Allelic exclusion

Last updated

Allelic exclusion is a process by which only one allele of a gene is expressed while the other allele is silenced. [1] This phenomenon is most notable for playing a role in the development of B lymphocytes, where allelic exclusion allows for each mature B lymphocyte to express only one type of immunoglobulin. This subsequently results in each B lymphocyte being able to recognize only one antigen. [2] This is significant as the co-expression of both alleles in B lymphocytes is associated with autoimmunity and the production of autoantibodies. [3]

Contents

Many regulatory processes can lead to allelic exclusion. In one instance, one allele of the gene can become transcriptionally silent, resulting in the transcription and expression of only the other allele. [2] This could be caused in part by decreased methylation of the expressed allele. [4] Conversely, allelic exclusion can also be regulated through asynchronous allelic rearrangement. [5] In this case, both alleles are transcribed but only one becomes a functional protein. [2]

In B-lymphocytes

Allelic exclusion has been observed most often in genes for cell surface receptors and has been extensively studied in immune cells such as B lymphocytes. Allelic exclusion of immunoglobulin (Ig) heavy chain and light chain genes in B cells forms the genetic basis for the presence of only a single type of antigen receptor on a given B lymphocyte, which is central in explaining the ‘one B cell — one antibody’ rule. [6] The variable domain of the B-cell antigen receptor is encoded by the V, (D), and J gene segments, the recombination of which gives rise to Ig gene allelic exclusion. V(D)J recombination occurs imprecisely, so that while transcripts from both alleles are expressed, only one is able to give rise to a functional surface antigen receptor. If no successful rearrangement occurs on either chromosome, the cell dies.

Models

Stochastic

In the stochastic model, while the Ig rearrangement is proposed to be very efficient, the probability of functional allelic rearrangement is assumed to be very low as compared to the probability of non-functional rearrangement. [7] As a result, successful recombination of more than one functional Ig allele in one B cell statistically occurs very infrequently. [8]

Asynchronous recombination

In the asynchronous recombination models, the recombination process is controlled by timing of recombination-activating gene (RAG) recombinase and accessibility of each Ig allele within the chromatin structure. [7]

  1. Asynchronous Probabilistic Recombination Model: This probabilistic model relies on the mechanisms which control chromatin accessibility. The limited accessibility of Ig alleles due to chromatin structure leads to low efficiency of recombination therefore, the probability of biallelic rearrangement is negligible. [7]
  2. Asynchronous Instructive Recombination Model: The instructive model is based on the difference in timing of allele replication, wherein the alleles undergo recombination sequentially. In this model the second allele undergoes rearrangement only if the first rearrangement was unsuccessful. [7] [9]

Classic feedback inhibition

The feedback inhibition model is similar to the asynchronous recombination mode, but it emphasizes the mechanisms that maintain the rearrangement asynchrony. This model suggests that a recombination which gives rise to a functional B cell surface receptor will cause a series of signals which suppress further recombination. [10] Without these signals, allelic rearrangement will carry on.  The classic feedback model is empirically corroborated by observed recombination ratios. [10]

In Igκ and Igλ light chain genes

The allelic exclusion of light chain genes Igκ and Igλ is a process that is controlled by the monoallelic initiation of V(D)J recombination. While little is known about the mechanism leading to the allelic exclusion of Igλ genes, the Igκ locus is generally inactivated by RAG-mediated deletion of the exon Cκ. The V(D)J recombination step is a random and non-specific process that occurs one allele at a time where segments V, (D) and J are rearranged to encode the variable region, resulting in a fraction of functional genes with a productive V(D)J region. [11] Allelic exclusion is then enforced via feedback inhibition where the functional Ig gene inhibits V(D)J rearrangement of the second allele. While this feedback mechanism is mainly achieved through inhibition of the juxtaposition of V and D-J segments, the down-regulation of transcription and suppression of RAG accessibility also plays a role. [12]

In sensory neurons

Vomeronasal sensory neurons are found in the vomeronasal organ at the nasal septum base and their specialty is in pheromone detection. [13] [14] [15] [16] [17] [18] A vomeronasal receptor, V1R, exhibits allelic exclusion. When a V1R receptor gene is expressed, an odorant receptor gives negative feedback that prevents transcription of other V1R receptor genes. [13] [14] [15] [16] In mice vomeronasal sensory neurons, an odorant receptor coding sequence's exogenous transcription from a V1R promoter can stop endogenous V1R genes from being transcribed. [13] [14] [15] [16] They [13] also obtained data supporting monoallelic expression of V1rb2mv and V1rb2vg alleles and monogenic expression of the V1rb2 locus. [13]

Monoallelic expression was also found in mice olfactory receptor genes in olfactory sensory neurons. [14] [15] [16] An upstream cis-acting DNA region controls an olfactory receptor gene cluster's activation and resulted in monogenic expression of one olfactory receptor gene. [14] [15] [16] The expressed coding region's disruption or deletion resulted in expression of a second olfactory receptor gene. [15] Based on this, they [15] hypothesized that in order to enforce the "one receptor-one neuron rule” (Serizawa et al, 2003 [15] ), one olfactory receptor gene's random activation and the expressed gene product's negative feedback are necessary. [14] [15] [16]

Recent research

Intracellular GATA3 expression is a crucial component of T cell receptor beta (TCR𝛽) allelic exclusion in mammalian cells. [14] [15] [16] [19] [20] GATA3 transgenic overexpression by a 2.5- to 5-fold increase partly due to Gata3 transcriptional activation from monoallelic to biallelic primarily resulted in both alleles of TCR𝛽 recombining. [14] Intracellular GATA3 expression can divide wild-type immature thymocyte cell populations. [14] [15] [16] [19] [20] Although cells regardless of GATA3 expression level yielded functional TCR𝛽 sequences, there was nearly sole recombination of one Tcrb locus in lowly expressed GATA3 cells and constant recombination of both alleles in highly expressed GATA3 cells. [14]

V𝛽 Recombination signal sequences (RSSs) with poor qualities suppressed one allele's expression of two TCR𝛽 genes. [21] [22] These poor quality V𝛽 RSSs decreased the chances of upstream V𝛽 and V31 recombination on the same allele, which in turn enabled functional TCR𝛽 genes’ monoallelic assembly and expression. [21] [22] However, poor quality V𝛽 RSSs were unlikely to result in monogenic TCR𝛽 expression alone and might have involved other epigenetic processes. [21] [22] RSSs is involved in mammalian TCR𝛽 genes’ monogenic assembly and expression and may also be involved in other mammalian TCR-related genes. [21] Low quality V𝛽 recombinase targets randomly constrain two functional rearrangements’ production which imposes TCR𝛽 allelic exclusion. [22]

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), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the pathogen, called an antigen. Each tip of the "Y" of an antibody contains a paratope that is specific for one particular epitope on an antigen, allowing these two structures to bind together with precision. Using this binding mechanism, an antibody can 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">Major histocompatibility complex</span> Cell surface proteins, part of the acquired immune system

The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are called MHC molecules.

<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">Memory B cell</span>

In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiescent state, sometimes for decades. Their function is to memorize the characteristics of the antigen that activated their parent B cell during initial infection such that if the memory B cell later encounters the same antigen, it triggers an accelerated and robust secondary immune response. Memory B cells have B cell receptors (BCRs) on their cell membrane, identical to the one on their parent cell, that allow them to recognize antigen and mount a specific antibody response.

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.

Killer-cell immunoglobulin-like receptors (KIRs), are a family of type I transmembrane glycoproteins expressed on the plasma membrane of natural killer (NK) cells and a minority of T cells. At least 15 genes and 2 pseudogenes encoding KIR map in a 150-kb region of the leukocyte receptor complex (LRC) on human chromosome 19q13.4.

<span class="mw-page-title-main">CD19</span> Biomarker for B cell lineage

B-lymphocyte antigen CD19, also known as CD19 molecule, B-Lymphocyte Surface Antigen B4, T-Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein that in humans is encoded by the gene CD19. In humans, CD19 is expressed in all B lineage cells. Contrary to some early doubts, human plasma cells do express CD19, as confirmed by others. CD19 plays two major roles in human B cells: on the one hand, it acts as an adaptor protein to recruit cytoplasmic signaling proteins to the membrane; on the other, it works within the CD19/CD21 complex to decrease the threshold for B cell receptor signaling pathways. Due to its presence on all B cells, it is a biomarker for B lymphocyte development, lymphoma diagnosis and can be utilized as a target for leukemia immunotherapies.

<span class="mw-page-title-main">Immunoglobulin class switching</span> Biological mechanism

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. 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. 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.

B1 cells are a sub-class of B cell lymphocytes that are involved in the humoral immune response. They are not part of the adaptive immune system, as they have no memory, but otherwise, B1 cells perform many of the same roles as other B cells: making antibodies against antigens and acting as antigen-presenting cells. These B1 cells are commonly found in peripheral sites, but less commonly found in the blood. These cells are involved in antibody response during an infection or vaccination.

<span class="mw-page-title-main">CD83</span>

CD83 is a human protein encoded by the CD83 gene.

<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">VPREB1</span> Protein-coding gene in the species Homo sapiens

Immunoglobulin iota chain is a protein that in humans is encoded by the VPREB1 gene. VPREB1 has also recently been designated CD179A.

<span class="mw-page-title-main">FCGR2B</span>

Fc fragment of IgG receptor IIb is a low affinity inhibitory receptor for the Fc region of immunoglobulin gamma (IgG). FCGR2B participates in the phagocytosis of immune complexes and in the regulation of antibody production by B lymphocytes.

<span class="mw-page-title-main">LILRA3</span> Protein-coding gene in the species Homo sapiens

Leukocyte immunoglobulin-like receptor subfamily A member 3 (LILR-A3) also known as CD85 antigen-like family member E (CD85e), immunoglobulin-like transcript 6 (ILT-6), and leukocyte immunoglobulin-like receptor 4 (LIR-4) is a protein that in humans is encoded by the LILRA3 gene located within the leukocyte receptor complex on chromosome 19q13.4. Unlike many of its family, LILRA3 lacks a transmembrane domain. The function of LILRA3 is currently unknown; however, it is highly homologous to other LILR genes, and can bind human leukocyte antigen (HLA) class I. Therefore, if secreted, the LILRA3 might impair interactions of membrane-bound LILRs with their HLA ligands, thus modulating immune reactions and influencing susceptibility to disease.

<span class="mw-page-title-main">CD79A</span> Mammalian protein found in Homo sapiens

Cluster of differentiation CD79A also known as B-cell antigen receptor complex-associated protein alpha chain and MB-1 membrane glycoprotein, is a protein that in humans is encoded by the CD79A gene.

<span class="mw-page-title-main">CD79B</span> Mammalian protein found in Homo sapiens

CD79b molecule, immunoglobulin-associated beta, also known as CD79B, is a human gene.

Recombination signal sequences are conserved sequences of noncoding DNA that are recognized by the RAG1/RAG2 enzyme complex during V(D)J recombination in immature B cells and T cells. Recombination signal sequences guide the enzyme complex to the V, D, and J gene segments that will undergo recombination during the formation of the heavy and light-chain variable regions in T-cell receptors and immunoglobulin molecules.

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.

Monoallelic gene expression (MAE) is the phenomenon of the gene expression, when only one of the two gene copies (alleles) is actively expressed (transcribed), while the other is silent. Diploid organisms bear two homologous copies of each chromosome (one from each parent), a gene can be expressed from both chromosomes (biallelic expression) or from only one (monoallelic expression). MAE can be Random monoallelic expression (RME) or Constitutive monoallelic expression (constitutive). Constitutive monoallelic expression occurs from the same specific allele throughout the whole organism or tissue, as a result of genomic imprinting. RME is a broader class of monoallelic expression, which is defined by random allelic choice in somatic cells, so that different cells of the multi-cellular organism express different alleles.

References

  1. Korochkin LI, Grossman A (1981). "The Phenomenon of Allelic Exclusion". Gene Interactions in Development. Monographs on Theoretical and Applied Genetics. Vol. 4. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 108–124. doi:10.1007/978-3-642-81477-8_4. ISBN   978-3-642-81479-2.
  2. 1 2 3 Levin-Klein R, Bergman Y (December 2014). "Epigenetic regulation of monoallelic rearrangement (allelic exclusion) of antigen receptor genes". Frontiers in Immunology. 5: 625. doi: 10.3389/fimmu.2014.00625 . PMC   4257082 . PMID   25538709.
  3. Pelanda R (April 2014). "Dual immunoglobulin light chain B cells: Trojan horses of autoimmunity?". Current Opinion in Immunology. 27: 53–9. doi:10.1016/j.coi.2014.01.012. PMC   3972342 . PMID   24549093.
  4. Schroeder HW, Imboden JB, Torres RM (2019-01-01). "Chapter 4: Antigen Receptor Genes, Gene Products, and Coreceptors". In Rich R, Fleisher TA, Shearer WT, Schroeder HW (eds.). Clinical Immunology (Fifth ed.). London: Elsevier. pp. 55–77.e1. doi:10.1016/b978-0-7020-6896-6.00004-1. ISBN   978-0-7020-6896-6.
  5. Jackson A, Kondilis HD, Khor B, Sleckman BP, Krangel MS (February 2005). "Regulation of T cell receptor beta allelic exclusion at a level beyond accessibility". Nature Immunology. 6 (2): 189–97. doi:10.1038/ni1157. PMID   15640803. S2CID   24687496.
  6. Burnet FM (1959). The clonal selection theory of acquired immunity. Nashville, Temessee: Vanderbilt University Press. doi:10.5962/bhl.title.8281.
  7. 1 2 3 4 Vettermann C, Schlissel MS (September 2010). "Allelic exclusion of immunoglobulin genes: models and mechanisms". Immunological Reviews. 237 (1): 22–42. doi:10.1111/j.1600-065x.2010.00935.x. PMC   2928156 . PMID   20727027.
  8. Coleclough C, Perry RP, Karjalainen K, Weigert M (April 1981). "Aberrant rearrangements contribute significantly to the allelic exclusion of immunoglobulin gene expression". Nature. 290 (5805): 372–8. Bibcode:1981Natur.290..372C. doi:10.1038/290372a0. PMID   6783959. S2CID   2267279.
  9. Matthias P (2001-11-23). Faculty Opinions recommendation of Asynchronous replication and allelic exclusion in the immune system. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature (Report). doi: 10.3410/f.1002314.23155 .
  10. 1 2 "Immunoglobulin Heavy Chain Variable, Diversity, and Joining Region Gene Rearrangement". National Cancer Institute Thesaurus.
  11. Mostoslavsky R, Alt FW, Rajewsky K (September 2004). "The lingering enigma of the allelic exclusion mechanism". Cell. 118 (5): 539–44. doi: 10.1016/j.cell.2004.08.023 . PMID   15339659.
  12. Brady BL, Steinel NC, Bassing CH (October 2010). "Antigen receptor allelic exclusion: an update and reappraisal". Journal of Immunology. 185 (7): 3801–8. doi: 10.4049/jimmunol.1001158 . PMC   3008371 . PMID   20858891.
  13. 1 2 3 4 5 Capello L, Roppolo D, Jungo VP, Feinstein P, Rodriguez I (February 2009). "A common gene exclusion mechanism used by two chemosensory systems". The European Journal of Neuroscience. 29 (4): 671–8. doi:10.1111/j.1460-9568.2009.06630.x. PMC   3709462 . PMID   19200072.
  14. 1 2 3 4 5 6 7 8 9 10 Monahan K, Lomvardas S (2015-11-13). "Monoallelic expression of olfactory receptors". Annual Review of Cell and Developmental Biology. 31 (1): 721–40. doi:10.1146/annurev-cellbio-100814-125308. PMC   4882762 . PMID   26359778.
  15. 1 2 3 4 5 6 7 8 9 10 11 Serizawa S, Miyamichi K, Nakatani H, Suzuki M, Saito M, Yoshihara Y, Sakano H (December 2003). "Negative feedback regulation ensures the one receptor-one olfactory neuron rule in mouse". Science. 302 (5653): 2088–94. Bibcode:2003Sci...302.2088S. doi: 10.1126/science.1089122 . PMID   14593185. S2CID   26055164.
  16. 1 2 3 4 5 6 7 8 Lewcock JW, Reed RR (January 2004). "A feedback mechanism regulates monoallelic odorant receptor expression". Proceedings of the National Academy of Sciences of the United States of America. 101 (4): 1069–74. Bibcode:2004PNAS..101.1069L. doi: 10.1073/pnas.0307986100 . PMC   327152 . PMID   14732684.
  17. Shykind BM, Rohani SC, O'Donnell S, Nemes A, Mendelsohn M, Sun Y, et al. (June 2004). "Gene switching and the stability of odorant receptor gene choice". Cell. 117 (6): 801–15. doi: 10.1016/j.cell.2004.05.015 . PMID   15186780.
  18. Serizawa S, Ishii T, Nakatani H, Tsuboi A, Nagawa F, Asano M, et al. (July 2000). "Mutually exclusive expression of odorant receptor transgenes". Nature Neuroscience. 3 (7): 687–93. doi:10.1038/76641. PMID   10862701. S2CID   1019250.
  19. 1 2 Hosoya T, Maillard I, Engel JD (November 2010). "From the cradle to the grave: activities of GATA-3 throughout T-cell development and differentiation". Immunological Reviews. 238 (1): 110–25. doi:10.1111/j.1600-065X.2010.00954.x. PMC   2965564 . PMID   20969588.
  20. 1 2 Ho IC, Tai TS, Pai SY (February 2009). "GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiation". Nature Reviews. Immunology. 9 (2): 125–35. doi:10.1038/nri2476. PMC   2998182 . PMID   19151747.
  21. 1 2 3 4 Wu GS, Bassing CH (August 2020). "Inefficient V(D)J recombination underlies monogenic T cell receptor β expression". Proceedings of the National Academy of Sciences of the United States of America. 117 (31): 18172–18174. Bibcode:2020PNAS..11718172W. doi: 10.1073/pnas.2010077117 . PMC   7414081 . PMID   32690689.
  22. 1 2 3 4 Wu GS, Yang-Iott KS, Klink MA, Hayer KE, Lee KD, Bassing CH (September 2020). "Poor quality Vβ recombination signal sequences stochastically enforce TCRβ allelic exclusion". The Journal of Experimental Medicine. 217 (9). doi: 10.1084/jem.20200412 . PMC   7478721 . PMID   32526772.

Further reading