Lecture 7 – The Rhesus System (Part 1) PDF

SCIE 2040 – Transfusion Medicine 1 Textbook Chapter 5 Lecture 7 – The Rhesus System (Part 1) 5.1 History of Rh In 1939, Levine and Stetson discovered an antibody suspected to cause hemolytic disease of the fetus and newborn (HDFN), and a subsequent hemolytic trans...

SCIE 2040 – Transfusion Medicine 1 Textbook Chapter 5 Lecture 7 – The Rhesus System (Part 1) 5.1 History of Rh In 1939, Levine and Stetson discovered an antibody suspected to cause hemolytic disease of the fetus and newborn (HDFN), and a subsequent hemolytic transfusion reaction, in a woman. They hypothesized that there was a “factor” in the husband’s blood that was passed to the child, and that the mother was reacting to this “factor”. The factor was later identified as the D antigen. In 1941, Landsteiner and Wiener discovered an antibody produced by rabbits and guinea pigs when they were exposed to rhesus monkey red blood cells. These researchers went on to describe an antibody that reacted with 85% of the human red blood cells against which it was tested. Although what they discovered in the monkeys is now known as “anti-LW”, it was originally thought to be anti-D, and thus “Rhesus” or “Rh” stuck as the name of the blood group system. 5.2 RHD and RHCE Genes and Proteins The two Rh genes, RHD and RHCE, are located on chromosome 1. The RHD gene (D/d) codes for the D antigen only. An individual with the D antigen may be described as “D+” or “Rh(D)-positive.” If the D antigen is absent the individual is usually described as “D-“ or “Rh(D)-negative.” The “d” allele is an amorph; there is no d antigen. The absence of the D antigen occurs most commonly when the RHD gene is deleted, however nonfunctional, mutated, or partial RHD alleles also exist. The RHCE gene codes for the RhCE protein that carries both the C/c and E/e antigens. Note that “c” and “e” are indeed antigens, unlike “d”. Alleles of the RHCE gene include RHCE, RHcE, RHCe, and RHce, with each coding for the respective C/c and E/e antigens. The C and c proteins (and likewise the E and e proteins) differ by just a handful of amino acids that extend outside of the RBC membrane, allowing the body to potentially recognize these as foreign antigens. Other, less common expressions of these antigens may occur from other point mutations or from gene recombinations between both genes since the loci of the two are in close proximity on chromosome 1. 1 SCIE 2040 – Transfusion Medicine 1 Textbook Chapter 5 The Rh proteins are nonglycosylated (unlike the ABO or MNS blood group antigens) meaning that no carbohydrates are attached to the protein. RhD and RhCE are multipass proteins, each passing through the membrane a dozen times. They play structural roles in the cell and act as ion channels. Text, Figure 5-1: Simple Schematic of the Rh and Rh-Associated Proteins A third protein RhAG (Rh associated glycoprotein), coded for by the RHAG gene on chromosome 6, is also required for proper Rh expression. RhAG is not part of the Rh system, but without the protein multiple defects in the red blood cell membrane occur. Individuals who lack all Rh antigens (Rhnull phenotype) suffer from hemolytic anemia. Amorphic-type Rhnull results from deletion of the RHD gene and a mutation of the RHCE gene. Regulator type Rhnull results from mutations in the RHAG gene. Relatives of a regulator-type Rhnull may express a milder form of Rh antigen depression known as Rhmod. 5.3 Rh System Nomenclature In 1986, Tippett postulated that Rh genetic expression was controlled by two closely linked genes. This theory was later confirmed and expanded through molecular analysis and identification of RHD and RHCE. However, prior to Tippett’s theory, two other mechanisms of Rh inheritance were proposed. While neither was correct, they gave rise to the Rh terminology still in use today. 5.3.1 Fisher-Race and Rosenfield Fisher and Race suggested that there were three sets of alleles within the Rh system (D/d, C/e, E/e) that they were so closely linked, all would be inherited 2 SCIE 2040 – Transfusion Medicine 1 Textbook Chapter 5 together without an opportunity for crossing over. The Rh phenotype in Fisher-Race terminology is expressed as the presence or absence of D, C, c, E and e antigens. In 1962, Rosenfield proposed a corresponding numerical model for the Rh blood group antigens by listing the antigens numerically in order of discovery: Antigen D C E c e Rosenfield # 1 2 3 4 5 A minus sign in front of the number indicated an individual tested negative for that antigen, while no minus sign indicates they tested positive. For example: Reaction with Corresponding Antisera Rosenfield Nomenclature D C E c e + + 0 0 + Rh: 1, 2, -3, -4, 5 5.3.2 Wiener Haplotypes Wiener postulated that individuals inherit Rh antigens as a product of a single gene at a single locus. However, this single gene coded for an agglutinogen composed of multiple antigens. The D antigen is referred to as Rh0(D) and he developed a shorthand description of Rh haplotypes. The haplotypes and the corresponding antigens are listed below in order from most to least frequently found amongst those of European ethnicity. Wiener: R1 r R2 R0 r’ r’’ Rz ry Fisher-Race: DCe dce DcE Dce dCe dcE DCE dCE Here is a helpful way to remember the corresponding antigens for a given haplotype: Big “R” corresponds to the D antigen. Little r means no D antigen (d). The subscript or superscript corresponds to C/c and E/e: Sub/superscript: 1 or ‘ 2 or “ Letter (z or y) 0 or no script Antigen: Ce cE CE ce 5.4 Most Probable Genotype Expanding on the previous table, below is each haplotype with its relative frequency among different ethnic backgrounds: Frequency (%) by Ethnicity R1 r R2 R0 r’ r’’ Rz ry DCe dce DcE Dce dCe dcE DCE dCE European 42 37 14 4 2 1