P1PK blood group system explained

P1PK (formerly: P) is a human blood group system (International Society of Blood Transfusion system 003) based upon the A4GALT gene on chromosome 22. The P antigen (later renamed P1) was first described by Karl Landsteiner and Philip Levine in 1927.^[1] The P1PK blood group system consists of three glycosphingolipid antigens: P^k, P1 and NOR.^{[2] [3]} In addition to glycosphingolipids, terminal Galα1→4Galβ structures are present on complex-type N-glycans.^[4] The GLOB antigen (formerly P) is now the member of the separate GLOB (globoside) blood group system.

P1PK antigens

The P1PK antigens are carbohydrate antigens that include P^k (Gb3), P1 and NOR1, NOR_int and NOR2. All are synthesized by Gb3/CD77 synthase (α1,4-galactosyltransferase, P1/P^k synthase).^[5]

• P^k antigen is a receptor for Shiga toxins produced by Shigella dysenteriae and some strains of Escherichia coli, which may cause hemolytic uremic syndrome (HUS).^{[6] [7] [8]} It is also a receptor for Streptococcus suis (zoonotic bacterium which can cause bacterial meningitis).
• P1, P, P^k and LKE antigens all serve as receptors for P-fimbriated uropathogenic E. coli (cause of chronic urinary tract infections).

The presence or absence of P1 antigen depends on the A4GALT transcript level. It was found that differential binding of transcription factors early growth response 1 (EGR1) and runt-related transcription factor 1 (RUNX1) to the SNP rs5751348^[9] genomic region with the different genotypes in the A4GALT gene leads to differential activation of A4GALT expression, leading to two genotypes: P¹ and P².^{[10] [11]}

P1PK phenotypes

P1PK phenotypes are defined by reactivity to antibodies to anti-P₁, anti-P, anti-P^k anti-PP₁P^k. and anti-NOR antibodies.

• P₁ Phenotype: anti-P₁ (+), anti-P (+) and anti-PP₁P^k (+) and anti-P^k (-).Found in 95% of Blacks and 80% of Caucasians and 30% in Japanese.
• P₂ Phenotype: anti-P₁ (-), anti-P (+), antiPP₁P^k (+), and anti-P^k (-). Found in 5% of Blacks and 20% of Whites.
• Rare p phenotype (absence of P1PK antigens caused by null mutations in A4GALT): anti-P₁ (-), anti-P (-), anti-PP₁P^k (-), and anti-P^k (-). These individuals have a very strong anti-PP₁P^k which can be associated with delayed hemolytic transfusion reactions and early spontaneous abortions or hemolytic disease of the fetus and newborn (HDFN). Currently, 34 alterations, in 37 alleles, in the A4GALT gene have been found to abolish the enzyme activity, giving rise to the rare p phenotype.
• The rare NOR phenotype is caused by the presence of unique NOR1 and NOR2 glycosphingolipid antigens, terminating with Galα1 → 4GalNAcβ1. Such structure, found only in Rana ridibunda, is a result of mutation in the A4GALT gene, leading to p.Q211E substitution in Gb3/CD77 synthase (rs397514502).^{[12] [13] [14]}

P1PK antibodies

• Anti-P1 antibodies are present in up to two-thirds of P₂ individuals, and are usually clinically insignificant. When performing blood transfusion to an anti-P1 positive patient, only rare hemolytic transfusion reactions have been reported.^[15] Anti-P1 titers are often elevated in patients with liver flukes (fascioliasis), hydatid cyst disease and who are frequently exposed to birds (which may have P1-like substances in their excrement).^[6]
• Anti-P1P^k is composed of a mixture of anti-GLOB, anti-P1 and antiP^k in the serum of p individuals. Alloanti-GLOB is seen in the sera of P₁^k and P₂^k persons and is naturally occurring and predominantly IgM isotype (but may also be a mixture of IgM and IgG).^[6] The antibodies are capable of causing hemolytic transfusion reactions and hemolytic disease of the fetus and newborn (if IgG isotype and therefore capable of crossing the placenta).^[6] There is a relationship between anti-PP1P^k and early spontaneous abortion (the placenta is rich in P^k and GLOB antigens which are targeted by IgG isotype antibodies).^[6]
• Anti-NOR antibodies occur naturally in most individuals.^[16] They react with NOR1 and NOR2 antigens, causing a phenomenon called NOR polyagglutination.

Antibody detection

Anti-P1P^k antibodies are not usually detected with routine laboratory methods. It is possible to detect them using the Donath-Landsteiner test. This test is performed on 2 vials of blood at two different temperatures: 4 °C and 37 °C (body temperature). A test is interpreted as positive only after a patient's red blood cells have been incubated at both temperatures and subsequently hemolyzed.^[17]

References

1. Landsteiner. Karl. Levine. Philip. 1927. Further Observations on Individual Differences of Human Blood. Experimental Biology and Medicine. 24. 9. 941–942. 10.3181/00379727-24-3649. 88119106.
2. Kaczmarek. Radoslaw. Buczkowska. Anna. Mikolajewicz. Katarzyna. Krotkiewski. Hubert. Czerwinski. Marcin. P1PK, GLOB, and FORS blood group systems and GLOB collection: biochemical and clinical aspects. Do we understand it all yet?. Transfusion Medicine Reviews. 2014. 28. 3. 126–136. 10.1016/j.tmrv.2014.04.007. 24895151. subscription.
3. Hellberg. Åsa Hellberg. P1PK: a blood group system with an identity crisis. ISBT Science Series. 2020. 15. 40–45. 10.1111/voxs.12505. 201971613. subscription.
4. Szymczak-Kulus. Katarzyna. Weidler. Sascha. Bereznicka. Anna. Mikolajczyk. Krzysztof. Kaczmarek. Radoslaw. Bednarz. Bartosz. Zhang. Tao. Urbaniak. Anna. Olczak. Mariusz. Park. Enoch Y.. Majorczyk. Edyta. January 2021. Human Gb3/CD77 synthase produces P1 glycotope-capped N-glycans, which mediate Shiga toxin 1 but not Shiga toxin 2 cell entry. Journal of Biological Chemistry. 296. 100299. 10.1016/j.jbc.2021.100299. 33460651. 7949097. 0021-9258. free.
5. Kaczmarek. Radoslaw. Duk. Maria. Szymczak. Katarzyna. Korchagina. Elena. Tyborowska. Jolanta. Mikolajczyk. Krzysztof. Bovin. Nicolai. Szewczyk. Boguslaw. Jaskiewicz. Ewa. Czerwinski. Marcin. 2016-01-29. Human Gb3/CD77 synthase reveals specificity toward two or four different acceptors depending on amino acid at position 211, creating Pk, P1 and NOR blood group antigens. Biochemical and Biophysical Research Communications. en. 470. 1. 168–174. 10.1016/j.bbrc.2016.01.017. 26773500. 0006-291X. subscription.
6. Roback JD et al. AABB Technical Manual, 16th Ed. Bethesda: AABB Press, 2008.
7. Cooling LW, Walker KE, Gille T, Koerner TAW. Shiga Toxin Binds Human Platelets Via Globotriaoslyceramide (P^k antigen) and a Novel Platelet Glycosphingolipid. Infect Immun 1998; 66: 4355-66.
8. Beadling W, Cooling L. Immunohematology. In: McPherson RA, Pincus MR, eds. Henry's Clinical Diagnosis and Management by Laboratory Methods. 25th Ed. Philadelphia: Saunders, 2007: 618-68.
9. Web site: dbSNP: the NCBI database of genetic variation. 2020-08-18.
10. Yeh. Chih-Chun. Chang. Ching-Jin. Twu. Yuh-Ching. Hung. Shu-Ting. Tsai. Yi-Jui. Liao. Jia-Ching. Huang. Ji-Ting. Kao. Yu-Hsin. Lin. Sheng-Wei. Yu. Lung-Chih. The differential expression of the blood group P1-A4GALT and P2-A4GALT alleles is stimulated by the transcription factor early growth response 1. Transfusion. 2018. 58. 4. 1054–1064. 10.1111/trf.14515. 29399809. 4730839.
11. Westman. Julia S.. Stenfelt. Linn. Vidovic. Karina. Möller. Mattias. Hellberg. Åsa. Kjellström. Sven. Allele-selective RUNX1 binding regulates P1 blood group status by transcriptional control of A4GALT. Blood. 2018. 131. 14. 1811–1818. 10.1182/blood-2017-08-803080. 29438961. free.
12. Web site: rs397514502 RefSNP Report - dbSNP - NCBI. www.ncbi.nlm.nih.gov.
13. Duk. Maria. Reinhold. Bruce B. Reinhold. Vernon N. Kusnierz-Alejska. Grazyna. Lisowska. Elwira. Structure of a neutral glycosphingolipid recognized by human antibodies in polyagglutinable erythrocytes from the rare NOR phenotype. Journal of Biological Chemistry. 2001. 276. 44. 40574–40582. 10.1074/jbc.M102711200. 11504714. free.
14. Suchanowska. Anna. Kaczmarek. Radoslaw. Duk. Maria. Lukasiewicz. Jolanta. Smolarek. Dorota. Majorczyk. Edyta. Jaskiewicz. Ewa. Laskowska. Anna. Wasniowska. Kazimiera. Lisowska. Elwira. Czerwinski. Marcin. A single point mutation in the gene encoding Gb3/CD77 synthase causes a rare inherited polyagglutination syndrome. Journal of Biological Chemistry. 2012. 287. 45. 38220–38230. 10.1074/jbc.M112.408286. 22965229. 3488091. free.
15. Smith D, Aye T, Er LS, Nester T, Delaney M. Acute Hemolytic Transfusion Reaction due to Anti-P1: A Case Report and Review of Institutional Experience. . Transfus Med Hemother . 2019 . 46 . 5 . 380–383 . 31832064 . 10.1159/000490897 . 6876609 .
16. Duk. Maria. Kusnierz-Alejska. Grazyna. Korchagina. Elena Y. Bovin. Nicolai B. Bochenek. Stanislawa. Lisowska. Elwira. Anti-α-galactosyl antibodies recognizing epitopes terminating with α1,4-linked galactose: human natural and mouse monoclonal anti-NOR and anti-P1 antibodies. Glycobiology. 2005. 15. 2. 109–118. 10.1093/oxfordjournals.glycob.a034964. 15342552. free.
17. Mais DD. ASCP Quick Compendium of Clinical Pathology, 2nd Ed. Chicago: ASCP Press, 2009.

External links

• P at BGMUT Blood Group Antigen Gene Mutation Database at NCBI, NIH