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1170 Part IX: Lymphocytes and Plasma Cells Chapter 75: Functions of B Lymphocytes and Plasma Cells in Immunoglobulin Production 1171

IMMUNOGLOBULIN VARIABLE-REGION sion and genetic polymorphism, antibodies produced by B-cell malig-
Despite the tremendous potential for diversity in Ig V gene expres-
STRUCTURE nancies or normal B cells of unrelated persons may share common
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idiotypic determinants. These common idiotypes, designated cross-
IMMUNOGLOBULIN VARIABLE-REGION reactive idiotypes (CRIs), were defined initially on IgM autoantibodies,
SUBGROUPS such as rheumatoid factors. However, CRIs may be found on antibodies
Despite the large number of different immunoglobulin variable regions that do not have anti–self-reactivity. Molecular studies demonstrate that
that can be generated through the mechanisms just described, each several of these CRIs represent serologic markers for expression of con-
antibody polypeptide can be assigned to one of a relatively small num- served immunoglobulin variable-region genes with little or no somatic
ber of variable-region subgroups. Comparisons of the amino acid mutation.
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sequences of a large number of different monoclonal immunoglobulin
proteins reveal four segments of limited amino acid sequence diversity IMMUNOGLOBULIN ALLOTYPES
between different antibody heavy- or light-chain variable regions. Each
of these segments is designated as an immunoglobulin variable-region HEAVY-CHAIN ALLOTYPES
framework region (FR), see Fig. 75-7. Each immunoglobulin polypep-
tide can be assigned to one of a relatively small number of variable- Human immunoglobulins have inherited differences in structure, termed
region subgroups based upon the primary structure of its first three FRs. allotypes. These genetic markers usually are detected with agglutinating
Moreover, each subgroup has characteristic FRs that distinguish it from sera from individuals naturally immunized through transfusion or
other variable-region subgroups. pregnancy. These antibodies recognize minor amino acid sequence
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Satisfying expectations that immunoglobulin subgroups defined variations in the constant regions of γ, α, and κ chains. No definite
families of highly related antibody V genes, variable-region amino acid allotypic differences have been detected on μ, δ, or λ chains. On ε chains,
subgroup homologies extend to the nucleic acid sequence level. 92–94 a monoclonal antibody to IgE defined an allotype that was common to
Cloned immunoglobulin V genes whose deduced amino acid sequences persons of all races except for a few individuals of Asian or Melanesian
belong to a given subgroup generally share greater than 80 percent background.
nucleic acid sequence homology. The human heavy-chain variable The α-chain allotypes, designated Am allotypes, are on the heavy
regions can be grouped into seven subgroups, whereas κ or λ light chains of the IgA subclass. The γ-chain allotypes are on the heavy
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chains can be divided into six and 11 subgroups, respectively. chains of the IgG , IgG , and IgG subclasses and are designated G m,
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3
1
Crystallographic data of immunoglobulin variable regions indi- G m, and G m, respectively. More than 24 Gm allotypic markers have
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cate that amino acids within the first and third FRs of either the light been identified serologically. All the heavy-chain constant-region genes
or heavy chain form β bonds on the external surface of the molecule. reside on chromosome 14. Therefore, different combinations of heavy-
These regions form relatively compact structures on the external chain allotype markers are inherited as haplotypic units, in an autoso-
solvent-accessible face of the antibody molecule that are not adjacent mal codominant manner. The frequency of the various allelic markers
to the classic antibody-combining site for antigen. Accordingly, amino differs among ethnic groups. 4,96,97
acid differences noted between the different variable-region subgroups Particular immunoglobulin allotypes have been associated with
are amenable to recognition by antisubgroup antibodies. susceptibility or resistance to infectious diseases or the relative
immune response to particular vaccines. 98,99 This could reflect link-
age disequilibrium between particular polymorphic immunoglobulin
IMMUNOGLOBULIN IDIOTYPES variable region genes and constant region genes encoding particular
Antisubgroup antibodies must be distinguished from antiidiotypic immunoglobulin allotypes. Also, most humanized IgG monoclonal
1
antibodies. Positioned between the FRs are three segments of extreme antibodies licensed for therapy have κ light chains of the Km(3) allo-
hypervariability in both light- and heavy-chain sequences. The third type and γ heavy chains of the G m or G m allotype. As such,
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96
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1
1
1
3
hypervariable region is generated through the recombinatorial process patients lacking such allotypes, who are treated with such monoclo-
that joins the antibody light-chain V gene with the J segment of the light nal antibodies, may develop antiallotypic antibodies against G m or
1
chain or the V gene with the somatically generated DJ segment of the Km(3) determinants, respectively found on the heavy or light chain of
H
H
antibody heavy chain. The diversity in first and second hypervariable the therapeutic antibody. 100
regions in part reflects germline DNA-encoded differences between dis-
parate antibody V genes, a diversity often noted even between V genes
of the same subgroup. During an immune response, somatic hyper- LIGHT-CHAIN ALLOTYPES
5,33
mutation subsequent to V gene rearrangement also may play an impor- The κ light-chain allotypes are designated Km allotypes (formerly
tant role in increasing the amino acid sequence diversity noted within called inv). At least three major Km allotypes exist, designated Km(1),
these regions. These hypervariable regions on both chains fold together 1 Km(1,2), and Km(3), which may be recognized serologically or via
to form the antigen-combining site. Hence, each of these regions of molecular techniques. Patients with B-cell malignancies who are
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3,4
hypervariability is designated a CDR (see Fig. 75–7). treated with allogeneic hematopoietic stem cell transplantation have
During secondary immune responses, extensive amino acid sub- been noted to have better survival outcomes when there is disparity in
stitutions may occur in the CDRs. In contrast, amino acid replacement the κ light-chain allotypes between donor and recipient, presumably
mutations occur much less frequently in the FRs than would be antic- because of an enhanced capacity to mount a graft-versus-leukemia
ipated if the nucleic acid substitutions were occurring randomly. As a effect. 101
consequence, the subgroup determinants that characterize an entire Seven Jλ-Cλ gene segments are telomeric to the upstream Vλ
variable-region subgroup may be relatively resilient to somatic hyper- genes, but only four such segments are functional, namely Jλ1-Cλ1,
mutation. On the other hand, the CDRs may form determinants of Jλ2-Cλ2, Jλ3-Cλ3, and Jλ7-Cλ7 (see Fig. 75–5). These segments respec-
unique specificity that contribute to the epitopes recognized by antiid- tively encode the four identified isotypes of λ light chains, termed
iotypic antibodies. Mcg Ke Oz , Mcg Ke Oz , Mcg Ke Oz , and Mcp Ke Oz , which were
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Kaushansky_chapter 75_p1159-1174.indd 1170 9/21/15 12:11 PM