MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

Imunotolerance

Peripheral immune tolerance by N-acetylgalactosamine (pGal)

  • Carried out in the liver
  • Discovered in recent years
  • Tagging molecules with a sugar known as N-acetylgalactosamine (pGal)
    • Could mimic this process, sending the molecules to the liver where tolerance to them develops.
  • We can attach any molecule we want to pGal and it will teach the immune system to tolerate it
  • Hubbell's pGal compounds in humans

Initial phase I safety trials have already been carried out in people with celiac disease

Phase I safety trials are under way in multiple sclerosis

N-acetylgalactosamine - a cancer-associated sugar derivative

  • Conformation panorama of N-acetylgalactosamine and further rationalize the biological role of this aminosugar derivative as part of the Tn antigen
  • Nebo spíš ne antigen tumorů, ale další z mechanismů navodění imunotolerance tumorů. Antigeny tumurů by měly před vakcinací být tedy zbaveny N-acetylgalactosaminu, aby došlo k imunitní reakci nikoliv další toleranci.
  • Overexpression and exposition of GalNAc molecules on the cell membrane is clinically associated with cancer metastasis
  • Overexpression of this molecule is undoubtedly associated with poor patient prognosis and the development of metastasis in a wide range of cancers
    • To invade other tissues through noncovalent interactions with lectins of the target tissue
  • pubs.acs.org/doi/10.1021/acs.jpca.2c04595
  • Whole-cell tumor vaccines desialylated to uncover tumor antigenic Gal/GalNAc epitopes elicit anti-tumor immunity
  • Aberrant sialoglycans on the surface of tumor cells shield potential tumor antigen epitopes, escape recognition, and suppress activation of immunocytes
  • Desialylating sialoglycans on tumor cells could present tumor antigens with Gal/GalNAc residues and overcome glyco-immune checkpoints
  • MGL is the lectin that exclusively binds terminal Gal/GalNAc epitopes of tumor-associated glycan
  • It is an antigen-uptake receptor for the internalization of Gal/GalNAc carrying immunogens delivered into MHC class I and II compartments,
    • Thus improving DC performance to facilitate MHC-restricted antigen presentation to T cells
      • Increasing antigen-specific CD8 + T-cell activation
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC9620617/
  • The process of O-glycosylation is complex and takes place in the Golgi apparatus, regulated by specific enzymes called ppGalNAc transferases. The incomplete synthesis or truncated forms of O-glycans such as Tn, STn, T and ST antigens are commonly seen in cancer states. The increased expression of these truncated glycans is associated with increased invasion potential, leading to metastasis and poor prognosis in a wide range of cancers.
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC10340074/
  • 111 primary breast cancers assessed for binding of HPA and labelling characteristics
  • Dolichos biflorus agglutinin and soybean agglutinin
    • Recognise N-acetylgalactosamine,
  • Griffonia simplicifolia agglutinin II
    • Recognises N-acetylglucosamine
  • Limax flavus agglutinin, Sambucus nigra agglutinin and Maackia amurensis lectin I
    • Recognise sialic acids
  • HPA-binding partners expressed by cancer cells are predominantly N-acetylgalactosamine glycans
  • Some recognition of N-acetylglucosamine species is also likely
  • www.sciencedirect.com/science/article/abs/pii/S0065128104700550
  • O-GlcNAcylation of glucose transporter 4 (GLUT-4), is enhanced in GLUT1-overexpressing muscles (14). Most proteins involved in the malignant transformation of cells, including ß-catenin, p53, the pRb family, and c-Myc, are known to undergo O-GlcNAcylation (4). In colorectal and lung cancer tissues, O-GlcNAcylation and OGT expression are significantly enhanced, and O-GlcNAcylation promotes the growth of colorectal and lung cancer cells (15). Noticeably, O-GlcNAcylation is involved in both T2DM and colorectal cancer.
  • Recent meta-analyses in epidemiological studies have demonstrated that T2DM is a risk factor for colorectal cancer (16) and that the underlying mechanism may involve hyperglycemia, hyperinsulinemia, and insulin resistance (17). Thus, we hypothesized that O-GlcNAcylation may play an important role in colorectal cancer occurring concurrently with T2DM.
  • www.spandidos-publications.com/10.3892/ol.2020.11665

Formation process of antifreeze glycosylated proteins (AFGP)

  • Class of glycoproteins that act as biological antifreeze agents in certain species of fishes, insects, bacteria, fungi, and plants. (36) These proteins are typically composed of repeating Thr–Ala–Ala units that appear glycosylated through the threonine residue with the disaccharide b-d-galactosyl-(1 › 3)-?-d-N-acetylgalactosamine. This process is similar to the Tn antigen formation process, since the linkage of the disaccharide to the protein is also realized through the anomeric hydroxyl group.
  • pubs.acs.org/doi/10.1021/acs.jpca.2c04595

GalNAc and GalN amino sugars can support the growth of Escherichia coli

Mutations in glycosidases - Schindler and Fabry diseases

  • Deposition of undegraded carbohydrates.
  • Schindler and Fabry diseases are caused by the incomplete degradation of carbohydrates with terminal a-N-acetylgalactosamine and a-galactose
  • Glycosidase that removes ?-N-acetylgalactosamine, and the structure with bound ligand
  • ?-galactosidase A (?-GAL)
  • ?-NAGAL deficiency leads to tissue deposits and an accumulation of oligosaccharides and glycopeptides in urine.
  • Related enzyme ?-GAL, mutations lead to Fabry disease, an X-linked recessive condition initially described in 1898
    • Chronic pain, progressive vascular deterioration, ocular abnormalities, skin lesions, and/or cardiac abnormalities
  • Both ?-NAGAL and ?-GAL belong to family 27 and clan D in the classification of glycoside hydrolases

Krevní skupiny

  • A-NAGAL and a-GAL produce type O “universal donor”
    • Blood from type A and type B blood
  • A-NAGAL structure will aid in the engineering of improved enzymes for blood conversion.
  • The ?-NAGAL enzyme converts A antigen into O antigen
  • ?-GAL recognizes the blood group B antigen
  • This process requires over a gram of purified enzyme per unit of blood [20], so engineering ?-NAGAL and ?-GAL with improved enzymatic properties remains an important goal.

Schistosoma mansoni

  • A-galactosidase (a-GAL) and a-N-acetylgalactosaminidase (a-NAGAL) are two glycosyl hydrolases
  • Responsible for the neglected tropical disease schistosomiasis, also contains functionally important ?-GAL and ?-NAGAL proteins. As infection, parasite maturation and host interactions are all governed by carefully-regulated glycosylation processes, inhibiting S. mansoni's ?-GAL and ?-NAGAL activities could lead to the development of novel chemotherapeutics.

N-acetyl-D-glucosamine (GlcNAc)

  • One of the basic constituents of mammal cartilage, which is known to help repair deteriorating cartilage and relieve pain and inflammation in osteoarthritis
O úroveň výše

Poslední aktualizace: 30. 9. 2024 0:47:23