Rh blood group system
Encyclopedia
The Rh blood group system (including the Rh factor) is one of thirty current human blood group systems
. Clinically, it is the most important blood group system after ABO
. At Present, the Rh blood group system consists of 50 defined blood-group antigens, among which the 5 antigens D, C, c, E, and e are the most important. The commonly-used terms Rh factor, Rh positive and Rh negative refer to the D antigen only. Besides its role in blood transfusion
, the Rh blood group system, the D antigen, in particular, is a relevant cause of the hemolytic disease of the newborn
or erythroblastosis fetalis for which prevention is key.
s. 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.
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. 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. 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."
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 to the discoverers.
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 (see below).
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 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).
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. There are in fact two linked genes (RHCE
and RHD
), one with multiple specificities and one with a single specificity. 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.
s, whose structure suggest that they are ion channel
s. 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) and the RHCE gene which encodes the RhCE protein with the C, E, c and e antigens (and variants). 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.
† Figures taken from a study performed in 1948 on a sample of 2000 people in the United Kingdom. Note that the R0 haplotype is much more common in people of sub-Saharan African origin.
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
.
gene differs in various populations.
) (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 epitope
s 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.
protein and biochemical analysis of the RhD protein complex indicates that the RhD protein is one of three subunits of an ammonia transporter
. Three recent studies 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.
) in Europe was very low before the advent of the domestic cat.
The practical implication of this is that people with this sub-phenotype will have a product labeled as "D positive" when donating blood. When receiving blood, they are sometimes typed as a "D negative", though this is the subject of some debate. Most "Weak D" patients can receive "D positive" blood without complications. However, it is important to correctly identify the ones that have to be considered D+ or D-. This is important, since most blood banks have a limited supply of "D negative" blood and the correct transfusion is clinically relevant. In this respect, genotyping of blood groups has much simplified this detection of the various variants in the Rh blood group system.
terminology) is not an accurate reflection of the antigens encountered since many (e.g. Rh38) have been combined, reassigned to other groups, or otherwise removed.
Human blood group systems
The International Society of Blood Transfusion currently recognises 30 major blood group systems . Thus, in addition to the ABO antigens and Rhesus antigens, many other antigens are expressed on the red blood cell surface membrane...
. Clinically, it is the most important blood group system after ABO
ABO blood group system
The ABO blood group system is the most important blood type system in human blood transfusion. The associated anti-A antibodies and anti-B antibodies are usually IgM antibodies, which are usually produced in the first years of life by sensitization to environmental substances such as food,...
. At Present, the Rh blood group system consists of 50 defined blood-group antigens, among which the 5 antigens D, C, c, E, and e are the most important. The commonly-used terms Rh factor, Rh positive and Rh negative refer to the D antigen only. Besides its role in blood transfusion
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
, the Rh blood group system, the D antigen, in particular, is a relevant cause of the hemolytic disease of the newborn
Hemolytic disease of the newborn
Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis fetalis, is an alloimmune condition that develops in a fetus, when the IgG molecules produced by the mother pass through the placenta...
or erythroblastosis fetalis for which prevention is key.
Rh factor
An individual either has, or does not have, the "Rhesus factor" on the surface of their red blood cellRed blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
s. 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
ABO blood group system
The ABO blood group system is the most important blood type system in human blood transfusion. The associated anti-A antibodies and anti-B antibodies are usually IgM antibodies, which are usually produced in the first years of life by sensitization to environmental substances such as food,...
blood type
Blood type
A blood type is a classification of blood based on the presence or absence of inherited antigenic substances on the surface of red blood cells . These antigens may be proteins, carbohydrates, glycoproteins, or glycolipids, depending on the blood group system...
. 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
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
or placental exposure during pregnancy.
History of discoveries
In 1939, Drs. Philip LevinePhilip Levine (physician)
Philip Levine was an imuno-hematologist whose clinical research advanced knowledge on the Rhesus factor, Hemolytic disease of the newborn and blood transfusion.-Life and career :...
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
Hemolytic disease of the newborn
Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis fetalis, is an alloimmune condition that develops in a fetus, when the IgG molecules produced by the mother pass through the placenta...
in its most severe form. It was recognized that the serum of the reported woman agglutinated
Agglutination (biology)
Agglutination is the clumping of particles. The word agglutination comes from the Latin agglutinare, meaning "to glue."This occurs in biology in three main examples:...
with red blood cells of about 80% of the people although the then known blood groups, in particular ABO
ABO blood group system
The ABO blood group system is the most important blood type system in human blood transfusion. The associated anti-A antibodies and anti-B antibodies are usually IgM antibodies, which are usually produced in the first years of life by sensitization to environmental substances such as food,...
were matched. No name was given to this then for the first time described agglutinin
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
. In 1940, Drs. Karl Landsteiner
Karl Landsteiner
Karl Landsteiner , was an Austrian-born American biologist and physician of Jewish origin. He is noted for having first distinguished the main blood groups in 1900, having developed the modern system of classification of blood groups from his identification of the presence of agglutinins in the...
and Alexander S. Wiener
Alexander S. Wiener
Alexander Solomon Wiener , a lifelong resident of New York City, was recognized internationally for his contributions to medicine. He was an outstanding leader in the fields of forensic medicine, serology, and immunogenetics. His pioneer work led to discovery of the Rh factor in 1937, along with Dr...
reported a serum that also reacted with about 85% of different human red blood cells. This serum was produced by immunizing rabbits with red blood cells from Rhesus macaque
Rhesus Macaque
The Rhesus macaque , also called the Rhesus monkey, is one of the best-known species of Old World monkeys. It is listed as Least Concern in the IUCN Red List of Threatened Species in view of its wide distribution, presumed large population, and its tolerance of a broad range of habitats...
. 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."
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
Rhesus Macaque
The Rhesus macaque , also called the Rhesus monkey, is one of the best-known species of Old World monkeys. It is listed as Least Concern in the IUCN Red List of Threatened Species in view of its wide distribution, presumed large population, and its tolerance of a broad range of habitats...
was classified in the Landsteiner-Wiener antigen system (antigen LW, antibody anti-LW) in honor to the discoverers.
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 (see below).
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
Exchange transfusion
An exchange transfusion is a medical treatment in which apheresis is used to remove one person's red blood cells or platelets and replace them with transfused blood products...
and very importantly the prevention of it by screening and prophylaxis.
Rh nomenclature
The Rh blood group system has two sets of nomenclatures: one developed by Fisher and 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 separate gene 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).
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. There are in fact two linked genes (RHCE
RHCE (gene)
Blood group Rh polypeptide is a protein that in humans is encoded by the RHCE gene. RHCE has also recently been designated CD240CE ....
and RHD
RHD (gene)
Rh blood group, D antigen also known as Rh polypeptide 1 or cluster of differentiaion 240D is a protein that in humans is encoded by the RHD gene....
), one with multiple specificities and one with a single specificity. 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.
Rh system antigens
The proteins which carry the Rh antigens are transmembrane proteinTransmembrane protein
A transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as...
s, whose structure suggest that they are ion channel
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
s. 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) and the RHCE gene which encodes the RhCE protein with the C, E, c and e antigens (and variants). 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.
| 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. Note that the R0 haplotype is much more common in people of sub-Saharan African origin.
| Rh Phenotype | CDE | Patients (%) | Donors (%) |
|---|---|---|---|
| Rr | CcDe | 37.4 | 33.0 |
| RR | CcDEe | 35.7 | 30.5 |
| RR | CDe | 5.7 | 21.8 |
| rr | ce | 10.3 | 11.6 |
| Rr | cDEe | 6.6 | 10.4 |
| RR | cDe | 2.8 | 2.7 |
| RR | cDE | 2.8 | 2.4 |
| rr’’ | cEe | – | 0.98 |
| RR | CDE | – | 0.03 |
| rr’ | Cce | 0.8 | – |
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
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
. 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
Rh disease
Rh disease is one of the causes of hemolytic disease of the newborn...
is preventable in modern antenatal care by injections of IgG anti-D antibodies (Rho(D) Immune Globulin
Rho(D) Immune Globulin
Rho Immune Globulin is a medicine given by intramuscular injection that is used to prevent the immunological condition known as Rhesus disease...
). 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
Caucasian race
The term Caucasian race has been used to denote the general physical type of some or all of the populations of Europe, North Africa, the Horn of Africa, Western Asia , Central Asia and South Asia...
.
- 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:
- AnemiaAnemiaAnemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
that creates the newborn's pallor (pale appearance). - JaundiceJaundiceJaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
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 bilirubinBilirubinBilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...
(one of the end products of red blood cell destruction). - Enlargement of the newborn's liver and spleen.
- The newborn may have severe edemaEdemaEdema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
of the entire body. - Dyspnea or difficulty breathing.
- Anemia
Population data
The frequency of Rh factor blood types and the RhD neg alleleAllele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
gene differs in various populations.
| Population | Rh(D) Neg | Rh(D) Pos | Rh(D) Neg alleles |
|---|---|---|---|
| Basque people Basque people The Basques as an ethnic group, primarily inhabit an area traditionally known as the Basque Country , a region that is located around the western end of the Pyrenees on the coast of the Bay of Biscay and straddles parts of north-central Spain and south-western France.The Basques are known in the... |
21–36% | 65% | approx 60% |
| other Europeans | 16% | 84% | 40% |
| African American African American African Americans are citizens or residents of the United States who have at least partial ancestry from any of the native populations of Sub-Saharan Africa and are the direct descendants of enslaved Africans within the boundaries of the present United States... |
approx 7% | 93% | approx 26% |
| Native Americans Native Americans in the United States Native Americans in the United States are the indigenous peoples in North America within the boundaries of the present-day continental United States, parts of Alaska, and the island state of Hawaii. They are composed of numerous, distinct tribes, states, and ethnic groups, many of which survive as... |
approx 1% | 99% | approx 10% |
| African descent | less 1% | over 99% | 3% |
| Asian | less 1% | over 99% | 1% |
Inheritance
The D antigen is inherited as one gene (RHDRHD (gene)
Rh blood group, D antigen also known as Rh polypeptide 1 or cluster of differentiaion 240D is a protein that in humans is encoded by the RHD gene....
) (on the short arm of the first chromosome
Chromosome 1 (human)
Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 247 million nucleotide base pairs, which are the basic units of information for DNA...
, 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
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
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 epitope
Epitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope...
s 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.
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. The three dimensional structure of the related RHCGRHCG
Rh family, C glycoprotein, also known as RHCG, is a protein which in humans is encoded by the RHCG gene.- Function :RHCG plays a critical role in ammonium handling and pH homeostasis in the kidney. The structure of the RHCG protein indicates that it has a hydrophobic ammonia-conducting channel thus...
protein and biochemical analysis of the RhD protein complex indicates that the RhD protein is one of three subunits of an ammonia transporter
Ammonia transporter
Ammonia transporters are structurally related membrane transport proteins called Amt proteins , methylammonium/ammonium permeases or RhAG, RhBG, and RhCG Rh family members in mammals. The RhAG, RhBG and RhCG proteins constitute solute carrier family 42...
. Three recent studies have reported a protective effect of the RhD-positive phenotype, especially RhD heterozygosity, against the negative effect of latent toxoplasmosis
Toxoplasmosis
Toxoplasmosis is a parasitic disease caused by the protozoan Toxoplasma gondii. The parasite infects most genera of warm-blooded animals, including humans, but the primary host is the felid family. Animals are infected by eating infected meat, by ingestion of feces of a cat that has itself...
on psychomotor performance in infected subjects. RhD-negative compared to RhD-positive subjects without anamnestic
Medical history
The medical history or anamnesis of a patient is information gained by a physician by asking specific questions, either of the patient or of other people who know the person and can give suitable information , with the aim of obtaining information useful in formulating a diagnosis and providing...
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.
Origin of RHD polymorphism
For a long time, the origin of RHD polymorphism was an evolutionary enigma . Before the advent of modern medicine, the carriers of the rarer allele (e.g. RhD-negative women in a population of RhD positives or RhD-positive men in a population of RhD negatives) were at a disadvantage as some of their children (RhD-positive children born to preimmunised RhD-negative mothers) were at a higher risk of fetal or newborn death or health impairment from hemolytic disease. It was suggested that higher tolerance of RhD-positive heterozygotes against Toxoplasma-induced impairment of reaction time and Toxoplasma-induced increase of risk of traffic accident could counterbalance the disadvantage of the rarer allele and could be responsible both for the initial spread of the RhD allele among the RhD-negative population and for a stable RhD polymorphism in most human populations. It was also suggested that differences in the prevalence of Toxoplasma infection between geographical regions (0–95%) could also explain the striking variation in the frequency of RhD-negative alleles between populations. According to some parasitologists it is possible that the better psychomotor performance of RhD-negative subjects in the Toxoplasma-free population could be the reason for spreading of the “d allele” (deletion) in the European population. In contrast to the situation in Africa and certain (but not all) regions of Asia, the abundance of wild cats (definitive hosts of Toxoplasma gondiiToxoplasma gondii
Toxoplasma gondii is a species of parasitic protozoa in the genus Toxoplasma. The definitive host of T. gondii is the cat, but the parasite can be carried by many warm-blooded animals . Toxoplasmosis, the disease of which T...
) in Europe was very low before the advent of the domestic cat.
Weak D
In serologic testing, D positive blood is easily identified. Units which are D negative are often retested to rule out a weaker reaction. This was previously referred to as Du, which has been replaced. By definition, weak D phenotype is characterized by negative reaction with anti-D reagent at immediate spin (IS), negative reaction after 37C incubation, and positive reaction at anti-human globulin (AHG) phase. Weak D phenotype can occur in several ways. In some cases, this phenotype occurs because of an altered surface protein that is more common in people of European descent. An inheritable form also occurs, most often in African-Americans, as a result of a weakened form of the R0 gene. Weak D may also occur as "C in trans," whereby a C gene is present on the opposite chromosome to a D gene (as in the combination R0r’, or "Dce/dCe"). The testing is difficult, since using different anti-D reagents, especially the older polyclonal reagents, may give different results.The practical implication of this is that people with this sub-phenotype will have a product labeled as "D positive" when donating blood. When receiving blood, they are sometimes typed as a "D negative", though this is the subject of some debate. Most "Weak D" patients can receive "D positive" blood without complications. However, it is important to correctly identify the ones that have to be considered D+ or D-. This is important, since most blood banks have a limited supply of "D negative" blood and the correct transfusion is clinically relevant. In this respect, genotyping of blood groups has much simplified this detection of the various variants in the Rh blood group system.
Other Rh group antigens
Currently, 50 antigens have been described in the Rh group system; among those described here, the D, C, c, E and e antigens are the most important. The others are much less frequently encountered or are rarely clinically significant. Each is given a number, though the highest assigned number (CEST or RH57 according to the ISBTInternational Society of Blood Transfusion
The International Society of Blood Transfusion , is a scientific society, founded in 1935, which aims to promote the study of blood transfusion, and to spread the know-how about the manner in which blood transfusion medicine and science best can serve the patient's interests. The society's central...
terminology) is not an accurate reflection of the antigens encountered since many (e.g. Rh38) have been combined, reassigned to other groups, or otherwise removed.
External links
- Rh at BGMUTBGMUTThe BGMUT Database documents allelic variations in the genes encoding for human blood group systems. It was set up in 1999 through an initiative of the Human Genome Variation Society . Since 2006, it has been a part of the dbRBC resource of NCBI at the NIH...
Blood Group Antigen Gene Mutation Database at NCBINational Center for Biotechnology InformationThe National Center for Biotechnology Information is part of the United States National Library of Medicine , a branch of the National Institutes of Health. The NCBI is located in Bethesda, Maryland and was founded in 1988 through legislation sponsored by Senator Claude Pepper...
, NIH - Article commemorating the first appearance of the Rh factor in the New York Times
- Rare Blood Types, A database and information on Rare Blood Types.
- Rhesus Negative Network, Educating the rh negative world about the rare blood types.