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Keywords:

  • leukocyte markers;
  • tissue distribution;
  • cell receptor;
  • ectoenzymes;
  • calcium homeostasis

Abstract

  1. Top of page
  2. Abstract
  3. THE CD38 GENE FAMILY
  4. TISSUE DISTRIBUTION OF CD38 AND CD157
  5. CD38 AS A RECEPTOR
  6. CD157 AS A RECEPTOR
  7. CD38 AND CD157 ENZYMATIC FUNCTIONS
  8. CD38 AND DISEASE
  9. CD157 AND DISEASE
  10. ROLE OF THE CD38 FAMILY IN OTHER HUMAN DISEASES
  11. EMERGING WORKING HYPOTHESIS
  12. Acknowledgments
  13. LITERATURE CITED

CD38 (also known as T10) was identified in the late 1970s in the course of pioneering work carried out at the Dana-Farber Cancer Center (Boston, MA) that focused on the identification of surface molecules involved in antigen recognition. CD38 was initially found on thymocytes and T lymphocytes, but today we know that the molecule is found throughout the immune system, although its expression levels vary. Because of this, CD38 was considered an “activation marker,” a term still popular in routine flow cytometry. This review summarizes the findings obtained from different approaches, which led to CD38 being re-defined as a multifunctional molecule. CD38 and its homologue CD157 (BST-1), contiguous gene duplicates on human chromosome 4 (4p15), are part of a gene family encoding products that modulate the social life of cells by means of bidirectional signals. Both CD38 and CD157 play dual roles as receptors and ectoenzymes, endowed with complex activities related to signaling and cell homeostasis. The structure-function analysis presented here is intended to give clinical scientists and flow cytometrists a background knowledge of these molecules. The link between CD38/CD157 and human diseases will be explored here in the context of chronic lymphocytic leukemia, myeloma and ovarian carcinoma, although other disease associations are also known. Thus CD38 and CD157 have evolved from simple leukocyte activation markers to multifunctional molecules involved in health and disease. Future tasks will be to explore their potential as targets for in vivo therapeutic interventions and as regulators of the immune response. © 2013 International Clinical Cytometry Society

CD38, also known as T10, epitomizes a story shared by several other molecules, identified within a project aimed at probing the cell surface of human leukocytes using murine monoclonal antibodies (mAbs), reagents which became available in the late 1970s. Both probes and targets were unknown, prompting scientists to devise original strategies in order to identify the structure and functions of the target molecules. The Leukocyte Workshop adopted a strategy that proved successful in the early days of HLA studies: when two or more mAbs reacted with the same target, they were said to form a cluster centered on an unknown molecule. This approach (Cluster Designation, CD) made it possible to identify an amazing number of surface molecules in a limited number of years. However, it took many more years to identify the functions exerted in vivo by the majority of these molecules, an effort still far from being concluded.

CD38 was identified during the pioneering work of E.L. Reinherz (Dana-Farber Cancer Center, Boston, MA) [1], focused on the identification of membrane molecules involved in antigen recognition. The fact that those studies were performed in a medical institution influenced the first part of CD38′s life history. The molecule was found in thymocytes and in activated normal lymphocytes, and also in selected leukemias and myelomas [2]. Its initial deployment in clinical diagnosis gave CD38 the label of “activation marker,” a term still quite popular in routine flow cytometry.

This review will attempt to summarize and update the findings obtained from different areas of research, which led to the redefinition of CD38 as a multifunctional molecule. We now know that CD38 is joined by CD157 (also referred to as bone marrow stromal cell antigen 1, BST-1) in being part of a gene family coding for products that modulate the social life of cells by means of bidirectional signals (from outside to inside and vice versa). Besides being receptors, the same molecules act also as ectoenzymes, endowed with complex activities.

A complete analysis of the structure and functions of CD38 and CD157 in humans is intended to give clinical scientists and flow cytometrists access to background knowledge which is usually found only within the realm of basic science [3]. The hope is that this set of information may improve the reading and comprehension of results obtained daily in clinics.

THE CD38 GENE FAMILY

  1. Top of page
  2. Abstract
  3. THE CD38 GENE FAMILY
  4. TISSUE DISTRIBUTION OF CD38 AND CD157
  5. CD38 AS A RECEPTOR
  6. CD157 AS A RECEPTOR
  7. CD38 AND CD157 ENZYMATIC FUNCTIONS
  8. CD38 AND DISEASE
  9. CD157 AND DISEASE
  10. ROLE OF THE CD38 FAMILY IN OTHER HUMAN DISEASES
  11. EMERGING WORKING HYPOTHESIS
  12. Acknowledgments
  13. LITERATURE CITED

CD38 and CD157 genes are located on human chromosome 4 (4p15) [4, 5] (Fig. 1). Over 98% of the 70 kb CD38 gene is represented by intronic sequences. The gene encompasses 8 exons: the largest, exon 1, determines the intracytoplasmic and transmembrane regions and the 33 membrane-proximal amino acids of the extracellular region [6, 7]. CD38 expression appears to be under quite complex multilayered transcriptional regulation. The first layer of control lies in the promoter region characterized by the lack of a TATA box and the presence of a CpG island [6], a methylation-controlled region more frequently associated with housekeeping than tissue-specific genes. A second layer of control is likely to be upstream of the CpG island, where potential binding site for transcription factors (e.g., T cell transcription factor-1, nuclear factor for interleukin-6) lie [6], while a third level of gene control lies within the first intron of the CD38 gene. The 5′-end of the intron 1 contains responsive elements for retinoic acid [8] and peroxisome proliferator-activated receptor γ (PPARγ) [9]. Intron 1 is also the location of a single nucleotide polymorphism (SNP) [10] that binds the transcription factor E2A [11] and whose variants are differentially expressed in pathology (vide infra).

image

Figure 1. Schematic representation of human chromosome 4, with attention to CD38 (and its regulatory elements) and CD157. The right side shows the schematic features of membrane CD38 and CD157 proteins.

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The CD157 gene extends for over 35 kb, very close to its paralogue CD38 and consists of nine exons [4, 12]. CD38 and CD157 are highly conserved, as demonstrated by the fact that exons 2-8 are similar in length and maintain the same phase of intron insertion [13]. The 5′-flanking region of the human CD157 gene shows consensus sequences for interferon responsive elements (γ-IREs and ISRE-like), for nuclear transcription factors (E2A, AP2, AP3, PEA3, C/EBP, CREB, Sp1), for cytokine-responsive factors (NF-IL-6, NF-κB), and for p53 [4]. This gene also lacks a TATA box, suggesting multiple transcription start sites [4, 14]. All these elements suggest that the CD157 gene may be upregulated by events such as DNA damage, inflammation and infection, whereas NF-IL-6 and NF-κB binding sites may explain the increased expression of the CD157 molecule in patients affected by rheumatoid arthritis [12].

TISSUE DISTRIBUTION OF CD38 AND CD157

  1. Top of page
  2. Abstract
  3. THE CD38 GENE FAMILY
  4. TISSUE DISTRIBUTION OF CD38 AND CD157
  5. CD38 AS A RECEPTOR
  6. CD157 AS A RECEPTOR
  7. CD38 AND CD157 ENZYMATIC FUNCTIONS
  8. CD38 AND DISEASE
  9. CD157 AND DISEASE
  10. ROLE OF THE CD38 FAMILY IN OTHER HUMAN DISEASES
  11. EMERGING WORKING HYPOTHESIS
  12. Acknowledgments
  13. LITERATURE CITED

CD38 expression was first observed on thymocytes and T lymphocytes [15]. Today, CD38 is considered virtually ubiquitous, at least in the immune system, but with variable expression levels. Table 1 lists the main tissues and cells where CD38 and CD157 are detectable. Because CD157 joined the family relatively later, data on its distribution is still limited.

Table 1. Distribution of CD38 and CD157 in normal human tissues
 CD38CD157
Lymphoid  
BloodT cells (precursors, activated)Neutrophils
 B cells (precursors, activated)Eosinophils
 Myeloid cells (monocytes, macrophages, dendritic cells)Basophils
 NK cellsMonocytes
 ErythrocytesMacrophages
 PlateletsPlasmocytoid dendritic cells
Cord BloodT and B lymphocytes, monocytes 
Bone MarrowPrecursorsB cells precursors
 Plasma cellsMyeloid precursors
  Stromal cells
ThymusCortical thymocytes 
Lymph nodesGerminal center B cellsFollicular dendritic cells
Spleen Reticular cells (white pulp)
Non-lymphoid  
Liver Fetal B cell progenitors
Vessels Mast cells
BrainPurkinje cells 
 Cultured astrocytes 
 Cerebellum 
EyeCornea 
 Retinal gangliar cells 
ProstateEpithelial cells 
GutIntraepithelial lymphocytesBrush border, epithelial cells of villi
 Lamina propria lymphocytesPeyer's patches
  Stromal cells in cryptopatches
  Isolated lymphoid follicles
Peritoneum Mesothelial cells
  Macrophages/peritoneal exudates
Pancreasβ-cellsα and β-cells
MuscleSarcolemma (smooth and striated muscle) 
BoneOsteoclasts 
KidneyGlomeruliCollecting tubuli

Flow cytometric analyses indicate that human CD157 is constitutively expressed by myeloid cells in peripheral blood mononuclear cells (PBMCs). The molecule is also expressed by synovial, vascular endothelial and follicular dendritic cells [16]. Moreover, CD157 is also present on other cell types and tissues, such as dermal fibroblasts, human mast cells from lung, uterus, foreskin, and peritoneal mesothelial cells, among others [17-21]. CD157 was recently reported to be expressed in Paneth cells, where it mediates the effects of calorie restriction and rapamycin on murine intestinal stem cell function [22].

CD38 AS A RECEPTOR

  1. Top of page
  2. Abstract
  3. THE CD38 GENE FAMILY
  4. TISSUE DISTRIBUTION OF CD38 AND CD157
  5. CD38 AS A RECEPTOR
  6. CD157 AS A RECEPTOR
  7. CD38 AND CD157 ENZYMATIC FUNCTIONS
  8. CD38 AND DISEASE
  9. CD157 AND DISEASE
  10. ROLE OF THE CD38 FAMILY IN OTHER HUMAN DISEASES
  11. EMERGING WORKING HYPOTHESIS
  12. Acknowledgments
  13. LITERATURE CITED

An initial function attributed to CD38 was the regulation of activation and proliferation of human T lymphocytes. Early functional studies of unidentified molecules were pursued by monitoring the effects induced by the engagement of different domains of the target by a panel of specific mAbs. The rationale was that effects induced by ligation with a surrogate mAb would mimick those induced by a ligand still unknown at the time. CD38 engagement was followed by the activation of selected PBMC populations [23]. The identification of a first putative ligand was obtained by exploiting the observation that human T lymphocytes tended to adhere to endothelial cells [24]. Experiments blocking this adhesion concluded that CD31 [also known as PECAM-1, a member of the immunoglobulin (Ig) superfamily crucial to leukocyte adhesion and transmigration [25]] was a non-substrate ligand for CD38. It was later demonstrated that CD38/CD31 interactions trigger the same signaling cascade and recapitulate the biological events observed using agonistic mAbs [26, 27]. The interplay between CD38 and CD31 is crucial for leukocyte migration through the endothelium [28]. The CD38/CD31 cross-talk has been extensively analyzed in a number of different environments ranging from T to B, NK, and myeloid cells, in normal and pathological conditions [29]. CD38-mediated signals are regulated at distinct levels: the first level concerns the ultrastructural organization of the molecule, which exists both in monomeric [2] and dimeric [30] (or multimeric) type I forms [31]. A flip-flop mechanism of membrane positioning has been recently proposed, with a type III form of CD38 displaying its catalytic site in the cytoplasm [32]. The second level is based on the dynamic localization of CD38 in lipid microdomains within the plasma membrane. Lateral associations with other proteins, which vary according to the cell lineage, determine a third level of control. Lipid raft localization and association with professional signaling complexes are pre-requisites for signals mediated through CD38 [33].

CD157 AS A RECEPTOR

  1. Top of page
  2. Abstract
  3. THE CD38 GENE FAMILY
  4. TISSUE DISTRIBUTION OF CD38 AND CD157
  5. CD38 AS A RECEPTOR
  6. CD157 AS A RECEPTOR
  7. CD38 AND CD157 ENZYMATIC FUNCTIONS
  8. CD38 AND DISEASE
  9. CD157 AND DISEASE
  10. ROLE OF THE CD38 FAMILY IN OTHER HUMAN DISEASES
  11. EMERGING WORKING HYPOTHESIS
  12. Acknowledgments
  13. LITERATURE CITED

The receptor and signaling features of CD157 have also been investigated by using agonistic mAbs to mimic putative ligand(s). By doing so, it has been demonstrated that CD157 ligation induces tyrosine phosphorylation of a 130 kDa protein, identified as focal adhesion kinase (FAK), in myeloid cell lines [34, 35], and that CD157 engagement regulates Ca2+ homeostasis and mediates superoxide (O2−) production in the human myelomonocytic U937 line [36]. Accumulating evidence indicates that CD157 is a key player in the control of leukocyte adhesion, migration and diapedesis [37, 38]. In this context, CD157 behaves as a receptor by establishing lateral interactions with other transmembrane molecules, thus overcoming its structural limitation (i.e., of being a GPI-anchored molecule) and acquiring the ability to transduce signals [13]. In more detail, CD157 interacts with β1 and β2 integrins, and Ab-induced cross-linking of CD157 promotes relocation of these complexes into detergent-resistant membrane domains [21]. Moreover, CD157 effectively contributes to the integrin-driven signaling network, which is critical during leukocyte transmigration, leading to optimal phosphorylation of tyrosine kinase receptors and activation of PI3K and MAPK signaling cascades [39].

CD38 AND CD157 ENZYMATIC FUNCTIONS

  1. Top of page
  2. Abstract
  3. THE CD38 GENE FAMILY
  4. TISSUE DISTRIBUTION OF CD38 AND CD157
  5. CD38 AS A RECEPTOR
  6. CD157 AS A RECEPTOR
  7. CD38 AND CD157 ENZYMATIC FUNCTIONS
  8. CD38 AND DISEASE
  9. CD157 AND DISEASE
  10. ROLE OF THE CD38 FAMILY IN OTHER HUMAN DISEASES
  11. EMERGING WORKING HYPOTHESIS
  12. Acknowledgments
  13. LITERATURE CITED

The enzymatic functions of the two proteins were investigated after the enzyme ADP-ribosyl cyclase (ADPRC, purified from the mollusk Aplysia californica) was observed to display a striking similarity in protein sequence with human CD38 [40]. CD38 is a multifunctional enzyme that catalyzes the synthesis of cyclic ADP-ribose (cADPR) from nicotinamide adenine dinucleotide (NAD+) and also mediates the hydrolysis of cADPR to ADPR [41-44]. In acidic conditions, CD38 catalyzes the generation of nicotinic acid adenine dinucleotide phosphate (NAADP) from nicotinamide adenine dinucleotide phosphate (NADP+) [45]. cADPR, ADPR, and NAADP bind different receptors and channels involved in the regulation of cytoplasmic Ca2+ fluxes, activating signaling pathways critical for several biological processes [e.g., lymphocyte proliferation [46, 47], cardiac [48] and intestinal longitudinal muscle contraction [49], glucose-induced insulin release in pancreas [50]]. The role of CD38 and of its products in regulating a wide range of physiological functions is indicated by the multiple defects revealed in CD38 knock-out (KO) mice. These include impairment of neutrophil chemotaxis, defective oxytocin (OT) release, and aberrant social behavior [51].

The recombinant soluble extracellular domain of CD38 mediates ADP-ribosylation of cysteine residues of several proteins, including CD38 itself [52]. CD38 is also modified by ecto-ADP-ribosyltransferases (ARTs). Arginine ADP-ribosylation results in inactivation of both cyclase and hydrolase activities, whereas cysteine ADP-ribosylation leads only to inhibition of the hydrolase activity. Arginine ADP-ribosylation causes a decrease in intracellular cADPR and a subsequent decrease in Ca2+ influx, with consequent death of activated T lymphocytes [53]. Moreover, CD38 is the major NAD glycohydrolase (NADase) in mammalian cells, regulating intracellular NAD+ levels. CD38 thus modulates the activity of sirtuins, intracellular NAD+-dependent deacetylases implicated in ageing, cell protection and energy metabolism [54, 55].

CD157 also cleaves extracellular NAD+, generating cADPR and ADPR [13, 36]. However, the catalytic efficiency of CD157 in generating cADPR is even lower than that of CD38 [13].

The products derived from NAD+ cleavage operated by CD38 or CD157 can also act as extracellular immunomodifiers [56]. Emerging data indicate that these products may operate outside the cell as paracrine factors [57]. Moreover, the catalytic reactions generate substrates for ARTs and poly-ADP-ribose polymerases (PARPs) involved in cell signaling, DNA repair and apoptosis [56].

CD38 is also found in soluble form in normal and pathological fluids [58] and in exosomes, which are membrane vesicles secreted by B cells and likely a component of an intercellular communication network [59].

CD38 AND DISEASE

  1. Top of page
  2. Abstract
  3. THE CD38 GENE FAMILY
  4. TISSUE DISTRIBUTION OF CD38 AND CD157
  5. CD38 AS A RECEPTOR
  6. CD157 AS A RECEPTOR
  7. CD38 AND CD157 ENZYMATIC FUNCTIONS
  8. CD38 AND DISEASE
  9. CD157 AND DISEASE
  10. ROLE OF THE CD38 FAMILY IN OTHER HUMAN DISEASES
  11. EMERGING WORKING HYPOTHESIS
  12. Acknowledgments
  13. LITERATURE CITED
Chronic Lymphocytic Leukemia (CLL)

CLL is a common adult leukemia which results from the accumulation of small B (CD19+/CD5+/CD23+) lymphocytes in blood, bone marrow (BM), lymph nodes (LN), and other lymphoid tissues [60]. The latter districts represent permissive niches, where lymphocytes can proliferate in response to microenvironmental signals [61]. Elevated expression of CD38 in CLL cells is generally associated with advanced disease stage, higher incidence of lymphadenopathy, high-risk cytogenetics, shorter lymphocyte doubling time, shorter time to first treatment and poorer response to therapy. Besides being a prognostic marker, CD38 is a component of a molecular network which delivers growth and survival signals to CLL cells [62]. CD38 acts as a receptor in leukemic cells and its signals are mediated by ZAP70, another negative prognostic factor for the disease and a limiting factor for CD38-mediated activation [33, 63]. CD38 can work in association with chemokines and their receptors, mainly CXCL12/CXCR4, influencing the migratory responses and contributing to the recirculation of neoplastic cells from blood to lymphoid organs [64] and with specific adhesion molecules belonging to the integrin family [65, 66]. CD38 engagement by means of the ligand CD31 (or surrogate agonistic mAb) triggers the activation of an intracellular signaling pathway and these signals increase chemotaxis as well as proliferation of neoplastic B cells. Together, this evidence contributes to the current view of CLL as a chronic disease in which the host's microenvironment promotes leukemic cell growth and also controls the sequential acquisition and accumulation of genetic alterations [62].

Multiple Myeloma (MM)

MM is a malignancy characterized by accumulation of monoclonal plasma cells in BM, a high concentration of monoclonal Igs in serum and urine, and lytic bone lesions. The proliferation of neoplastic plasma cells in MM interferes with the normal production of blood cells, while the monoclonal Ig impairs humoral immunity.

There are several issues suggesting that CD38 plays significant role(s) in MM. First, CD38 is expressed by plasma cells (normal and tumoral) at top levels of cell surface density. Secondly, experiments in murine models showed that CD38 is a key regulator of OT levels in biological fluids while OT is also released by human osteoblasts [67]. A receptor for OT (OTR) is detectable on myeloma cells and derived lines (Malavasi F., unpublished results, 2012). CD38 is expressed by osteoblasts and osteoclasts, where it implements signals leading to IL-6 release and inhibition of bone resorption [68, 69].

In light of these considerations, plasma cells (and their malignant counterpart) and bone niches are good testing grounds for assessing the presence of a connection between ectoenzymes and neuropeptides [70]. The system is closed, and nucleosides represent additional signals to those led by cytokines/chemokines and other conventional regulators: ATP and NAD+ operating in loco may complement the physiological regulatory systems of plasma cells.

Acute Promyelocytic Leukemia (APL)

APL is a unique subtype of acute leukemia, which causes an arrest of leukocyte differentiation at the promyelocyte stage. Retinoic acid (RA) is included in therapeutical protocols for its ability to induce the differentiation of leukemic cells into mature granulocytes. This therapy may be associated with retinoic acid syndrome (RAS), a clinical manifestation characterized by fever, dyspnea, pulmonary edema and infiltrates [71]. Normal granulocytes are CD38-, while RA-treated APL cells express high amounts of the molecule [72, 73]. The aberrant expression of CD38 on leukemic cells enhances their propensity to interact with CD31, expressed by lung endothelial cells, resulting in a local production of inflammatory cytokines, apoptosis of endothelial cells and eventually contributing to the development of RAS [71].

CD157 AND DISEASE

  1. Top of page
  2. Abstract
  3. THE CD38 GENE FAMILY
  4. TISSUE DISTRIBUTION OF CD38 AND CD157
  5. CD38 AS A RECEPTOR
  6. CD157 AS A RECEPTOR
  7. CD38 AND CD157 ENZYMATIC FUNCTIONS
  8. CD38 AND DISEASE
  9. CD157 AND DISEASE
  10. ROLE OF THE CD38 FAMILY IN OTHER HUMAN DISEASES
  11. EMERGING WORKING HYPOTHESIS
  12. Acknowledgments
  13. LITERATURE CITED
Ovarian Cancer

Leukocyte extravasation is a process which shares similarities with metastatic infiltration to secondary organs. CD157 is expressed by mesothelial cells, which share biological properties and embryological origin with ovarian surface epithelial cells [18]. A working hypothesis was that CD157 might be expressed by epithelial ovarian cancer cells, guiding interactions between tumor cells and mesothelium. If confirmed, CD157 could be involved in the control of ovarian cancer dissemination. This hypothesis was independently supported by a report that BST-1/CD157 was among genes that were differentially expressed in primary cultures of epithelial ovarian cancer cells when compared to their normal counterparts [74]. The results obtained have confirmed the hypothesis: indeed, CD157 is expressed by >90% of epithelial ovarian cancers and is involved in the interactions between epithelial ovarian cancer cells, extracellular matrix proteins and mesothelial cells. All these steps ultimately control migration of tumor cells and invasion of surrounding tissues. High expression of CD157 in human ovarian cancers is associated with clinical aggressiveness, confirming the role of CD157 as an independent prognostic factor of tumor relapse shortly after surgery [75]. The functional contribution of CD157 to the progression of epithelial ovarian cancer relies on its ability to switch on a differentiation program, which allows neoplastic cells to overcome the rules of epithelial tissue architecture, turning it towards a more mesenchymal state. The outcome of clinical relevance in clinics is that these events boost the malignant progression of the disease [76].

Parkinson's Disease

The BST-1/CD157 gene has recently been associated with Parkinson's disease. Indeed, BST-1 SNPs rs11931532, rs12645693, rs4698412, and rs4538475 were identified as risk factors in sporadic late-onset Parkinson's disease in a Japanese genome-wide association (GWA) study. rs4538475 showed the strongest association [77]. The association between BST-1 (rs4698412 SNP) and Parkinson's disease was confirmed in the European population [78], even if not present in a Northern Han Chinese population [79]. A meta-analysis of GWA studies performed on a Northern American and European population indicates that BST-1 did surpass the threshold for genome-wide significance [80]. A conclusion is that ethnicity significantly influences the association between BST-1/CD157 locus and Parkinson's disease.

ROLE OF THE CD38 FAMILY IN OTHER HUMAN DISEASES

  1. Top of page
  2. Abstract
  3. THE CD38 GENE FAMILY
  4. TISSUE DISTRIBUTION OF CD38 AND CD157
  5. CD38 AS A RECEPTOR
  6. CD157 AS A RECEPTOR
  7. CD38 AND CD157 ENZYMATIC FUNCTIONS
  8. CD38 AND DISEASE
  9. CD157 AND DISEASE
  10. ROLE OF THE CD38 FAMILY IN OTHER HUMAN DISEASES
  11. EMERGING WORKING HYPOTHESIS
  12. Acknowledgments
  13. LITERATURE CITED

Other human diseases showing correlation with CD38 or CD157 are reviewed in [13]. The polymorphisms associated with genetic susceptibility to CLL have also been studied in other diseases, including systemic lupus erythematosus (SLE), where the CC genotype increases susceptibility to and the GC genotype confers protection from discoid rash development [81].

High ratios of CD8+/CD38+ T lymphocytes predict disease progression in HIV-infected adults [82]. HIV infection is clinically characterized by increased expression of CD38, apparently not directly caused by the infection [83]. Highly active anti-retroviral therapy (HAART), the standard treatment in both pediatric and adult HIV infection, leads to viral suppression with decreased CD38 expression, increased CD4+ T lymphocyte counts, recovery of immune functions against opportunistic infections and a good clinical outcome in most patients.

Recent studies have combined traditional diagnostic tests (viral load, CD4+ T lymphocyte counts, and immunophenotyping) with an evaluation of CD38 activation. A study involving small sample of patients has shown that (i) CD38 expression levels in CD8+ T lymphocytes and (ii) lymphoproliferative assays in response to mycotic antigens provide additional parameters for monitoring patients with discordant immune-virological responses to HAART [84].

CD38 expression has been also matter of technological debate, in terms of mAb used [see the discrepancy reported [3]] or protocols adopted. To this end, concerted efforts are being made to standardize CD38 protocols in order to obtain comparable evaluation of the marker molecule in HIV-infected patients. A recent paper provided a platform based on flow cytometry with fluorosphere MFI values, color compensation along with biological controls which assure technologically stable analysis. This standardized protocols have been adopted by the laboratories of South African National Health Service for the evaluation of the CD8+/CD38+ ratios for monitoring HIV patients [85].

CD38 is also reported as target of autoantibodies in type 1 and type 2 diabetes mellitus [86, 87], as well as in SLE (Pavòn et al., 2013 in press).

Results from CD38 KO mice have highlighted a role for CD38 in the release of OT from the neurohypophysis [51]. The clinical diagnosis of a deficit in short-term social memory in these mice has drawn the attention to human conditions sharing this feature, such as autism spectrum disorder (ASD). Indeed, some polymorphisms of the CD38 gene (rs6449197, rs3796863, and rs1800561) are associated with ASD [88, 89]. Beside this, it has recently been reported that a quantitative trait of CD38 expression correlates with social functions in ASD [90]. The study was performed by analyzing CD38 expression in lymphoblastoid cell lines derived from PBMCs of ASD patients, which has been showed to be lower than CD38 expression in similar lines obtained from the parents. A possible explanation is that reduced cell surface expression negatively influences the enzymatic performances of CD38 in ASD, leading to a malfunction of the CD38/OT axis in this disorder [51, 91]. A further step of the study investigated the role of retinoids in upregulating cell surface CD38, potentially suggesting a new therapeutic approach [92, 93].

EMERGING WORKING HYPOTHESIS

  1. Top of page
  2. Abstract
  3. THE CD38 GENE FAMILY
  4. TISSUE DISTRIBUTION OF CD38 AND CD157
  5. CD38 AS A RECEPTOR
  6. CD157 AS A RECEPTOR
  7. CD38 AND CD157 ENZYMATIC FUNCTIONS
  8. CD38 AND DISEASE
  9. CD157 AND DISEASE
  10. ROLE OF THE CD38 FAMILY IN OTHER HUMAN DISEASES
  11. EMERGING WORKING HYPOTHESIS
  12. Acknowledgments
  13. LITERATURE CITED

From a phylogenetic perspective, the human CD38 and BST-1 genes share gene structure [6]. A similar intron/exon organization is also shared by their respective orthologs in mouse, chicken and frog, and by the ADPRCs from Aplysia, Schistosoma mansoni and the purple sea urchin (Strongylocentrotus purpuratus) (NCBI and Ensembl genome databases). Thus the ADPRCs are believed to derive from a common ancestral gene. As the common taxonomic denominator of the ADPRC-bearing species is that they all belong to the bilateria (i.e., animals with front/back and left/right symmetry), this suggests that the origin of the ADPRCs dates back to the last common bilaterian ancestor, about 555 million years ago (mya).

Read from an applied perspective, the evidence derived from a phylogenetic analysis of the CD38 family prompts the hypothesis that early CD38/CD157 precursors were components of innate immunity, and that their passage to the surface of immune cells evolved in parallel with the transition to adaptive immunity (Fig. 2). We hypothesized that CD38 (CD157 having not been considered in this context yet) might be part of a circuit generating activation or suppression of immune responses according to the environment. CD38 would also be a component of one of the multiple strategies adopted by tumoral cells to fool the immune system. The enzymes CD39 (ectonucleoside triphosphate diphosphohydrolase 1) and CD73 (ecto-5′ nucleotidase) govern a metabolic pathway leading to the generation of adenosine (ADO) and likely to immunosuppression when ADO is taken up by specific receptors expressed by lymphocytes. This pathway is flanked by different mechanisms guided by NAD+, which is consumed by the CD38/CD157 ectoenzymes and—in some systems—by ART2. Endogenous signals released during physiological or pathological conditions may contribute to alarm the innate immune system, accompanied by the production of pro-inflammatory cytokines. In addition, extracellular NAD+ may influence the immune system by altering the balance between activation and suppression led by specific lymphocyte subsets in different districts and organs.

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Figure 2. Phylogeny of the CD38 family.

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CD38 has recently been associated with functions exerted by regulatory T cells (Tregs) in murine models. High CD38 espression in Foxp3+/CD4+ T cell populations correlates with extremely powerful modulatory properties of CD4+ regulatory T lymphocytes [94]. Furthermore, CD38 is part of the Treg transcriptional signature [95, 96]. The role of CD38 has been confirmed in CD38 KO mice, where NAD+ influences the survival, phenotype and function of Treg cells and provides proof-of-principle that acting on the ART2/P2X7 system may be a new strategy for manipulating these cells in vivo [97]. A recent report states that CD8+/CD38high T lymphocytes have strong immunosuppressive capabilities in vitro and in vivo. This subset possesses a regulatory potential that could work together with the innate immune response and control immune homeostasis during inflammation [98].

PC-1 (also known as CD203a) is a cell surface enzyme with nucleotidase pyrophosphatase phosphodiesterase (ENPP1) activity [99]. We have recently verified the existence of a new pathway led by the CD38/PC-1 network, which provides substrates to CD73 and consequently feeds the production of ADO in different organs (Fig. 3). Detailed knowledge about this pathway has been hindered by the fact that PC-1/CD203a had only been studied in human cells to answer questions mainly related to diabetes, and by technical difficulties in analyzing ADO and different substrates in vitro and in biological fluids (Horenstein et al., 2013 submitted). However, a link between CD38 and CD73 was highlighted some years ago [100].

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Figure 3. Distribution of CD38, PC-1/CD203a, CD39, and CD73 in human thymus, lymph node and spleen assessed by immunohistochemistry.

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It is not known to what extent this unconventional ectoenzyme network will be able to contribute to the generation of local tolerance in different disease models, such as the BM microenvironment in MM (Fig. 4) and the mesenchymal stem cell (MSC) niche in recurrent pregnancy losses (Cecati et al., 2013 submitted). Preliminary results demonstrate the existence of the CD38/PC-1/CD73 axis in different cells, where tolerance plays a part in maintaining homeostasis. Studies are currently being conducted in MM and melanoma patient samples to determine a possible strategy of immune escape operated by CD38 and CD157. In these samples, a chain of ectoenzymes capable of generating ADO independently from CD39 has already been confirmed (Morandi et al., in preparation).

image

Figure 4. Schematic model of human bone marrow highlighting crosstalk taking place among plasma cells, osteoblasts, osteoclasts, endothelium, and stroma.

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There are still several unanswered questions concerning CD38 and CD157. One deals with CD38 tissue distribution, which ranges from discrete expression during lymphocyte differentiation to a limited presence during the physiological resting state of both T and B cells. The molecule is strongly re-expressed by cells undergoing activation and in selected leukemias. In contrast to the notion of CD38 as an activation marker, terminally differentiated plasma cells (and derived tumors) express the highest surface density among human cells. This means that ontogeny has still a lot to teach and to unveil.

Furthermore, the fact that CD38 and CD157 are ectoenzymes should no longer be considered oddities in leukocyte biology; on the contrary, more than 4% of the molecules expressed on the surface of human cells show enzymatic features [101].

Nucleotide-metabolizing ectoenzymes constitute a subgroup of a larger family of ectoenzymes, involved in the catabolism and scavenging of extracellular nucleotides. This process results in the synthesis of compounds that play critical roles in cell homeostasis and metabolism, and not simply nucleotide recycling. Initially it was thought that nucleotide-metabolizing ectoenzymes would operate in environments containing only trace amounts of the substrate and that the final product would be used prevalently inside the cell. This view has later been revised, and it is now known that substrates and final products are not topologically confined to one side or other of the plasma membrane.

The author's laboratory tackled these issues by (i) focusing exclusively on human model, (ii) using the ontogeny and phylogeny of these molecules as a source of physiological clues, and (iii) trying to infer information from disease, the best experiments performed by nature itself.

The aim of this paper was to review old and new facts enriching the field related to the CD38 family products and on the role of ectoenzymes in general. Even though interpretations are kept to a minimum, the perspective of this Laboratory has inevitably pervaded the vision of the gene family.

In conclusion, CD38 and CD157 have shifted from being considered simple activation markers of leukocyte populations to being recognized as molecules exerting multiple functions in health and disease. A last daunting task is now to demonstrate that these surface structures may become appropriate targets for in vivo therapeutic interventions (Chillemi et al., 2013 submitted) and regulators of the immune response (Horenstein et al., 2013 submitted).

Acknowledgments

  1. Top of page
  2. Abstract
  3. THE CD38 GENE FAMILY
  4. TISSUE DISTRIBUTION OF CD38 AND CD157
  5. CD38 AS A RECEPTOR
  6. CD157 AS A RECEPTOR
  7. CD38 AND CD157 ENZYMATIC FUNCTIONS
  8. CD38 AND DISEASE
  9. CD157 AND DISEASE
  10. ROLE OF THE CD38 FAMILY IN OTHER HUMAN DISEASES
  11. EMERGING WORKING HYPOTHESIS
  12. Acknowledgments
  13. LITERATURE CITED

Valeria Quarona and Antonella Chillemi are students of the PhD Program “Biomedical Sciences and Oncology”, University of Torino. Andrea Zito provided much-appreciated technical assistance. The Fondazione Ricerca Medicina Sperimentale (FIRMS) provided valuable assistance and support to this research project.

LITERATURE CITED

  1. Top of page
  2. Abstract
  3. THE CD38 GENE FAMILY
  4. TISSUE DISTRIBUTION OF CD38 AND CD157
  5. CD38 AS A RECEPTOR
  6. CD157 AS A RECEPTOR
  7. CD38 AND CD157 ENZYMATIC FUNCTIONS
  8. CD38 AND DISEASE
  9. CD157 AND DISEASE
  10. ROLE OF THE CD38 FAMILY IN OTHER HUMAN DISEASES
  11. EMERGING WORKING HYPOTHESIS
  12. Acknowledgments
  13. LITERATURE CITED
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