Immunoglobulin class switching

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Mechanism of class-switch recombination that allows isotype switching in activated B cells. Class switch recombination.png
Mechanism of class-switch recombination that allows isotype switching in activated B cells.

Immunoglobulin class switching, also known as isotype switching, isotypic commutation or class-switch recombination (CSR), is a biological mechanism that changes a B cell's production of immunoglobulin from one type to another, such as from the isotype IgM to the isotype IgG. [1] During this process, the constant-region portion of the antibody heavy chain is changed, but the variable region of the heavy chain stays the same (the terms variable and constant refer to changes or lack thereof between antibodies that target different epitopes). Since the variable region does not change, class switching does not affect antigen specificity. Instead, the antibody retains affinity for the same antigens, but can interact with different effector molecules.

Contents

Mechanism

Class switching occurs after activation of a mature B cell via its membrane-bound antibody molecule (or B cell receptor) to generate the different classes of antibody, all with the same variable domains as the original antibody generated in the immature B cell during the process of V(D)J recombination, but possessing distinct constant domains in their heavy chains. [2]

Naïve mature B cells produce both IgM and IgD, which are the first two heavy chain segments in the immunoglobulin locus. After activation by antigen, these B cells proliferate. If these activated B cells encounter specific signaling molecules via their CD40 and cytokine receptors (both modulated by T helper cells), they undergo antibody class switching to produce IgG, IgA or IgE antibodies. During class switching, the constant region of the immunoglobulin heavy chain changes but the variable regions do not, and therefore antigenic specificity, remains the same. This allows different daughter cells from the same activated B cell to produce antibodies of different isotypes or subtypes (e.g. IgG1, IgG2 etc.). [3]

In humans, the order of the heavy chain exons is as follows:

  1. μ - IgM
  2. δ - IgD
  3. γ3 - IgG3
  4. γ1 - IgG1
  5. α1 - IgA1
  6. γ2 - IgG2
  7. γ4 - IgG4
  8. ε - IgE
  9. α2 - IgA2 [4]

Class switching occurs by a mechanism called class switch recombination (CSR) binding. Class switch recombination is a biological mechanism that allows the class of antibody produced by an activated B cell to change during a process known as isotype or class switching. During CSR, portions of the antibody heavy chain locus are removed from the chromosome, and the gene segments surrounding the deleted portion are rejoined to retain a functional antibody gene that produces antibody of a different isotype. Double-stranded breaks are generated in DNA at conserved nucleotide motifs, called switch (S) regions, which are upstream from gene segments that encode the constant regions of antibody heavy chains; these occur adjacent to all heavy chain constant region genes with the exception of the δ-chain. DNA is nicked and broken at two selected S-regions by the activity of a series of enzymes, including activation-induced (cytidine) deaminase (AID), uracil DNA glycosylase and apyrimidic/apurinic (AP)-endonucleases. [5] [6] AID begins the process of class switching by deaminating (removing an amino group from) cytosines within the S regions, converting the original C bases into deoxyuridine and allowing the uracil glycosylase to excise the base. This allows AP-endonucleases to cut the newly-formed abasic site, creating the initial SSBs that spontaneously form DSBs. [7] The intervening DNA between the S-regions is subsequently deleted from the chromosome, removing unwanted μ or δ heavy chain constant region exons and allowing substitution of a γ, α or ε constant region gene segment. The free ends of the DNA are rejoined by a process called non-homologous end joining (NHEJ) to link the variable domain exon to the desired downstream constant domain exon of the antibody heavy chain. [8] In the absence of non-homologous end joining, free ends of DNA may be rejoined by an alternative pathway biased toward microhomology joins. [9] With the exception of the μ and δ genes, only one antibody class is expressed by a B cell at any point in time. While class switch recombination is mostly a deletional process, rearranging a chromosome in "cis", it can also occur (in 10 to 20% of cases, depending upon the Ig class) as an inter-chromosomal translocation mixing immunoglobulin heavy chain genes from both alleles. [10] [11]

Cytokines responsible for class switching

T cell cytokines modulate class switching in mouse (Table 1) and human (Table 2). [12] [13] These cytokines may have suppressive effect on production of IgM.

Table 1. Class switching in mice
T cellsCytokinesImmunoglobulin classes
IgG1IgG2aIgG2bIgG3IgG4IgE
Th2 IL-4↑↓↓↓↓↑
IL-5↑
Th1 IFNγ↓↑↓↑↓↓
Treg TGFβ↑↓↑
IL-10 [14] ↑
Table 2. Class switching in humans
T cellsCytokinesImmunoglobulin classes
IgG1IgG2IgG3IgG4IgAIgE
Th2 IL-4↑↓↑↑
IL-5↑
Th1 IFNγ↓↑↓
Treg TGFβ↓↑
IL-10 [15] [16] ↑↑

Gene regulatory sequences responsible for class switching

In addition to the highly repetitive structure of the target S regions, the process of class switching needs S regions to be first transcribed and spliced out of the immunoglobulin heavy chain transcripts (where they lie within introns). Chromatin remodeling, accessibility to transcription and to AID and synapsis of broken S regions are under the control of a large super-enhancer, located downstream the more distal Calpha gene, the 3' regulatory region (3'RR). [17] In some occasions, the 3'RR super-enhancer can itself be targeted by AID and undergo DNA breaks and junction with Sμ, which then deletes the Ig heavy chain locus and defines locus suicide recombination (LSR). [18]

See also

Related Research Articles

<span class="mw-page-title-main">Antibody</span> Protein(s) forming a major part of an organisms immune system

An antibody (Ab) is the secreted form of a B cell receptor; the term immunoglobulin can refer to either the membrane-bound form or the secreted form of the B cell receptor, but they are, broadly speaking, the same protein, and so the terms are often treated as synonymous. Antibodies are large, Y-shaped proteins belonging to the immunoglobulin superfamily which are used by the immune system to identify and neutralize foreign objects such as bacteria and viruses, including those that cause disease. Antibodies, however, can be generated to recognize virtually any molecule in existence. Each antibody recognizes one or more specific antigens. This term literally means "antibody generator", as it is the presence of an antigen that drives the formation of an antigen-specific antibody. Each tip of the "Y" of an antibody contains a paratope that specifically binds to one particular epitope on an antigen, allowing the two molecules to bind together with precision. Using this mechanism, antibodies can effectively "tag" a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly.

<span class="mw-page-title-main">Immunoglobulin D</span> Antibody isotype

Immunoglobulin D (IgD) is an antibody isotype that makes up about 1% of proteins in the plasma membranes of immature B-lymphocytes where it is usually co-expressed with another cell surface antibody called IgM. IgD is also produced in a secreted form that is found in very small amounts in blood serum, representing 0.25% of immunoglobulins in serum. The relative molecular mass and half-life of secreted IgD is 185 kDa and 2.8 days, respectively. Secreted IgD is produced as a monomeric antibody with two heavy chains of the delta (δ) class, and two Ig light chains.

<span class="mw-page-title-main">Immunoglobulin M</span> One of several isotypes of antibody

Immunoglobulin M (IgM) is the largest of several isotypes of antibodies that are produced by vertebrates. IgM is the first antibody to appear in the response to initial exposure to an antigen; causing it to also be called an acute phase antibody. In humans and other mammals that have been studied, plasmablasts in the spleen are the main source of specific IgM production.

<span class="mw-page-title-main">Activation-induced cytidine deaminase</span> Enzyme that creates mutations in DNA

Activation-induced cytidine deaminase, also known as AICDA, AID and single-stranded DNA cytosine deaminase, is a 24 kDa enzyme which in humans is encoded by the AICDA gene. It creates mutations in DNA by deamination of cytosine base, which turns it into uracil. In other words, it changes a C:G base pair into a U:G mismatch. The cell's DNA replication machinery recognizes the U as a T, and hence C:G is converted to a T:A base pair. During germinal center development of B lymphocytes, error-prone DNA repair following AID action also generates other types of mutations, such as C:G to A:T. AID is a member of the APOBEC family.

<span class="mw-page-title-main">Immunoglobulin heavy chain</span> Large polypeptide subunit of an antibody

The immunoglobulin heavy chain (IgH) is the large polypeptide subunit of an antibody (immunoglobulin). In human genome, the IgH gene loci are on chromosome 14.

V(D)J recombination is the mechanism of somatic recombination that occurs only in developing lymphocytes during the early stages of T and B cell maturation. It results in the highly diverse repertoire of antibodies/immunoglobulins and T cell receptors (TCRs) found in B cells and T cells, respectively. The process is a defining feature of the adaptive immune system.

<span class="mw-page-title-main">B-cell receptor</span> Transmembrane protein on the surface of a B cell

The B-cell receptor (BCR) is a transmembrane protein on the surface of a B cell. A B-cell receptor is composed of a membrane-bound immunoglobulin molecule and a signal transduction moiety. The former forms a type 1 transmembrane receptor protein, and is typically located on the outer surface of these lymphocyte cells. Through biochemical signaling and by physically acquiring antigens from the immune synapses, the BCR controls the activation of the B cell. B cells are able to gather and grab antigens by engaging biochemical modules for receptor clustering, cell spreading, generation of pulling forces, and receptor transport, which eventually culminates in endocytosis and antigen presentation. B cells' mechanical activity adheres to a pattern of negative and positive feedbacks that regulate the quantity of removed antigen by manipulating the dynamic of BCR–antigen bonds directly. Particularly, grouping and spreading increase the relation of antigen with BCR, thereby proving sensitivity and amplification. On the other hand, pulling forces delinks the antigen from the BCR, thus testing the quality of antigen binding.

<span class="mw-page-title-main">Hyper IgM syndrome</span> Primary immune deficiency disorders

Hyper IgM syndrome is a rare primary immune deficiency disorders characterized by low or absent levels of serum IgG, IgA, IgE and normal or increased levels of serum IgM.

<span class="mw-page-title-main">Hyper-IgM syndrome type 5</span> Primary immune deficiency disorder

The fifth type of hyper-IgM syndrome has been characterized in three patients from France and Japan. The symptoms are similar to hyper IgM syndrome type 2, but the AICDA gene is intact.

<span class="mw-page-title-main">Immunoglobulin light chain</span> Small antibody polypeptide subunit (immunoglobin)

The immunoglobulin light chain is the small polypeptide subunit of an antibody (immunoglobulin).

<span class="mw-page-title-main">Isotype (immunology)</span>

In immunology, antibodies are classified into several types called isotypes or classes. The variable (V) regions near the tip of the antibody can differ from molecule to molecule in countless ways, allowing it to specifically target an antigen . In contrast, the constant (C) regions only occur in a few variants, which define the antibody's class. Antibodies of different classes activate distinct effector mechanisms in response to an antigen . They appear at different stages of an immune response, differ in structural features, and in their location around the body.

<span class="mw-page-title-main">IGLL1</span> Protein-coding gene in the species Homo sapiens

Immunoglobulin lambda-like polypeptide 1 is a protein that in humans is encoded by the IGLL1 gene. IGLL1 has also recently been designated CD179B.

<span class="mw-page-title-main">IGHM</span> Gene in the species Homo sapiens

Ig mu chain C region is a protein that in humans is encoded by the IGHM gene.

Immunoglobulin heavy locus, also known as IGH, is a region on human chromosome 14 that contains a gene for the heavy chains of human antibodies.

<span class="mw-page-title-main">IGHE</span>

Ig epsilon chain C region is a protein that in humans is encoded by the IGHE gene.

Immunoglobulin lambda locus, also known as IGL@, is a region on the q arm of human chromosome 22, region 11.22 (22q11.22) that contains genes for the lambda light chains of antibodies.

<span class="mw-page-title-main">Hyper-IgM syndrome type 4</span> Medical condition

Hyper-IgM syndrome type 4 is a form of Hyper IgM syndrome which is a defect in class switch recombination downstream of the AICDA gene that does not impair somatic hypermutation.

Somatic hypermutation is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it. A major component of the process of affinity maturation, SHM diversifies B cell receptors used to recognize foreign elements (antigens) and allows the immune system to adapt its response to new threats during the lifetime of an organism. Somatic hypermutation involves a programmed process of mutation affecting the variable regions of immunoglobulin genes. Unlike germline mutation, SHM affects only an organism's individual immune cells, and the mutations are not transmitted to the organism's offspring. Because this mechanism is merely selective and not precisely targeted, somatic hypermutation has been strongly implicated in the development of B-cell lymphomas and many other cancers.

Antibody structure is made up of two heavy-chains and two light-chains. These chains are held together by disulfide bonds. The arrangement or processes that put together different parts of this antibody molecule play important role in antibody diversity and production of different subclasses or classes of antibodies. The organization and processes take place during the development and differentiation of B cells. That is, the controlled gene expression during transcription and translation coupled with the rearrangements of immunoglobulin gene segments result in the generation of antibody repertoire during development and maturation of B cells.

Locus suicide recombination (LSR) constitutes a variant form of class switch recombination that eliminates all immunoglobulin heavy chain constant genes. It thus terminates immunoglobulin and B-cell receptor (BCR) expression in B-lymphocytes and results in B-cell death since survival of such cells requires BCR expression. This process is initiated by the enzyme activation-induced deaminase upon B-cell activation. LSR is thus one of the pathways that can result into activation-induced cell death in the B-cell lineage.

References

  1. ↑ Bauer G (2020). "The variability of the serological response to SARS-corona virus-2: Potential resolution of ambiguity through determination of avidity (functional affinity)". Journal of Medical Virology . 93 (1): 311–322. doi:10.1002/jmv.26262. PMC   7361859 . PMID   32633840.
  2. ↑ Eleonora Market, F. Nina Papavasiliou (2003) V(D)J Recombination and the Evolution of the Adaptive Immune System PLoS Biology1(1): e16.
  3. ↑ Stavnezer J, Amemiya CT (2004). "Evolution of isotype switching". Semin. Immunol. 16 (4): 257–75. doi:10.1016/j.smim.2004.08.005. PMID   15522624.
  4. ↑ Parham, Peter (2015). The Immune System (4th ed.). Garland Science.
  5. ↑ Durandy A (2003). "Activation-induced cytidine deaminase: a dual role in class-switch recombination and somatic hypermutation". Eur. J. Immunol. 33 (8): 2069–73. doi:10.1002/eji.200324133. PMID   12884279. S2CID   32059768.
  6. ↑ Casali P, Zan H (2004). "Class switching and Myc translocation: how does DNA break?". Nat. Immunol. 5 (11): 1101–3. doi:10.1038/ni1104-1101. PMC   4625794 . PMID   15496946.
  7. ↑ Stavnezer J, Guikema JE, Schrader CE (2008). "Mechanism and Regulation of Class Switch Recombination". Annu. Rev. Immunol. 26: 261–292. doi:10.1146/annurev.immunol.26.021607.090248. PMC   2707252 . PMID   18370922.
  8. ↑ Lieber MR, Yu K, Raghavan SC (2006). "Roles of nonhomologous DNA end-joining, V(D)J recombination, and class switch recombination in chromosomal translocations". DNA Repair (Amst.). 5 (9–10): 1234–45. doi:10.1016/j.dnarep.2006.05.013. PMID   16793349.
  9. ↑ Yan CT, Boboila C, Souza EK, Franco S, Hickernell TR, Murphy M, Gumaste S, Geyer M, Zarrin AA, Manis JP, Rajewsky K, Alt FW (2007). "IgH class switching and translocations use a robust non-classical end-joining pathway". Nature. 449 (7161): 478–82. Bibcode:2007Natur.449..478Y. doi:10.1038/nature06020. PMID   17713479. S2CID   4341381.
  10. ↑ Reynaud S, Delpy L, Fleury L, Dougier HL, Sirac C, Cogné M (May 2005). "Interallelic class switch recombination contributes significantly to class switching in mouse B cells". Journal of Immunology. 174 (10): 6176–83. doi: 10.4049/jimmunol.174.10.6176 . PMID   15879114.
  11. ↑ Laffleur B, Bardet SM, Garot A, Brousse M, Baylet A, Cogné M (2014). "Immunoglobulin genes undergo legitimate repair in human B cells not only after cis- but also frequent trans-class switch recombination". Genes and Immunity. 15 (5): 341–6. doi: 10.1038/gene.2014.25 . PMID   24848929.
  12. ↑ Janeway CA Jr.; Travers P; Walport M; Shlomchik MJ (2001). Immunobiology (5th ed.). Garland Publishing. ISBN   978-0-8153-3642-6. (via NCBI Bookshelf).
  13. ↑ Male D, Brostoff J, Roth DB, Roitt I (2006). Immunology, 7th ed. Philadelphia: Mosby Elsevier, ISBN   978-0-323-03399-2 (pbk.)
  14. ↑ Shparago, N.; Zelazowski, P.; Jin, L.; McIntyre, T. M.; Stuber, E.; Peçanha, L. M.; Kehry, M. R.; Mond, J. J.; Max, E. E. (1996-05-01). "IL-10 selectively regulates murine Ig isotype switching". International Immunology . 8 (5): 781–790. doi: 10.1093/intimm/8.5.781 . ISSN   0953-8178. PMID   8671667.
  15. ↑ Brière F, Servet-Delprat C, Bridon JM, Saint-Remy JM, Banchereau J (February 1994). "Human interleukin 10 induces naive surface immunoglobulin D+ (sIgD+) B cells to secrete IgG1 and IgG3". The Journal of Experimental Medicine. 179 (2): 757–62. doi:10.1084/jem.179.2.757. PMC   2191366 . PMID   8294883.
  16. ↑ Malisan F, Brière F, Bridon JM, Harindranath N, Mills FC, Max EE, Banchereau J, Martinez-Valdez H (March 1996). "Interleukin-10 induces immunoglobulin G isotype switch recombination in human CD40-activated naive B lymphocytes". The Journal of Experimental Medicine. 183 (3): 937–47. doi:10.1084/jem.183.3.937. PMC   2192363 . PMID   8642297.
  17. ↑ Pinaud E, Marquet M, Fiancette R, Péron S, Vincent-Fabert C, Denizot Y, Cogné M (2011). The IgH locus 3' regulatory region: pulling the strings from behind. Advances in Immunology. Vol. 110. pp. 27–70. doi:10.1016/B978-0-12-387663-8.00002-8. ISBN   978-0-12-387663-8. PMID   21762815.
  18. ↑ Péron S, Laffleur B, Denis-Lagache N, Cook-Moreau J, Tinguely A, Delpy L, Denizot Y, Pinaud E, Cogné M (May 2012). "AID-driven deletion causes immunoglobulin heavy chain locus suicide recombination in B cells". Science. 336 (6083): 931–4. Bibcode:2012Sci...336..931P. doi:10.1126/science.1218692. PMID   22539552. S2CID   1513560.
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