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Kell blood group system

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KELL KIDD DUFFY BLOOD GROUP SYSTEMS

Kell Blood Group SystemDr. RAFIQ AHMAD, MBBS/MD, MTM, FSAP

IntroductionHistoryNomenclatureProteins/Genes and their functionsAntigensAntibodiesClinical Significance

Kell-HistoryFirst blood group antigen to be identified after the discovery of antiglobulin test (Coombs test).KEL1 or K(Kelleher) identified in 1946 KEL2 or k(cellano) identified in 1949Kpa , Kpb and K null phenotype discovered in 1957.

NomenclatureNumber of Kell antigens: 35ISBT symbol: KELISBT number: 006Gene symbol: KEL Gene name: Kell blood group CD number CD238 In fetus Kell antigen appears very early during erythropoiesis, K 10 -11 week old fetus, and k in 6 weeks old fetus

Kell Antigens Number: 35 The K antigen is one of the most clinically significant Kell antigens.Specificity: Protein: Amino acid sequence determines the specificity of Kell antigens

Kell AntigensAntigen-carrying molecules: Glycoprotein with enzymatic functionThe Kell glycoprotein is a transmembrane, single-pass protein that carries the Kell antigens. It is an endothelin-3-converting enzyme; it cleaves "big" endothelin-3 to produce an active form that is a potent vasoconstrictor

Kell GeneticsGene-Chromosome 7q33Name KELOrganized into 19 exons of coding sequenceProduct Kell glycoproteinGENETICS: alleles K, k, Kpa , Kpb , Jsa , and Jsb are in "linkage disequilibrium"; no gene exists which carries both K and Kpa or Jsa , or both Kpa and Jsa . A. K/k, Kpa /Kpb and Jsa /Jsb inherited in autosomal, codominant fashion. McLeod syndrome is inherited in X-linked fashion.

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Kell GeneticsMolecular basis:The KEL gene encodes the Kell antigens.KEL is highly polymorphic. It has two major codominant alleles, k and K, which result from a SNP (698CT), and the corresponding k and K antigens differ by a single amino acid change (T193M).

Kell Frequencies ~100%:k, Kpb, Ku, Jsb, K11, K12, K13, K14, K18, K19, Km, K22, K26, K27K antigen: 2%in Blacks,9%in Caucasians, up to25%in Arabs~2%:Kpa, U1a~0.01%:Jsa(0.01% in Caucasians, 20% in Blacks), Kpc, K23Others: K17 (~0.3%), K24 (rare), VLAN (rare), K16 (unknown) K-k+in 91% Caucasians and 98% Blacks

ANTIGENIC STRUCTURE: Kell antigens located on red cell membrane glycoprotein(CD238) 4- 5 N-glycans present; no O glycosylation

Kell Antigens

Kell Antigen- Its FunctionsKell glycoprotein is an endothelin-3-converting enzyme (big endothelins- ET3-- vasoconstriction)

Kell glycoprotein is a memberof the Neprilysin (M13) sub-family of zinc endopeptidases and has sequence and structural homology with neutral endopeptidase,(CALLA,enkephalinase) and endothelin-converting enzyme ECE-1.

Kell structure Xk Kell linked to Xk protein through a disulfide bondXk integral membrane protein which expresses the Kx blood group antigen(XK1) . XK gene encoding Kx antigen is located on X chromosome at Xp21.1 ,as a separate blood group system

Onset of expression of the components of the Kell blood group complex Expression of both Kell and XK is limited to the erythroid lineage,expression of Kell, but not of XK, was noted in bipotent erythroid- megakaryocyte progenitors. Thus the expression of Kell and XK is independent, and this is in keeping with previous studies, with transfected cells, that showed that coexpression of Kell and XK is not necessary for transport of the proteins to the cell surface - Jeffrey et al ., TRANSFUSION,2005

PhenotypeCaucasians PercentageAfrican- AmericanPercentageRBB Dammamk919890%K+k+8.829.1%K0.2RARE0.9%Kp aRARE00.1%Kp b97.7100100%Kp(a+b+)2.3RARE-Kp c0.320-Js(a+b-)01-Js(a-b+)10080-

Kell AntigensKELL 1(K): low incidence antigen, 9% whites .3.5% in blacks .KELL 2(k): High incidence antigen in all populations This polymorphism arises due to SNP in exon 6, Met193Thr

KELL antigensKpa(KEL3): 2%whites NOT IN BLACKSKpb( KEL4):It is the common allele, the codon is CGG. Kpa/ Kpb /Kpc differ from the common allele by single base change in the same codon in exon 8, TGG and CAG respectively. Js a(KEL6): confined to African ethnicity 16% prevalence

Other KELL antigensLow prevalence antigens: Ul a, K23, KYO(single amino acid substitution)

High prevalence antigens : k, Kpb,Jsb, K11,K14 OTHER HIGH INCIDENCE ANTIGEN: K12, K13, K18,K19,K22,TOU, RAZ,KALT, KTIM

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Kx antigenExpressed most strongly on red cells that lack Kell antigens, ie., K0 red cellsOnly antigen in Kx systemX linked recessive gene Xk at Xp21BLOOD GROUP SYSTEM:019A part of dimeric amino acid transporter, covalent linkage to type 2 membrane Kell glycoprotein

K null (K0) and Kmod phenotypesK0: No kell antigens detectable in RBC Immunised individuals produce anti-Ku (anti-KEL5) Anti Ku recognises universal Kell antigen (Ku)on all cells, except K0Might be by nonsense/missense/splice site mutationsIt has single specificity , can cause both HDFN and hemolytic reactions

Kmod phenotypeKmod is an inherited rare RBC phenotype characterized by weak but detectable expressionof high-incidence Kell antigensHomozygous or heterozygous for missense mutations in kell glycoproteinSome produce anti Ku,but nonreactive with Kmod cells

Mcleod phenotype- serologyThey can make 2 alloantibodies after transfusion anti KL , mixture of anti Kx and anti Km.

Km antigen is found in all red cells other than K0 red cells /Mcleod phenotype.

LyonizationI-McLeod phenotypeMixed populations of Kx+ and Kx red cells, or of red cells with strong and weak Kell antigen expression are recognized in many female carriers of genes responsible for the McLeod phenotype.The proportion of McLeod phenotype red cells in female McLeod carriers usually varies from 5% to 85% . This dual population is often difficult to detect serologically, especially if Kell antibodies and not anti-Kx are used, but flow cytometry permits an accurate estimationof the two red cell populations

McLeod phenotypeAll Kell antigens are depressed ,Xk absent on red cellsDeletion of that part of the chromosome containing Xk Minority of X linked CGD have this phenotype includes the deletion of locus for a X linked GD and Xk locus Clinical features:

Mcleod Syndrome

Clinical features:Acanthocytic red cells, elevated CK ,Other muscular and neurological defects.

Weak expression of Kell antigensOther inherited causes for weak expression of kell phenotypewhen glycophorin C and D are absent (Leach phenotype); when a portion of the extracellular domain of glycophorin Cand D, specifically exon 3, is deleted (some Gerbich negative phenotypes).Acquired causes: AIHA, ITP, microbial infection

Tissue expressionKell protein detected in testis ,skeletal muscle, lymphoid tissuesNot found in WBCs or platelets

Action of Enzymes on Kell AntigensPapainFicin Resistant Trypsin Alpha chymotripsin

2ME/ DTT/ AET Mixture of trypsin Sensitiveand chymotrypsin

Effect of EnzymesEnhanced antibody activity:Cleavage of glycoprotein leads to:Decreased activity :

Cleavage of glycoprotein leads to

1.Reduces the negative charge on RBC2.Reduces the steric hindrance3.Making cells more hydrophobic It is seen in Rh, Kidd, P, lewis, I antigensloss of antigens ,it is seen in Fy a, Fyb, MNS systems

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Kell Antibodies-Anti- KAnti K and anti k Usually IgG ( IgG1)Causes severe HDFN and HTR Anti K -the most common immune red cell antibody other than ABO/Rh system Most anti K appears due to blood transfusion, few are due to microbial infection ,few in healthy donorsK is less immunogenic than D

Kell antibodiesAnti K found in 1/1000 pregnant womenIncidence of HDFN due to anti K -1/20000 pregnanciesThe frequency of HDFN due to anti K is lower as the mother is immunised by transfusion not by pregnancyIn most cases fetus is K negativeHDN due to anti K severe when immunization is due to previous pregnancy

K-HDFN Pathogenesis Kell glycoprotein appears earlier in erythropoiesis than D antigensAnti K induced phagocytosis of K+ erythroid progenitors FEATURES:Lower levels of reticulocytes /AF bilirubin / erythroblastsLess severe post natal hyperbilirubinemiaTreatment: recombinant erythropoietin

K-HDFN ManagementThere is no correlation between antibody titer and degree of inhibition

Neonates with Kell HDFN require less phototherapy and exchange transfusions.

Because of the destruction of red cell precursor cells as well, treatment with erythropoietin may be more effective in neonates with Kell HDFN compared to Rh HDFN

Other antibodiesAnti k cause severe hemolytic reactions, but less commonAnti Kpb is an auto antibody in AIHAanti Js a,anti Js b are rare, causing DHTRsAnti Ku in K0 individuals, reacts with all samples except K0

The End!! Thank you