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Immunoglobulin genetics

Immunoglobulin genetics
Author:
Jolan Walter, MD, PhD
Section Editor:
Jennifer M Puck, MD
Deputy Editor:
Anna M Feldweg, MD
Literature review current through: Jan 2024.
This topic last updated: Feb 02, 2023.

INTRODUCTION — The genetics of immunoglobulin during both B cell development in the bone marrow and the induction of the humoral immune response are presented here. A website devoted to immunoglobulin genetics is also available [1]. Discussions of B cell development, the structure of immunoglobulins, and the humoral immune response are reviewed separately. (See "Normal B and T lymphocyte development" and "Structure of immunoglobulins" and "The adaptive humoral immune response".)

Terminology — Immunoglobulin molecules are Y-shaped molecules composed of four chains: two identical light chains and two identical heavy chains (figure 1). The terms "immunoglobulin" (Ig) and "antibody" are generally used interchangeably. This topic review preferentially uses the term "immunoglobulin," which can refer to a single molecule or collectively to all immunoglobulins considered together.

FORMS OF IMMUNOGLOBULIN — Immunoglobulin exists in two forms: secreted and membrane bound, which are identical except for differences in the C-terminal portion, where one has a transmembrane anchor region and the other does not. These two different forms are generated by differential splicing of messenger ribonucleic acid (mRNA) [2].

Secreted — Secreted immunoglobulin is made mainly by plasma cells and may bind to microbes and act to neutralize, opsonize, fix complement, or serve other functions.

Membrane bound — Membrane-bound immunoglobulin, in association with signal-transducing molecules, Igalpha and Igbeta, serves as a receptor for antigen on the surface of B cells (BCR) (figure 2). The role of the BCR is to recognize, bind, and present antigen specific for the variable region. This also creates a tonic signal for B cell survival during B cell development.

IMMUNOGLOBULIN GENE ORGANIZATION — There are several classes of immunoglobulin that are categorized by a unique heavy chain structure: IgG, IgM, IgA, IgD, and IgE. There are also subclasses of IgG (IgG1 to 4) and of IgA (IgA1 and IgA2). In addition, there are two different types of immunoglobulin light chains, kappa and lambda. Immunoglobulin heavy chains and each type of light chain are encoded by genes in different loci. The table shows the locations of these gene complexes on human chromosomes (table 1). (See "Structure of immunoglobulins".)

Genes capable of encoding a complete immunoglobulin heavy or light chain do not exist as such within the deoxyribonucleic acid (DNA) of most cells. The complete genes are assembled by the union of separate gene segments, termed "rearrangement." These segments are widely separated in germ cells and in all somatic cells, except for B lymphocytes. Within B lymphocytes, these genes become rearranged to create a "mature" immunoglobulin gene that can encode a functional protein. This rearrangement process is the core of the immune system's ability to generate antibodies capable of recognizing the tremendous variety of antigenic structures in nature.

An immunoglobulin heavy chain gene is assembled from four types of gene segments (figure 3):

The heavy chain variable region (VH)

The heavy chain joining region (JH)

The heavy chain constant region (CH)

The diversity gene segment (D)

An immunoglobulin light chain gene is assembled from three types of gene segments (figure 4). These are:

The light chain variable region (VL)

The light chain joining region (JL)

The light chain constant region (CL)

The nomenclature of the gene segments derives from names assigned to portions of immunoglobulin heavy or light chains based upon an analysis of their amino acid sequences (see "Structure of immunoglobulins"). Thus, the variable region shows great variation from one immunoglobulin chain to another. The constant region, as its name implies, is invariant within an immunoglobulin class or subclass. The joining and diversity regions were the names given to areas between variable and constant, each having its own characteristic sequence pattern. The variable regions of the heavy and light chains together form the antibody-combining site. This is the portion of the immunoglobulin molecule that makes contact with antigen. (See "Overview of therapeutic monoclonal antibodies".)

The organization of immunoglobulin heavy and light chain genes is very similar.

The immunoglobulin heavy chain locus on chromosome 14 has been completely sequenced [1,3,4]. It spans 957 kilobase pairs of DNA and contains a total of 123 VH genes. Only 39 of these genes are functional. Note that not all VH loci in all individuals will contain the same number of VH genes due to deletions in the region that can be inherited allelically (the same is true of VL loci). This leads to some individual variation in the number of V genes that can be expressed at each locus. There are 26 D genes, 6 JH genes (along with 3 nonfunctional JH pseudogenes), and 11 CH region genes (figure 3). Each of these CH genes corresponds to a particular immunoglobulin class or subclass. (See "Structure of immunoglobulins".)

The kappa locus on chromosome 2 consists of 79 Vkappa genes, only 49 of which are functional (ie, capable of encoding a complete Vkappa light chain segment). The others are pseudogenes that contain lethal mutations that prevent expression or translation of functional protein. The Vkappa genes are followed by five Jkappa genes and one Ckappa gene (figure 4) [1,5]. The human lambda locus on chromosome 22 is somewhat different, being composed of 73 Vlambda (of which 33 are functional), 7 Jlambda, and 7 Clambda genes (some of which are pseudogenes) [1,6].

Immunoglobulin V genes may also be found in other chromosomal locations where they cannot be expressed. These loci are called orphons and are believed to have arisen via gene conversions that have been maintained during evolution. VH orphons can be found on chromosomes 15 and 16 [7]. A Vkappa orphon is found near the centromere of chromosome 2 [8]. Most genes in orphon loci are pseudogenes. Since they are not used to create mature immunoglobulin genes, there is no selection pressure to limit the accumulation of mutations that destroy the ability of these genes to encode a functional protein.

VH and VL genes are grouped into V gene families based upon nucleotide sequence homology. V genes that are greater than 80 percent homologous are said to belong to the same family. Homology between families is generally less than 75 percent. Human VH genes have been divided into seven families designated V1 to V7 [3]. Similarly, human Vkappa and Vlambda genes have been divided into 4 and 10 families, respectively [5,6]. D genes are also grouped into six families [3].

A typical V gene consists of two exons separated by an intron. The first V gene exon encodes most of the leader sequence, or signal peptide, a structure analogous to those found in many secreted proteins. This is the first part of the protein synthesized (the amino terminus), and this peptide interacts with the endoplasmic reticulum, which is important in the intracellular transport and processing of the protein. The signal peptide is removed from the immunoglobulin molecule before it appears in the membrane or is secreted. The second V gene exon encodes the majority of the V region (approximately 95 amino acids). D genes are variable in length and may encode 1 to 15 amino acids. J genes encode 15 to 20 amino acids. (See "Structure of immunoglobulins".)

IMMUNOGLOBULIN GENE REARRANGEMENT — The creation of a mature, expressible immunoglobulin heavy or light chain gene requires the assembly of randomly selected gene "modules" taken from groups of similar elements scattered widely over many kilobases of DNA, and this process is termed "rearrangement" [9]. With heavy chain gene rearrangement, the 3' end of a diversity (D) gene is brought to the 5' end of a heavy chain joining region (JH) gene (figure 3). This is called D-JH rearrangement. Next, the 3' end of a heavy chain variable region (VH) gene is juxtaposed to DJH (V-DJH rearrangement). Light chains undergo only one rearrangement event, light chain variable region (VL) to light chain joining region (JL) (figure 4).

V(D)J recombination — Immunoglobulin gene rearrangement is regulated by complex interactions between special DNA sequences, DNA-binding factors, and DNA-modifying enzymes [9]. V, D, and J genes all have flanking regions called "recombination signal sequences." These are important in the mechanism of rearrangement. The heptamer (7 base pairs [bp]) and nonamer (9 bp) sequences are separated by a spacer of either 12 or 23 bp (figure 5). A gene with a flanking sequence containing a 12-bp spacer may only join to a gene whose flanking sequence has a 23-bp spacer. This is called the 12- to 23-bp rule. These sequences are recognized by DNA-binding proteins, such as nucleases and ligases with specific activity of opening of the DNA hairpin and splicing with nonhomologous end joining mechanisms. The conservation of these flanking sequences in many species indicates their importance in the rearrangement mechanism.

Role of RAG proteins — The process of gene rearrangement (V(D)J recombination) begins with complex regulatory mechanisms that affect the chromatin structure of the DNA regions to be cut and ligated. This regulation and selective unmasking or unpackaging of DNA help to ensure that the splicing mechanism does not go awry and lead to pathogenic translocations [9]. The gene splicing that occurs in immunoglobulin gene rearrangement is mediated via one or more complexes of proteins that cut the two DNA sites that will be joined and ligate the DNA, thereby holding the two segments in their newly spliced configuration. Recombination-activating gene 1 (RAG1) and RAG2, referred to collectively here as RAG genes, encode lymphoid-specific proteins that are expressed during the early stages of T cell and B cell development and initiate the process of V(D)J recombination by introducing DNA double-strand breaks at the junction between the heptamer and a coding element [10].

RAG1 binds directly to the recombination signal sequences and also binds RAG2, which functions as a reader of the histones surrounding the DNA and stabilizer of DNA-RAG1 interaction [9]. Two RAG1 and two RAG2 proteins combine to create a heterotetramer complex, which makes a double-stranded break in the DNA and recruits several additional molecules that complete the juxtaposition of the coding DNA ends and their ligation. RAG mutations have been linked to severe combined immunodeficiency but also a widening spectrum of other immune disorders in children and adults [10,11]. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'RAG complex (initiation of recombination)'.)

This second stage of the V(D)J recombination event is facilitated by several factors collectively called the "nonhomologous end joining" complex. Similarly to RAG mutations, pathogenic mutations in many of the members of this complex are linked to combined immunodeficiency phenotype (Ku70, Ku80, DNA-dependent protein kinase catalytic subunit, Xrcc4, DNA ligase IV, or Artemis). (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'Nonhomologous DNA end joining (recombination and DNA repair)'.)

In the bone marrow, recognition of polyvalent self-antigens by immature B cells promotes reexpression of the RAG genes and continued rearrangement of kappa and, if necessary, lambda light chain genes to generate a novel light chain that is no longer self-reactive [12-15]. This process, called "receptor editing," is considered an important central B cell tolerance checkpoint. In fact, it is found to be reduced in patients and animal models of RAG deficiency and is proposed to contribute to autoreactive B cells and autoimmunity [16,17].

Formation of KRECs — During gene rearrangement, the DNA that was between the two rearranging genes is formed into a closed DNA circle. In maturing B cells, after exhaustive rearrangement of the Vkappa segments, a specific by-product is created, which contains the joined intronic recombination signal sequence (RSS) and K deleting element (Kde) and Ckappa. These circular DNA byproducts are called kappa-deleting recombination excision circles (KRECs) (figure 4), and the B cell is class-switching to Clambda [18]. A similar mechanism occurs in developing T cells, giving rise to T cell receptor excision circles (TRECs).

The KRECs produced during immunoglobulin gene rearrangement are retained in the nucleus of the B cell. They are not replicated during subsequent cell divisions, but they persist in the nucleus of one of the progeny cells after division. Thus, the fraction of the B cells bearing these circles gradually diminishes with successive rounds of cell division during development in the bone marrow. A small fraction of mature B cells in the circulation will have these DNA circles in their nuclei. The number of KRECs in peripheral blood lymphocyte DNA can be measured by quantitative polymerase chain reaction (PCR), and this can be used as a marker of the rate of B cell generation [18]. For example, the number of KRECs is very low in patients with absent or severely reduced B cells such as X-linked agammaglobulinemia or a subset of patients with common variable immunodeficiency [19,20]. KREC measurement is being studied as a clinical marker of B cell development and for newborn screening for defects of B cell development [20,21]. This type of assay is analogous to measurement of TRECs, which are used in newborn screening for T cell and combined immunodeficiencies [22]. (See "Newborn screening for inborn errors of immunity", section on 'Screening for SCID and other T cell defects' and "Newborn screening for inborn errors of immunity", section on 'Screening for B cell defects'.)

ANTIBODY DIVERSITY — Several mechanisms generate immunoglobulin region (combining site) diversity in both secreted and membrane-bound immunoglobulin molecules:

Multiple variable (V), diversity (D), and joining (J) genes (germline-encoded diversity)

Rearrangement diversity with imprecise joining of gene segments

Nongermline-encoded nucleotides (N regions)

Pairing of heavy and light chains (combinatorial diversity)

Somatic mutation [23]

Clonal redemption [24,25]

Gene replacements (receptor editing) [26]

These mechanisms allow for highly efficient use of a relatively small portion of the genome to generate population of antibody specificities so diverse that, no matter what antigens are encountered, a complementary antibody may be found. Some of these mechanisms (eg, receptor editing, clonal redemption) also ensure that autoreactive prone clones are purged during the diversification process and considered as "B cell tolerance checkpoints."

Note that all of the mechanisms that create antibody diversity also add significant cellular wastage. A series of gene rearrangements may create nonfunctional genes by altering the reading frame or by producing an early termination codon. In addition, several germline V genes are pseudogenes and encode nonfunctional proteins. In order to produce a first functional B cell receptor (BCR) and later immunoglobulin, two successful series of rearrangements are required, one for heavy and one for light chain genes. Each series of rearrangements is susceptible to error. Since signaling through the BCR is essential in the survival of B cells, developing B cells can be lost to aberrant immunoglobulin gene rearrangements. The exact fraction of cells that is lost is unknown, but it is probably significantly greater than 50 percent [27].

Germline-encoded diversity — A large number of different heavy chain VDJ combinations may be assembled. The completely sequenced heavy chain variable region (VH) locus contains 39 usable VH genes, 26 D, and 6 heavy chain joining region (JH) genes (see 'Immunoglobulin gene organization' above). Assuming any VH can join to any D, and any D to any JH, 6084 different heavy chain VDJ units may therefore be assembled. The germline-encoded VH diversity is amplified by 156-fold, simply by combining VH gene segments with various D and JH segments. This may be an overestimate because it appears that some VH genes preferentially rearrange [28]. However, it is clear that the multiplicative nature of immunoglobulin gene rearrangement greatly extends the diversity that can be encoded in the genome.

Rearrangement diversity — Since the joining of D to JH and VH to DJH (similarly, light chain variable region [VL] to light chain joining region [JL]) is not precise, it does not always occur at the same position in the gene segments. This results in different codons at the joints and in different complementarity-determining region (CDR) 3 lengths (figure 5).

Nongermline-encoded nucleotides — Nucleotides that are not encoded by genomic DNA may exist at the gene segment junctions. These nucleotides are believed to be inserted at the junction by the enzyme terminal deoxyribonucleotidyl transferase and are designated the N region. This process contributes to diversity by changing the length of the resultant protein, and, if a nonmultiple of three nucleotides is added, the reading frame is also shifted.

Combinatorial diversity — Additional diversity is created by the pairing of the heavy and light chains produced by the cell. Although a given VH cannot pair with all light chain V genes to form a functional antibody [29], the assembly of antibodies from two different component chains leads to another multiplicative increase in the possible repertoire of combining sites. The total number capable of being generated is equal to the product of the number of different heavy chains and the number of different light chains that can form functional pairs. As an example, 3198 different possible combinations may arise because there are 39 functional VH genes and 82 Vkappa and Vlambda genes. Even if not all of these pairs are functional, this represents an approximately 15- to 30-fold increase over germline-encoded diversity.

The parts of the immunoglobulin V region that contact antigen are called "complementarity-determining regions" (CDRs) (see "Structure of immunoglobulins"). The CDRs 1 and 2 are encoded by the 5' regions of VH genes, and they reflect predominantly germline-encoded sequence diversity. All of the rearrangement mechanisms described above create diversity within the most 3' CDR3, built up from the 3' end of a VH, a D, and the 5' end of a JH gene. One analysis estimates the overall number of potential heavy chain CDR3 sequences to be on the order of 1014 [23].

Somatic hypermutation — Somatic hypermutation (SHM) is another important mechanism for generating variation in V regions [23]. At some time after rearrangement is complete, the heavy and light chain V genes may accumulate point mutations in any CDR or framework region. One gene may collect up to 10 or more nucleotide changes, some fraction of which result in an amino acid substitution. These changes may alter antibody affinity or may even alter specificity. This process is important in the phenomenon of affinity maturation that occurs in germinal centers, although it may also be found outside these areas [30]. (See "The adaptive humoral immune response".)

SHM is often induced in B cells after CD40-CD40L interaction with follicular helper T cells and executed by B cell intrinsic activation induced cytidine deaminase (AID) and uracil DNA glycosylase (UNG). Defects in this pathway are linked to hyperimmunoglobulin M syndrome [31]. (See "Hyperimmunoglobulin M syndromes", section on 'Pathogenesis'.)

Clonal redemption — A variant of SHM is coined "clonal redemption." Anergic B cells with BCRs specific for both foreign and self-antigens can be rescued from anergy and autoreactivity in a secondary immune response via SHM and undergo class-switching to IgG in the process of clonal redemption [24,25]. This process has been examined in healthy individuals with viral infections [24,25] and among patients with Toll-like receptor (TLR) defects [32] and AID deficiency [33].

Gene replacements — Gene replacements (receptor editing) occur during B cell development and antibody responses. These underlie selective processes critical for the formation of the primary and secondary antibody repertoires. (See "Normal B and T lymphocyte development" and "The adaptive humoral immune response".)

ALLELIC EXCLUSION — Since there are two copies of each chromosome within a cell, it is theoretically possible that a B cell may produce two different immunoglobulin heavy chains or two different light chains. This could result in the formation of several different antibodies in a single cell. However, this does not occur because of a phenomenon termed "allelic exclusion." During the null B cell stage, diversity-heavy chain joining region (D-JH) rearrangement usually occurs in both heavy chain loci before variable-diversity heavy chain joining region (V-DJH) joining. If the first V-DJH rearrangement on one chromosome is successful, a complete IgM (mu) heavy chain mRNA is made, IgM heavy chain protein is synthesized and complexed with surrogate light chains, then expressed on the cell surface as the pre-B cell receptor (pre-BCR). (See "Normal B and T lymphocyte development".)

In addition to triggering rearrangement of light chain genes, the pre-BCR appears also to provide a negative signal inhibiting further heavy chain gene rearrangement on the other chromosome [27,34]. If the first heavy chain gene rearrangement is unsuccessful, no IgM heavy chain protein can be expressed, and the locus on the other chromosome is free to rearrange. If both rearrangements are unsuccessful, no immunoglobulin can be formed, and the cell soon dies by apoptosis (programmed cell death). Thus, only cells with one productive heavy chain rearrangement go on to rearrange light chain genes.

The kappa light chain genes usually rearrange before lambda genes. Successful kappa gene rearrangement allows formation of a complete immunoglobulin molecule, which seems to shut down further gene rearrangement, at least for a time (receptor editing may occur if the immunoglobulin is specific for self-antigen) (see "Normal B and T lymphocyte development"). If kappa rearrangement is unsuccessful (on both chromosomes), lambda genes then recombine. If no rearrangement produces a functional light chain, again no immunoglobulin can be formed, and the cell dies. Thus, this process of allelic exclusion ensures that a given B cell will produce only a single immunoglobulin specificity resulting from the combination of one heavy chain with one light chain. In an individual heterozygous with respect to a particular polymorphic heavy or light chain constant gene, a given B cell will produce antibodies of only one allotype. (See "Structure of immunoglobulins".)

CLASS-SWITCHING — After the mature B cell stage, a cell may change from production of IgM and IgD to synthesis of IgG, IgA, or IgE. This process is called "class-switching" (figure 6) [35]. This is a stable change in the cell's genome and is transmitted to all progeny cells. Since class-switching yields the same variable diversity heavy chain joining region (VDJH) in association with a different heavy chain constant region (CH) region, antigen specificity and idiotypic determinants remain unchanged. Only the heavy chain isotype is altered relative to the immunoglobulin that was produced before the switch. (See "Structure of immunoglobulins".)

A single cell can produce both IgM and IgD by differential splicing of mRNA (figure 7). The predominant mechanism of class-switching is somewhat similar to the process of VDJH rearrangement in DNA. In the DNA, 5' to each of the CH genes (except Cdelta), there are 1 kb or more of a characteristic repetitive sequence, such as (GAGCT)n or (GGGT)n. These are called switch sequences (or switch regions or S regions). When a cell undergoes a class-switch, the S region 5' to Cmu is brought to the S region 5' to a downstream C region (eg, g1) (figure 6). The intervening DNA is either inverted or excised (looped out), just as in V gene recombination, although distinct cellular machinery is required to accomplish this recombination of single-stranded mRNA [35].

The fate of the DNA intervening between recombined sequences appears to be the same in V gene recombination and class-switching. However, the heptamer and nonamer V gene recombination sequences and S sequences are very different, and RAG1 and RAG2 are not involved in the class-switch. Factors of somatic mutation and class-switching are shared. A description of the cellular interactions and factors regulating class-switching can be found separately. (See "The adaptive humoral immune response".)

The genetics of IgG subclasses are discussed separately. (See "IgG subclasses: Physical properties, genetics, and biologic functions", section on 'Allotypes'.)

CLONAL DISTRIBUTION OF B CELLS — Each mature B cell expresses a more or less unique set of immunoglobulin heavy (H) and light (L) chain gene rearrangements and H + L combination. Each represents a genetically distinct clone [27]. All of the progeny B cells generated by mitosis of that cell (clonal expansion) are considered to belong to the same clone since they are genetically identical. Some divergence may occur during clonal expansion since an individual cell of a clone may class-switch or somatically mutate its variable genes differently from its siblings. Depending on one's point of view, one may designate the progeny of these genetic events as constituting new clones, yet they all remain clonally related since they originated from one cell. Thus, the circulating pool of B lymphocytes is comprised of many genetically distinct clones, each of which may have anywhere from one to thousands of members.

SUMMARY

Genes capable of encoding a complete immunoglobulin (Ig) heavy or light chain do not exist as such within the deoxyribonucleic acid (DNA) of most cells. Instead, complete genes are assembled within B cells by the union of separate gene segments to create a "mature" immunoglobulin gene that can encode a functional protein. This rearrangement is critical to creating a diverse antibody repertoire capable of interacting with the tremendous variety of antigenic structures in nature. (See 'Immunoglobulin gene organization' above.)

An immunoglobulin light chain gene is assembled from three types of gene segments. These are the heavy chain gene segments for the variable (VH), joining (JH), and constant (CH) regions, and another type of gene segment called D (diversity) (figure 3). Similarly, light chain variable region (VL), joining region (JL), and constant region (CL) gene segments (figure 4). (See 'Immunoglobulin gene organization' above.)

Immunoglobulin gene rearrangement is regulated by complex interactions between special DNA sequences, DNA-binding factors, and DNA-modifying enzymes. (See 'Immunoglobulin gene rearrangement' above.)

Several mechanisms of generating diversity contribute to the structural variations found within the combining site of an immunoglobulin molecule. These mechanisms include germline-encoded diversity, imprecise joining during rearrangement, nongermline-encoded nucleotides region diversity, combinatorial diversity, somatic hypermutation (SHM), and receptor editing. (See 'Antibody diversity' above.)

Once a mature B cell is producing IgM and IgD, it may "class-switch" to make IgG, IgA, or IgE. The cell then continues to make the isotype to which it has committed for the rest of its life, as does all of that cell's progeny. (See 'Class-switching' above.)

Each mature B cell expresses a unique set of immunoglobulin heavy (H) and light (L) chain gene rearrangements and H + L combination and represents a genetically distinct clone. Thus, the circulating pool of B lymphocytes is comprised of many genetically distinct clones, each of which may contain from one to thousands of members. (See 'Clonal distribution of B cells' above.)

The process for B cell receptor (BCR) expression and concomitant immunoglobulin secretion can be impaired in several variants of immune deficiencies. Pattern of changes in immunoglobulin levels and the BCR repertoire may give clues for the underlying genetic defect. (See 'Role of RAG proteins' above and 'Somatic hypermutation' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Francisco A Bonilla, MD, PhD, who contributed as an author, and E Richard Stiehm, MD, who contributed as a Section Editor, to earlier versions of this topic review.

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References

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