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The Rh blood group system is a
human blood group system
The term human blood group systems is defined by the International Society of Blood Transfusion (ISBT) as systems in the human species where cell-surface antigens—in particular, those on blood cells—are "controlled at a single gene locus or by ...
. It contains proteins on the surface of red blood cells. After the
ABO blood group system
The ABO blood group system is used to denote the presence of one, both, or neither of the A and B antigens on erythrocytes. For human blood transfusions, it is the most important of the 43 different blood type (or group) classification system ...
, it is the most likely to be involved in transfusion reactions. The Rh blood group system consists of 49 defined blood group
antigens, among which the five antigens D, C, c, E, and e are the most important. There is no d antigen. Rh(D) status of an individual is normally described with a ''positive'' (+) or ''negative'' (−) suffix after the
ABO
The ABO blood group system is used to denote the presence of one, both, or neither of the A and B antigens on erythrocytes. For human blood transfusions, it is the most important of the 43 different blood type (or group) classification system ...
type (e.g., someone who is A+ has the A antigen and Rh(D) antigen, whereas someone who is A− has the A antigen but lacks the Rh(D) antigen). The terms ''Rh factor'', ''Rh positive'', and ''Rh negative'' refer to the Rh(D) antigen only. Antibodies to Rh antigens can be involved in
hemolytic transfusion reactions and antibodies to the Rh(D) and Rh antigens confer significant risk of
hemolytic disease of the fetus and newborn
Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis foetalis, is an alloimmune condition that develops in a fetus at or around birth, when the IgG molecules (one of the five ...
.
Nomenclature
The Rh blood group system has two sets of nomenclatures: one developed by
Ronald Fisher
Sir Ronald Aylmer Fisher (17 February 1890 – 29 July 1962) was a British polymath who was active as a mathematician, statistician, biologist, geneticist, and academic. For his work in statistics, he has been described as "a genius who ...
and
R. R. Race
Robert Russell Race CBE FRS FRCP FRCPath MRCS (28 November 1907 – 15 April 1984) was a British medical doctor and human geneticist. He was Director of the Medical Research Council Blood Group Unit, of the Lister Institute of Preven ...
, the other by . 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
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
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 of the 2 copies of chromosome 1, each contributing to production of multiple antigens. In this theory, a gene R
1 is supposed to give rise to the "blood factors" Rh
0, rh′, and rh″ (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 are partially correct: 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 proved to be correct. On the other hand, Wiener's theory that there is only one gene has proved to be incorrect, as has the Fisher–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.
Antigens
The proteins which carry the Rh antigens are
transmembrane protein
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequent ...
s, whose structure suggest that they are
ion channels. 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 blood cells drawing](https://upload.wikimedia.org/wikipedia/commons/3/32/Rh_blood_cells_drawing.svg)
Rh
phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological pr ...
s are readily identified through 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 upon the statistical distributions of genotypes in the patient's place of origin.
R
0 (cDe or Dce) is today most common in Africa. The allele was thus often assumed in early blood group analyses to have been typical of populations on the continent; particularly in areas below the Sahara. Ottensooser et al. (1963) suggested that high R
0 frequencies were likely characteristic of the ancient
Judea
Judea or Judaea ( or ; from he, יהודה, Standard ''Yəhūda'', Tiberian ''Yehūḏā''; el, Ἰουδαία, ; la, Iūdaea) is an ancient, historic, Biblical Hebrew, contemporaneous Latin, and the modern-day name of the mountainous sou ...
Jews, who had emigrated from
Egypt
Egypt ( ar, مصر , ), officially the Arab Republic of Egypt, is a transcontinental country spanning the northeast corner of Africa and southwest corner of Asia via a land bridge formed by the Sinai Peninsula. It is bordered by the Medit ...
prior to their dispersal throughout the
Mediterranean Basin and Europe on the basis of high R
0 percentages among
Sephardi
Sephardic (or Sephardi) Jews (, ; lad, Djudíos Sefardíes), also ''Sepharadim'' , Modern Hebrew: ''Sfaradim'', Tiberian: Səp̄āraddîm, also , ''Ye'hude Sepharad'', lit. "The Jews of Spain", es, Judíos sefardíes (or ), pt, Judeus sefa ...
and
Ashkenazi Jews
Jews ( he, יְהוּדִים, , ) or Jewish people are an ethnoreligious group and nation originating from the Israelites Israelite origins and kingdom: "The first act in the long drama of Jewish history is the age of the Israelites""The ...
compared to native
Europe
Europe is a large peninsula conventionally considered a continent in its own right because of its great physical size and the weight of its history and traditions. Europe is also considered a subcontinent of Eurasia and it is located entirel ...
an populations and the relative genetic isolation of Ashkenazim. However, more recent studies have found R
0 frequencies as low as 24.3% among some
Afroasiatic
The Afroasiatic languages (or Afro-Asiatic), also known as Hamito-Semitic, or Semito-Hamitic, and sometimes also as Afrasian, Erythraean or Lisramic, are a language family of about 300 languages that are spoken predominantly in the geographic su ...
-speaking groups in the Horn of Africa, as well as higher R
0 frequencies among certain other Afroasiatic speakers in
North Africa
North Africa, or Northern Africa is a region encompassing the northern portion of the African continent. There is no singularly accepted scope for the region, and it is sometimes defined as stretching from the Atlantic shores of Mauritania in ...
(37.3%) and among some
Palestinians in the
Levant
The Levant () is an approximate historical geographical term referring to a large area in the Eastern Mediterranean region of Western Asia. In its narrowest sense, which is in use today in archaeology and other cultural contexts, it is ...
(30.4%). On the contrary, at a frequency of 47.2% of the population of Basque country having the lack of the D antigen, these people display the highest frequency of the Rh negative phenotype.
• Figures taken from a study performed in 1948 on a sample of 2000 people in the United Kingdom.
Rh antibodies
Rh antibodies are
Immunoglobulin G (IgG) antibodies which are acquired through exposure to Rh-positive blood (generally either through pregnancy or transfusion of blood products). The D antigen is the most immunogenic of all the non-ABO antigens. Approximately 80% of individuals who are D-negative and exposed to a single D-positive unit will produce an anti-D antibody. The percentage of alloimmunization is significantly reduced in patients who are actively
exsanguinating.
All Rh antibodies ''except'' D display dosage (antibody reacts more strongly with red cells homozygous for an antigen than cells heterozygous for the antigen (EE stronger reaction vs Ee).
If anti-E is detected, the presence of anti-c should be strongly suspected (due to combined genetic inheritance). It is therefore common to select c-negative and E-negative blood for transfusion patients who have an anti-E and lack the c antigen (in general, a patient will not produce antibodies against their own antigens). Anti-c is a common cause of delayed hemolytic transfusion reactions.
Hemolytic disease of the newborn
The hemolytic condition occurs when there is an incompatibility between the blood types of the mother and fetus. There is also potential incompatibility if the mother is Rh negative and the father is positive. When any incompatibility is detected, the mother often receives an injection at 28 weeks gestation and at birth to avoid the development of antibodies towards 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: "''hema''" (blood) and "''lysis''" (solution) 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 or Rh disease. Here, sensitization to Rh D antigens (usually by feto-maternal transfusion during pregnancy) may lead to the production of maternal
IgG
Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG ...
anti-D antibodies which can pass through the
placenta
The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...
. This is of particular importance to D negative females at or below childbearing age, because any subsequent pregnancy may be affected by the
Rh D hemolytic disease of the newborn
Rh disease (also known as rhesus isoimmunization, Rh (D) disease, and blue baby disease) is a type of hemolytic disease of the fetus and newborn (HDFN). HDFN due to anti-D antibodies is the proper and currently used name for this disease as the ...
if the baby is D positive. The vast majority of
Rh disease
Rh disease (also known as rhesus isoimmunization, Rh (D) disease, and blue baby disease) is a type of hemolytic disease of the fetus and newborn (HDFN). HDFN due to anti-D antibodies is the proper and currently used name for this disease as the ...
is preventable in modern
antenatal
Prenatal development () includes the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal devel ...
care by injections of IgG anti-D antibodies (
Rho(D) Immune Globulin
Rho(D) immune globulin (RhIG) is a medication used to prevent RhD isoimmunization in mothers who are RhD negative and to treat idiopathic thrombocytopenic purpura (ITP) in people who are Rh positive. It is often given both during and followin ...
). The incidence of Rh disease is mathematically related to the frequency of D negative individuals in a population, so Rh disease is rare in old-stock populations of Africa and the eastern half of Asia, and the Indigenous peoples of Oceania and the Americas, but more common in other genetic groups, most especially Western Europeans, but also other West Eurasians, and to a lesser degree, native Siberians, as well as those of mixed-race with a significant or dominant descent from those (e.g. the vast majority of Latin Americans and Central Asians).
* 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
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...
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 (difficulty breathing)
Other animals with Rh-like antigens causing hemolytic disease of the newborn
Rh disease only occurs in human fetuses however a similar disease called Neonatal isoerythrolysis (NI) can be observed in animal species of newborn horses, mules, pigs, cats, cattle, and dogs. What differs between Rh disease and NI is the pathogenesis of hemolysis between human fetuses and the animal species. With human mothers, the maternal antibodies are formed from the sensitization of foreign antigens of her unborn fetus’s red blood cells passing through the placenta causing hemolysis before birth, with other animals however, these maternal antibodies are not passed through the placenta but through colostrum. The newborn animal is without NI but soon develops hemolytic anemia after initial ingestion of its mother’s colostrum that contain antibodies that can be absorbed through the newborn’s intestines and are incompatible to its red blood cell antigen. After 48 hours of birth, the newborn may be allowed to nurse from its mother as her antibodies can no longer be absorbed through the neonate’s intestines. Because the most active newborn animals consume the most colostrum, they may be the ones who are most affected by the blood incompatibility of antigen and antibody.
Rh proteins outside of human species
Rh molecules can be found in many different living organisms from worms, bacteria, algae, and other vertebrates. These Rh molecules from different animals have the same biochemical function-differing slightly in their amino acid sequences. The Rh proteins in other species, however, do not correspond with the Rh blood group or antigens found on human red blood cells. One such example would be the nematode ''Caenorhabditis elegans''. Because this worm does not have red blood cells, it cannot have Rh antigens, excluding it from having a Rh blood type. These Rh proteins therefore do not bind to red blood cells; they operate independently. Instead of transporting CO2 from the proteins of human red blood cells, ''C. elegan’s'' Rh proteins transport NH3 out of its body.
Population data
According to a comprehensive study, the worldwide frequency of Rh-positive and Rh-negative blood types is approximately 94% and 6%, respectively. The same study concluded that the share of the population with Rh-negative blood type is set to fall further in the future primarily due to low population growth in
Europe
Europe is a large peninsula conventionally considered a continent in its own right because of its great physical size and the weight of its history and traditions. Europe is also considered a subcontinent of Eurasia and it is located entirel ...
. The frequency of Rh factor blood types and the RhD neg
allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
gene differs in various populations.
Genetics
![Rh blood inheritance](https://upload.wikimedia.org/wikipedia/commons/a/ab/Rh_blood_inheritance.svg)
The D antigen is inherited as one gene (
RHD) (on the short arm of the
first chromosome, p36.13–p34.3) with various alleles. Typically, Rhesus positive people have an intact RHD gene while negative people lack the gene (or have mutations in it). However, there are exceptions: for instance, Japanese and black Africans may have an intact gene that is not expressed or only at very low levels. The gene codes for the RhD
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
on the red blood cell membrane. D− individuals who lack a functional ''RHD'' gene do not produce the D antigen, and may be immunized by D+ blood.
The D antigen is a dominant trait. If both of a child's parents are ''Rh negative,'' the child will definitely be ''Rh negative''. Otherwise the child may be ''Rh positive'' or ''Rh negative,'' depending on the parents' specific genotypes.
The
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 epitope is the specific piece of the antigen to which an antibody binds. The p ...
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, also found on chromosome 1. It has been shown that the ''RHD'' gene arose by duplication of the ''RHCE'' gene during primate evolution. Mice have just one RH gene.
The RHAG gene, which is responsible for encoding Rh-associated glycoprotein (RhAG), is found on chromosome 6a.
The polypeptides produced from the RHD and RHCE genes form a complex on the red blood cell membrane with the Rh-associated glycoprotein.
[Mais, DD. ASCP Quick Compendium of Clinical Pathology, 2nd Ed. Chicago, ASCP Press, 2009.]
Function
On the basis of structural homology it has been proposed that the product of RHD gene, the RhD protein, is a
membrane transport protein
A membrane transport protein (or simply transporter) is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral transmembra ...
of uncertain specificity (CO
2 or NH
3) and unknown physiological role. The three-dimensional structure of the related
RHCG
Rh family, C glycoprotein, also known as RHCG, is a protein that 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; indicate ...
protein and biochemical analysis of the RhD protein complex indicates that the RhD protein is one of three subunits of an
ammonia transporter
Ammonia transportersTC# 1.A.11 are structurally related membrane transport proteins called Amt proteins (ammonia transporters) in bacteria and plants, methylammonium/ammonium permeases (MEPs) in yeast, or Rhesus (Rh) proteins in chordates. In huma ...
. Three recent studies
have reported a protective effect of the RhD-positive phenotype, especially RhD
heterozygosity
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
, against the negative effect of latent
toxoplasmosis
Toxoplasmosis is a parasitic disease caused by '' Toxoplasma gondii'', an apicomplexan. Infections with toxoplasmosis are associated with a variety of neuropsychiatric and behavioral conditions. Occasionally, people may have a few weeks or mont ...
on psychomotor performance in infected subjects. RhD-negative compared to RhD-positive subjects without
anamnestic titres of anti-''
Toxoplasma
''Toxoplasma gondii'' () is an obligate intracellular parasitic protozoan (specifically an apicomplexan) that causes toxoplasmosis. Found worldwide, ''T. gondii'' is capable of infecting virtually all warm-blooded animals, but felids, such as d ...
'' 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
homozygote
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
s decreased with duration of the infection while the performance of RhD-negative homozygotes decreased immediately after the infection. The overall change in reaction times was always larger in the RhD-negative group than in the RhD-positive.
RHD polymorphism
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.
Natural selection aside, the RHD-RHCE region is structurally predisposed to many mutations seen in humans, since the pair arose by gene duplication and remain similar enough for
unequal crossing over
Unequal crossing over is a type of gene duplication or deletion event that deletes a sequence in one strand and replaces it with a duplication from its sister chromatid in mitosis or from its homologous chromosome during meiosis. It is a type of ...
to occur.
[ In addition to the case where D is deleted, crossover can also produce a single gene mixing exons from both ''RHD'' and ''RHCE'', forming the majority of partial D types.]
Weak D
In serologic testing, D positive blood is easily identified. Units that 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 37 °C 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, 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.
Partial D
It is important to differentiate weak D (due to a ''quantitative'' difference in the D antigen) from partial D (due to a ''qualitative'' difference in the D antigen). Simply put, the weak D phenotype is due to a reduced number of D antigens on a red blood cell. In contrast, the partial D phenotype is due to an alteration in D-epitopes. Thus, in partial D, the number of D antigens is not reduced but the protein structure is altered. These individuals, if alloimmunized to D, can produce an anti-D antibody. Therefore, partial D patients who are donating blood should be labeled as D-positive but, if receiving blood, they should be labeled as D-negative and receive D-negative units.
In the past, partial D was called 'D mosaic' or 'D variant.' Different partial D phenotypes are defined by different D epitopes on the outer surface of the red blood cell membrane. More than 30 different partial D phenotypes have been described.
Rhnull phenotype
Rhnull individuals have no Rh antigens (no Rh or RhAG) on their red blood cells. This rare condition has been called "Golden Blood". As a consequence of Rh antigen absence, Rhnull red blood cells also lack LW and Fy5 and show weak expression of S, s, and U antigens.
Red blood cells lacking Rh/RhAG proteins have structural abnormalities (such as stomatocytosis
Hereditary stomatocytosis describes a number of inherited, mostly autosomal dominant human conditions which affect the red blood cell and create the appearance of a slit-like area of central pallor (stomatocyte) among erythrocytes on peripheral b ...
) and cell membrane defects that can result in hemolytic anemia
Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). This most commonly ...
.
Only 43 individuals have been reported to have it worldwide. Only nine active donors have been reported. Its properties make it attractive in numerous medical applications, but scarcity makes it expensive to transport and acquire.
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 (CEVF or RH61 according to the ISBT 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.
Some of the other Rh "antigens" are f ("ce", RH6), Ce (RH7), Cw (RH8), Cx (RH9), V (RH10), Ew (RH11), G (RH12), Tar (RH40), VS (RH20), Dw (RH23), and CE (RH22). Some of these groups, including f, Ce and CE, describe grouping of some existing groups. Others, like V, describe an 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 epitope is the specific piece of the antigen to which an antibody binds. The p ...
created by some other mutation on the ''RHD'' and ''RHCE'' genes. V in particular is caused by a mutation on ''RHCE''.
History
The term "Rh" was originally an abbreviation of "Rhesus factor". It was discovered in 1937 by Karl Landsteiner
Karl Landsteiner (; 14 June 1868 – 26 June 1943) was an Austrian-born American biologist, physician, and immunologist. He distinguished the main blood groups in 1900, having developed the modern system of classification of blood groups from ...
and Alexander S. Wiener, who, at the time, believed it to be a similar antigen found in rhesus macaque
The rhesus macaque (''Macaca mulatta''), colloquially rhesus monkey, is a species of Old World monkey. There are between six and nine recognised subspecies that are split between two groups, the Chinese-derived and the Indian-derived. Generally ...
red blood cells. It was subsequently discovered that the human factor is not identical to the rhesus monkey factor, but by then, "Rhesus Group" and like terms were already in widespread, worldwide use. Thus, notwithstanding it is a misnomer, the term survives (e.g., ''rhesus blood group system'' and the obsolete terms ''rhesus factor'', '' rhesus positive'', and ''rhesus negative'' – all three of which actually refer specifically and ''only'' to the Rh D factor and are thus misleading when unmodified). Contemporary practice is to use "Rh" as a term of art instead of "Rhesus" (e.g., "Rh Group", "Rh factors", "Rh D", etc.).
The significance of their discovery was not immediately apparent and was only realized in 1940, after subsequent findings by Philip Levine and Rufus Stetson. The serum that led to the discovery was produced by immunizing rabbits with red blood cells from a rhesus macaque
The rhesus macaque (''Macaca mulatta''), colloquially rhesus monkey, is a species of Old World monkey. There are between six and nine recognised subspecies that are split between two groups, the Chinese-derived and the Indian-derived. Generally ...
. 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.
In 1939, Phillip Levine and Rufus Stetson published in a first case report the clinical consequences of non-recognized ''Rh factor'', hemolytic transfusion reaction
Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but mod ...
, and hemolytic disease of the newborn
Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis foetalis, is an alloimmune condition that develops in a fetus at or around birth, when the IgG molecules (one of the five ...
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
The ABO blood group system is used to denote the presence of one, both, or neither of the A and B antigens on erythrocytes. For human blood transfusions, it is the most important of the 43 different blood type (or group) classification system ...
were matched. No name was given to this agglutinin
An agglutinin is a substance in the blood that causes particles to coagulate and aggregate; that is, to change from fluid-like state to a thickened-mass (solid) state.
Agglutinins can be antibodies that cause antigens to aggregate by binding t ...
when described. In 1940, Karl Landsteiner
Karl Landsteiner (; 14 June 1868 – 26 June 1943) was an Austrian-born American biologist, physician, and immunologist. He distinguished the main blood groups in 1900, having developed the modern system of classification of blood groups from ...
and Alexander S. Wiener made the connection to their earlier discovery, reporting a serum that also reacted with about 85% of different human red blood cells.
In 1941, Group O: a patient of Dr. Paul in Irvington, NJ, delivered a normal infant in 1931; this pregnancy was followed by a long period of sterility. The second pregnancy (April, 1941) resulted in an infant with icterus gravis. In May 1941, the third anti-Rh serum (M.S.) of Group O became available.
Based on the serologic similarities, '' Rh factor'' was later also used for antigens, and ''anti-Rh'' for antibodies, found in humans such as those 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
The rhesus macaque (''Macaca mulatta''), colloquially rhesus monkey, is a species of Old World monkey. There are between six and nine recognised subspecies that are split between two groups, the Chinese-derived and the Indian-derived. Generally ...
was classified in the Landsteiner-Weiner antigen system (antigen LW, antibody anti-LW) in honor of 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.
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), hemolytic disease of the newborn (including exchange transfusion), and very importantly the prevention of it by screening and prophylaxis
Preventive healthcare, or prophylaxis, consists of measures taken for the purposes of disease prevention.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental hea ...
.
The discovery of fetal cell-free DNA in maternal circulation by Holzgrieve et al. led to the noninvasive genotyping of fetal Rh genes in many countries.
References
External links
Rh
at BGMUT Blood Group Antigen Gene Mutation Database at NCBI
The National Center for Biotechnology Information (NCBI) is part of the United States National Library of Medicine (NLM), a branch of the National Institutes of Health (NIH). It is approved and funded by the government of the United States. The ...
, NIH
The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...
{{transfusion medicine
Blood
Blood antigen systems
Transfusion medicine