The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. These reaction products are essential for the regulation of intracellular Ca(2+), the most ancient and universal cell signaling system. The entire family of enzymes controls complex processes, including egg fertilization, cell activation and proliferation, muscle contraction, hormone secretion, and immune responses. Over the course of evolution, the molecules have developed the ability to interact laterally and frontally with other surface proteins and have acquired receptor-like features. As detailed in this review, the loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications in mice. CD38 is a powerful disease marker for human leukemias and myelomas, is directly involved in the pathogenesis and outcome of human immunodeficiency virus infection and chronic lymphocytic leukemia, and controls insulin release and the development of diabetes. Here, the data concerning diseases are examined in view of potential clinical applications in diagnosis, prognosis, and therapy. The concluding remarks try to frame all of the currently available information within a unified working model that takes into account both the enzymatic and receptorial functions of the molecules.
Endotoxin shock is the result of activation of the immune system by endotoxin/LPS, a component of Gram-negative bacteria. CD14, a GPI-anchored glycoprotein expressed strongly by monocyte/macrophages, is one of several receptors for endotoxin/LPS. The role of CD14 in bacterial-induced and LPS-induced shock was tested in CD14-deficient mice produced by gene targeting in embryonic stem cells. CD14-deficient mice were found to be highly resistant to shock induced by either live Gram-negative bacteria or LPS; however, at very high concentrations of LPS or bacteria, responses through non-CD14 receptors could be detected. Surprisingly, CD14-deficient mice also showed dramatically reduced levels of bacteremia, suggesting an unexpected role for CD14 in the dissemination of Gram-negative bacteria.
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. V C 2013 International Clinical Cytometry Society
CD14 is a myelomonocytic differentiation antigen expressed by monocytes, macrophages, and activated granulocytes and is detectable with the monoclonal antibodies MO2, MY4, and LeuM3. Analyses of complementary DNA and genomic clones of CD14 show that it has a novel structure and that it maps to chromosome 5 within a region containing other genes encoding growth factors and receptors; it may therefore represent a new receptor important for myeloid differentiation. In addition, the CD14 gene is included in the "critical" region that is frequently deleted in certain myeloid leukemias.
Chromosomal rearrangements with duplication of the lamin B1 (LMNB1) gene underlie autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), a rare neurological disorder in which overexpression of LMNB1 causes progressive central nervous system demyelination. However, we previously reported an ADLD family (ADLD-1-TO) without evidence of duplication or other mutation in LMNB1 despite linkage to the LMNB1 locus and lamin B1 overexpression. By custom array-CGH, we further investigated this family and report here that patients carry a large (∼660 kb) heterozygous deletion that begins 66 kb upstream of the LMNB1 promoter. Lamin B1 overexpression was confirmed in further ADLD-1-TO tissues and in a postmortem brain sample, where lamin B1 was increased in the frontal lobe. Through parallel studies, we investigated both loss of genetic material and chromosomal rearrangement as possible causes of LMNB1 overexpression, and found that ADLD-1-TO plausibly results from an enhancer adoption mechanism. The deletion eliminates a genome topological domain boundary, allowing normally forbidden interactions between at least three forebrain-directed enhancers and the LMNB1 promoter, in line with the observed mainly cerebral localization of lamin B1 overexpression and myelin degeneration. This second route to LMNB1 overexpression and ADLD is a new example of the relevance of regulatory landscape modifications in determining Mendelian phenotypes.
In vitro studies have previously shown that the myelomonocytic differentiation antigen CD14 is a receptor for a complex consisting of lipopolysaccharide (LPS) and LPS-binding protein. To investigate the role of CD14 in vivo and its relationship to induction of LPS-induced endotoxin shock, transgenic mice expressing human CD14 were produced. These mice express human CD14 strongly on the surface of their monocytes, neutrophils, and Thy-l(+) lymphocytes and are hypersensitive to LPS, as evidenced by their increased susceptibility to endotoxin shock. These results document the importance of CD14 in vivo as a primary mediator of this lethal syndrome. Furthermore, these mice provide an important model for testing the therapeutic effects of agents directed specifically against the human, as opposed to the murine, CD14 protein in preventing LPS-induced endotoxin shock.Endotoxin shock is a life-threatening syndrome usually preceded by a Gram-negative infection, which is frequently followed by bacteremia and the release of endotoxin [lipopolysaccharide (LPS)] into the circulation. The endotoxin or LPS is responsible for initiating a cascade of events, including an initial release of cytokines and activation of the coagulation, fibrinolytic, and complement systems, eventually leading to severe pathological sequelae (for review, see ref. 1). Recent studies are beginning to unravel the molecular events occurring in the initial stages ofthis syndrome. In vitro studies have shown that LPS binds to a serum protein, LPS-binding protein (LBP); this complex then binds to a receptor, CD14, present primarily on the surface of monocytes, triggering these cells to become activated and to release cytokines, including tumor necrosis factor a, a primary mediator of the precipitating events occurring in endotoxin shock (2-5). Such activation occurs with very low levels of LPS (>1 ng/ml), similar to circulating levels described in patients undergoing endotoxin shock. Identification of CD14 as a receptor for this complex by using in vitro techniques strongly suggests that CD14 may be a primary mediator of the initial events occurring in vivo in endotoxin shock.CD14 is a 53-to 55-kDa glycoprotein expressed strongly on the surface of monocytes (6-8). Detailed immunofluorescence and biochemical studies have shown that CD14 is also synthesized and expressed by neutrophils, although at lower levels (refs. 9-12 and A.H., B.Z.T., and S.M.G., unpublished work). We previously cloned both the human and murine CD14-encoding genes (13-15); examination of their deduced amino acid sequences revealed that CD14 is not structurally related to any other known receptor proteins identified to date, although it does contain a series of leucinerich repeats found in a number of unrelated proteins from diverse species. CD14 does, however, share one property with several other membrane proteins-i.e., it is anchored to the membrane by linkage to glycosyl-phophatidylinositol (GPI) (16); treatment with phosphatidylinositolphospholipase C (P1-PLC), which cleav...
Dendritic cell (DC) maturation is characterized by the gain or loss of immunological functions and by expression of distinctive surface receptors. CD38 is an ectoenzyme that catalyzes the synthesis of cyclic ADP ribose (a potent second messenger for Ca 2+ release), as well as a receptor that initiates transmembrane signaling upon engagement with its counterreceptor CD31 or with agonistic monoclonal antibodies. Since CD38 is expressed by resting monocytes, we aimed to monitor CD38 expression during the differentiation of human monocyte-derived DC (MDDC) and to investigate the possibility that CD38 plays a functional role during DC maturation. CD38 is down-modulated during differentiation into immature MDDC and expressed again upon maturation. The extent of CD38 expression is dependent on the stimulus adopted (LPS G IFN-+ G CD40 cross-linking). Although weak, IFN-+ consistently induces DC maturation. De novo-synthesized CD38 is enzymatically active, and its expression in mature (m) MDDC is dependent on NF-‹ B activity. However, CD38 is not merely a maturation marker but also mediates signaling in mMDDC, where it maintains its functions as a receptor. Activation via agonistic anti-CD38 mAb induces up-regulation of CD83 expression and IL-12 secretion, whereas disruption of CD38/CD31 interaction inhibits CD83 expression, IL-12 secretion and MDDC-induced allogeneic T cell proliferation.
The absence of mutations in the IgV genes, together with the presence of ZAP-70 and CD38, are the most reliable negative prognostic markers for chronic lymphocytic leukemia (CLL) patients. Several lines of evidence indicate that CD38 may be not only a diagnostic marker but also a key element in the pathogenetic network in CLL. First, CD38 is a receptor that induces proliferation and increases survival of CLL cells. Second, CD38 signals start upon interaction with the CD31 ligand expressed by stromal and nurselike cells. Third, CD38/CD31 contacts upregulate CD100, a semaphorin involved in sustaining CLL growth. Fourth, evidence that nurselike cells express high levels of CD31 and plexin-B1, the high-affinity ligand for CD100, offers indirect confirmation for this model of receptor cross-talk. IntroductionChronic lymphocytic leukemia (CLL) is defined as a proliferation of B lymphocytes that express surface CD19 or CD20, CD5, CD23, and low levels of immunoglobulin (Ig), CD79, and CD22. 1 CLL is a heterogeneous disease: some patients experience a slowly progressive clinical course but most will eventually enter an advanced phase and require recurrent treatment. A significant number of CLL patients show an active form of the disease from the early stages, characterized by refractoriness to treatment, infectious and autoimmune complications, and a relatively rapid fatal outcome. 2 Unlike most other B-lymphoproliferative disorders, little is known about the pathogenesis of CLL. The main challenge lies in determining the cellular origin of the disease and, consequently, the degree of immunocompetence of CLL cells. However, no common key cytogenetic abnormalities have been identified that might otherwise offer pathogenetic clues. 3,4 Heterogeneity in the clinical behavior of CLL makes it difficult to identify which patients will benefit most from earlier or more aggressive treatment and those who should be treated with more conservative and less toxic approaches. Clinical researchers have long sought to identify a marker (or markers) for use as a prognostic tool. 5 The earliest staging systems for CLL relied on disease burden parameters. The Rai and Binet systems were the first to determine a correlation between survival and different measures of disease burden. 6,7 Histologic patterns of bone marrow (BM) involvement have also been used as a valid adjunct. 8 However, these classifications fail to distinguish patients who will eventually progress to an aggressive form of the disease from those who have a more stable form. Likewise, lymphocyte doubling time (LDT), which is calculated by determining the number of months it takes the absolute lymphocyte count to double, shares the same drawback. Although it offers meaningful evidence about disease kinetics 9 and is therefore widely used as a measure of disease aggressiveness, treatment decisions based solely on LDT may come too late for patients who eventually prove to have aggressive forms of the disease.During the past 15 years, several soluble molecules have been used a...
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