B-lymphocyte antigen CD20 or CD20 is B lymphocyte cell-surface molecule.
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 MS4A1gene 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).
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]
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:
conserved expression CD20 is expressed on the surface of virtually all mature B-cells. The expression on malignous B-cells is also relatively constant.
limited off-target toxicity Anti-CD20 therapy does not affect hematopoietic stem cells and plasma cells, since they do not express CD20. It is important for B-cell repopulation following the therapy and retaining humoral protection against previously encountered pathogens via plasma cells, respectively.
epitope stability The extracellular loops of CD20 are conserved sequences and undergo only a little
post-translational modifications. It provides stable and predictable binding epitopes for mAbs.
Mechanism
Mechanism of action of anti-CD20 effects include:[11][17]
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 :
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]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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.
ISBN978-0-7817-6519-0.
^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.
ISBN978-3-8055-7851-6.
PMID15564720.
^Cooper K, Anthony Leong AS-Y (2003). Manual of diagnostic antibodies for immunohistology (2nd ed.). London: Greenwich Medical Media.
ISBN978-1-84110-100-2.
^"Diabetes Mellitus". The Lecturio Medical Concept Library. Retrieved 9 July 2021.
Further reading
Macardle PJ, Nicholson IC (2003). "CD20". Journal of Biological Regulators and Homeostatic Agents. 16 (2): 136–138.
PMID12144126.
Tamayose K, Sato N, Ando J, Sugimoto K, Oshimi K (December 2002). "CD3-negative, CD20-positive T-cell prolymphocytic leukemia: case report and review of the literature". American Journal of Hematology. 71 (4): 331–335.
doi:
10.1002/ajh.10224.
PMID12447967.
S2CID23999423.
Shirakawa T, Li A, Dubowitz M, Dekker JW, Shaw AE, Faux JA, et al. (June 1994). "Association between atopy and variants of the beta subunit of the high-affinity immunoglobulin E receptor". Nature Genetics. 7 (2): 125–129.
doi:
10.1038/ng0694-125.
PMID7920628.
S2CID24026689.
Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174.
doi:
10.1016/0378-1119(94)90802-8.
PMID8125298.
Szepetowski P, Perucca-Lostanlen D, Gaudray P (June 1993). "Mapping genes according to their amplification status in tumor cells: contribution to the map of 11q13". Genomics. 16 (3): 745–750.
doi:
10.1006/geno.1993.1257.
PMID8325649.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156.
doi:
10.1016/S0378-1119(97)00411-3.
PMID9373149.