Lewis, Ii, and P1PK Systems

• Lewis System History are not alleles
• Lewis antigens

  • In the Lewis System, there are 2 main antigens (Lea and Leb) which can lead to three common phenotypes: Le(a+b-), Le(a-b+), Le(a-b-)
• Lewis antigens

  • in addition to RBC's they are found on platelets, endothelium, kidney, genitourinary, and gastrointestinal epithelium cells
• Lewis antigens

  • lewis antigens are not synthesized by RBCs, but are passively absorbed onto the RBC membranes form a soluble Lewis glycolipid present in the plasma
• Lewis antigen

  • it is though that the GI tract is the primary source of the LE glycolipid in plasma
• Lewis antigens

  • these antigens are not intrinsic to the RBC membrane, so they can float off the red cells and stick to other plasma lipoproteins
  • for example, in pregnant women, there is an increase in plasma volume and a 4x increase in plasma lipoproteins. Because of this, they may appear Le(a-b-) transiently as the Le antigen is decreased on RBCs (diluted out)
• Lewis antigens

  • Le antigen also decreases on stored red cells so Le phenotyping should be done sooner rather than later to avoid false negatives
• biochemistry and synthesis of Lewis Antigens

  • antigen synthesis depends on the interaction of 2 distinct fucotransferases
  • the LE gene (FUT3)
  • the secretor gene (FUT2)
  • these enzymes fucosylate type 1 chains
  • FUT2 recognizes the type 1 chain precursor to form type 1 chain H substance
• synthesis of Lewis antigen

  • FUT2 enables A,B, and H antigens to be secreted by coding for the production of the enzyme a1,2-fucose transferase
  • This adds a fucose to the type 1 chain forming H substance in secretions
• synthesis of Lewis antigen

  • FUT3 is responsible for the presence of the LE antigens
  • the product of this gene is a transferase that adds a fucose to the residue as well
• Lea

  • the Lea antigen is characterized by an a1-4-fucose attachement to the subterminal N-acetylglucosamine residue
• Leb

  • The Leb antigen is determined by the same a1-4-fucose attachment to the subterminal N-acetylglucosamine residue with the addition of the H determinant - the a1,2-fucose attached to the terminal galactose residue
  • in secretors, this interaction occurs preferentially over Lea formation
• Secretors

  • some precursor chains are not acted upon by the secretor transferase, but may accept a fucose from the Lewis transferase, forming Lea
  • Therefore, both Lea and Leb may be found in secretions but only Leb absorbs onto the red cells
• anti-Lea

  • this is a common antibody that can be naturally occurring or immune stimulated
  • Le(a-b+) secrete Lea in their plasma and have a small amount on their RBCs - don't usually make anti-Lea
• anti-Lea

  • will see anti-Lea with Le(a-b-) individuals (usually will see anti-Leb also)
  • most anti-Lea are clinically insignificant because they react at RT and not at 37 degrees
  • most are IgM, with some IgG
• anti-Lea

  • does not cause HDFN because the antigen is a very low level on fetal cells
  • enzyme treated cells enhances the reaction
• anti-Leb

  • this is not as common as anti-Lea
  • it may be seen in Le(a-b-) along with anti-Lea
  • it can be made by Le(a+b-) because they don't have Leb at all
  • it is typically IgM and RT reacting
  • enzyme treated cells enhances the reaction
• I and i antigens

  • I and i are ubiquitous antigens on all cell membranes
  • their products are transferase enzymes that attach repeating units of Gal and GlcNAc to the ABO precursor substance
  • The I gene codes for branching of the precursor substance
• Ii antigen structure

  • i antigen is linear
  • it is predominantly found on cord blood cells
  • I antigen is branched
  • we gradually convert from i to I during the first 18 months of life; not all i is converted to I, some i is still present on adult cells
• Ii antigen structure

  • rare adult individuals termed iadult do not express I antigens on their RBCs
  • The I and i antigen sites are considered uncompleted ABH active chains
  • When ABH are removed from the RBCs more I antigens are expressed (the I structure is located beneath the ABH antigens)
• Ii antigens

  • I and i serve as substrates and scaffolds for the synthesis of ABH and other type 2 chain antigens
  • The i phenotype is characteristic of neonatal RBCs and maturing RBCs
  • can sometimes see increased i in people with chronic hemolytic disorders and stressed erythropoiesis
  • The I phenotype is common for mature RBCs in adults
  • as you age, I goes up and i goes down
• anti-I

  • anti-I is common in the serum of healthy individuals, often occurs as anti-IH
  • it reacts with all adult cells, including the patient's own, all reagent cells, and all donor cells (strongest reaction with O and A2 cells)
  • it doesnt react with cord blood cells
• Anti-I

  • anti-I is usually IgM and is a cold agglutinin (reacts best at 4-10 degrees C), reactions also are enhanced with albumin and enzyme treated RBCs
  • anti-I can interfere with ABO typing, antibody detection, and compatibility testing; need to avoid RT testing and use IgG specific AHG
• Mycoplasma pneumoniae infection is a common cause of autoanti-I
• anti-i

  • autoanti-i is an uncommon cold agglutinin
  • IgM antibody
  • weakly reactive at 4-10 degrees
  • most reactive with cord blood and iadult RBCs
• anti-i

  • patient with infectious mononucleosis often have transient, but very potent, anti-i
  • autoanti-I and autoanti-i are significant in cold agglutinin syndrome (CAS) and mixed type autoimmune hemolytic anemia
• P1PK antigens

  • these antigens are very similar to the ABO system antigens
  • includes P, P1, Pk, and P2
  • they are high prevalence antigens on the RBCs of nearly everyone, they are the most prevalent red cell glycolipid
• P1PK antigens

  • P and Pk are also on lymphocytes, platelets, kidney, lung, heart, endothelium, placenta, and synovium cells
  • Pk is the precursor of all globo-series glycospoingolipids
  • there is a rare, null phenotype, p
• P1 antigen

  • P1 consists of P1 and P antigens
  • 75% of adults have P1 and it is mostly on RBCs
  • the strength of the antigen decreases during storage
  • it can also be found in secretions like plasma and hydatid cyst fluid (cyst of a tapeworm)
• anti-P1

  • naturally occurring IgM
  • weak RT agglutinin
  • increases in patients with hydatid cyst disease, fascioliasis (liver fluke), and bird handlers
  • can see a combo antibody: anti-IP1
• anti-P1

  • the antibody can be neutralized with hydatid cyst fluid of P1 substance derived from pigeon eggs; this helps when dealing with multiple antibodies
• anti-P

  • anti-P is produced in individuals with paroxysmal cold hemoglobinuria (PCH)
  • in PCH IgG autoanti-P attaches complement whn cold (think fingers and toes); as the red cells circulate, they begin to lyse and release hgb
• p Blood Types

  • p individuals can make anti-P1, anti-P2, and anti-Pk (anti-PP1Pk)
  • it is a potent natural antibody and reacts with all red cells except for other p
  • predominantly IgM with some IgG
  • as very potent hemolysins, the antibodies are associated with HDFN and spontaneous abortions
• p Blood types

  • the placenta is rich in P and Pk antigens, so it is a target for maternal antibodies
  • both p and Pk individuals need to get antigen negative blood for transfusion
• Secretors

  • for secretors, only Leb will absorb onto red cells
  • this is probably because the higher concentration of Leb in the plasma allow Leb soluble antigen to compete more successfully for sites of absorption onto the red cell membrane
  • as a result, the red cells of these individuals always phenotypes as Le(a-b+) even though both Lea and Leb soluble antigens are present in the secretions and plasma
• • The combination of Lewis plus secretor status determines whether Lea or Leb is expressed on the RBCs and whether Lea or both Lea and Leb are expressed in the plasma and secretions
  • Since Le antigens are assembled in the plasma, if the Le gene is present some type of LE antigen will be present in the secretions and the plasma regardless of the secretor status
• Lewis system - Secretor status determines which Lewis antigen is present

  • sese with Le: Lea is expressed (absorbed) on the RBCs and is present in plasma and secretions
  • Se (FUT2): if the secretor gene is present with Le, Leb is expressed on RBCs,a nd Lea and Leb are present in plasma and secretiosn
• nonsecretor is Lewis A in secretions, secretor will have Lewis A and B in secretions, but only B in red cells
• More...

  • lele: this genotype does not produce Lea or Leb regardless on the other genes present
  • red cells will have the phenotype Le(a-b-) and there are no Lewis antigens in the plasma or the secretions