Red Cell Antigens: Kell and Duffy

• Blood group systems are crucial for red cell membrane functions, including molecule transport, complement pathway activity, cell adhesion, structural integrity, and enzymatic activities.
• Red cell antigens can act as microbial receptors; Duffy antigens (Fya, Fyb) bind malarial parasites.

Major Antigens, Phenotype Frequencies, Ethnic Associations, and Biochemical Characteristics

• Kell: Major antigens: K (K1), k (K2/cellano), Kpa, Kpb, Jsa, Jsb
  • K (K1): 90% frequency
  • Kpa: 2% frequency
  • Kpb: 99.9% frequency
  • Jsa: 20% in Blacks, 0.1% in Caucasians
  • Jsb: 80-100% frequency
  • Biochemical: Disulfide-bonded regions on glycoproteins, sensitive to sulfhydryl reagents.
• Duffy: Major antigens: Fya, Fyb, Fy3
  • Fya: 66% in Caucasians, 99% in Asians, 10% in Blacks
  • Fyb: 83% in Caucasians, 18.5% in Asians, 23% in Blacks
  • Fy(a-b-): 68% in African-American Blacks
  • Biochemical: Destroyed by enzymes; act as receptors for Plasmodium vivax
• Kidd: Major antigens: Jka, Jkb, Jk3
  • Blacks: 51.1% Jk(a+b-)
  • Caucasians: 50.3% Jk(a+b+)
  • Biochemical: Enhanced by enzymes
• Lutheran: Major antigens: Lua, Lub
  • 92.4% Lu(a-b+)
  • 7.4% Lu(a+b+)
  • 0.2% Lu(a+b-)
  • Biochemical: Not affected by enzymes
• Lewis: Major antigens: Lea, Leb
  • Nonsecretors: Le(a+b-)
  • Le(a+b+) rare
  • Biochemical: Glycoproteins/glycolipids in secretions/plasma; adsorb onto RBC membrane; depends on Hh, Se, Le genes
• I: Major antigens: I, i
  • Newborns: i antigen
  • Adults: I antigen
  • Biochemical: i (linear) converts to I (branched) during maturation
• P1PK: Major antigens: P1, Pk, P
  • P, Pk, and LKE are high-frequency
  • P1 in plasma and hydatid cyst fluid
• MNS: Major antigens: M, N, S, s, U
  • S-s-U- in African Americans
  • M/N coded by glycophorin A
  • S/s/U coded by glycophorin B
• HLA: Major antigens: A, B, C, DR, DQ, DP
  • Diverse
  • Found on leukocytes/tissue cells; coded by MHC genes (chromosome 6); Class I/II/III
• Platelet: Major antigen: HPA-1a (or P1A1)
  • Platelet proteins elicit immune responses

Genetic Mechanisms for Antigens

• Kell: Located on chromosome #7; Sets of alleles include K and k, Kpa and Kpb, Jsa and Jsb, KEL11 and KEL17 (Wka).
• Duffy: Located on Chromosome #1; Codominant alleles Fya & Fyb; Silent allele, Fy, amorph autosomal recessive inheritance of Fy/Fy results in Fy(a-b-) phenotype; Common Duffy mutation (GATA box).
• Kidd: Located on Chromosome #18
• Lutheran: 19 antigens exist (chromosome 19); Lunull phenotype is rare, inherited recessively
• Lewis: Depends on Hh, Se, and Le genes; le, h, and se do not produce products → amorphs (recessive).
• I: I and i antigens are not antithetical antigens; They form on the precursor A, B, and H chains of RBCs.
• P1PK: Globoside blood group system: P antigen (Chrom 22)
• MNS: M and N are coded by glycophorin A (Chromosome #4); S, s, and U are coded by glycophorin B (Chromosome #4); Absence of glycophorin B (GPB) results in S–s–U–
• HLA: Genes that code for HLA are part of the MHC -- Chromo #6 ---> Major Histocompatibility Complex; Individuals inherit one haplotype from each parent.
• Platelet: Platelet proteins can elicit immune responses; The most common platelet antibody is directed against HPA-1a (or P1A1)

Antibody Characteristics and Clinical Relevance

• Kell: Antibody Characteristics: IgG, agglutinate best in IAT, usually do not bind complement, no effect when treated with enzymes; Anti-K (K1) is most common.
  • Clinical Relevance: Associated with hemolytic transfusion reactions (HTRs) and hemolytic disease of the fetus and newborn (HDFN).
• Duffy: Antibody Characteristics: IgG, do not bind complement, stimulated by transfusion or pregnancy, do not react with enzyme-treated RBCs; Anti-Fy3 reacts with enzyme treated cells.
  • Clinical Relevance: Not a common cause of HDFN; Anti-Fya and anti-Fyb are most common; Anti-Fy3 can be made by null phenotype-- Fy(a-b-).
• Kidd: Antibody Characteristics: IgG, clinically significant, may bind complement, detection aided by enzymes, LISS, and PEG.
  • Clinical Relevance: Implicated in HTRs and HDFN; Common cause of delayed HTRs; Usually appear with other antibodies when detected.
• Lutheran: Antibody Characteristics: Anti-Lua: IgM and IgG, reacts best at room temperature, shows mixed-field pattern, not clinically significant; Anti-Lub: IgG, reacts best at AHG, shows mixed-field pattern.
  • Clinical Relevance: Anti-Lub is associated with transfusion reactions (clinically significant).
• Lewis: Antibody Characteristics: IgM, agglutination can occur at IS, 37°C, and AHG, enzymes enhance anti-Leb reactivity, anti-Lea binds complement.
  • Clinical Relevance: Not clinically significant; Neutralization can confirm the presence or eliminate reactions with Lewis antibody.
• I: Antibody Characteristics: Cold-reacting, IgM, bind complement; Reactions are avoided by prewarming; Often found as an anti-IH.
  • Clinical Relevance: Not clinically significant; Autoanti-I is associated with Mycoplasma pneumoniae and cold hemagglutinin disease; Anti-i is associated with infectious mononucleosis.
• P1PK: Antibody Characteristics: Different antibodies within this system; Anti-P1 is usually IgM, can be naturally occurring, and is rarely clinically significant; Anti-PP1Pk (Anti-Tja) is a potent IgG antibody that can cause severe HTRs and HDFN.
  • Clinical Relevance: Anti-PP1Pk (Anti-Tja) is clinically significant and can cause severe HTRs and HDFN.
• MNS: Antibody Characteristics: IgM and IgG; Variable reactions depend on reagent pH.
  • Clinical Relevance: Rarely encountered in HDFN; N-like antibodies found in dialysis patients from formaldehyde-sterilized instruments.
• HLA: Antibody Characteristics: Produced as a result of transfusion and/or pregnancy.
  • Clinical Relevance: Antibodies have been associated with platelet refractoriness and transfusion reactions; Matching for organ and HPC transplants.
• Platelet: Antibody Characteristics: Directed against HPA-1a (or P1A1).
  • Clinical Relevance: May cause neonatal alloimmune thrombocytopenia (NAIT) and posttransfusion purpura (PTP).

Unique Characteristics, Disease Association, and Biologic Functions

• Kell: Unique Characteristics: McLeod phenotype associated with RBC abnormalities (acanthocytosis) and neurologic defects.
  • Disease Association/Biologic Functions: McLeod syndrome is associated with chronic granulomatous disease (impaired phagocytosis).
• Duffy: Unique Characteristics: Fy(a-b-) phenotype common in African Americans.
  • Disease Association/Biologic Functions: Resistance to Plasmodium vivax malaria; Fya and Fyb antigens act as receptors for malarial parasites to enter RBCs.
• Kidd: Unique Characteristics: Antibodies often appear with other antibodies.
  • Disease Association/Biologic Functions: Common cause of delayed HTRs.
• Lewis: Unique Characteristics: Lewis antigens are found in secretions and plasma, adsorbing onto RBCs.
  • Disease Association/Biologic Functions: No specific strong disease associations noted in the document.
• I: Unique Characteristics: i antigen present in newborns, converts to I antigen in adults.
  • Disease Association/Biologic Functions: Autoanti-I is associated with Mycoplasma pneumoniae infection and cold hemagglutinin disease; Anti-i is associated with infectious mononucleosis and lymphoproliferative disease.
• HLA: Unique Characteristics: Important for immune regulation and transplant compatibility.
  • Disease Association/Biologic Functions: Associated with susceptibility to certain diseases (e.g., diabetes, celiac disease, narcolepsy); Matching is crucial for organ and hematopoietic progenitor cell (HPC) transplants to prevent rejection and graft-versus-host disease (GVHD).
• Platelet: Unique Characteristics: Antibodies can cause NAIT and PTP.
  • Disease Association/Biologic Functions: Neonatal alloimmune thrombocytopenia (NAIT): destruction of newborn platelets by maternal antibody; Posttransfusion purpura (PTP): destruction of platelets after transfusion.