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; OMA:MS4A1 - orthologs
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 B lymphocyte cell-surface molecule.

Contents

It is a 33-37 kDa non-glykosylated protein. CD20 is expressed on the surface of B-cells from the pre-B phase, the expression is lost in terminally differentiated plasma cells. [5] [6]

CD20 is used as a therapeutical target of B-cell malignancies and autoimmune diseases. [6]

Gene

In humans CD20 is encoded by the MS4A1 gene localized to 11q12. [7] [8]

The gene is 16 kbp long and consists of 8 exons. There are at least 3 mRNA transcripts (resulting from alternative splicing), that are all translated into an identical full-lenght CD20 protein product. [6] [8] 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. [9]

MS4A1 gene is 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 non-lymphoid tissues. [8]

Structure

CD20 is a transmembrane protein consisting of four hydrophobic transmembrane domains, one intracellular domain and two extracellular loops. There are three different forms of CD20 according to variable phosphorylation.

CD20 is located on the cell surface as homo-dimeric and homo-tetrameric oligomers. It is associated with other cell-surface and cytoplasmic proteins connected to the signal transduction (CD53, CD81, CD82).

CD20 is also known to be physically coupled to major histocompatibility complex class II (MHCII), CD40 and B-cell receptor (BCR). [6]

Function

The biological function of CD20 as well as its natural ligand is not fully elucidated. [6] [10]

CD20 deletion in mice does not impair B-cell differentiation, isotype switch, maturation, proliferation or tissue localization. However, CD20−/− mice show decreased humoral immunity responses in both T-cell dependent and T-cell independent manner. [6]

Functional studies suggest that CD20 molecule is required for efficient BCR signaling. It possibly acts as a calcium channel (CD20 has structural similarities with some known ion channels) or is directly connected to calcium flux.

It is not fully understood, if other molecular pathways or B and T-cell interactions might be affected by CD20 levels on the B-cell surface. [6] [11]

Expression

CD20 is expressed on all stages of B cell development from pre-B cells in the bone-marrow through immature, naive, mature and memory cells in lymphoid tissues and blood. The expression is lost on plasma blasts and plasma cells. [12] [13]

CD20 is a marker of B cell malignancies. 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]

Even though B cells represent the majority of CD20+ cells, a subset of CD3+ T cells also expresses CD20. CD20+ T cells are mostly CD8+ effector memory T cells with proinflammatory features. Further work is needed to understand the contribution of these cells to immune responses. [16]

Anti-CD20 monoclonal antibodies

The targeting of CD20 molecule is highly effective way to deplete B-cell populations. [11] Thus, anti-CD20 monoclonal antibodies (mAbs) play a crucial role in the management of B cell malignancies as well as some inflammatory and autoimmune diseases. The first anti-CD20 mAb approved by FDA in 1997 was Rituximab , defining a new epoch in hematooncology.

The advantages of CD20 as a therapeutic target are:

Mechanism

Mechanism of action of anti-CD20 effects include: [11] [17]

In clinical practise

Examples of anti-CD20 mAbs and their approval status: [17]

Generic nameFormatIndicationApproval status

(FDA/EMA)

Rituximab chimeric IgG1 NHL 1998/1997
Ibritumomabmouse IgG1NHL2002/2004
Ofatumumabhuman IgG1 CLL 2009/2009
Obinutuzumabhumanized IgG1CLL2013/2014
Ocrelizumabhumanized IgG1 MS 2017/under review
Veltuzumabhumanized IgG1NHL, CLL, ITP clinical trials
Ublituximabchimeric IgG1CLL, MSclinical trials
Ocaratuzumabhumanized IgG1CLLclinical trials

CD20 is the target of the mAbs 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. [18]

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 [19] and preliminary results from a Phase III trial were negative. [20]

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

Clinical significance

Diabetes mellitus

A link between the immune system's B cells and diabetes mellitus has been determined. [23]

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. [24]

Related Research Articles

<span class="mw-page-title-main">DNA vaccine</span> Vaccine containing DNA

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, including marsupials 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">Memory B cell</span> Cell of the adaptive immune system

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.

<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">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> Protein found in humans

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">Fas receptor</span> Protein found in humans

The Fas receptor, also known as Fas, FasR, apoptosis antigen 1, cluster of differentiation 95 (CD95) or tumor necrosis factor receptor superfamily member 6 (TNFRSF6), is a protein that in humans is encoded by the FAS gene. Fas was first identified using a monoclonal antibody generated by immunizing mice with the FS-7 cell line. Thus, the name Fas is derived from FS-7-associated surface antigen.

<span class="mw-page-title-main">CCL21</span> Mammalian protein found in Homo sapiens

Chemokine ligand 21 (CCL21) is a small cytokine belonging to the CC chemokine family. This chemokine is also known as 6Ckine, exodus-2, and secondary lymphoid-tissue chemokine (SLC). CCL21 elicits its effects by binding to a cell surface chemokine receptor known as CCR7. The main function of CCL21 is to guide CCR7 expressing leukocytes to the secondary lymphoid organs, such as lymph nodes and Peyer´s patches.

<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.

<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">CD81</span> Mammalian protein found in Homo sapiens

CD81 molecule, also known as CD81, is a protein which in humans is encoded by the CD81 gene. It is also known as 26 kDa cell surface protein, TAPA-1, and Tetraspanin-28 (Tspan-28).

<span class="mw-page-title-main">CD7</span> Mammalian protein found in Homo sapiens

CD7 is a protein that in humans is encoded by the CD7 gene.

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

Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biological effects on T cell function but overall has an immune inhibitory effect. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.

<span class="mw-page-title-main">CD200</span> Protein-coding gene in the species Homo sapiens

OX-2 membrane glycoprotein, also named CD200 is a human protein encoded by the CD200 gene. CD200 gene is in human located on chromosome 3 in proximity to genes encoding other B7 proteins CD80/CD86. In mice CD200 gene is on chromosome 16.

<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">Trogocytosis</span>

Trogocytosis is when a cell nibbles another cell. It is a process whereby lymphocytes conjugated to antigen-presenting cells extract surface molecules from these cells and express them on their own surface. The molecular reorganization occurring at the interface between the lymphocyte and the antigen-presenting cell during conjugation is also called "immunological synapse".

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. 1 2 3 4 5 6 7 Pavlasova G, Mraz M (June 2020). "The regulation and function of CD20: an "enigma" of B-cell biology and targeted therapy". Haematologica. 105 (6): 1494–1506. doi:10.3324/haematol.2019.243543. PMC   7271567 . PMID   32482755.
  7. ↑ 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.
  8. 1 2 3 "Entrez Gene: MS4A1 membrane-spanning 4-domains, subfamily A, member 1".
  9. ↑ Ang Z, Paruzzo L, Hayer KE, Schmidt C, Torres Diz M, Xu F, et al. (November 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.
  10. ↑ 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.
  11. 1 2 3 Casan JM, Wong J, Northcott MJ, Opat S (2 December 2018). "Anti-CD20 monoclonal antibodies: reviewing a revolution". Human Vaccines & Immunotherapeutics. 14 (12): 2820–2841. doi:10.1080/21645515.2018.1508624. PMC   6343614 . PMID   30096012.
  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. ↑ de Sèze J, Maillart E, Gueguen A, Laplaud DA, Michel L, Thouvenot E, et al. (23 March 2023). "Anti-CD20 therapies in multiple sclerosis: From pathology to the clinic". Frontiers in Immunology. 14: 1004795. doi: 10.3389/fimmu.2023.1004795 . PMC   10076836 . PMID   37033984.
  17. 1 2 Marshall MJ, Stopforth RJ, Cragg MS (4 October 2017). "Therapeutic Antibodies: What Have We Learnt from Targeting CD20 and Where Are We Going?". Frontiers in Immunology. 8: 1245. doi: 10.3389/fimmu.2017.01245 . PMC   5632755 . PMID   29046676.
  18. ↑ "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.
  19. ↑ 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.
  20. ↑ "ME-studie med negative resultater". Dagens Medicin (in Norwegian). Retrieved 6 January 2022.
  21. ↑ "Trubion announces Pfizer's decision to discontinue development of TRU-015 for RA". Trubion Pharmaceuticals, Inc. press release. 15 June 2010.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ "Diabetes Mellitus". The Lecturio Medical Concept Library. Retrieved 9 July 2021.

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