Rh blood group system

                            Rh blood group system

• Rh factor

  An individual either has, or does not have, the "Rhesus factor" on the surface of their red blood cells. This term strictly refers only to the most immunogenic D antigen of the Rh blood group system, or the Rh- blood group system. The status is usually indicated by Rh positive (Rh+ does have the D antigen) or Rh negative (Rh- does not have the D antigen) suffix to the ABO blood type. However, other antigens of this blood group system are also clinically relevant. These antigens are listed separately (see below: Rh nomenclature). In contrast to the ABO blood group, immunization against Rh can generally only occur through blood transfusion or placental exposure during pregnancy in women.

  [edit]History of discoveries

  In 1939, Drs. Philip Levine and Rufus Stetson published in a first case report the clinical consequences of non-recognized Rh factor, hemolytic transfusion reaction and hemolytic disease of the newborn in its most severe form.^[1] It was recognized that the serum of the reported woman agglutinated with red blood cells of about 80% of the people although the then known blood groups, in particular ABO were matched. No name was given to this then for the first time described agglutinin. In 1940, Drs. Karl Landsteiner and Alexander S. Wiener reported a serum that also reacted with about 85% of different human red blood cells.^[2] This serum was produced by immunizing rabbits with red blood cells from Rhesus macaque. The antigen that induced this immunization was designated by them as Rh factor "to indicate that rhesus blood had been used for the production of the serum."^[3]
  Based on the serologic similarities Rh factor was later also used for antigens, and anti-Rh for antibodies, found in humans such as the previously described by Levine and Stetson. Although differences between these two sera were shown already in 1942 and clearly demonstrated in 1963, the already widely used term "Rh" was kept for the clinically described human antibodies which are different from the ones related to the Rhesus monkey. This real factor found in Rhesus macaque was classified in the Landsteiner-Wiener antigen system (antigen LW, antibody anti-LW) in honor of the discoverers.^[4][5] It was recognized that the Rh factor was just one in a system of various antigens. Based on different models of genetic inheritance, two different terminologies were developed; both of them are still in use
  The clinical significance of this highly immunizing D antigen (i.e. Rh factor) was soon realized. Some keystones were to recognize its importance for blood transfusion including reliable diagnostic tests, and hemolytic disease of the newborn including exchange transfusion and very importantly the prevention of it by screening and prophylaxis.
  The discovery of fetal free DNA in maternal circulation by Holzgrieve et al. led to the noninvasive genotyping of fetal Rh genes in many countries.

  [edit]Rh nomenclature

  The Rh blood group system has two sets of nomenclatures: one developed by Ronald Fisher and R.R. Race, the other by Wiener. Both systems reflected alternative theories of inheritance. The Fisher-Race system, which is more commonly in use today, uses the CDE nomenclature. This system was based on the theory that a separategene controls the product of each corresponding antigen (e.g., a "D gene" produces D antigen, and so on). However, the d gene was hypothetical, not actual.
  The Wiener system used the Rh-Hr nomenclature. This system was based on the theory that there was one gene at a single locus on each chromosome, each contributing to production of multiple antigens. In this theory, a gene R₁ is supposed to give rise to the “blood factors” Rh₀, rh’, and hr” (corresponding to modern nomenclature of the D, C and e antigens) and the gene r to produce hr’ and hr” (corresponding to modern nomenclature of the c and e antigens).^[6]
  Notations of the two theories are used interchangeably in blood banking (e.g., Rho(D) meaning RhD positive). Wiener's notation is more complex and cumbersome for routine use. Because it is simpler to explain, the Fisher-Race theory has become more widely used.
  DNA testing has shown that both theories are partially correct.^{[citation needed]} There are in fact two linked genes, the RHD gene which produces a single immune specificity (anti-D) and the RHCE gene with multiple specificities (anti-C, anti-c, anti-E, anti-e). Thus, Wiener's postulate that a gene could have multiple specificities (something many did not give credence to originally) has been proven correct. On the other hand, Wiener's theory that there is only one gene has proven incorrect, as has the Fischer-Race theory that there are three genes, rather than the 2. The CDE notation used in the Fisher-Race nomenclature is sometimes rearranged to DCE to more accurately represent the co-location of the C and E encoding on the RhCE gene, and to make interpretation easier.

  [edit]Rh system antigens

  The proteins which carry the Rh antigens are transmembrane proteins, whose structure suggest that they are ion channels.^[7] The main antigens are D, C, E, c and e, which are encoded by two adjacent gene loci, the RHD gene which encodes the RhD protein with the D antigen (and variants)^[8] and the RHCE gene which encodes the RhCE protein with the C, E, c and e antigens (and variants).^[9] There is no d antigen. Lowercase "d" indicates the absence of the D antigen (the gene is usually deleted or otherwise nonfunctional).
  Rh phenotypes are readily identified by identifying the presence or absence of the Rh surface antigens. As can be seen in the table below, most of the Rh phenotypes can be produced by several different Rh genotypes. The exact genotype of any individual can only be identified by DNA analysis. Regarding patient treatment, only the phenotype is usually of any clinical significance to ensure a patient is not exposed to an antigen they are likely to develop antibodies against. A probable genotype may be speculated on, based on the statistical distributions of genotypes in the patient's place of origin.

  Rh phenotypes and genotypes

  Phenotype expressed on cell	Genotype expressed in DNA		Prevalence (%) †
  	Fisher-Race notation	Wiener notation
  D+ C+ E+ c+ e+ (RhD+)	Dce/DCE	R0RZ	0.0125
  	Dce/dCE	R0rY	0.0003
  	DCe/DcE	R1R2	11.8648
  	DCe/dcE	R1r’’	0.9992
  	DcE/dCe	R2r’	0.2775
  	DCE/dce	RZr	0.1893
  D+ C+ E+ c+ e- (RhD+)	DcE/DCE	R2RZ	0.0687
  	DcE/dCE	R2rY	0.0014
  	DCE/dcE	RZr’’	0.0058
  D+ C+ E+ c- e+ (RhD+)	DCe/dCE	R1rY	0.0042
  	DCE/dCe	RZr’	0.0048
  	DCe/DCE	R1RZ	0.2048
  D+ C+ E+ c- e- (RhD+)	DCE/DCE	RZRZ	0.0006
  	DCE/dCE	RZrY	<0.0001
  D+ C+ E- c+ e+ (RhD+)	Dce/dCe	R0r’	0.0505
  	DCe/dce	R1r	32.6808
  	DCe/Dce	R1R0	2.1586
  D+ C+ E- c- e+ (RhD+)	DCe/DCe	R1R1	17.6803
  	DCe/dCe	R1r’	0.8270
  D+ C- E+ c+ e+ (RhD+)	DcE/Dce	R2R0	0.7243
  	Dce/dcE	R0r’’	0.0610
  	DcE/dce	R2r	10.9657
  D+ C- E+ c+ e- (RhD+)	DcE/DcE	R2R2	1.9906
  	DcE/dcE	R2r’’	0.3353
  D+ C- E- c+ e+ (RhD+)	Dce/Dce	R0R0	0.0659
  	Dce/dce	R0r	1.9950
  D- C+ E+ c+ e+ (RhD-)	dce/dCE	rrY	0.0039
  	dCe/dcE	r’r’’	0.0234
  D- C+ E+ c+ e- (RhD-)	dcE/dCE	r’’rY	0.0001
  D- C+ E+ c- e+ (RhD-)	dCe/dCE	r’rY	0.0001
  D- C+ E+ c- e- (RhD-)	dCE/dCE	rYrY	<0.0001
  D- C+ E- c+ e+ (RhD-)	dce/dCe	rr’	0.7644
  D- C+ E- c- e+ (RhD-)	dCe/dCe	r’r’	0.0097
  D- C- E+ c+ e+ (RhD-)	dce/dcE	rr’’	0.9235
  D- C- E+ c+ e- (RhD-)	dcE/dcE	r’’r’’	0.0141
  D- C- E- c+ e+ (RhD-)	dce/dce	rr	15.1020

  † Figures taken from a study performed in 1948 on a sample of 2000 people in the United Kingdom.^[10] Note that the R₀ haplotype is much more common in people of sub-Saharan African origin.

  Rh Phenotypes in Patients and Donors in Turkey^[11]

  Rh Phenotype	CDE	Patients (%)	Donors (%)
  R 1r	CcDe	37.4	33.0
  R 1R 2	CcDEe	35.7	30.5
  R 1R 1	CDe	5.7	21.8
  rr	ce	10.3	11.6
  R 2r	cDEe	6.6	10.4
  R 0R 0	cDe	2.8	2.7
  R 2R 2	cDE	2.8	2.4
  rr’’	cEe	–	0.98
  R ZR Z	CDE	–	0.03
  rr’	Cce	0.8	–

  [edit]Hemolytic disease of the newborn

  Main article: Hemolytic disease of the newborn
  The hemolytic condition occurs when there is an incompatibility between the blood types of the mother and the fetus. There is also potential incompatibility if the mother is Rh negative and the father is positive. When any incompatibility is detected, the mother receives an injection at 28 weeks gestation and at birth to avoid the development of antibodies toward the fetus. These terms do not indicate which specific antigen-antibody incompatibility is implicated. The disorder in the fetus due to Rh D incompatibility is known as erythroblastosis fetalis.

  • Hemolytic comes from two words: "hemo" (blood) and "lysis" (destruction) or breaking down of red blood cells
  • Erythroblastosis refers to the making of immature red blood cells
  • Fetalis refers to the fetus.

  When the condition is caused by the Rh D antigen-antibody incompatibility, it is called Rh D Hemolytic disease of the newborn (often called Rhesus disease or Rh disease for brevity). Here, sensitization to Rh D antigens (usually by feto-maternal transfusion during pregnancy) may lead to the production of maternal IgG anti-D antibodies which can pass through the placenta. This is of particular importance to D negative females at or below childbearing age, because any subsequent pregnancy may be affected by the Rhesus D hemolytic disease of the newborn if the baby is D positive. The vast majority of Rh disease is preventable in modern antenatal care by injections of IgG anti-D antibodies (Rho(D) Immune Globulin). The incidence of Rhesus disease is mathematically related to the frequency of D negative individuals in a population, so Rhesus disease is rare in East Asians, South Americans, and Africans, but more common in Caucasians.
  • Symptoms and signs in the fetus:
    • Enlarged liver, spleen, or heart and fluid buildup in the fetus' abdomen seen via ultrasound.
  • Symptoms and signs in the newborn:
    • Anemia that creates the newborn's pallor (pale appearance).
    • Jaundice or yellow discoloration of the newborn's skin, sclera or mucous membrane. This may be evident right after birth or after 24–48 hours after birth. This is caused by bilirubin (one of the end products of red blood cell destruction).
    • Enlargement of the newborn's liver and spleen.
    • The newborn may have severe edema of the entire body.
    • Dyspnea or difficulty breathing.

  [edit]Population data

  The frequency of Rh factor blood types and the RhD neg allele gene differs in various populations.

  Population data for the Rh D factor and the RhD neg allele^[12]

  Population	Rh(D) Neg	Rh(D) Pos	Rh(D) Neg alleles
  Basque people	21–36%[13]	65%	approx 60%
  other Europeans	16%	84%	40%
  African American	approx 7%	93%	approx 26%
  Native Americans	approx 1%	99%	approx 10%
  African descent	less 1%	over 99%	3%
  Asian	less 1%	over 99%	1%

  [edit]Inheritance

  The D antigen is inherited as one gene (RHD) (on the short arm of the first chromosome, p36.13-p34.3) with various alleles. Though very much simplified, one can think of alleles that are positive or negative for the D antigen. The gene codes for the RhD protein on the red cell membrane. D- individuals who lack a functional RHD gene do not produce the D antigen, and may be immunized by D+ blood.
  The epitopes for the next 4 most common Rh antigens, C, c, E and e are expressed on the highly similar RhCE protein that is genetically encoded in the RHCE gene. It has been shown that the RHD gene arose by duplication of the RHCE gene during primate evolution. Mice have just one RH gene.^[14]

  [edit]Function

  The structure homology data suggested that the product of RHD gene, the RhD protein, acts as an membrane transport protein of uncertain specificity (CO₂ or NH₃) and unknown physiological role.^[15][16] The three dimensional structure of the related RHCG protein and biochemical analysis of the RhD protein complex indicates that the RhD protein is one of three subunits of an ammonia transporter.^[17][18] Three recent studies^[19][20][21] have reported a protective effect of the RhD-positive phenotype, especially RhD heterozygosity, against the negative effect of latent toxoplasmosis on psychomotor performance in infected subjects. RhD-negative compared to RhD-positive subjects without anamnestic titres of anti-Toxoplasma antibodies have shorter reaction times in tests of simple reaction times. And conversely, RhD-negative subjects with anamnestic titres (i.e. with latent toxoplasmosis) exhibited much longer reaction times than their RhD-positive counterparts. The published data suggested that only the protection of RhD-positive heterozygotes was long term in nature; the protection of RhD-positive homozygotes decreased with duration of the infection while the performance of RhD-negative homozygotes decreased immediately after the infection.