Cd38 gene polymorphism and chronic lymphocytic leukemia. This first phase of b cell development is antigen independent and leads to. T and b lymphocyte differentiation, is lost during the intermediate stages of maturation. Cd38 crosslinking induces the proliferation and maturation of t2 b lymphocytes. In humans, it is expressed at high levels on plasma cells and activated t and b cells, natural killer nk lymphocytes, myeloblasts, and erythroblasts. It is an adpribosyl hydrolase expressed at variable levels on hematopoietic cells and in some nonhematopoietic tissues such as brain, muscles, and kidney. For instance, human progenitor b cells express cd38 on surface but lose this expression after maturation whereas murine b cells express cd38 throughout its. Cd38 high transitional human b cells reveals different regulatory profiles.
Peripheral blood was collected from pss patients n 34 and gender matched healthy controls hc, n 20, and the proportion of b cell subsets characterized by anticd19, antiigd and anti cd38 antibodies. Studies in animal models indicate that cd38 functional expression confers protection against infection by several bacterial and parasitic. In mature bcells cd38 is induced when naive bcells are activated, peaks when they enter the germinal center and decreases during centrocytecentroblast maturation, being completely absent in memory bcells 6. Ligation of cd38 on murine b cells with agonistic anti. Pdf cd38 expression in early bcell precursors contributes. Table 1 cd38 expression on murine b cell subsets subset prepro b prob preb im b t1 b t2 b mature b mz b pc b gc b b1 b cd38 expression 1 1 1 11 11 111 11 1111 2121 11111 abbreviations. Indeed, with a backbone of six antibodies cd38, cd27, cd10, cd19.
Cd38 antigen is one of the antigens expressed by human plasma c e l l. It also induces tyrosine phosphorylation of several substrates and a low increase in intracellular calcium, but this signaling cascade ultimately results in proliferation, reduced apoptosis, and isotype switching igg1, among other effects, signifying a role for cd38 in b cell. Here, we report that cd38 is expressed from the earliest stages of bcell development. Cd38 has a genetic polymorphism, characterized by a cg variation in the regulatory region of intron 1. Then, the proliferation, differentiation, and apoptosis in response to anti cd38 stimulation were studied.
Cd38 is a 45,000 molecular weight transmembrane protein that is expressed in immature and mature lymphocytes. Sep 22, 2016 a precise identification and phenotypic characterization of human b cell subsets is of crucial importance in both basic research and medicine. Here, we report that cd38 is expressed from the earliest stages of b. Cd38 expression levels in chronic lymphocytic leukemia b cells are.
A novel in vitro model of early human adult b lymphopoiesis that. Cd24 expression and b cell maturation shows a novel. In humans, it is expressed at high levels on plasma cells and activated t. Transitional b cells represent a central developmental stage in. Cd38 expression in early b cell precursors contributes to erk. Iga b cell development is particularly associated with tgf. In the literature, flow cytometry studies for the phenotypic characterization of b lymphocytes are mainly focused on the description of a particular cell stage, or of specific cell stages observed in a single type of sample. Cd11b, cd19, cd24, cd38, cd27, igm, and igd for subsetting, and 30 variable. Therefore, pi3k activation appears to be directly linked to the growtharresting effects of cd38 ligation 2628. Cd38 expression is tightly regulated in normal bcell development. Ligation of cd38 on mature murine spleen b cells also. T and blymphocyte differentiation, is lost during the intermediate stages of maturation. However, the expression and function of cd38 during b cell differentiation in mice is poorly understood. Transitional b cells in early human b cell development time.
Cd38 is a cell surface glycoprotein with cyclic adp ribose hydrolase activity, but its biological roles are just beginning to be understood. Soluble cd38 significantly prolongs the lifespan of memory b. Cd38 also functions in cell adhesion, signal transduction and calcium signaling. Cd38 through the life of a murine b lymphocyte vences. Cd38 expression levels in chronic lymphocytic leukemia b. However, the surface expression of cd38 is under complex control and varies during lymphocyte development, activation and differenti ation. Characterization of a cd38like 78kilodalton soluble. Cd38, a surface protein whose expression increases upon normal bcell activation, is a marker of disease aggression in bcell chronic lymphocytic leukemia bcll.
In humans, it is expressed at high levels on plasma cells and activated t and b cells. Nov, 2014 signaling through the preb cell receptor induces a few rounds of proliferation. Cd38 is a multifunctional protein widely expressed in cells from the immune system and as a soluble form in biological fluids. Figure 1 summarizes the process of early b cell development and figure 2 provides an overview of the characteristics of early b cell subsets in human and mouse fig. Memory b cells in the lung participate in protective. Primary biliary cholangitis pbc, an autoimmune disease, clinically presents as chronic cholestasis and nonsuppurative. Nov 30, 2020 cd38 is expressed in b cell precursors, germinal center b cells, and plasma cells 37, 38. B cell memory and plasma cell development sciencedirect.
Probability state modeling analysis of cd38, cd10, and cd19 upregulation in early human bcell development c. Pbmcs or b cells were stained for 20 min with fluorescent conjugates of cd19 alexa fluor 700, cd38percp. Cd38 is expressed in several types of nonhodgkin lymphoma nhl and constitutes a promising target for antibodybased therapy. Identification and characterization of plasma cells. B example showing the sorting strategy used to isolate preb red. Pdf on feb 1, 2000, p deterre and others published cd38 in t and bcell functions find, read and cite all the research you need on researchgate. Daratumumab displays in vitro and in vivo antitumor. Therefore, to identify the effect b cell cd38 has on fdc cd38 ligand, we administered soluble cd38 scd38. Cd38 is a 45 kd type ii transmembrane glycoprotein also known as t10.
B cells in lung, mln, and spleen for 160 d after a primary infection fig. However, the expression and function of cd38 during b. Cd38 is a 45 kda transmembrane receptor expressed in b lymphocytes and other cells from the immune system. Signaling through the preb cell receptor induces a few rounds of proliferation. However, the relative order of cd19 and cd10 upregulation is not well established, with numerous conflicting published reports. However, the expression and function of cd38 during bcell differentiation in mice is poorly understood. Genetic loss of nfat2 nfatc1 impairs b cell development. In this study, we tried to identify b cell subsets in peripheral blood which may be responsible for disease activities of pss. One major difference however is that murine pro and preb cells depend on il7 for survival and differentiation, whereas human b cell development is il7 independent lebien 2000. However, some differences in expression have been reported between human and mouse 29, 39. Characterization of a cd38like 78kilodalton soluble protein. We found that the size and volume of fdc networks were expanded during gc development.
Within the bcell compartment, cd38 is expressed at high levels by b lineage progenitors in bm and by b lymphocytes in germinal center, in activated tonsils, and by terminally differentiated plasma cells. Analysis of different stages of b cell development in. As mentioned above, cd38 is highly expressed on transitional 2 t2 with an intermediate expression on transitional 1 t1 and mature m b lymphocytes. The anti cd38 mab, daratumumab jnj54767414, humax cd38, was recently granted breakthrough therapy designation by the fda for mm that is refractory to a pi and imid. The initial stages of b cell development are antigenindependent and involve. Preffer5 1verity software house, topsham, maine 04086 usa 2laboratory of flow cytometry, roswell park cancer institute, buffalo, ny 14063 usa. An integrated multiomic single cell atlas to redefine human b cell. Cd38 expression in early bcell precursors contributes to. Bcell precursors have been extensively studied in mouse and human systems and there is general agreement that cd34 and cd38 help identify early bcell progenitors. Coexpression of cd5 and cd10 occurs in b cell lymphomas, including dlbcl, follicular lymphoma, mantle cell lymphoma, cllsll, other small cell b cell lymphomas, and precursor b lymphoblastic leukemialymphoma, and is of uncertain clinical significance. Flow cytometric analysis of bcell lymphoproliferative disorders.
There are no known specific markers for memory b cells in mice, although studies suggest that the cd38 low and cd38 high phenotypes are indicative of. Primary biliary cholangitis pbc, an autoimmune disease, clinically presents as chronic cholestasis and nonsuppurative destructive cholangitis. Highdimensional flowcytometric analysis of human bcell. Sorted bcell populations with purity greater than 95% were used for in vitro culture and rna extraction. Cd38 is expressed selectively during the activation of a. Therefore, it is possible that although cll b cells are resting, cd38 may be a marker of recent cell activation prior to entry into the periphery. Indepth characterization of cd24highcd38high transitional.
Roles of cd38 in the immune response to infection mdpi. In addition to regulation of apoptotic death in the b cell lineage, cd38 molecules transduce mitogenic signals. The various stages of bcell differentiation can be identified by evaluating the expression and levels of distinct cellsurface markers, which. Expression of cd38 by activated t and b lymphocytes was the starting point for functional studies aimed at dissecting the role of the molecule in the immune compartment. Probability state modeling analysis of cd38, cd10, and cd19. Clinical significance of cd38 and cd101 expression in pd. The emerging picture is highly complex and mostly dependent on the lineage considered and the activation status of the cell. Daratumumab darzalex is a firstinclass anti cd38 antibody approved for the treatment of relapsedrefractory rr multiple myeloma mm. Bcell development is a stepwise process initiated in the fetal liver and postnatal bone marrow and continued in the peripheral lymphoid organs upon encounter with antigens. Cd38 induces differentiation of immature transitional 2 b. Transitional b cells in early human b cell development. See all b cell development and differentiation markers products b cells are an integral part of the humoral immune response due to their ability to produce antibodies against foreign antigens.
Cd38 expression is upregulated by an array of inflammatory mediators, and it is frequently used as a cell activation marker. Clinical consequences of defects in bcell development journal of. Anti cd38 mabs elicit proliferation of human thymocytes, mature t cells, and nk cells. These and other studies indicate that cd38 is an important regulatory molecule on human, murine, and rat lymphocytes. Memory b cells in the lung participate in protective humoral. B cell mouse t1 b cell mouse t2 b cell marginal zone b cell follicular b cell activated germinal center from mouse b1 progenitor cell from mouse b2 progenitor cell b cell memory b cell plasmablast plasma cell human markers positive markers cd10neprilysin cd34 pax5 cd10neprilysin cd34 pax5 cd10neprilysin cd38 pax5 cd10neprilysin cd19.
Mar 01, 2020 cd38 expression was shown to be constitutively expressed during b cell development as well as in different b cell subpopulations. They originate from hematopoietic stem cells in the bone marrow, where they undergo several phases of antigenindependent development, leading to the. Here, cd38 is expressed from the earliest stages of bcell development, indicating that it might play a role in the process of b cell differentiation from resting mature b cell to plasma b cell. Incidence of bcell neoplasms, united states subtype incidence rate 20112012 new cases, 2016 per 100,000 lymphoid neoplasms 34. Detection of memory b cells and plasmablasts in mouse. An overview of b cells from discovery to therapy biorad. Jun 15, 2008 cd38 rules proliferation signals in chronic lymphocytic leukemia cll cells, suggesting that the molecule is not merely a prognostic marker but also a key element in the pathogenetic network underlying the disease. Here, we report that cd38 is expressed from the earliest stages of b cell development. Maturation of t and b lymphocytes in the assessment of the.
Probability state modeling analysis of cd38, cd10, and. Preprob, prob, preb and immature b cells from murine bone marrow all. Soluble cd38 significantly prolongs the lifespan of memory. Notably, although b cell development has primarily been studied in mice, human b cell development was shown to be similar naradikian et al. An overview of b cells from discovery to therapy mini. Novel strategy for phenotypic characterization of human b. Phenotypically distinct b cell development pathways map to. The developmental processes can be followed through analysis of cellsurface markers, such as igm, igd, cd10, cd19, cd20. Pdf regulation of dendritic cell trafficking by the adp. Cells free fulltext roles of cd38 in the immune response. By functioning as both a cyclase and a hydrolase, cd38 mediates lymphocyte activation, adhesion, and the metabolism of cadpr and naadp. Dec 23, 2004 cd38 is a widely distributed molecule in hematopoietic and nonhematopoietic cells.
Figure 1 isolation of b cells early in development. Genetic loss of nfat2 nfatc1 impairs b cell development of. Cd38 is a 45 000 molecular weight transmembrane protein that is expressed in immature and mature lymphocytes. Punt stranford jones owen kuby immunology eighth edition lecture powerpoint chapter 9 bcell. Apr 01, 2008 the main objective of this work was to analyze the role of cd38 during bcell development, particularly in the last stages taking place in the spleen.
In cll, cd38 expression is increasingly being recognized as. Flow cytometric analysis of bcell lymphoproliferative. The initial stages of b cell development are antigenindependent and involve the generation of several intermediary precursor cells that arise from b lymphocyte progenitor cells including preprob cells, prob. First, the expression of cd38 was evaluated among t1, t2, and m subsets. Cd38 crosslinking in mature b cells has a different outcome. Daratumumab displays in vitro and in vivo antitumor activity. Preprob, prob, preb, and immature b cells from murine bone marrow all stained positive for cd38.
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