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 Table of Contents  
REVIEW ARTICLE
Year : 2015  |  Volume : 6  |  Issue : 3  |  Page : 93-105

Neural cell adhesion molecule(cluster of differentiation 56) in health and disease


1 Department of Adult Hematology/BMT, Comprehensive Cancer Center, King Fahad Medical City, Riyadh, Saudi Arabia
2 National Blood and Cancer Center, King Abdullah Road, Riyadh, Saudi Arabia

Date of Web Publication18-Sep-2015

Correspondence Address:
Syed Z. A Zaidi
Department of Adult Hematology/BMT, Comprehensive Cancer Center, King Fahad Medical City, P. O. Box: 59046, Riyadh 11525
Saudi Arabia
Login to access the Email id

Source of Support: Nil., Conflict of Interest: There are no conflicts of interest.


DOI: 10.4103/1658-5127.165655

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  Abstract 

Cluster of differentiation (CD) 56, a member of the immunoglobulin superfamily, and an isoform of neural cell adhesion molecule (NCAM), was the first cell adhesion molecule to be identified. NCAM (CD56) plays an important role both in human health and in disease. Human NCAM gene is located on chromosome 11q23. CD56 antigen is a 175–185-kD cell surface glycoprotein expressed on all subsets of human natural killer (NK) cells except a small minority of CD56 NK-cell, on subsets of CD4+/CD8+ T-cells, interleukin-2-activated thymocytes, bone marrow macrophages, osteoclasts, and on adrenal gland and neural tissues. NCAM is important in calcium independent cell-cell interactions that mediate homotypic and heterotypic cell-cell and cell-matrix adhesions. At least 27 alternatively spliced NCAM mRNAs are produced giving a wide diversity to NCAM isoforms sharing a similar structural organization. NCAM in the cerebellum and cerebral cortex mediates homophilic adhesion of neural cells, and plays an important role in brain development, emotions, and memory functions. While CD56+ NK-cells play an important role in defense against infections, tumor remission, normal pregnancy and graft rejection. Malignancies expressing CD56 are usually aggressive, with more potential for metastasis and extramedullary/central nervous system involvement, and may respond to new CD56-linked targeted therapies.

Keywords: Cluster of differentiation 56, infection, malignancies, natural killer-cells, neural cell adhesion molecule


How to cite this article:
Zaidi SZ, Motabi IH, Al-Shanqeeti A. Neural cell adhesion molecule(cluster of differentiation 56) in health and disease. J Appl Hematol 2015;6:93-105

How to cite this URL:
Zaidi SZ, Motabi IH, Al-Shanqeeti A. Neural cell adhesion molecule(cluster of differentiation 56) in health and disease. J Appl Hematol [serial online] 2015 [cited 2018 Jan 17];6:93-105. Available from: http://www.jahjournal.org/text.asp?2015/6/3/93/165655


  Introduction Top


Cluster of differentiation (CD) 56, a member of the immunoglobulin (Ig) superfamily, and an isoform of neural cell adhesion molecule (NCAM), is thefirst cell adhesion molecule to have been identified. At least 27 alternatively spliced NCAM mRNAs produce several isoforms.[1] Human NCAM gene is located on chromosome 11q23. The CD56 antigen, recognized by the monoclonal antibodies anti-Leu-19 and NKH-1 in tissues, is a 175–185-kD type-1 cell surface glycoprotein [Figure 1].[2],[3] CD56 contains a 689 amino acid extracellular domain which contains 5 Ig-like C2-type domains, 2 fibronectin type-3 domains and 6 potential N-glycosylation sites [partially depicted in [Figure 1]. CD56 is expressed on all subsets of human natural killer (NKs) cells except a small minority of CD56 NKs, CD4+ and CD8+ subsets, interleukin-2 (IL-2)-activated thymocytes, blood monocyte subset, bone marrow macrophages, osteoclasts, adrenals, and neural tissues (neurons and glia).[2],[3]
Figure 1: Neural cell adhesion molecule/CD56 ribbon structure and immunohistochemical expression in natural killer/T-cell lymphoma. (a) Neural cell adhesion molecule IgI-IgII quaternary ribbon structure and homophilic binding shown using the A-B dimer. Two IgI-IgII molecules form a cross shaped homodimer. Molecule A is shown in blue and molecule B in magenta with their individual domains labeled IgI and IgII.[3] (b) Immunohistochemistry revealing strong cluster of differentiation expression in a nasal-type natural killer/T-cell lymphoma (×400)

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NCAM is important for calcium independent cell-cell interactions that mediate cell-cell and cell-matrix adhesions. CD56 has a clear function in homotypic binding to CD56 molecules on other cells. CD56 in the cerebellum and cerebral cortex (on neurons, astrocytes, and Schwann cells) predominantly mediates hemophilic adhesion of neural cells.[4] CD56+ NKs are important in defense against viral infections, tumor remission, and graft rejection.[5]

Malignancies expressing CD56 are usually aggressive, with more potential for metastasis and extramedullary/central nervous system (CNS) involvement, and may respond to new CD56-linked targeted therapies. This aspect will be reviewed later elsewhere due to space limitations.


  Cd56 in Normal Development Top


Neuronal Development and Intercellular Communication

During development, CD56 is abundantly expressed in the fetal nervous system, involving its adhesion mechanisms, formation of the neural circuit, and development of the muscles.[4],[6] IgCAMs are involved in brain development, and in maintenance and function of the neural network in adults.[7] Additionally, heterophilic adhesion by CD56 occurs between neuronal cells and chondroitin sulfate proteoglycans of cell matrix. NCAM maintains groups of cells at key sites during early development and in adulthood.

The binding of NCAM to cells leads to signaling events, some of which result in changes in gene expression.[2] NCAMs induce neurite outgrowth through fibroblast growth factor receptor (FGFR) and acts on p59Fyn signaling pathway. The developmental events (including cell migration, proliferation, and differentiation) can result both from their adhesive and signaling properties.[2]

The hypothesized combined factors that control the expression of CAMs during early neural development include the coordinate expression of homeobox and paired box (Hox and Pax) proteins in the neural axis leading to the differential expression of particular CAM genes.[8]

Functional assays of Schwann cell migration and axon growth of CNS neurons suggest physiological significance for the glial cell line-derived neurotrophic factor and its receptor NCAM.[9],[10]

CD56 in Emotions and Learning-Role of Fibroblast Growth Factor Loop Peptide

A plethora of work suggests that NCAM is required in the adult brain for different behavioral functions.[11] Posttranslational attachment of polysialic acid (PSA) to NCAM (PSA-NCAM) provides an additional mechanism for synaptic control. NCAM180, an isoform enriched at postsynaptic sites in CNS, may have prominent role in synaptic stability and memory formation.[11],[12] NCAM and PSA-NCAM regulate emotion, learning, memory processes, including the modulation of learning induced by emotional aspects. Plappert et al. experiments on null mutant (NCAM −/−) mice and their wild type littermates (NCAM +/+) mice suggest NCAM role in the relevant brain areas, like amygdala and/or the hippocampus.[13] A 15-amino acid peptide, mimicking second FnIII module of NCAM, termed the fibroblast growth loop (FGL) peptide, binds to and activate FGFR1 and stimulates neurite outgrowth.[14] FGL strongly enhances spatial memory, spatial learning, and emotional learning.[11] The evidence supports the use of NCAM-related compounds, like FGL peptide, for the treatment of devastating neurological disorders like Alzheimer's disease (AD).[11]

In summary, NCAM is functional during development and in neuroplastic processes underlying memory formation in mature brain.[13],[15]


  Ageing and Cd56 Top


CD6 may have a role in senescence and creation of a functionally distinct immunologic environment in old age. Ageing in the immune system leads to contraction of the lymphocyte repertoire causing loss of adaptive immunity with relative preservation of innate immunity. There is a decline in the absolute number of CD4+ and CD8+ T-lymphocytes and B-cells with relative increase in CD56+ NKs, such that the overall lymphocyte count does not change.[16] Thymic involution and a dramatic reduction in the naïve T-cell pool and relative increase in memory T-cells occur. Progressive exhaustion of CD8+ subset causes loss of costimulatory molecules (CD28), shortening of telomeres, and terminal differentiation to end stage.[17]

By monitoring of T-cells senescence, Lemster et al. have shown an age-dependent de novo induction of CD56 in fresh T-cells from blood.[18] These unusual T-cells expressing high levels of Bcl2, p16, and p53, had limited or completely lost ability to undergo cell division. CD56 cross-linking without T-cell receptor (TCR) ligation on CD56+ T-cells resulted in extensive protein phosphorylation, NF-κB activation, Bax down-regulation and production of various humoral factors.[18] Authors proposed that CD56+ T-cells are unique effectors capable of mediating TCR-independent immune cascades and possibly increased protective immunity in the elderly.[18]


  Cd56 in Pregnancy and Abortions Top


CD56 may facilitate implantation of fertilized ovum in endometrial bed and progression of early phase of pregnancy. The preimplantation endometrium and early pregnancy decidua possess a unique immune environment, characterized by the presence of large numbers of uterine-specific NK-cells (uNKs) (also called decidual-NK), along with progesterone levels and smaller population of macrophages.[19]

The uNKs reach 70–80% of total leukocytes infirst trimester, then start to decline, and return to basal levels at the end of pregnancy.[20] These uNKs consist of CD56high CD16 CD3 type.

When compared with the two major subsets of peripheral blood NK-cells (pbNKs), uNKs have different gene microarray profile with immunomodulatory potential exclusive to uNKs.[21] Although they contain cytotoxic granules and express killer immunoglobulin-like receptor (KIR), they are weakly cytolytic exvivo.[21] Recruitment and functional properties of uNKs are influenced by IL-15 and IL-11, produced by the decidua, and progesterone.[22],[23],[24],[25] Lack of inflammatory and cytotoxic lymphocytes, together with the interactions between uNKs and fetal trophoblasts, create an environment permissive to embryo implantation and good pregnancy outcome.[21],[25],[26],[27]

The causes of spontaneous abortion are mainly chromosomal anomalies (50–60% of early spontaneous abortions); and/or maternal factors.[28],[29] NKs may determine the fate of pregnancy and are important in abortion with normal chromosomes.[30] CD56+ CD16 NKs secrete various cytokines, including macrophage colony-stimulating factor (M-CSF) and granulocyte macrophage-CSF, that promote placental growth. CD56+ 16 3 NKs in decidua of chromosomally normal abortions were significantly lower than those of chromosomally abnormal abortions.[28]

Among the many KIRs, KIR2DL4 is phylogenetically conserved, nonpolymorphic class Ib, human leukocyte antigen G (the only KIR member expressed by all human NKs).

Yan et al. reveal that KIR2DL4 protein level on pbNKs cells was much higher in normal pregnant women than early recurrent spontaneous abortions patients, indicating KIR2DL4 role in maintaining pregnancy.[31]

A shift of Th1-dominant to Th2-dominant status by fashionable paternal lymphocyte immunization might play a role in maintaining successful pregnancies.[32] However, a systematic review of the literature indicated that more studies are needed to confirm or refute the role of pbNKs or pbNK parameters assessments as a predictive test for screening women who may benefit from immunotherapy.[33]


  Infections and Variable Cd56 Expression on Natural Killer-Cell Subsets Top


Innate and adaptive immune responses cooperate to protect the host against microbial infections. NK-cells provide a link between innate and adaptive immunity. CD56+ NKs provide innate immunity against microbes. They can lyse tumor and virally transformed target cells without prior sensitization in the early stages of an immune response. NK-mediated pathogen recognition and NKs activation, involves toll-like receptors (TLRs) and activating KIRs.[34] TLRs are germ-line encoded pattern-recognition receptors that recognize pathogens triggering innate responses and shaping subsequent adaptive immune responses. Certain TLRs (TLR1, 2, 4, 5, and 6) are expressed on the cell surface, whereas others (TLR3, 7, 8, and 9) are localized in intracellular compartments (i.e., endosomes). Therefore, their ligands require internalization to generate signals.[34]

NK-cells constitute 10–15% of the circulating lymphocytes and have cytolytic activity against pathogen infected cells.[35] The highest CD56 expression is by NKs of the liver and decidua. Based on cell surface density of CD56 and CD16, NKs are divided into CD56dim CD16+ NKs (more cytotoxic and 90% of blood total NKs) and CD56bright CD16 (~10%) which are immunoregulatory working principally through cytokine production. Although CD56 NKs exist in healthy individuals, but are very low percent of total blood NKs. NK-cell subsets according to CD56 expression differ in surface/cytoplasmic molecules and functional properties [Table 1]. Activated NKs express CD69, while apoptotic NKs express dim annexin-v.
Table 1: Some differences in surface/cytoplasmic molecules and functional properties of NK-cell subsets according to CD56 expression[36],[37]


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Viral infections may have a significant impact on NKs maturation, promoting the expansion of phenotypically and functionally aberrant NK subpopulations. An imbalance of NKs subsets, has been detected in hematopoietic stem cell transplantation (HSCT) recipients for high risk leukemias and experiencing human cytomegalovirus (HCMV) infection/reactivation. Curiously, NKs developing after CMV reactivation may contain "memory-like" or "long-lived" NKs that could exert a potent antileukemia effect.[34] The role of various subsets of NKs in some of the most common infections is summarized in the following paragraphs.

HIV Infection

NKs arefirst line of defence against acute viral infections and influence the course of chronic viral infections, like HIV-1 and hepatitis C virus (HCV). Chronic stages of these infections have a negative impact on NKs function and promote the appearance of phenotypically and functionally abnormal NK-cells including CD56 negative NK-cells [Figure 2].[36] A subset of CD3 CD56 CD16+ NKs subset is highly expanded during chronic HIV-1 infection and a subset of it are CD7+ CD56 CD16+ NK-cells. These are activated mature NKs that may have recently engaged target cells.[38]
Figure 2: Changes in distribution of peripheral blood natural killer cells subsets (CD56 bright, CD56dim, and CD56) in patients with acute or chronic HIV/hepatitis C virus infection, pre- and post-antiviral treatment and/or immunotherapy. Variation in the relative size of the CD56−, CD56dim and CD56bright natural killer cell subset after therapy is depicted by arrows. CD56− natural killer cells are increased in numbers during chronic hepatitis C virus or HIV infection. HAART: highly active antiretroviral therapy[36]

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An aberrant CD56 NKs subset is greatly expanded in HIV-viremia.[34] The number and percentage of CD16+ CD56+ NKs (>90% NKs in healthy adults) are severely decreased even in HIV-seropositive nonAIDS subjects with >800 CD4+ cells/mm 3; and CD16+ CD56 subset, that is rare in healthy adults, is elevated.[34] CD3 CD56dim subset expands in primary HIV infection compared to healthy controls.[39] Tarazona et al. demonstrated the decreased expression of CD56 on peripheral blood CD8bright T-cells from HIV-infected individuals.[40] Low CD56+ NKs may lead to a rapid progression (within 70 months following seroconversion) to AIDS.[41]

Hepatitis C Virus Infection

CD56+ NKs are important in HCV infection. Decreased hepatic CD56+ NKs in late-stage HCV disease may be a risk factor for the development of hepatocellular carcinoma.[42] Paradoxically, increased CD56bright NKs that produce more interferon-gamma (IFN-γ) might contribute to T-cell polarization and liver damage.[43],[44]

Lin et al. observed that CD3 CD56+ NKs are decreased in HCV-infected patients.[42] Additionally, without pegylated-interferon-alpha (PEG-IFN-α)-2b stimulation, HCV patients had fewer activated bright (CD3 CD56+bright CD69+) and activated dim (CD3 CD56+dim CD69+) NKs compared to controls, suggesting alteration in immunoregulatory and cytotoxic function of NKs. Moreover, dim (CD3 CD56+dim) NK-cell turnover is enhanced in the sustained viral responder patients. By increasing dim NK-cell activation and augmenting NK-cell cytotoxicity through increased perforin/granzyme release, PEG-IFN-α may augment the decline in HCV RNA.[42] Pretreatment higher percentage of CD56 NKs is a predictor of peg-IFN-α and ribavirin treatment failure, and may identify patients likely to benefit from novel combination regimens including HCV protease inhibitors.[45]

Like HIV-1-infected patients, a skewed CD56 NK population with limited polyfunctionality expands in patients with chronic HCV making CD56 NKs a possible cellular immunological biomarker of HCV treatment outcome that merits further investigation.[45]

Björkström et al. reported that CD56 NKs are increased during chronic HCV or HIV infection.[36] Treatment with IFN-α and ribavirin, for chronic HCV, or highly active antiretroviral therapy for chronic HIV, returns the CD56 NKs to levels found in healthy individuals [36] [Figure 2].

Epstein–Barr Virus Infection

CD56bright NKs controls the primary Epstein–Barr virus (EBV) infection by eliminating infected B-cells and augmenting the antigen-specific T-cell response via release of immunomodulatory cytokines.[46] NKs were significantly elevated up to a month following diagnosis of infectious mononucleosis and increased CD56bright cells with enhanced ability to kill EBV-infected cell lines were observed at diagnosis.[46]

Cytomegalovirus Infection

HCMV infection is common when T-cell immunity is impaired like in HIV-infection, congenitally immunodeficient and patients undergoing HSCT. A dramatic expansion of NKG2C+ NKs happens in HCMV (and HIV1) infections.[44] In HSCT recipients, CD56+ NKs maturation is skewed toward highly differentiated stages that look like "memory-like" NKs possibly contributing to the control of HCMV reactivation.[34] In the absence of NKG2C, the activating KIRs may contribute in the control of CMV infections.[34],[47] A reduced risk of HCMV reactivation has been reported in solid organ transplant recipients expressing two or more activating KIRs, HSCT recipient from donors expressing two or more activating KIRs.[34],[48]

Recent studies suggested a correlation between early HCMV reactivation and reduction of leukemia relapses after allogeneic HSCT in adult patients.[49],[50] A fraction of HCMV-reactivating patients showed an unusual hypofunctional CD56 CD16+ (mostly mature KIR + NKG2A ) NKs subset expansion previously reported in HIV and HCV infections.[34],[51]

Tuberculosis

Tuberculosis is another prevalent human disease where CD56+ NK T-cells have role in early eradication of the disease by antituberculous therapy. Veenstra et al. found that high counts of CD3dim/CD56+ NK T-cells at diagnosis correlated significantly with negative sputum culture after 8 weeks of treatment.[52] Interestingly, a higher absolute pbNKs count, which may be the result of an inability of these cells to migrate into infected tissues, was partially indicative of a slow response to treatment.[52]

Increased percentage of CD56bright NKs was found in individuals with positive tuberculin skin test. They are protected from active tuberculosis by the CD56bright NKs secreting high amounts of IFN-γ.[53] A direct interaction with extracellular mycobacteria may induce NK activation and cytokine secretion by these innate cells.[34],[53],[54]

Malaria

Malaria, along with tuberculosis and infection with HIV, is one of the three most important infectious diseases worldwide. Blood CD56+ T-cells are important in the immune response to intracellular pathogens like Plasmodium falciparum and Plasmodium vivax. In both mouse and human models of malaria, NKs are major source of proinflammatory cytokine IFN-γ during the early phase of infection.[55] Watanabe et al. found that the proportion of CD56+ T-cells, CD57+ T-cells, and γδ T-cells (i.e., all unconventional T-cells with NK markers) had increased in early phase of infection with P. falciparum or P. vivax.[56]


  Neuronal Degenerative Disorders Top


The NCAM, is a key mediator of axonal/dendritic growth, branching, synaptic strength, and plasticity and is important in cognitive function (see above). NCAM has been attributed to susceptibility risk for neuropsychiatric disorders like schizophrenia, bipolar disorder, depression, and anxiety disorder, and AD that have cognitive dysfunction as a core feature.[57] The isoform NCAM180 interacts with cytoskeletal components and may be important in synaptic stability and memory formation.[12] PSA-NCAM is a highly glycosylated form of NCAM that is required for synaptic plasticity and is increased during learning and memory formation.[12],[58] How alterations in NCAM may disrupt normal connectivity leading to cognitive dysfunction is being explored to understand complexities of various neuropsychiatric and neurodegenerative disorders specifically schizophrenia and AD.[57]

Schizophrenia

Schizophrenia affects approximately 1% of the world's population [59] with psychosis being the most common clinical feature, but cognitive dysfunction (memory, executive control/information processing, and attention) may be more disabling and can predict long-term outcome.[60],[61] Though environmental risk factors also exist, several genes have been proposed as vulnerability loci, among them modulations in NCAM is also implicated.

In a meta-analysis of schizophrenia susceptibility loci, NCAM was ranked fourth.[62] The reported NCAM modulations in schizophrenia include: Single nucleotide polymorphisms in NCAM, polysialyltransferase ST8Sia II (STX), low PSA-NCAM and high NCAM cleavage.[57],[63],[64],[65],[66]

Increases in the levels of a soluble NCAM fragments, cleaved from NCAM by ADAM (a disintegrin and metalloprotease) type proteases specifically ADAM10 and ADAM17,[62],[67],[68],[69],[70] have been correlated with disease severity and duration in schizophrenia.[66],[71],[72],[73]

Mice lacking only NCAM180 display increased lateral ventricles (the most reliable morphological feature in the schizophrenic brain), and learning deficit and prepulse inhibition of acoustic startle;[74],[75] while mice lacking all isoforms of NCAM have abnormalities in the hippocampus and olfactory bulb, without ventricular enlargement.[76],[77],[78],[79],[80]

Alzheimer's Disease

AD, predominantly a disease of the elderly population except rare familial form, is the most common neurodegenerative disease, affecting more than 20 million people worldwide.[81],[82] Affected brain regions are hippocampus, frontal cortex in addition to general brain atrophy. Neurofibrillary plaques and tangles in the brain which are composed of amyloid b and Tau proteins, respectively, are the hallmark features of AD.[81],[82] Total amyloid b levels are important for the progression of AD and resulting cognitive dysfunction.[81],[83] Several NCAM modulations have been reported in in AD including low NCAM, high PSA-NCAM, high NCAM cleavage, low HNK-1 glycosylation, and low NCAM signaling.[57] The dysregulated production of amyloid b and Tau associated with AD also affects NCAM expression and function.

The peptide derivatives of NCAM are currently in clinical trials as a potential treatment for AD. An ideal AD drug would reduce amyloid b and/or Tau levels, foster neuronal connectivity, stop neuron loss, and improve cognition and memory.[57] The FGL peptide is a short NCAM peptide of the FGFR binding site from Glu681-Ala695, which seemingly meets these criteria and FGL may also have curative potential. Experiments suggest that regulating NCAM signaling in the brain may provide a novel treatment possibility for AD.[57]

Targeted inhibition of NCAM cleavage in the brain could help alleviate AD. However, currently available metalloprotease inhibitors produce various nonneuronal side effects such as rheumatoid arthritis (RA), tendonitis, fibroplasias, or exacerbate pulmonary disease or cancer.[84] PSA with NCAM may help in improving plasticity, thereby alleviate the learning and memory deficits [85],[86],[87] and allow axonal growth and synaptogenesis.[88],[89]


  Fetal Alcohol Spectrum Disorders Top


Fetal alcohol spectrum disorders (FASDs) are a group of conditions occurring in 1–5/1000 live births of alcoholic mothers, the most common preventable cause of mental retardation in the Western world. Severe cases of FASD shows growth deficiency, neurological abnormalities, and facial malformations.[90] Prenatal ethanol exposure disrupts domain interface between Ig1 and Ig4 of NCAM-L1 causing abnormal neuronal development.[91]


  Paroxysmal Nocturnal Hemoglobinuria Top


Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired bone marrow disease characterized by intravascular hemolysis, increased risk of thrombosis, and variable degrees of pancytopenia.[92] PNH results from an acquired mutation in the X-linked PIG-A gene in the hematopoietic stem cell (HSC), leading to a clone with deficient expression of glycosyl-phosphatidylinositol (GPI)-anchored proteins, especially the complement inhibitors CD59 and CD55 on erythrocytes, causing chronic intravascular hemolysis upon complement activation.[92] The clinical evolution of PNH requires clonal expansion of PIG-A-mutated HSC that may occur as small clone(s) in few healthy individuals.[92] Number of CD8+ T-cells expressing CD56 and activating NKRs increases in PNH which in some cases may exhibit increased lysis of GPI + (vs. GPI ) hematopoietic cells causing cytopenias.[93] However, multiple factors influence whether GPI-dependent lysis occurs.[93]


  Autoimmune Disorders Top


Multiple Sclerosis

Multiple sclerosis (MS) is an inflammatory/demyelinating disease of the CNS that is one of the leading causes of neurological disability in young adults. Pathogenetic studies have indicated that autoimmune T-cells targeting myelin components play a crucial role in mediating the inflammatory process, particularly in the early stages of relapsing–remitting MS.[94]

Takahashi et al. demonstrated that NK-cells in MS-remitting type (but not MS-relapsing type) show elevation of IL-5 mRNA and a higher percentage of CD95+ cells among the CD56+ NK-cells,[95],[96] indicating that NK-cells may regulate activation of autoimmune memory T-cells in an antigen nonspecific fashion to maintain the clinical remission in “CD95+ NK-high” MS patients.[95],[96] When MS was treated with IFN-β, an expansion of CD56bright NK-cells was observed with a concomitant decrease of CD56dim cells after 12 months of treatment.[44]

The search for new therapies in the recent past has focused on agents that affect lymphocyte function. Daclizumab, a humanized mAb that blocks the IL-2 binding site on the IL-2Rα chain (CD25), is among these novel agents. Administration of daclizumab strongly reduces brain inflammation in MS patients. Daclizumab therapy was associated with a gradual decline in circulating CD4+ and CD8+ T-cells and significant expansion of CD56bright NK-cells in >vivo, and this effect correlated highly with the treatment response.[44],[97]

Pertinently, because the regulatory properties of the newly described RUNX1 splice variants extend beyond CD56 to other RUNX1 target genes, the recent results of Gattenloehner et al.[98] could be therapeutically relevant for RUNX1-related gene regulation in a broad spectrum of clinical settings, including autoimmune diseases like MS.[94],[95],[96],[97]

Rheumatoid Arthritis, Systemic Lupus Erythematosus, and Autoimmune Thyroid Disorders

Although the identity of antigens driving T-cell oligoclonality in RA remains elusive, the physiologic inflammatory environment of RA is clearly permissive of the persistent oligoclonal expansion of CD28 T-cells that have acquired the prototypic NK receptor CD56. These CD56+ T-cells have features of senescence and are potential targets for therapy.[99] In RA, the synovial fluid of the patients almost exclusively contains CD56bright KIR NK-cells.[44]

In systemic lupus erythematosus, increased proportion of CD56bright NK-cells are described regardless of disease activity.[44]

CD56 has been detected in the thyroid follicular cells (thyrocytes) immunohistologically. In autoimmune disorders thyroid cells express the 140- and 180-kD forms of NCAM (not the 120 kD NCAM isoform which is predominantly expressed in normal and well differentiated tissues).[100] CD56 expression in thyrocytes of surgical specimens was found to be increased in 11/17 (64%) of Graves', in 5/25 (20%) of multinodular goitre and in occasional adenoma glands. It was often seen in areas infiltrated by macrophages.[100]

In another pilot study of thyroid FNAC, 96% of the samples positive for malignancy did not show any follicular cell with CD56 expression. CD56 may be an additional marker for ruling out papillary thyroid carcinoma (PTC) especially when used in conjunction with HBME-1 and Galectin-3.[101]


  Cd56 Isoforms Expression in Malignancies and Therapeutic Implications Top


Among all diseases, the role of CD56 in cancer is perhaps the most extensively studied one, and due to great heterogeneity of disorders and huge available data, a detailed review of it, along with anti-CD56 antibody therapies and NK-cell based cellular therapies, will be covered later elsewhere. Only the main highlights of the role of CD56 in cancer will be briefly covered here.

CD56 is variably expressed on many tumor cells [Table 2]. CD56 has a clear function in homotypic binding to CD56 molecules on other cells. Alternative mRNA splicing results in three major isoforms. A 120 kDa NCAM isoform connected by a GPI anchor to the cell membrane which is predominantly expressed in normal and well differentiated tissues. The 140 and 180 kDa isoforms (which contains a transmembrane domain) are found predominantly in less differentiated embryonic or malignant cell types, thereby expression of NCAM shifts from the NCAM120 isoform to the NCAM140 and NCAM180 isoforms in cancer.[136],[137],[138]
Table 2: Expression of CD56 in selected malignancies

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Many recent reports correlate CD56 overexpression with an aggressive clinical phenotype in a variety of hematological malignancies, including acute myeloid leukemia (both in acute promyelocytic leukemia [APL] and non-APL),[98],[122],[123],[124],[125],[126],[127],[128],[129],[130],[131],[132] acute lymphoblastic leukemia,[133],[134],[135] and Anaplastic large cell lymphoma.[112] Whereas CD56 expression is also reported in majority of cases of multiple myeloma,[121],[139],[140] NK-cell leukemia and lymphomas, γδ T-cell lymphomas,[35],[110] various cutaneous lymphomas,[109] T-cell large granular lymphocyte leukemia (aggressive forms),[35],[111] and blastic plasmacytoid dendritic cell neoplasm.[141],[142],[143] In myelodysplastic syndromes patients widespread numerical, structural and functional NK-cell defects have been recently reported; and deficiency of functionally competent NK-cells might contribute to disease progression through impaired immune surveillance.[144]

Several common solid tumors such as colorectal carcinoma with brain metastasis,[145] small cell lung cancer (SCLC),[104],[106],[107],[146],[147],[148] metastatic renal cancer,[113] melanoma,[103] neuroblastoma,[102],[103],[104] rhabdomyosarcoma,[102],[105] paraganglioma, pheochromocytoma, and brain tumors such as astrocytoma,[102],[104] Ewing sarcoma,[108] primary gastrointestinal leiomyomas,[114] small cell carcinoma of esophagus,[116] gastrointestinal stromal tumors,[114] and rare malignant neuroendocrine tumors like Merkel cell carcinoma also express CD56 frequently.[118] The reported frequencies in selected malignancies are summarized in [Table 2]. Malignancies expressing CD56 are usually aggressive, with more potential for metastasis and extramedullary/CNS involvement, and may respond to new CD56-linked targeted therapies.

From the spectrum of existing anti-CD56 compounds, an antibody–drug conjugates consisting of Anti-CD56 antibody attached to a potent antimicrotubular cytotoxic agent DM-1 (a maytasinoid effector molecule) is Lorvotuzumab mertansine (LM, also known as IMGN901).[119],[149],[150] Once bound to CD56, IMGN901 is internalized into a cancer cell and its DM1 is released to cause cell death via inhibition of tubulin polymerization. Overall it is the most advanced anti-CD56 therapeutic strategy and clinical usage has produced promising results in trials setting both as single agent (in many cancers), and in combination with chemotherapy (for myeloma and SCLC).[104],[117],[118],[119],[139],[140],[146],[149],[150],[151],[152],[153],[154],[155],[156],[157],[158],[159],[160]

Acknowledgments

Authors would like to thank for assistance provided by:

  • Dr. Mohammad Yunus, Associate Professor and Hematopathologist, Department of Pathology King Fahd Hospital of the University, College of Medicine University of Dammam, Dammam, Saudi Arabia (for professionally reviewing and editing the text)
  • Mr. AbdulRehman Zia Zaidi, Final year MBBS student at Alfaisal University, Riyadh, Saudi Arabia (in preparation of this manuscript).


Financial Support and Sponsorship

Nil.

Conflicts of Interest

There are no conflicts of interest.

 
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Introduction
Cd56 in Normal D...
Ageing and Cd56
Cd56 in Pregnanc...
Infections and V...
Neuronal Degener...
Fetal Alcohol Sp...
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Autoimmune Disorders
Cd56 Isoforms Ex...
Introduction
Cd56 in Normal D...
Ageing and Cd56
Cd56 in Pregnanc...
Infections and V...
Neuronal Degener...
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Paroxysmal Noctu...
Autoimmune Disorders
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