The FORS awakens: review of a blood group system reborn

Abstract

The presence of the FORS1 antigen on red blood cells was discovered relatively recently, and in 2012, the International Society of Blood Transfusion (ISBT) acknowledged FORS as blood group system number 031. This rare antigen is carried by a glycosphingolipid and formed by elongation of the P antigen. Most people have naturally occurring anti-FORS1 in their plasma. The clinical significance of these antibodies is unknown in the transfusion setting, but they can hemolyze FORS1+ erythrocytes in the presence of complement in vitro. First believed to be part of the ABO system, it was later shown that the gene encoding the glycosyltransferase giving rise to FORS1 expression is GBGT1. This gene had previously been deemed nonfunctional in humans, but a mutation, so far only detected in FORS1+ individuals, restores the enzymatic activity. Tissue distribution of the antigen in FORS1+ individuals has not been studied in detail, although the gene is expressed in several cell types. The antigen itself is known to be a receptor for various pathogens and toxins and has been detected in different forms of cancer, but the implications thereof are not fully understood. Immunohematology 2017;33:64–72.

ABO blood group antigens and differential glycan expression: Perspective on the evolution of common human enzyme deficiencies

“…Forssman synthase was considered non-functional until rare individuals with enzyme activity were identified ( Hult and Olsson, 2017 ). Individuals that possess the GBGT1.01.01 allele caused by NM_021996.5:c.887G>A (p.Arg296Gln), which is also known as rs375748588, are FORS1+ (2022a).…”

“…Anti-FORS1 antibodies are usually naturally occurring and mainly IgM ( Cohn et al., 2020 ; Hult and Olsson, 2017 ). Because these antibodies are rare, their clinical significance is not well known, but they may cause intravascular hemolysis ( Hult and Olsson, 2020 ).…”

“…P-fimbriated strains of E. coli can bind to FORS1, which may increase susceptibility to infection. In contrast, FORS1 expressing cells are less susceptible to Shiga toxin ( Cohn et al., 2020 ; Hult and Olsson, 2017 ). However, the exact tissue distribution of FORS1 antigen in humans is unknown.…”

Characterization of Human Medullary Thyroid Carcinoma Glycosphingolipids Identifies Potential Cancer Markers

“…A role for Forssman as a tumor-associated carbohydrate antigen has not yet been established. During the 1970ies-1980ies the presence of the Forssman glycosphingolipid both in normal human tissues as kidney and gastrointestinal mucosa [30,31], and in some human cancers as e.g., gastric, lung and liver cancer, was reported (reviewed in [32]). However, if this was the product of the Forssman synthase is not known.…”

A novel and highly specific Forssman antigen-binding protein from sheep polyomavirus

“…So far, only a small number of healthy individuals worldwide were found to carry an activating mutation within GBGT1. In these individuals, the resulting allele gives rise to a Forssman antigen-positive (FA+) erythrocyte phenotype, which is now recognized as the human FORS blood group [6][7][8] . Other reports of healthy human FA+ tissues are scarce, and human sera often contain natural anti-FA antibodies [9][10][11] .…”