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History and Genetics of Rh Isoimmunization: From Discovery to Current Diagnostics, Exercises of Cancer Cytogenetics

An in-depth summary of the history and genetics of rh isoimmunization, including the discovery of the rh antigen, causes and clinical findings, genetic expression, and diagnostic modalities. It covers the competition among laboratory scientists, clinical scientists, and the pharmaceutical industry in understanding and addressing this condition.

Typology: Exercises

2011/2012

Uploaded on 08/01/2012

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super-malik 🇮🇳

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I
N SUMMARY
I
SO
-I
MMUNIZATION
I
SOIMMUNIZATION
H
istory Of Rh Isoimmunization
T
he Rh story is one of multiple foci of independent investigations
O
ccurring at differen
t
sites
D
ifferent times
H
igh level of competition that can develop
L
aboratory scientists
C
linical scientists
P
harmaceutical industry
O
rtho Pharmace utical Company
T
rade name RhoGAM, three decades ago
R
h Isoimmunization affected approximately 1 percen t of
t
he pregnancies in the U.S. at the
b
eginning of this century
C
linical findings
H
emolytic anemia
E
dema of the fetal tissues known as
h
ydrops
(
eryhtroblastosis)
f
etalis
A
utopsy evidence of proliferation of red blood cells in multiple sites
L
arge of number o
f
immature red cells
1
930s
-
recognized as one clinical entity were
H
ydrops fetalis
I
cterus gravis neonatorum
C
ongenital anemia
E
rythroblastosis fetalis
W
orld War II lead to discovery of antigenic blood fac tors, which might result in immunization
a
nd caus
e
transfusion reac tions.
Major contributors
A
lexander Wiener
P
hilip Levine,
K
arl Landsteiner
C
auses of fetal hydrops
L
ymphatic Abnormalities
L
ymphangiectasia
C
ystic hygroma
T
urner's syndrome (XO)
N
oonan's syndrome
M
ultiple ptergium syndrome
P
ulmona
r
y Malformations
L
ymphangiectasia
C
hylothorax
C
ystic adenomatoid malformation
H
ypoplasia
O
ther
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ISO-IMMUNIZATION

ISOIMMUNIZATION

History Of Rh Isoimmunization

• The Rh story is one of multiple foci of independent investigations

– Occurring at different sites

– Different times

• High level of competition that can develop

– Laboratory scientists

– Clinical scientists

– Pharmaceutical industry

Ortho Pharmaceutical Company

  • Trade name RhoGAM, three decades ago
  • Rh Isoimmunization affected approximately 1 percent of the pregnancies in the U.S. at the beginning of this century Clinical findings
    • Hemolytic anemia
    • Edema of the fetal tissues known as hydrops (eryhtroblastosis) fetalis
    • Autopsy evidence of proliferation of red blood cells in multiple sites
    • Large of number of immature red cells
  • 1 930s - recognized as one clinical entity were
    • Hydrops fetalis
    • Icterus gravis neonatorum
    • Congenital anemia
    • Erythroblastosis fetalis
  • World War II lead to discovery of antigenic blood factors, which might result in immunization and cause transfusion reactions.
  • Major contributors
    • Alexander Wiener
    • Philip Levine,
    • Karl Landsteiner Causes of fetal hydrops  Lymphatic Abnormalities
    • Lymphangiectasia
    • Cystic hygroma
    • Turner's syndrome (XO)
    • Noonan's syndrome
    • Multiple ptergium syndrome
    • Pulmonary Malformations
    • Lymphangiectasia
    • Chylothorax
    • Cystic adenomatoid malformation
    • Hypoplasia
    • Other

ISO-IMMUNIZATION

 Hematologic

  • Fetal hemolytic anemia
  • α-Thalassemia
  • Fetomaternal or twin-to-twin transfusion  Congenital Infections
  • Viruses
  • Cytomegalovirus
  • Parvovirus B
  • Toxoplasmosis
  • Syphilis
  • Chagas Disease  Cardiovascular
  • Arrhythmias
  • Cardiomyopathy
  • Structural anomalies: lesions that result in increased right atrial pressure and volume
  • primarily with atrioventricular regurgitation
  • left sided obstructive lesions
  • Ebstein's anomaly
  • Premature closure of the foramen ovale
  • Intracardiac tumors (tuberous sclerosis)
  • Vascular malformations
  • Chorangioma of the placenta, chorionic or umbilical vessels
  • Hemangiomas (Hepatic, Klippel-Trenaunaysyndrome)  Other Causes
  • Obstructive uropathy
  • Congenital nephrosis
  • Chromosomal abnormalities
  • Trisomy 15, 18, 21
  • XX/XY
  • Neoplasms
  • Storage diseases
  • Bone diseases
  • Placental abnormalities
  • Neurologic abnormalities
  • Idiopathic Genetics and Biochemistry of the Rh Antigen Nomenclature
  • 1940, Landsteiner and Wiener - rabbit immune sera to rhesus monkey erythrocytes
  • Agglutinated the majority (85 percent) of human erythrocytes
  • Named this the Rh factor.
  • Agglutinated cells were called Rh positive
  • Disease caused by antibody directed against an erythrocyte surface antigen of the rhesus blood group system.
  • High degree of polymorphism Five major antigens can be identified
  • Many variant antigens
  • Three Systems of Categorization
  • Fisher-Race
  • Wiener system
  • HLA-like system of Rosenfield

ISO-IMMUNIZATION

Variants of D Antigen

  • Unique Rh antibodies have been used to identify more than 30 antigenic variants
  • Two of the most common
  • CW^ antigen
  • Du^ antigen
  • Heterogeneous group of clinically important D antigen variants most often found in African Americans
  • Du^ - positive individuals - quantitative decrease in expression of the normal D antigen,
  • Some Du^ variants are significantly different antigenically
  • Two cellular expressions responsible for the Du^ phenotype
  • Reduction in the number of D antigen sites with all epitopes represented
  • Expression of only some of the various D antigen epitopes with some epitopes missing Du^ Variant
  • Du^ - positive erythrocytes - bind anti-D typing sera
  • In some cases only by sensitive indirect antiglobulin methods
  • At least some Du^ - positive patients are capable of producing anti-D, presumably by sensitization to missing D epitopes.
  • Could result in a Du^ - positive mother becoming sensitized to her D-positive fetus Genetic Expression
  • Genetic locus for the Rh antigen on the short arm of chromosome 1
  • Within the Rh locus are two distinct structural genes adjacent to one another,
  • RhCcEe and RhD.
  • Likely share a single genetic ancestor,
  • Identical in more than 95 percent of their coding sequences
  • First gene codes for the C/c and E/e antigens
  • Second gene codes for the D antigen
  • D-negative lack the RhD gene on both their chromosomes.
  • D-negative patients have a deletion of the D gene on both their chromosomes 1
  • Expression of the Rh antigen on the erythrocyte membrane o Genetically controlled o Structure of the antigen o Number of specific Rh-antigen sites (e.g., D, E, C, c, or e) o Relatively constant amount of Rh antigen sites available o About 100,000 sites per cell o Evenly divided between C(c), D, and E(e) antigens Allelic Interactions
  • CDe/cde express less D antigen than cDE/cde.
  • CDe/cDE express less C antigen than CDe/cde Structure and location of antigens
  • The Rh antigens - polypeptides
  • Embedded in the lipid phase of the erythrocyte membrane
  • Distributed throughout the membrane in a nonrandom fashion
  • D antigen sites - spaced in a lattice-like pattern
  • 9 2 nm in Rh(D) heterozygotes
  • 6 4 nm in homozygotes
  • Rh polypeptides are polymorphic
  • MW of the D antigen 31,900 d
  • C(c) and E(e) antigen MW 33,100 d Biochemistry & Immunology
  • Rh polypeptide lies within the phospholipid bilayer of the membrane

ISO-IMMUNIZATION

  • Spans the membrane 13 times
  • Short segments extending outside the red cell
  • Extrude into the cytoplasm
  • D antigen appears very early in embryonic life - 38-day-old fetus
  • Expressed early in the erythroid cell series – pronormoblasts
  • Seven different D antigen epitopes have been identified or deduced using human monoclonal anti-D antibodies, and others may exist. One hypothesis suggests that these different epitopes are part of the same protein-lipid complex more or less expressed according to the depth of polypeptide Clinical Issues
  • Anti-D antibody titer of greater than 1:4 - considered Rh sensitized
  • Consider possibility that the fetus might be Rh negative
  • Fathered by another partner
  • Mismatched blood transfusion
  • Determining the paternal Rh-antigen status is reasonable
  • DNA analysis can be used to determine his zygosity
  • Father homozygous - all his children will be Rh positive
  • Father heterozygous - 50 percent likelihood that each pregnancy will negative fetus
  • Cordocentesis with analysis of fetal red blood cells
  • Blood sampling for fetal Rh antigen status at 18 to 20
  • Increased risks of fetal loss and fetomaternal hemorrhage Current Technology
  • The Rh locus on chromosome 1p34-p36 has been cloned have an Rh-
  • Polymerase chain reaction (PCR)
  • Uncultured amniocytes
  • 2 ml of amniotic fluid
  • 5 mg of chorionic villi. Ultrasound and Doppler Studies
  • Sonographic findings that might predict the severity of Erythrob
  • Avoid the need for invasive assessments o Pre-hydropic changes o Polyhydramnios o Placental thickness o Pericardial effusion o Dilation of the cardiac chambers lastosis fetalis o Chronic enlargement of the spleen and liver o Visualization of both sides of the fetal bowel wall, o Dilation of the umbilical vein

Figure removed due to copyright restrictions.

[Liley curve]

ISO-IMMUNIZATION

ISO-IMMUNIZATION