B l o o d G r o u p R e v i e w The Ok group system: an update

J.R. Storry

DOI: 10.21307/immunohematology-2021-004

This update of the Ok (OK) blood group system (Smart EA, Storry and is commonly referred to as BSG.5 BSG interacts with a JR. The OK blood group system: a review. Immunohematology number of in the membrane. It has been shown to 2010;26:124–6) focuses on new information on the role of basigin bind directly to members of the monocarboxylate transporters (BSG), the carrier molecule of the Ok blood group antigens. No further antigens have been identified since the original review. and act as a chaperone to the membrane for these proteins. In However, the role of BSG in continues to be explored. addition to its interaction with monocarboxylate transporters, Immunohematology 2021;37:18–19. BSG forms a lipid raft–associated complex in the membrane with CD44, glucose transporter 1 (GLUT1), and the epidermal Summary of the Ok Blood Group Antigens growth factor (EGF) receptor. For further details on the function of BSG, the interested reader is referred to the review To date, the Ok blood group system, system 24 in the by Muramatsu.5 International Society of (ISBT024), comprises three high-prevalence antigens: Oka, OKGV, Role of BSG in Infectious Disease and OKVM. Only one example of the OKGV− and OKVM− phenotypes has been described, each identified by the The role of BSG as an adhesion molecule and its role in the presence of a specific antibody to its respective high-prevalence stimulation of tumor growth and invasion were discussed in antigen.1,2 The Ok(a−) phenotype was identified in Japanese the original review.6 BSG was also shown to be an important people only,3 and the allele frequency in the gnomAD database receptor for a number of pathogens. Pushkarsky et al.7 showed is 0.1 percent in the so-called East Asian population.4 Table 1 20 years ago that BSG facilitated human immunodeficiency shows a summary of information regarding the Ok blood virus 1 (HIV-1) infection by interacting with virus-associated group system antigens. A and that the cytoplasmic region of the The Ok antigens are carried on basigin (CD147, extra- was important for enhancing HIV-1 replication.8 cellular matrix metalloproteinase inducer [EMMPRIN]), a Measles virus–associated cyclophilin B was shown to bind single-pass membrane protein and member of the immuno- to BSG on epithelial cells. Although leukocytes are the primary globulin (Ig) superfamily. There are two primary isoforms of target for the virus, other tissues are known to be infected. basigin (BSG); the first (BSG1) is a longer protein of 385 amino Watanabe et al.9 showed that virion-incorporated cyclophilin acids and three Ig domains, which is found in the retina. The B bound to BSG and hypothesized that this interaction could shorter, more widely distributed isoform (BSG2) of 269 amino account for symptoms such as pneumonia and diarrhea in acids and two Ig domains is found on red blood cells (RBCs) measles-infected patients.

Table 1. A summary of information regarding the three known Ok blood group system antigens

Nucleotide Predicted amino Occurrence in Phenotype ISBT allele name change in BSG Exon acid change Reference rs number Identified in gnomAD4 OK:1 or OK*01.01† Ok(a+) OK:–1 or OK*01.–01 c.274G>A 4 p.Glu92Lys 3 rs104894669 Japanese East Asian 0.1% Ok(a–) OK:–2 or OK*01.–02 c.176G>T 2 p.Gly59Val 1 rs1023817527 Iranian No data OKGV– OK:–3 or OK*01.–03 c.178G>A 2 p.Val60Met 2 rs2229662 Hispanic European 0.005% OKVM– †OK*01.01 encodes Oka, OKGV, and OKVM. Nucleotide changes are based on transcript basigin (BSG)-203 (ENST00000353555.9; https://www.ensembl. org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000172270;r=19:571277-583493;t=ENST00000353555). ISBT = International Society of Blood Transfusion; gnomAd = Genome Aggregation Database.

18 IMMUNOHEMATOLOGY, Volume 37, Number 1, 2021 Ok blood group system update

In 2011, an elegant and systematic screening identified 5. Muramatsu T. Basigin (CD147), a multifunctional trans- BSG as an important receptor for the malarial parasite, membrane glycoprotein with various binding partners. J Biochem 2016;159:481–90. falciparum, binding to the Rh5 ligand.10 The 6. Smart EA, Storry JR. The OK blood group system: a review. PfRh5 protein is important for commitment and invasion Immunohematology 2010;26:124–6. into the RBC, so identification of the RBC ligand was an 7. Pushkarsky T, Zybarth G, Dubrovsky L, et al. CD147 facilitates important finding. Interestingly, Ok(a−) RBCs showed a HIV-1 infection by interacting with virus-associated cyclo- philin A. Proc Natl Acad Sci U S A 2001;98:6360–5. weaker binding affinity for PfRh5 and were not as easily 8. Pushkarsky T, Yurchenko V, Laborico A, Bukrinsky M. CD147 11 invaded by P. falciparum. Aniweh et al. have shown that the stimulates HIV-1 infection in a signal-independent fashion. PfRh5–BSG interaction leads to Ca2+ signaling, downstream Biochem Biophys Res Commun 2007;363:495–9. phosphorylation, and transient remodeling of the RBC 9. Watanabe A, Yoneda M, Ikeda F, Terao-Muto Y, Sato H, Kai C. CD147/EMMPRIN acts as a functional entry receptor for membrane. measles virus on epithelial cells. J Virol 2010;84:4183–93. In addition to its important role in malarial infection, BSG 10. Crosnier C, Bustamante LY, Bartholdson SJ, et al. Basigin is was recently implicated as an alternative binding partner for a receptor essential for erythrocyte invasion by Plasmodium the SARS-CoV-2 virus responsible for COVID-19.12–14 falciparum. Nat ure 2011;4 80:534 –7. In summary, although there are few variants of BSG 11. Aniweh Y, Gao X, Hao P, et al. P. falciparum RH5-basigin interaction induces changes in the cytoskeleton of the host that appear to be immunogenic and give rise to blood group RBC. Cell Microbiol 2017 Sep;19(9). doi:10.1111/cmi.12747. antigens, our understanding of the role of BSG in health and 12. Wang K, Chen W, Zhang Z, et al. CD147-spike protein is a novel disease is expanding. route for SARS-CoV-2 infection to host cells. Signal Transduct Target Ther 2020;5:283. 13. Ahmetaj-Shala B, Vaja R, Atanur SS, George PM, Kirkby References NS, Mitchell JA. Cardiorenal tissues express SARS-CoV-2 entry and basigin (BSG/CD147) increases with age in 1. Karamatic Crew V, Daniels G, Poole J. A new variant in the Ok endothelial cells. JACC Basic Transl Sci 2020;5:1111–23. blood group system. Transfus Med 2003;13(Suppl 1):32. 14. Ulrich H, Pillat MM. CD147 as a target for COVID-19 treatment: 2. Karamatic Crew V, Thomas B, Gillen B, Poole J, Daniels G. suggested effects of azithromycin and stem cell engagement. A novel variant in the Ok blood group system. Transfus Med Stem Cell Rev Rep 2020;16:434–40. 2006;16(Suppl 1):41. 3. Spring FA, Holmes CH, Simpson KL, et al. The Oka blood group antigen is a marker for the M6 leukocyte activation Jill R. Storry, PhD, Technical Director, Immunohematology, Clinical antigen, the human homolog of OX-47 antigen, basigin and Immunology and , Department of Laboratory neurothelin, an immunoglobulin superfamily molecule that is Medicine, Office for Medical Services, Akutgatan 8, SE-22185, Lund, widely expressed in human cells and tissues. Eur J Immunol Sweden, [email protected]. 1997;27:891–7. 4. Karczewski KJ, Francioli LC, Tiao G, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 2020;581:434–43.

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