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ANTIGENS ASSOCIATED WITH POSSIBLE SUSCEPTIBILITY TO DISEASE
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Some blood groups are statistically associated with medical conditions or disease (Table 136–4).4,5,6,16 For example, blood group A is more common in persons with cancer of the salivary glands, stomach, colon, or ovary and with thrombosis (because of higher levels of coagulation factors VIII, V, and IX). Blood group O is more common in patients with duodenal and gastric ulcers, rheumatoid arthritis, and von Willebrand disease.
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Associations with infection arise when microorganisms carry structures homologous with blood group activity. The presence of blood group antibody and/or soluble blood group antigen in secretions may help confer protection. Having anti-B may offer protection against Salmonella, Shigella, Neisseria gonorrhoeae, and some Escherichia coli infections. An association exists between nonsecretion of ABH antigen and susceptibility to Candida albicans, Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae.6
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A number of disease associations with globoside have been identified. Streptococcus suis, which can cause meningitis and septicemia in humans, binds exclusively to Pk antigen. A class of toxins secreted by Shigella dysenteriae, Vibrio cholerae, and Vibrio parahaemolyticus have binding specificity for Gal(α1–4)-Gal(β1–4). In addition, globoside is the receptor of human parvovirus B19. Some strains of E. coli use the disaccharide receptor Gal(α1–4)-Galβ on uroepithelial cells to gain entry to the urinary tract receptors associated with P1, Pk, and P antigens.5,33 People with the rare p phenotype lack this disaccharide and are not susceptible to acute pyelonephritis from such E. coli strains nor to infection by human parvovirus B19.
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PHENOTYPES ASSOCIATED WITH DISEASE RESISTANCE
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Erythrocytes lacking Fya and Fyb antigens are not infected by the malarial parasite Plasmodium vivax or by the simian malarial parasite Plasmodium knowlesi. These parasites attach to the Fy(a–b–) RBC membrane, but penetration does not take place. The Fy6 antigen is the critical receptor for P. vivax attachment.5 Plasmodium falciparum attaches to RBC glycophorins and their O-linked oligosaccharides (carrying NeuAc). RBCs with the following phenotypes have a decreased rate of infection: M–N– (GPA-deficient), S–s–U– (GPB-deficient), Ge– (Leach type or GPC/GPD-deficient), and Cad-positive and Tn-positive RBCs (which have abnormal O-linked sugars).
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DISEASES ASSOCIATED WITH ALTERED ANTIGEN EXPRESSION
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Antigen expression can be altered with inherited or acquired disease. Inherited changes are fixed and consistent; acquired changes can disappear with remission or recovery. In some diseases, antigen expression weakens; in others, antigen expression increases or new antigens appear.
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Weakened ABH expression on RBCs has been noted in acute myeloid leukemias and may result from reduced transferase activity.5,16 Normal antigen expression returns with disease remission. Transient weakened expression of target antigen also occurs in some cases of autoimmune hemolytic anemia. Weak Rh, Kell, Kidd, LW and AnWj blood group activity has been reported with concurrent autoantibody.5,16,40
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Increased expression of i on RBCs is associated with inherited disorders, such as thalassemia, sickle cell disease, Diamond-Blackfan syndrome, and hereditary erythroblastic multinuclearity with a positive acidified serum test (HEMPAS). Increased i expression also is noted with acquired conditions that decrease the red cell maturation time in the marrow, such as myeloblastic or sideroblastic myeloblastic erythropoiesis, refractory anemia, and excessive phlebotomy.16,23 Expression of the de novo antigen Tn is caused by a galactosyltransferase deficiency acquired by somatic mutation in a population of stem cells. The antigen is present on RBCs, platelets, and granulocytes arising from these stem cells. This condition (seen as persistent mixed-field agglutination because of the presence of both normal and abnormal cells) causes other RBC changes, such as depressed MN expression, enhanced H, and reduced NeuAc content. Tn antigen exposure is associated with myelodysplastic syndrome and acute myelomonocytic leukemia.16 Other antigens (T, Tk) occur as a result of infection when microbes produce enzymes that remove some sugars (NeuAc) and expose new ones. Group A individuals can appear to acquire a B antigen when bacterial deacetylase removes the acetyl group on GalNAc.4,16 This phenomenon is associated with severe infection, gastrointestinal lesions, and malignancies.
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RBCs may acquire blood group activity when they adsorb material from certain microorganisms. Group B activity has been associated with E. coli86 and Proteus vulgaris infection, and K antigen with Enterococcus faecium. Acquired Jkb-like activity has been associated with E. faecium and Micrococcus infections, although the mechanism is not clear.41
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DISEASES ASSOCIATED WITH ABSENT ANTIGENS OR NULL PHENOTYPES
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The Rhnull phenotype is associated with hereditary stomatocytosis, hemolytic anemia (usually mild and well compensated), and a lack of proteins carrying Rh antigens. The Rh protein resides in the RBC membrane, interacts with other membrane proteins and possibly the membrane skeleton, and may help regulate or organize the lipids within the red cell membrane bilayer.9,10 Hence, it is an important determinant of membrane shape and expression of other antigens. Rhnull cells have depressed expression or absence of S, s, U, LW, and Fy5 antigens.
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Most Rhnull red cells are stomatocytes or occasionally spherocytes and demonstrate increased osmotic fragility, increased potassium permeability, and higher potassium pump activity. They have reduced cation and water content and a relative deficiency of membrane cholesterol. Although these abnormalities are assumed to contribute to shortened in vivo survival, Rhnull RBCs survive normally in splenectomized patients, suggesting their removal is related more to splenic clearance because of shape rather than some other intrinsic factor.
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Two genetic mechanisms account for the Rhnull phenotype. Persons with the amorphic type are homozygous for the silent RHCE gene on a deleted RHD background. Individuals with the more common regulator type of Rhnull have normal RH genes but an altered (silenced) RHAG gene. RhAG is required for expression of Rh antigens. Individuals with the Rhmod phenotype have similar membrane and clinical anomalies associated with Rhnull syndrome but demonstrate some Rh antigen expression. The reduced expression of Rh antigens results from the presence of an altered form of RhAG.24,26,42
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Numerous males (but no females) with the McLeod phenotype have been identified. These individuals have acanthocytosis, decreased RBC survival, very weak expression of Kell blood group antigens, lack of Kx antigen on RBCs, and a well-compensated hemolytic anemia.43
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Kx antigen is carried on the Xk protein encoded by the XK gene on the X chromosome, which interacts with the RBC membrane skeleton and helps stabilize the membrane. The absence of Kx is associated with a lipid deficiency in the membrane bilayer that may be critical to the Kell glycoprotein and general RBC discoid shape. RBCs with the McLeod phenotype show a defect in water transport, increased mobility of phosphatidylcholine across the membrane, and increased phosphorylation of protein band 3 and β-spectrin.43
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After age 40 years, patients with the McLeod phenotype develop a slowly progressive form of muscular dystrophy that is associated with areflexia, choreiform movements, and cardiomegaly, leading to cardiomyopathy. They have elevated levels of serum creatine kinase and carbonic anhydrase III. Some patients with the McLeod phenotype and X-linked chronic granulomatous disease (CGD) have a deletion of both the XK and Phox-91 genes (Chap. 66). The McLeod phenotype results from deletions or nucleotide changes in the XK gene.44
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Gerbich-Negative Phenotype
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The GYPC on chromosome 2 encodes two proteins: GPC, with antigens Ge3 and Ge4 (the Ge2 portion is “hidden” by the Ge4-bearing terminal end), and its shorter partner GPD, with antigens Ge2 (now exposed) and Ge3. GPC and GPD interact with membrane skeleton proteins 4.1 and p55, which are involved in cell deformability and membrane stability. Gerbich-negative RBCs of the Leach type (Ge:–2, –3, –4) lack both GPC and GPD, have reduced protein 4.1, and elliptocytosis but exhibit normal survival in vivo.6,10
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Bombay (Oh) Phenotype
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Rare people lack A, B, and H antigens and have naturally occurring anti-A, anti-B, and anti-H in their plasma. Such people are said to have the Bombay (Oh) phenotype. In rare people with the Le(a–b–) Bombay phenotype, the gene that encodes the Fuc transporter is silenced. As a consequence, all cells lack Fuc. Without Fuc, neutrophils lack sialyl LeX and thus cannot roll and ingest bacteria. These patients have a high white blood cell count and severe recurrent infections. The condition is called leukocyte adhesion deficiency II (LADII) or congenital disorder of glycosylation II (CDG II).45,46
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I-Negative Phenotype (i Adult)
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The gene encoding the I-branching β-1,6-N-acetylglucosaminyltransferase (GCNT2) has three alternative forms of exon 1, with common exons 2 and 3. Mutations in exon 2 or 3 silence GCNT2 and give rise to the form of I-negative phenotype associated with congenital cataracts in Asians.47,48 Mutations in exon 1C (IGnTC or IGnT3) silence the gene in RBCs but not in other tissues, and lead to the I-negative phenotype (i adult) without cataracts.49
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Antigens of the Colton blood group system are carried on the water transporter (aquaporin [AQP1]). Although an absence of this protein from the RBC membrane was thought to be incompatible with life, in reality these rare individuals have been shown only to be unable to maximally concentrate urine.50
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The MER2 antigen in the RAPH blood group system is carried on CD151. Rare individuals who lack CD151 have chronic renal failure, skin ulcers, and deafness.51
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Other Null Phenotypes
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Patients with null phenotypes can develop RBC antibodies that make it difficult to find compatible blood to avoid the otherwise serious hemolytic transfusion reactions. For example, people with the Bombay phenotype (Oh or Hnull) demonstrate no red cell abnormality but make potent hemolytic anti-H as well as anti-A and anti-B. These antibodies are incompatible with all RBCs except those from other persons with the Bombay phenotype. Likewise, p individuals (PP1Pk-negative) or Pk individuals (P-negative) can make hemolytic antibodies to the antigens they lack. Anti-PP1Pk and anti-P also are associated with spontaneous abortions in the first trimester.16 Women with such antibodies (notably IgG anti-P), even those with a history of spontaneous abortions, have delivered viable infants after plasmapheresis.52
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Null phenotypes in the MNSs and Lutheran systems are interesting because several types of null phenotypes are known. Within the MNSs blood group system, people may lack GPA (En[a–] or MN-negative), GPB (SsU-negative), or both (MkMk phenotype). The rare Lu(a–b–) phenotype is caused by a dominant inhibitor called In(Lu), by homozygous pairing of the silent allele Lu, or by a recessive sex-linked inhibitor XS2.5,16 Only the LuLu-type null (recessive Lu[a–b–]) is associated with antibody production because the inhibitor type nulls produce small amounts of Lutheran antigen. In(Lu) type, Lu(a–b–) RBCs have low expression of CD44 and AnWj, and have varying degrees of poikilocytosis and acanthocytosis. RBCs of this type tend to hemolyze more quickly during storage, even though they demonstrate normal osmotic fragility.53 Inactivating nucleotide changes in KLF1, which encodes an altered transcription factor, cause the InLu phenotype.30
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The Jk(a–b–) phenotype is caused by the silent alleles JkJk or the dominant inhibitor In(Jk). RBCs having the Jk(a–b–) phenotype resist lysis in 2M urea,54 a reagent commonly used in automated platelet counting systems; resulting in erroneously high platelet counts. No significant clinical abnormalities have been identified to date, although Jk(a–b–) individuals have reduced ability to concentrate urine.55
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The following diagnoses are made easily by simply typing the RBCs with appropriate antisera: Rh syndrome, McLeod syndrome, and LAD II.