples, we identified a glycomic fingerprint that was predictive of future CVD events but independent of CD4 counts, diabetes, age, and birth sex, suggesting that the plasma glycome may serve as a biomarker for specific HIV-associated sequelae. Our findings constitute the discovery of novel glycan biomarkers that could classify patients with HIV with elevated risk for CVD and reveal the untapped prognostic potential of the plasma glycome in human disease.-Oswald, D. M., Sim, E. S., Baker, C., Farhan, O., Debanne, S. M., Morris, N. J., Rodriguez, B. G., Jones, M. B., Cobb, B. A. Plasma glycomics predict cardiovascular disease in patients with ART-controlled HIV infections.


Asunto(s)
Antivirales/uso terapéutico , Carbohidratos/sangre , Enfermedades Cardiovasculares/complicaciones , Glicómica , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Adulto , Biomarcadores/sangre , Enfermedades Cardiovasculares/sangre , Femenino , Glicosilación , Infecciones por VIH/sangre , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Prueba de Estudio Conceptual
5.
Cell Immunol ; 333: 2-8, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-29759530

RESUMEN

The glycobiology of the immune response is a topic that has garnered increased attention due to a number of key discoveries surrounding IgG function, the specificity of some broadly neutralizing anti-HIV antibodies, cancer immunoregulation by galectin molecules and others. This review is the opening article in a Special Edition of Cellular Immunology focused on glycoimmunology, and has the goal of setting the context for these articles by providing a mini-review of how glycans impact immunity. We also focus on some of the technological and methodological advances in the field of glycobiology that are being deployed to lower the barrier of entry into the glycosciences, and to more fully interrogate the glycome and its function.


Asunto(s)
Glicómica/métodos , Animales , Anticuerpos Neutralizantes/inmunología , Galectinas/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Humanos , Inmunoglobulina G/inmunología , Polisacáridos/inmunología
6.
Trends Immunol ; 39(7): 523-535, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29759949

RESUMEN

Carbohydrates, or glycans, are as integral to biology as nucleic acids and proteins. In immunology, glycans are well known to drive diverse functions ranging from glycosaminoglycan-mediated chemokine presentation and selectin-dependent leukocyte trafficking to the discrimination of self and non-self through the recognition of sialic acids by Siglec (sialic acid-binding Ig-like lectin) receptors. In recent years, a number of key immunological discoveries are driving a renewed and burgeoning appreciation for the importance of glycans. In this review, we highlight these findings which collectively help to define and refine our knowledge of the function and impact of glycans within the immune response.


Asunto(s)
Inmunidad/inmunología , Polisacáridos/inmunología , Animales , Quimiocinas/inmunología , Humanos , Leucocitos/inmunología , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/inmunología
7.
PLoS One ; 12(7): e0180688, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28742882

RESUMEN

While Toll-like receptors (TLRs) represent one of the best characterized innate immune pathways, evidence suggests that TLRs are not restricted to innate leukocytes and some epithelial cells, but are also expressed in T cells. Specifically, published evidence focusing on FoxP3+ regulatory T cells demonstrate that they express functional TLR2, which is already known among the TLR family for its association with immune suppression; however, little is known about the relationship between T cell-intrinsic TLR2 binding and cytokine production, T cell differentiation, or T cell receptor (TCR) stimulation. Here, we demonstrate that TCR and TLR2 co-stimulation provides a T cell-intrinsic signal which generates a dramatic, synergistic cytokine response dominated by IL-10. Importantly, the response was not seen in either CD4+CD25+ or CD4+FoxP3+ Tregs, yet resulted in the expansion of a suppressive CD4+CD25+CD62L-CD44+CD45Rbhi effector/memory T cell subset not typically associated with immune inhibition. This study reveals the striking ability of a prototypical innate immune receptor to trigger a potent and suppressive IL-10 response in effector/memory T cells, supporting the notion that TLR2 is a co-regulatory receptor on T cells.


Asunto(s)
Interleucina-10/inmunología , Antígenos Comunes de Leucocito/inmunología , Linfocitos T Reguladores/inmunología , Receptor Toll-Like 2/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Células Cultivadas , Femenino , Subunidad alfa del Receptor de Interleucina-2/inmunología , Masculino , Ratones Endogámicos C57BL , Receptores de Antígenos de Linfocitos T/inmunología
8.
Proc Natl Acad Sci U S A ; 113(26): 7207-12, 2016 06 28.
Artículo en Inglés | MEDLINE | ID: mdl-27303031

RESUMEN

IgG carrying terminal α2,6-linked sialic acids added to conserved N-glycans within the Fc domain by the sialyltransferase ST6Gal1 accounts for the anti-inflammatory effects of large-dose i.v. Ig (IVIg) in autoimmunity. Here, B-cell-specific ablation of ST6Gal1 in mice revealed that IgG sialylation can occur in the extracellular environment of the bloodstream independently of the B-cell secretory pathway. We also discovered that secreted ST6Gal1 is produced by cells lining central veins in the liver and that IgG sialylation is powered by serum-localized nucleotide sugar donor CMP-sialic acid that is at least partially derived from degranulating platelets. Thus, antibody-secreting cells do not exclusively control the sialylation-dependent anti-inflammatory function of IgG. Rather, IgG sialylation can be regulated by the liver and platelets through the corresponding release of enzyme and sugar donor into the cardiovascular circulation.


Asunto(s)
Linfocitos B/metabolismo , Inmunoglobulina G/metabolismo , Ácidos Siálicos/metabolismo , Sialiltransferasas/metabolismo , Animales , Plaquetas/metabolismo , Hígado/metabolismo , Ratones Noqueados , Ovalbúmina/inmunología , Polisacáridos/metabolismo , Procesamiento Proteico-Postraduccional , Sialiltransferasas/genética , beta-D-Galactósido alfa 2-6-Sialiltransferasa
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