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2346 Part XIII: Transfusion Medicine Chapter 136: Erythrocyte Antigens and Antibodies 2347

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RBC membrane in vivo, at the lower temperatures in the extremities, Within other systems, anti-Sd , anti-Vw, and anti-Wr are found
and activate the complement cascade in the core of the body. Because in up to 2 percent of normal people. Other, less-common antibody spec-
such IgM antibodies dissociate from RBCs at higher temperatures, their ificities in approximate order of descending occurrence are anti-M, -S,
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reactivity may be detected in routine antiglobulin tests (using polyspe- -N, -Ge, -K, -Lu , -Di , and -Xg . Rh antigens are thought to reside only
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cific antiglobulin) by virtue of the complement components that remain on RBCs, but apparent naturally occurring anti-D has been reported in
bound to the red cell membrane. 11,16 0.15 percent of Rh-negative donors and anti-E in more than 0.1 percent
of Rh-positive donors when more sensitive enzyme detection methods
Immunoglobulin A are used. Examples of naturally occurring anti-C, anti-C , and anti-C
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IgA is the primary Ig in body secretions, where it exists predominantly also have been described. 4–6
as a dimer with a secretory component (Chap. 75). IgA does not cross Some naturally occurring antibodies exist as autoagglutinins (e.g.,
the placenta or fix complement, but aggregated IgA can activate the anti-H and anti-I). Patients with autoimmune hemolytic anemia can
alternative pathway of complement, and IgA can trigger cell-mediated produce many antibodies to low-prevalence antigens with no specific
events. Multimeric IgA antibodies in serum are seen as hemagglutinins stimulus, in addition to autoantibody. 5,6,16,40
in blood bank tests and most often are associated with anti-A or anti-B.
Characteristics of Naturally Occurring Alloantibodies
Most naturally occurring antibodies are IgM, but some have an IgG
IMMUNOGLOBULIN IN THE FETUS AND component and a few are predominantly IgG. Some anti-A or anti-B
NEWBORN may even be of the IgA class. Antibodies that cause direct agglutination
Initially, the fetus acquires low levels of maternal IgG, probably by dif- of saline-suspended RBCs most commonly are of the IgM class. How-
fusion across the placenta. These levels rise significantly between 20 and ever, even IgG antibodies may cause agglutination of RBCs when they
33 weeks’ gestation as a selective transport system matures and maternal bind antigens that are present at high density on the RBC membrane,
IgG is actively transported across the placenta. Thus, almost all blood such as the ABO or MN antigens. With the exception of anti-A and
group antibodies detected in the fetus and newborn originate from the anti-B, most common naturally occurring antibodies do not react at
mother and disappear within the first few months of life. body temperature and are considered clinically insignificant. However,
Actual fetal antibody production begins shortly before birth with if they are found to react at 37°C, providing crossmatch-compatible
low levels of IgM, followed by IgG and IgA several weeks after birth. blood for transfusion is prudent.
Anti-A and anti-B usually are readily detected by age 2 to 6 months.
Because of this late immune response in the newborn and because ANTIBODIES GENERATED IN RESPONSE TO
maternal antibody is so predominant at birth, blood bank standards IMMUNIZATION: IMMUNE ANTIBODIES
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permit abbreviated testing on neonates younger than 4 months. If
available, the mother’s serum is used (and preferred) for identifying Blood Group Associations and Occurrence of Immune
antibodies in a newborn and for crossmatching RBC components. Antibodies
Immune antibodies are produced following exposure to foreign RBC
NATURALLY OCCURRING ANTIBODIES antigens through pregnancy or transfusion. The primary immune
response is seen several weeks to several months after the first exposure
Naturally Occurring Antibodies in Development to antigen. IgM usually is associated with early primary responses, but
An antibody is said to be naturally occurring when it is found in the whether it is always the first antibody class made is unclear. In most
serum of an individual who has not been exposed to the antigen through individuals, IgG soon predominates. This process is characteristic of a
transfusion or pregnancy. These antibodies most likely are heteroagglu- thymus-dependent immune response, where T cells help induce B cells
tinins produced in response to substances in the environment that are to undergo isotype switching from IgM to IgG.
similar to those on RBC antigens. In a secondary or anamnestic response, antibody concentration
Evidence supporting this concept has come from studies on the starts to increase several days to several weeks following exposure, and
formation of anti-B in chickens. Chicks raised in a normal environ- IgG may rise to very high levels. Some IgG antibodies remain detect-
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ment made anti-B within the first 30 days of life, whereas chicks raised able for decades after a stimulus. Others, especially Kidd antibodies, can
in a germ-free environment did not make anti-B by day 60. Naturally disappear after several months and are more commonly associated with
occurring anti-A and anti-B in humans, also called isoagglutinins, can delayed hemolytic transfusion reactions. 5,6,16
increase in titer following ingestion or inhalation of suitable bacteria. 58 Immune antibodies are found more commonly in individuals who
However, a great many antigens that likely are not present in the have been multiply transfused than in multiparous women. This situa-
environment have been associated with naturally occurring antibodies, tion occurs because in pregnancy the immunizing dose of red cells often
so the stimulus for naturally occurring antibodies is not clearly known. is too small to elicit a primary response and the foreign antigens are
limited to those of the father. 16
Blood Group Associations and Presence of Naturally Occurring Anti-D used to be the most common immune antibody, but with
Antibodies the advent of Rh matching of donors and recipients in the late 1940s
Naturally occurring alloantibodies are commonly associated with the and use of RhIg prophylaxis since the 1970s, its incidence has sharply
carbohydrate antigens of the ABO, LE, and P1PK blood group systems. decreased. Anti-D is present in 0.27 to 0.56 percent of transfusion recip-
Anti-A and anti-B are expected in people who lack the corresponding ients, 0.10 to 0.20 percent of pregnant women, and 0.16 to 0.25 percent
antigens, as are antibodies specific for H, PP1P , or P antigens. Naturally of healthy blood donors. 16
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occurring antibodies reactive with A1, Le , Le , or P1 determinants also In contrast, the occurrence of immune antibodies other than
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are seen frequently. Carbohydrate antigens, especially those with repet- anti-D has increased. Specificities other than anti-D have been reported
itive epitopes, can stimulate B cells to make specific antibody without in approximately 0.6 percent of transfusion recipients, 0.14 percent of
the aid of helper T cells. Such thymus-independent immune responses pregnant women, and 0.19 percent of healthy blood donors. Pooled
typically result in antigen-specific antibodies of the IgM class. data from three 5-year periods and approximately 300,000 patients

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