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828 Part VI: The Erythrocyte Chapter 54: Hemolytic Anemia Resulting from Immune Injury 829

10 to 12 weeks of life. However, because new B cells develop daily be less clonally restricted than those occurring in chronic cold aggluti-
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in the marrow throughout life and because B cells may somatically nin disease, but this finding is not universal. Whether IGHV4–34
mutate their Ig receptors, self-tolerance in the B cell compartment is also encodes most heavy-chain variable regions of all naturally occur-
never assured. Analogy to observations in NZB (New Zealand black) ring or postinfectious cold agglutinins remains to be determined.
mice 146,147 suggests the peritoneal cavity is a privileged compartment The increased production of cold agglutinins in response to infec-
that shelters autoreactive B cells from host RBCs, allowing them to tion with M. pneumoniae may be secondary to the fact that the oligosac-
escape deletion, later to produce anti-RBC autoantibodies with appro- charide antigens of the I/i type serve as specific Mycoplasma receptors.
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priate T-cell help. The strong predominance of IgG antibodies in AHA This process may lead to altered antigen presentation involving a com-
suggests B-cell isotype switching, which is consistent with the idea of plex between a self-antigen (I/i) and a non–self-antigen (Mycoplasma).
an antigen-driven process. Moreover, because T-cell help is necessary Alternatively, the anti-i cold agglutinins may arise as a consequence
for inducing B-cell isotype switching, the pathway(s) to autoantibody of polyclonal B cell activation, as occurs in infectious mononucleosis
induction in AHA also may involve an abnormal or unique mode of (Chap. 82).
antigen presentation to T cells. 148 The mechanism(s) whereby dissimilar infectious agents (e.g., spi-
rochetes and several types of virus) induce the immune system to pro-
Origin of Cold Agglutinins duce Donath-Landsteiner antibodies with specificity for the human P
A high proportion of monoclonal IgM cold agglutinins with either blood group antigen (see “Serologic Features” below) is not known.
anti-I or anti-i specificity have heavy-chain variable regions encoded
by IGHV4–34 (immunoglobulin heavy chain variable region), for-
merly designated IGHV4.21. 143,149–151 IGHV4–34 encodes a distinct PATHOGENESIS
idiotype identified by the rat monoclonal antibody 9G4. This idiotype Pathogenic Effects of Warm Antibodies
is expressed both by the cold agglutinins themselves and on the sur- Warm autoantibodies to RBCs in AHA are pathogenic. In contrast to
face immunoglobulin of B cells synthesizing cold agglutinins or related autologous RBCs, labeled RBCs lacking the antigen targeted by the
immunoglobulins possessing IGHV4–34 sequences. Using the 9G4 autoantibodies may survive normally in patients with warm-antibody
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monoclonal antibody as a probe, this idiotype was found not only in a AHA. 10,164,165 Furthermore, transplacental passage of IgG anti-RBC auto-
very high proportion of circulating B cells and marrow lymphoplasma- antibodies from a mother with AHA to the fetus can induce intrauterine
cytoid cells of patients with lymphoma-associated chronic cold aggluti- or neonatal hemolytic anemia. Finally, despite notable exceptions and
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nin disease, but also in a smaller proportion of B cells in the blood and differences related to IgG subclass of the autoantibody, in general, an
lymphoid tissues of normal adult donors and in the spleens of 15-week inverse relationship between the quantity of RBC-bound IgG antibody
human fetuses. These data suggest B cells expressing the IGHV4–34 and RBC survival is noted in serial studies performed on animals and
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gene (or a closely related sequence) are present throughout ontogeny. patients. 167–172
Therefore, chronic cold agglutinin disease may represent a marked, In warm-antibody AHA, the patient’s RBCs typically are coated
unregulated expansion of a subset (clone) of such B cells. with IgG autoantibodies with or without complement proteins.
Light-chain V-region gene use in anti-I cold agglutinins is highly Autoantibody-coated RBCs are trapped by macrophages in the Billroth
selective. A strong bias toward use of the κ III variable region subgroup cords of the spleen and, to a lesser extent, by Kupffer cells in the liver
(Vκ-III) is observed. 150–153 Light-chain selection among anti-i cold agglu- (Chap. 68). 164,167,168,170–174 The process leads to generation of spherocytes
tinins, however, is much more variable and includes the λ type. 150–154 and fragmentation and ingestion of antibody-coated RBCs. 175,176 The
Observations that pathologic cold agglutinins are synthesized with macrophage has surface receptors for the Fc region of IgG, with pref-
distinct and highly selected V-region sequences must be viewed against erence for the IgG and IgG subclasses 177,178 and surface receptors for
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the background of two other subsequent observations. First, IGHV4–34 opsonic fragments of C3 (C3b and C3bi) and C4b. 179–181 When present
or related IGHV genes also may encode the heavy-chain variable regions together on the RBC surface, IgG and C3b/C3bi appear to act coop-
of other types of antibodies, such as rheumatoid factor autoantibodies eratively as opsonins to enhance trapping and phagocytosis. 170,171,180–184
and alloantibodies to a variety of blood group antigens, including poly- Although RBC sequestration in warm-antibody AHA occurs primarily
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peptide determinants such as Rh. Second, normal human antibodies in the spleen, 164,171–173 very large quantities of RBC-bound IgG 167,168,174 or
to an exogenous carbohydrate antigen, Haemophilus influenzae type b the concurrent presence of C3b on the RBCs 167,170,171 may favor trapping
capsular polysaccharide, also are encoded by a restricted set of IGHV in the liver.
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genes and Ig light-chain V genes. Thus, regulation of Ig gene use for Interaction of a trapped RBC with splenic macrophages may result
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production of anti-I or anti-i cold agglutinins may not differ fundamen- in phagocytosis of the entire cell. More commonly, a type of partial
tally from normal antibody formation to other carbohydrate antigens. phagocytosis results in spherocyte formation. As RBCs adhere to mac-
In the setting of B-cell lymphoma or Waldenström macroglob- rophages via the Fc receptors, portions of RBC membrane are internal-
ulinemia, cold agglutinins may be produced by the malignant clone ized by the macrophage. Because membrane is lost in excess of contents,
itself. Two patients with lymphoma and monoclonal cold agglutinin the noningested portion of the RBC assumes a spherical shape, the
were identified as having a karyotypically abnormal B-cell clone that shape with the lowest ratio of surface area to volume. 175,176,185 Spherical
produced a cold agglutinin identical to that found in their sera. 158,159 Tri- RBCs are more rigid and less deformable than normal RBCs. As such,
somy 3 has been the most frequently observed karyotypic abnormality spherical RBCs are fragmented further and eventually destroyed in
in patients with non-Hodgkin lymphoma and cold agglutinins. 158,160 future passages through the spleen. Spherocytosis is a consistent and
Normal human sera generally have naturally occurring polyclonal diagnostically important hallmark of AHA, and the degree of sphero-
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cold agglutinins in low titer (usually 1/64 or less). Otherwise healthy cytosis correlates well with the severity of hemolysis. 10
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persons may develop elevated titers of cold agglutinins specific for I/i Direct complement-mediated hemolysis with hemoglobinuria is
antigens during certain infections (e.g., M. pneumoniae, Epstein-Barr unusual in warm-antibody AHA, even though many warm autoanti-
virus, cytomegalovirus). In contrast to other forms of cold agglutinin bodies fix complement. The failure of C3b-coated RBCs to be hemo-
disease, hyperproduction of these postinfectious cold agglutinins is lyzed by the terminal complement cascade (C5–C9) has been attributed,
transient. Some evidence indicates postinfectious cold agglutinins may at least in part, to the ability of complement regulatory proteins (factors

Kaushansky_chapter 54_p0823-0846.indd 828 9/19/15 12:27 AM