CD20

Last updated
MS4A1
Protein MS4A1 PDB 1S8B.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases MS4A1 , B1, Bp35, CD20, CVID5, LEU-16, MS4A2, S7, membrane spanning 4-domains A1, FMC7
External IDs OMIM: 112210 MGI: 88321 HomoloGene: 7259 GeneCards: MS4A1
Orthologs
SpeciesHumanMouse
Entrez

931

12482

Ensembl

ENSG00000156738

ENSMUSG00000024673

UniProt

P11836

P19437

RefSeq (mRNA)

NM_152866
NM_021950
NM_152867

NM_007641

RefSeq (protein)

NP_068769
NP_690605
NP_690606

NP_031667

Location (UCSC) Chr 11: 60.46 – 60.47 Mb Chr 19: 11.23 – 11.24 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

B-lymphocyte antigen CD20 or CD20 is expressed on the surface of all B-cells beginning at the pro-B phase (CD45R+, CD117+) and progressively increasing in concentration until maturity. [5]

Contents

In humans CD20 is encoded by the MS4A1 gene. [6] [7]

This gene encodes a member of the membrane-spanning 4A gene family. Members of this nascent protein family are characterized by common structural features and similar intron/exon splice boundaries and display unique expression patterns among hematopoietic cells and nonlymphoid tissues. This gene encodes a B-lymphocyte surface molecule that plays a role in the development and differentiation of B-cells into plasma cells. This family member is localized to 11q12, among a cluster of family members. Alternative splicing of the human MS4A1 gene results in at least three transcript variants (1 to 3) that encode the same protein. [7] Variants 1 and 2 are poorly translated due to inhibitory upstream open reading frames and stem-loop structures within their 5' untranslated regions. The relative abundance of translation-competent variant 3, as opposed to the poorly translated variants 1 and 2, may be a key determinant of CD20 levels in normal and malignant human B cells and their responses to CD20-directed immunotherapies. [8]

Function

The protein has no known natural ligand [9] and its function is to enable optimal B-cell immune response, specifically against T-independent antigens. [10] It is suspected that it acts as a calcium channel in the cell membrane. CD20 is induced in the context of microenvironmental interactions by CXCR4/SDF1 (CXCL12) chemokine signaling and the molecular function of CD20 has been linked to the signaling propensity of B-cell receptor (BCR) in this context. [11]

Expression

CD20 is expressed on all stages of B cell development except the first and last; it is present from late pro-B cells through memory cells, but not on either early pro-B cells or plasma blasts and plasma cells. [12] [13] It is found on B-cell lymphomas, hairy cell leukemia, B-cell chronic lymphocytic leukemia, and melanoma cancer stem cells. [14]

Immunohistochemistry can be used to determine the presence of CD20 on cells in histological tissue sections. Because CD20 remains present on the cells of most B-cell neoplasms, and is absent on otherwise similar appearing T-cell neoplasms, it can be very useful in diagnosing conditions such as B-cell lymphomas and leukaemias. However, the presence or absence of CD20 in such tumours is not relevant to prognosis, with the progression of the disease being much the same in either case. CD20 positive cells are also sometimes found in cases of Hodgkins disease, myeloma, and thymoma. [15]

Antibody FMC7 (Flinders Medical Centre) appears to recognise a conformational variant of CD20 [16] [17] also known as the FMC7 antigen. [18]

Clinical significance

CD20 is the target of the monoclonal antibodies rituximab, ocrelizumab, obinutuzumab, ofatumumab, ibritumomab tiuxetan, tositumomab, and ublituximab, which are all active agents in the treatment of all B cell lymphomas, leukemias, and B cell-mediated autoimmune diseases.

The anti-CD20 mAB ofatumumab (Genmab) was approved by FDA in October 2009 for chronic lymphocytic leukemia.

The anti-CD20 mAB obinutuzumab (Gazyva) was approved by FDA in November 2013 for chronic lymphocytic leukemia.

Ocrelizumab was approved by the FDA in March 2017 for multiple sclerosis as the first treatment of the primary progressive form of MS. Clinical trials in rheumatoid arthritis and systemic lupus erythematosus were discontinued in 2010 due to an infection related safety risk. [19]

Although phase II trials for the use of Rituximab in myalgic encephalomyelitis showed promising results, these could not be replicated in a large randomized controlled trial [20] and preliminary results from a Phase III trial were negative. [21]

Additional anti-CD20 antibody therapeutics under development (phase II or III clinical trials in 2008) include :

B cells, CD20, and diabetes mellitus

A link between the immune system's B cells and diabetes mellitus has been determined. [24] In cases of obesity, the presence of fatty tissues surrounding the body's major organ systems results in cell necrosis and insulin insensitivity along the boundary between them. Eventually, the contents of fat cells that would otherwise have been digested by insulin are shed into the bloodstream. An inflammation response that mobilizes both T and B cells results in the creation of antibodies against these cells, causing them to become less responsive to insulin by an as-yet-unknown mechanism and promoting hypertension, hypertriglyceridemia, and arteriosclerosis, hallmarks of the metabolic syndrome. Obese mice administered anti-B cell CD-20 antibodies, however, did not become less responsive to insulin and as a result, did not develop diabetes mellitus or the metabolic syndrome, the posited mechanism being that anti-CD20 antibodies rendered the T cell antibodies dysfunctional and therefore powerless to cause insulin insensitivity by a B cell antibody-modulated autoimmune response. The protection afforded by anti-CD-20 lasted approximately forty days—the time it takes the body to replenish its supply of B cells—after which repetition was necessary to restore it. Hence, it has been argued that diabetes mellitus be reclassified as an autoimmune disease rather than a purely metabolic one and focus treatment for it on immune system modulation. [25]

Related Research Articles

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A DNA vaccine is a type of vaccine that transfects a specific antigen-coding DNA sequence into the cells of an organism as a mechanism to induce an immune response.

<span class="mw-page-title-main">B cell</span> Type of white blood cell

B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasma membrane where they serve as a part of B-cell receptors. When a naïve or memory B cell is activated by an antigen, it proliferates and differentiates into an antibody-secreting effector cell, known as a plasmablast or plasma cell. In addition, B cells present antigens and secrete cytokines. In mammals, B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricius, a lymphoid organ where they were first discovered by Chang and Glick, which is why the B stands for bursa and not bone marrow, as commonly believed.

<span class="mw-page-title-main">CD23</span> Low-affinity" receptor for IgE

CD23, also known as Fc epsilon RII, or FcεRII, is the "low-affinity" receptor for IgE, an antibody isotype involved in allergy and resistance to parasites, and is important in regulation of IgE levels. Unlike many of the antibody receptors, CD23 is a C-type lectin. It is found on mature B cells, activated macrophages, eosinophils, follicular dendritic cells, and platelets.

<span class="mw-page-title-main">CD38</span> Protein-coding gene in the species Homo sapiens

CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase is a glycoprotein found on the surface of many immune cells (white blood cells), including CD4+, CD8+, B lymphocytes and natural killer cells. CD38 also functions in cell adhesion, signal transduction and calcium signaling.

<span class="mw-page-title-main">CD154</span> Protein-coding gene in humans

CD154, also called CD40 ligand or CD40L, is a protein that is primarily expressed on activated T cells and is a member of the TNF superfamily of molecules. It binds to CD40 on antigen-presenting cells (APC), which leads to many effects depending on the target cell type. In total CD40L has three binding partners: CD40, α5β1 integrin and integrin αIIbβ3. CD154 acts as a costimulatory molecule and is particularly important on a subset of T cells called T follicular helper cells. On TFH cells, CD154 promotes B cell maturation and function by engaging CD40 on the B cell surface and therefore facilitating cell-cell communication. A defect in this gene results in an inability to undergo immunoglobulin class switching and is associated with hyper IgM syndrome. Absence of CD154 also stops the formation of germinal centers and therefore prohibiting antibody affinity maturation, an important process in the adaptive immune system.

<span class="mw-page-title-main">Complement receptor 2</span> Mammalian protein found in Homo sapiens

Complement receptor type 2 (CR2), also known as complement C3d receptor, Epstein-Barr virus receptor, and CD21, is a protein that in humans is encoded by the CR2 gene.

<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">CD22</span> Lectin molecule

CD22, or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins. It is found on the surface of mature B cells and to a lesser extent on some immature B cells. Generally speaking, CD22 is a regulatory molecule that prevents the overactivation of the immune system and the development of autoimmune diseases.

CD70 is a protein that in humans is encoded by CD70 gene. CD70 is also known as a ligand for CD27.

<span class="mw-page-title-main">CD5 (protein)</span> Protein-coding gene in the species Homo sapiens

CD5 is a cluster of differentiation expressed on the surface of T cells and in a subset of murine B cells known as B-1a. The expression of this receptor in human B cells has been a controversial topic and to date there is no consensus regarding the role of this receptor as a marker of human B cells. B-1 cells have limited diversity of their B-cell receptor due to their lack of the enzyme terminal deoxynucleotidyl transferase (TdT) and are potentially self-reactive. CD5 serves to mitigate activating signals from the BCR so that the B-1 cells can only be activated by very strong stimuli and not by normal tissue proteins. CD5 was used as a T-cell marker until monoclonal antibodies against CD3 were developed.

<span class="mw-page-title-main">B-cell activating factor</span> Mammalian protein found in Homo sapiens

B-cell activating factor (BAFF) also known as tumor necrosis factor ligand superfamily member 13B and CD257 among other names, is a protein that in humans is encoded by the TNFSF13B gene. BAFF is also known as B Lymphocyte Stimulator (BLyS) and TNF- and APOL-related leukocyte expressed ligand (TALL-1) and the Dendritic cell-derived TNF-like molecule.

<span class="mw-page-title-main">C-C chemokine receptor type 7</span> Protein-coding gene in the species Homo sapiens

C-C chemokine receptor type 7 is a protein that in humans is encoded by the CCR7 gene. Two ligands have been identified for this receptor: the chemokines ligand 19 (CCL19/ELC) and ligand 21 (CCL21). The ligands have similar affinity for the receptor, though CCL19 has been shown to induce internalisation of CCR7 and desensitisation of the cell to CCL19/CCL21 signals. CCR7 is a transmembrane protein with 7 transmembrane domains, which is coupled with heterotrimeric G proteins, which transduce the signal downstream through various signalling cascades. The main function of the receptor is to guide immune cells to immune organs by detecting specific chemokines, which these tissues secrete.

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

CD83 is a human protein encoded by the CD83 gene.

<span class="mw-page-title-main">IKZF1</span> Protein-coding gene in the species Homo sapiens

DNA-binding protein Ikaros also known as Ikaros family zinc finger protein 1 is a protein that in humans is encoded by the IKZF1 gene.

<span class="mw-page-title-main">PRDM1</span> Protein-coding gene in the species Homo sapiens

PR domain zinc finger protein 1, or B lymphocyte-induced maturation protein-1 (BLIMP-1), is a protein in humans encoded by the gene PRDM1 located on chromosome 6q21. BLIMP-1 is considered a 'master regulator' of hematopoietic stem cells, and plays a critical role in the development of plasma B cells, T cells, dendritic cells (DCs), macrophages, and osteoclasts. Pattern Recognition Receptors (PRRs) can activate BLIMP-1, both as a direct target and through downstream activation. BLIMP-1 is a transcription factor that triggers expression of many downstream signaling cascades. As a fine-tuned and contextual rheostat of the immune system, BLIMP-1 up- or down-regulates immune responses depending on the precise scenarios. BLIMP-1 is highly expressed in exhausted T-cells – clones of dysfunctional T-cells with diminished functions due to chronic immune response against cancer, viral infections, or organ transplant.

<span class="mw-page-title-main">Lymphocyte-activation gene 3</span>

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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">Trogocytosis</span>

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B10 cells are a sub-class of regulatory B-cells that are involved in inhibiting immune responses in both humans and mice. B10 cells are named for their ability to produce inhibitory interleukin: Interleukin-10 (IL-10). One of their unique abilities is that they suppress the innate and adaptive immune signals, making them important for regulating the inflammatory response. Like the B cell, the B10 cell requires antigen specific binding to the surface of CD5 receptor to illicit a response from the T-cell. Once an antigen binds to the CD19 receptor, immediate downregulation in B-cell receptor (BCR) signal expression occurs and mediates the release of IL-10 cytokines. In mice and humans, B10 cells are distinguishable in their expression of measurable IL-10 due to the lack of unique cell surface markers expressed by regulatory B cells. However, IL-10 competence is not limited to any one subset of B cells. B10 cells do not possess unique phenotypic markers or transcription factors for further identification. B10 cells predominantly localize in the spleen, though they are also found in the blood, lymph nodes, Peyer's patches, intestinal tissues, central nervous system, and peritoneal cavity. B10 cells proliferate during inflammatory and disease responses.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000156738 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000024673 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Hardy R (2008). "Chapter 7: B Lymphocyte Development and Biology". In Paul W (ed.). Fundamental Immunology (Book) (6th ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 237–269. ISBN   978-0-7817-6519-0.
  6. ↑ Tedder TF, Streuli M, Schlossman SF, Saito H (January 1988). "Isolation and structure of a cDNA encoding the B1 (CD20) cell-surface antigen of human B lymphocytes". Proceedings of the National Academy of Sciences of the United States of America. 85 (1): 208–212. Bibcode:1988PNAS...85..208T. doi: 10.1073/pnas.85.1.208 . PMC   279513 . PMID   2448768.
  7. 1 2 "Entrez Gene: MS4A1 membrane-spanning 4-domains, subfamily A, member 1".
  8. ↑ Ang Z, Paruzzo L, Hayer KE, Schmidt C, Torres-Diz M, Xu F, et al. (September 2023). "Alternative splicing of its 5' UTR limits CD20 mRNA translation and enables resistance to CD20-directed immunotherapies". Blood. 142 (20): 1724–1739. doi: 10.1182/blood.2023020400 . PMC   10667349 . PMID   37683180. S2CID   261620430.
  9. ↑ Cragg MS, Walshe CA, Ivanov AO, Glennie MJ (2005). "The biology of CD20 and its potential as a target for mAb therapy". B Cell Trophic Factors and B Cell Antagonism in Autoimmune Disease. Current Directions in Autoimmunity. Vol. 8. pp. 140–74. doi:10.1159/000082102. ISBN   978-3-8055-7851-6. PMID   15564720.
  10. ↑ Kuijpers TW, Bende RJ, Baars PA, Grummels A, Derks IA, Dolman KM, et al. (January 2010). "CD20 deficiency in humans results in impaired T cell-independent antibody responses". The Journal of Clinical Investigation. 120 (1): 214–222. doi:10.1172/JCI40231. PMC   2798692 . PMID   20038800.
  11. ↑ Pavlasova G, Borsky M, Svobodova V, Oppelt J, Cerna K, Novotna J, et al. (September 2018). "Rituximab primarily targets an intra-clonal BCR signaling proficient CLL subpopulation characterized by high CD20 levels". Leukemia. 32 (9): 2028–2031. doi:10.1038/s41375-018-0211-0. PMID   30030508. S2CID   49895265.
  12. ↑ Walport M, Murphy K, Janeway C, Travers PJ (2008). Janeway's Immunobiology (7th ed.). New York: Garland Science. ISBN   978-0-8153-4123-9.
  13. ↑ Bonilla FA, Bona CA (1996). "5". Textbook of Immunology. Boca Raton: CRC. p. 102. ISBN   978-3-7186-0596-5.
  14. ↑ Fang D, Nguyen TK, Leishear K, Finko R, Kulp AN, Hotz S, et al. (October 2005). "A tumorigenic subpopulation with stem cell properties in melanomas". Cancer Research. 65 (20): 9328–9337. doi: 10.1158/0008-5472.CAN-05-1343 . PMID   16230395.
  15. ↑ Cooper K, Anthony Leong AS-Y (2003). Manual of diagnostic antibodies for immunohistology (2nd ed.). London: Greenwich Medical Media. ISBN   978-1-84110-100-2.
  16. ↑ Polyak MJ, Ayer LM, Szczepek AJ, Deans JP (July 2003). "A cholesterol-dependent CD20 epitope detected by the FMC7 antibody". Leukemia. 17 (7): 1384–1389. doi: 10.1038/sj.leu.2402978 . PMID   12835728.
  17. ↑ Serke S, Schwaner I, Yordanova M, Szczepek A, Huhn D (April 2001). "Monoclonal antibody FMC7 detects a conformational epitope on the CD20 molecule: evidence from phenotyping after rituxan therapy and transfectant cell analyses". Cytometry. 46 (2): 98–104. doi:10.1002/cyto.1071. PMID   11309819.
  18. ↑ Deans JP, Polyak MJ (February 2008). "FMC7 is an epitope of CD20". Blood. 111 (4): 2492, author reply 2493-2492, author reply 2494. doi: 10.1182/blood-2007-11-126243 . PMID   18263793.
  19. ↑ "Roche and Biogen Idec Announce Their Decision to Discontinue the ocrelizumab Clinical Development Programme in Patients with Rheumatoid Arthritis". investors.biogen.com. Retrieved 6 January 2022.
  20. ↑ Fluge Ø, Rekeland IG, Lien K, Thürmer H, Borchgrevink PC, Schäfer C, et al. (May 2019). "B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial". Annals of Internal Medicine. 170 (9): 585–593. doi:10.7326/M18-1451. PMID   30934066. S2CID   91186383.
  21. ↑ "ME-studie med negative resultater". Dagens Medicin (in Norwegian). Retrieved 6 January 2022.
  22. ↑ "Trubion announces Pfizer's decision to discontinue development of TRU-015 for RA". Trubion Pharmaceuticals, Inc. press release. 15 June 2010.
  23. ↑ Note: information included in this article only found in table present in print version of article.Morrow Jr KJ (15 June 2008). "Methods for Maximizing Antibody Yields". Genetic Engineering & Biotechnology News . Mary Ann Liebert, Inc. p. 36. Archived from the original on 13 February 2009. Retrieved 6 July 2008.
  24. ↑ Winer DA, Winer S, Shen L, Wadia PP, Yantha J, Paltser G, et al. (May 2011). "B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies". Nature Medicine. 17 (5): 610–617. doi:10.1038/nm.2353. PMC   3270885 . PMID   21499269.
  25. ↑ "Diabetes Mellitus". The Lecturio Medical Concept Library. Retrieved 9 July 2021.

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