Forssman expression on human erythrocytes: biochemical and genetic evidence of a new histo-blood group system

Abstract

Key Points• A new histo-blood group system was discovered, based on the identification of Forssman glycolipid antigen on human red blood cells.• A newly described polymorphism in the GBGT1 gene activates the encoded enzyme to synthesize Forssman antigen. IntroductionCarbohydrate histo-blood group antigens, first recognized on red blood cells (RBCs) in 1900, 1 have been suggested to be part of our innate immune response. 2 Major carbohydrate histo-blood groups in man include the ABO, P1PK, H, Lewis, I, and GLOB systems in which glycoproteins and glycolipids carry immunodominant terminal sugars, 3 defining polymorphic antigens. Other mammals also express carbohydrate histo-blood groups, such as ABO, 4 fucoseless B antigen (Galili), 5 and Forssman (Fs) 6,7 but their expression on RBCs varies among species. Although the biologic function of polymorphic carbohydrates on RBCs is unresolved, these antigens can be used as receptors by pathogens [8][9][10][11] and their expression in tissues and bodily secretions are thus believed to reflect microbial selection. 8 In response to blood-group-mimicking glycans on bacterial surfaces, naturally occurring antibodies with the capacity to neutralize various microorganisms are formed. However, these antibodies also constitute substantial transfusion and transplantation barriers. 3,12 In 1987, 3 families with a supposed ABO subgroup named A pae were reported. 13 Although Helix pomatia lectin reacted strongly and polyclonal anti-A weakly with RBCs from some family members, monoclonal (MAb) anti-A reagents were later shown to be nonreactive, thus presenting an apparent paradox. The biochemical and genetic background of this enigmatic phenotype has remained unknown, as has its biologic consequences. We hypothesized that an explanation may be found by studying the glycolipids of this phenotype. 14 Here we report the identification of Fs glycolipids, normally found only on RBCs of selected nonprimate mammals, are strongly expressed on human A pae RBCs. In nonprimates, Fs antigen is synthesized by Fs synthase (globoside 3-␣-N-acetyl-D-galactosaminyltransferase, EC2.4.1.88), 7 an enzyme homologous to the ABO transferase. We also reveal a genetic polymorphism in the human Fs gene (GBGT1) that alters the enzymatically inactive human protein 15 Methods SamplesFive and 3 RBC units were collected from each of 2 unrelated A pae individuals (A pae #1 and A pae #2, respectively) from 2 of the originally reported families. 13 GlycolipidsGlycolipid preparation. Lysed blood units were thawed and total neutral glycolipids with Ͻ 20 sugar residues were isolated (see supplemental Methods, where control glycolipid preparations are also described; available on the Blood Web site; see the Supplemental Materials link at the top of the online article).Open-column chromatography. Total glycolipids (ϳ 110 mg) from each of A pae #1 and #2 were fractionated by silica chromatography column (5g silica/100 mg lipid; Silica 60, Merck) in a system of chloroform (C) methanol (M) solvent mixes (supplemental Metho...

Humoral response to a viral glycan correlates with survival on PROSTVAC-VF

“…This survival correlation further validates anti-Fs di responses as a potential biomarker for PROSTVAC-VF and extends its clinical significance from mCRPC patients receiving PROSTVAC-VF as a single agent to include patients with radiographically evident metastases receiving combination therapy. (32,33). Third, the chicken embryo dermal cells used as host cells for production of the poxviruses express blood group A (34) and the Forssman antigen (35,36).…”

FORS, a new histo-blood group: A current review

“…The A pae positive family members showed a divergent Ab and lectin reaction pattern of the RBCs. The Helix pomatia lectin resulted in a strong reaction, polyclonal Ab anti-A gave a weak response and monoclonal Ab anti-A were nonreactive, thus presenting an apparent paradox [1,5].…”

“…Several years later a group of Swedish researchers showed that, Fs glycolipid, usually only found in the RBCs of non-primate mammals, was strongly expressed in human RBCs of the subgroup A pae [1].…”

“…Lola et al found a single point mutation in the GBGT1 gene that makes the human Fs synthase activity and gives origin to a rare phenotype that was previously misclassified as an AB0 subgroup, A pae , and referred that the Fs glycolipid is transmitted hereditarily [1,2,6]. …”

“…Major carbohydrate histo-blood groups in man include the AB0, H, I, Lewis, P 1 P K , H and GLOB systems in which glycoproteins and glycolipids carry immunodominant terminal sugars, defining polymorphic Ag. Other mammals also express carbohydrate histo-blood groups, such as AB0, and Fs but their expression on RBCs varies among species [1].…”