B lymphocytes express several surface molecules other than the B cell receptors (BCR) that function as markers of differentiation as well as molecules that can fine tune BCR signaling. Current research has identified a function for most antigens that were previously classified as markers of lymphocyte differentiation. CD72 is one such molecule that was originally discovered as a marker of B cell differentiation using conventional serological and classical genetic techniques. Subsequently generation of monoclonal antibodies helped its definition as a molecule that can affect B cell growth and differentiation on its own or in the context of BCR signaling. Initially Sato and Boyse described an activity in sera from C3H.I mice immunized with 1.29 ascites tumor cells that reacted only with a subset of spleen cells after it was absorbed to remove an unknown reactivity. Subsequently the cell type in the spleen recognized by this antiserum was identified as the B cell (Sato and Boyse 1976). Early studies identified CD72 as an antigen expressed on early pre-B and mature B cells but not on plasma cells. This serum was designated as anti-Lyb2 and the antigen identified by the antiserum was given the name Lyb 2.1. Genetic studies demonstrated that Lyb2 was specified by a gene on chromosome 4 that was closely linked to the Ly-19 and Ly-32 loci. Later biochemical studies established that antibodies to Lyb2, Ly19, and Ly32 were all recognizing the same molecule (Wu and Bondada 2002). The Lyb 2.1 allele was expressed in a subset of mouse strains such as C57Br, C58J, C58L, CBA/J, DBA/2 mice as defined by reactivity with this antiserum and the allele in BL/6 mice as Lyb 2.2 (Sato and Boyse 1976). Two monoclonal antibodies, 9-6-1 and 10.1.D2 were generated by Yakura et al. and Subbarao et al. respectively that allowed an analysis of functional properties of Lyb 2 and recognition that it was not simply a differentiation marker but affected B cell function (Wu and Bondada 2002). These and other monoclonal antibodies demonstrated that there are four alleles for the Lyb2 locus in the mouse (Wu and Bondada 2002). After molecular cloning of the gene for Lyb2 and the characterization of the human analogue, the name Lyb2 was changed to CD72 to be consistent with the nomenclature for other cluster differentiation antigens (Nakayama et al. 1989). The human analogue was subsequently identified both by molecular cloning and by isolation of monoclonal antibodies. Two recent reviews have summarized the function of murine and human CD72 molecules and their ligands (Mizui et al. 2009; Wu and Bondada 2009). Despite its original discovery as a B cell-specific molecule, new functions for this molecule are being discovered such as in natural killer (NK) cells and mast cells (Alcón et al. 2009; Kataoka et al. 2010). This entry will review the molecular nature and function of the CD72 molecule in the context of B lymphocyte activation and differentiation.
CD72 is a 45 kDa type II glycoprotein of 359 amino acids in human (354 in mouse) that exists as a dimer on the cell surface (trimers have also been identified) (Robinson et al. 1993; Wu and Bondada 2009). The oligomerization may involve the alpha-helical coiled-coil stalk region in the extracellular domain which is known to facilitate receptor oligomerization. The presence of 11 cysteines in the extracellular domain and two each in the transmembrane and cytoplasmic domain may also have a role in the formation of CD72 oligomers. Remarkably all the cysteines except the residue at position 178 are highly conserved among all the mammalian CD72 proteins (human, chimpanzee, mouse, rat, dog, porcine, and bovine). The cysteines thought to form the intramolecular disulfide bridge are also conserved between the mammalian and the avian forms of CD72. There is a single N-linked glycosylation site at position 136 in the mouse sequence, which is also conserved in the mammalian isoforms. The C-terminal domain has a c-type lectin-like structure similar to CD23 and the asialoglycoprotein found on natural killer cells, but the nature of the carbohydrate moiety recognized by CD72 has not been defined (Nakayama et al. 1989). Similar lectin-like domain is found in CD72 molecules from human, mouse, rat, chimpanzee, dog, and chicken. Surprisingly, sequence homology analysis predicts that the c-type lectin domain in the bovine isoform of CD72 shows less homology to other species and may be truncated (http://www.ncbi.nlm.nih.gov/sites/homologene/1350). The alleles of CD72 found in mouse strains are considered complex alleles as they exhibit multiple differences in amino acid sequence which are more often found in the extracellular domain (Wu and Bondada 2002). Alternate splicing may be involved in the CD72 polymorphisms in the mouse. The intracellular domain of CD72 exhibits greater conservation among different mouse strains and across the species. The cytoplasmic domain has three tyrosines that are potential phosphorylation sites and their role in CD72 signaling will be discussed further in the later sections.
Early studies showed that antibodies to CD72 inhibited T-dependent antibody responses to the particulate antigen, sheep erythrocytes (SRBC) suggesting that CD72 may be involved in cell-cell interactions or as a receptor for cytokines (Yakura et al. 1982). Accordingly, it was demonstrated that biotinylated membrane CD5 isolated from T cells bound to CD72 expressing cell lines leading to the proposal that CD5 and CD72 might form a ligand receptor pair (Wu and Bondada 2002). However, subsequent studies with fusion proteins of CD5 and the Fc region of human Ig failed to detect binding of such proteins to CD72 expressing cells suggesting that CD72 ligand may be distinct from CD5 (Bikah et al. 1998). In 2000 Kumanogoh et al. provided unequivocal evidence that CD72 binds to CD100, a member of semaphorin family of molecules (Sema 4D) that is expressed frequently in the nervous system but also in the immune system (Kumanogoh and Kikutani 2004). This finding and the generation of CD72 knockout mice (Pan et al. 1999) have helped advance the understanding of the physiological role of CD72.
Functional Role of CD72
CD72 ligation induces blast transformation and proliferation of purified murine B cells which was initially interpreted to suggest that CD72 provides a positive signal to B cells (Subbarao and Mosier 1983). Anti-CD72 antibodies inhibited T-dependent antibody response to SRBC, which required the antibodies to be present at early stages of B cell activation with the SRBC (Yakura et al. 1982). One interpretation of these studies was that anti-CD72 enhances polyclonal B cell expansion at the expense of antigen-specific B cells reducing the antibody response to SRBC. Accordingly, anti-CD72 was shown to enhance polyclonal B cell activation induced by T-helper cell lines. Subsequently, several studies have shown that CD72 ligation synergizes with B cell receptor (BCR) signaling, which would have predicted an expansion of antigen-specific B cells (Wu et al. 2001) (Wu and Bondada 2002) . In the light of the discovery that CD72 can be present on dendritic cells (DC) also and that T cell CD100 binds CD72, the effects of anti-CD72 on SRBC response may be more complex, since the early studies did not test for the presence of DCs in the purified cell populations (Kikutani and Kumanogoh 2003; Kumanogoh and Kikutani 2004; Yakura et al. 1982). Hence, the ability of anti-CD72 antibodies to modulate antibody responses to T-independent antigens, in particular TNP-Ficoll (which is a well-established activator of B cells without T cell help) was tested. Consistent with the findings on synergy between anti-CD72 and anti-BCR antibodies, CD72 ligation enhanced antigen-specific responses to TNP-Ficoll (Wu 2002). These later studies showed for the first time that CD72 may also affect B cell differentiation into antibody secreting cells.
Despite the extensive data showing positive effects of CD72 ligation in B cells, three observations suggested that CD72 may actually be a negative regulator of B cells. Thus Wu et al. showed that in a cell line model CD72 may have a role in B cell apoptosis (Wu et al. 1998). The B cells from CD72 deficient mice exhibited a small increase in B cell proliferation in response to BCR ligation (Pan et al. 1999). The crucial finding that CD72 associated with an SH2 domain containing protein tyrosine phosphatase, SHP-1 lent strong support to the concept that CD72 may be a negative regulator of B cells, which will be discussed further in the section on CD72 mediated signaling (Wu and Bondada 2002; Wu and Bondada 2009). In spite of this evidence in favor of CD72 being a negative regulator, CD72 deficient mice remain relatively healthy although a few aged CD72 deficient mice develop autoantibodies (Li et al. 2008). Analysis of mice transgenic for hen-egg white lysozyme bred to CD72 knockout mice suggested that CD72 may have a role in the antigen-induced B cell anergy. Interestingly, CD100 (Semaphorin 4D) deficient mice exhibited an expansion of marginal zone B cells and development of a variety of autoantibodies such as anti-ssDNA, anti-dsDNA, rheumatoid factors, and anti-ribonucleoprotein (Kumanogoh et al. 2005). Somewhat unexpectedly, mice doubly deficient for CD100 and CD72 did not develop autoimmune disease suggesting that CD100 may be having effects on non-B cells.
Although CD72 deficiency does not result in an autoimmune phenotype in wild type C57BL/6, recent studies have suggested that a specific CD72 allele is involved in causing autoimmune lupus-like diseases in mice with an autoimmune susceptible background such as MRL. Four allelic forms of CD72 have been identified in mice, Cd72 a , Cd72 b , Cd72 c , and Cd72 d (Tung et al. 1986); the one associated with autoimmunity is Cd72 c . The extracellular domain of CD72c significantly differs from CD72 encoded by the other three alleles as it contains a seven amino acid deletion in the C-type lectin-like domain (Robinson et al. 1992; Ying et al. 1995). NOD mice, a murine model of autoimmune diabetes, and lupus prone strains such as MRL and AKR all express the CD72c allele (Robinson et al. 1992; Rojas et al. 2003; Ying et al. 1995) and it has been suggested that CD72c is a weaker negative regulator of BCR signaling and B cell activation compared to other CD72 alleles (Xu et al. 2013). Additional studies indicate that the glomerulonephritis and vasculitis phenotypes of MRL-Fas lpr lupus mice, which originally expressed CD72c, can be rescued by transgenesis with the Cd72 b – but not Cd72 c – expressing bacterial artificial chromosome (Oishi et al. 2013). Decreased IgG3 and anti-dsDNA antibody titers are associated with these reduced inflammatory phenotypes. Interestingly, the number of T cells, especially the CD4−CD8− double negative lpr T cells, is reduced with the reconstitution of CD72b (Oishi et al. 2013). This suggests that feedback signaling by CD72 to T cells through CD100 may influence T cell activation. Alternatively, the change in B cell activation status may indirectly impact T cell activation. In summary, these studies suggest that Cd72 polymorphism affects the severity of lupus disease.
Signaling Mechanisms Important for the Functional Effects of CD72 in B Cells
Summary of observations supporting the concept that CD72 ligation can trigger BCR independent positive signals as well as positively regulate BCR-mediated signals
Induced ERK activation in BCR deficient A20 cell line
Activated JNK in SHP-1 deficient splenic B cells
Rescued BCR ligation – induced apoptosis in immature and Xid B cells
Induced differential signals when compared to BCR ligation
CD72 induced while BCR reduced Blimp-1 expression
CD72 activated ERK, JNK, Lyn, Blk, Btk but not Syk, while BCR can activate all these kinases
B cell development in CD72 deficient mice
Reduced numbers of mature B cells in the bone marrow, spleen, lymph nodes, and Peyer’s patches
Reduced numbers of follicular B cells in the spleen
BCR ligation in CD72 deficient BAL-17 cell line
Less BCR-induced Ca2+ influx
Impaired BCR-mediated phosphorylation of CD19, Btk, Vav and PLCγ2 and association of CD19 with PI-3 kinase
Reduced ERK, JNK, and p38 MAPK activation
To address the long-standing conflicts that CD72 does not negatively regulate polyclonal BCR signaling induced by anti-IgM antibodies in mature B cells but strongly inhibits lupus-like disease, Akatsu et al. hypothesized and tested whether CD72 recognizes lupus-related self-antigen and specifically regulates self-reactive B cells without affecting general B cell activation (Akatsu et al. 2016). Their seminal report demonstrates that CD72, through its C-type lectin-like domain, specifically recognizes the endogenous TLR7 ligand, Sm/ribonucleoprotein (Sm/RNP), thereby inhibiting the production of anti-Sm/RNP antibody. Importantly, CD72c, the lupus-susceptible allele discussed earlier, binds to Sm/RNP less strongly, as supported by X-ray crystallography studies showing a significant difference of surface charges between the binding sites of C-type lectin-like domains of CD72c and CD72a alleles. Because autoimmune B cells reactive to Sm/RNP play a crucial role in the development of lupus (Berland et al. 2006; Christensen et al. 2006; Han et al. 2015; James et al. 1995), these results indicate that CD72 may prevent the development of lupus by inhibiting the B cell response to Sm/RNP. Interestingly, these results are consistent with the previous reports that indicate a failure of CD72c compared to other CD72 alleles in decreasing autoimmune lupus-like diseases (Oishi et al. 2013; Xu et al. 2013).
CD72 Signaling in Other Immune Cell Types
In addition to B cells, CD72 was also found to be expressed on mast cells and NK cells (Alcón et al. 2009; Kataoka et al. 2010). In contrast to the resting B cells, there appears to be a constitutive phosphorylation of CD72 and association of CD72 with SHP-1 in resting human mast cells (Kataoka et al. 2010; Wu et al. 1998). Therefore, CD72 may help maintain the steady state of the mast cells. Simultaneous activation of CD72 and KIT further enhanced the phosphorylation of CD72 and the recruitment of SHP-1 to CD72. Subsequently, the CD72-SHP-1 complex can reduce the KIT-dependent human mast cell activities: growth of mast cells, stem cell factor-induced mast cell chemotaxis, chemokine ligand 2 production, but not the IgE/FcεRI-mediated degranulation. Interestingly, a follow-up study on murine mast cells demonstrates several differences of CD72 negative regulation between mouse and human mast cells (Kataoka et al. 2015). At a functional level, CD72 ligation still suppresses KIT-mediated mast cell activation but unlike human mast cells, it also inhibits IgE/FcεRI-mediated degranulation in mouse mast cells. At the signaling level, unlike in human mast cells, CD72 ligation in mouse mast cells does not change the phosphorylation of SHP-1. In contrast, ligation of CD72 induced the phosphorylation of Cbl-b, an ubiquitin ligase, that has been shown to negatively regulate inflammatory cytokines produced by IgE-activated mast cells (Gustin et al. 2006). Thus, there is a species-specific difference in CD72-dependent inhibitory signaling mechanism between mouse and human mast cells.
Unlike B cells, not all NK cell express CD72 on their surface. Activation of NK cells by IL-2 can further increase the CD72 expression on NK cells. Upon stimulation with IL-12 and IL-18, NK cells that expressed CD72 produced significantly less IFN-γ than those expressing none or low levels of CD72 (Alcón et al. 2009). Ectopic expression of CD72 in the CD72 deficient murine NK-cell line, KY2 cells, inhibits cytokine-induced IFN-γ production in NK cells. Both ITIM motifs are required for inhibition of IFN-γ secretion by CD72. Interestingly, although the extracellular domain of CD72 was also shown to be required for inhibitory effect of CD72, ligation of CD72 on NK cells with anti-CD72 had no effect on IFN-γ production by NK cells. Thus, it still remains to be determined whether binding of CD72 to its natural ligand could have any impact on the function of NK cells.
Functional Effects and Disease Associations of Human CD72
The positive and negative regulatory effects of CD72 signaling in BCR dependent and independent activation suggest a potential role for CD72 in autoimmunity and cancer. The developmental stage of B cells where CD72 exhibits differential effects upon CD100 interaction in the context of BCR signaling could influence the outcome of B cell responses in health and disease. Differential regulation of CD72 and BCR induced response to protein kinase A and IFN-γ-mediated signaling events suggest potential alternative CD72 mediated regulatory pathways to overcome signals that downregulate BCR-induced proliferation and differentiation signals (Wu 2002; Wu and Bondada 2002; Wu and Bondada 2009). Defective CD72 signaling events are likely to influence the B cell selection, expansion, and immune response thus contributing to autoreactive B cells in the bone marrow and/or abnormal expansion in response to antigenic and microenvironmental stimuli in the periphery.
Polymorphisms in the negative regulatory receptor FcRγIIb (Ile232thr) are associated with systemic lupus erythematosus (SLE) in humans, mainly in Asian populations. Because both FcRγIIb and CD72 contain ITIM motifs, Hitomi and colleagues investigated the human CD72 polymorphisms for a possible association with SLE (Hitomi et al. 2004). Although no association with susceptibility to SLE was identified, the CD72 *1 allele, which contains a single 13-bp repeat in intron 8, was significantly associated with nephritis in Japanese patients. An alternatively spliced CD72 transcript that replaced 42 amino acids of the extracellular domain with 49 amino acids, caused by skipping of exon 8 and inclusion of exon 9 was detected in these patients. The ratio of alternatively spliced/common isoforms was found to be increased in individuals with *2/*2 genotype, which contains two 13-bp repeats in intron 8, when compared with *1/*1 or *1/*2 genotypes. Interestingly, significant association of the inhibitory FcRγIIb receptor 232thr/thr genotype with SLE detected only in the Asian but not Caucasian cohorts was observed only within the CD72 *1/*1 genotype (Odds ratio of 4.63, P = 0.009). Thus CD72 *2 allele may decrease risk for human SLE conferred by FCGR2B 232thr/thr, possibly by increasing the alternatively spliced isoform of CD72 (Hitomi et al. 2004). Subsequently it was found that expression of CD72 *2 polymorphism was linked to low serum IgG levels (Hitomi et al. 2012). Further analysis of the exon skipped isoform (designated CD72Deltaex8) and the full length isoform by expressing them in lymphoma cells and fibroblasts showed that the CD72Deltaex8 isoform was not expressed at the cell surface but was retained in the endoplasmic reticulum (ER). Consistent with lack of expression at the cell surface, the CD72 *2 allele did not inhibit negative signaling by the full length CD72 *1 allele. Interestingly, expression of CD72Deltaex8 increased apoptosis of B cells due to increased ER stress. The CD72Deltaex8 was detectable in CD72 *1 individuals but was increased in CD72 *2 homozygotes. It is hypothesized that the ER retained isoform of CD72 may increase apoptosis of self-reactive B cells in FcRγIIb (Ile232thr) individuals and thus offer protection from autoimmunity (Hitomi et al. 2012). In addition to the CD72 polymorphisms, surface modulated CD72 may also play a regulatory role in activation of B cells in SLE. Soluble CD72 (sCD72) is shown to be significantly increased in SLE patients mainly in those with renal involvement (Vadasz et al. 2016; Vadasz et al. 2014). While the increased sCD72 may become a potential biomarker for renal involvement in SLE, the role of sCD72 in the pathogenesis of SLE remains to be tested. It is possible that the shedding of surface CD72 in B cells results in reduced negative regulation of B cells leading to hyperactivation of autoreactive B cells. This is supported by recent report by Vadasz et al. who showed reduced levels of CD72 expression in activated B cells of SLE patients compared to normal controls. The lower expression of CD72 was inversely correlated with SLE disease activity and was associated with lupus nephritis, the presence of anti-dsDNA antibodies, and low levels of complement (Vadasz et al. 2014).
In addition to alterations in signaling mechanisms intrinsic to CD72 expression, CD72-CD100 interactions in the context of T-B collaboration also have been demonstrated to impact autoimmunity. This was exemplified by the report from Besliu et al. (2011) who showed increases in CD100+ T cells in the peripheral blood mononuclear cells from patients with systemic sclerosis, a connective tissue disease, characterized by immune abnormalities, chronic inflammation and fibrosis of skin and internal organs with microvascular damage and thrombosis. Both in human and mouse, CD100 has been shown to influence T cell activation, CD40 ligand-induced B cell aggregation and survival (Kikutani and Kumanogoh 2003; Kumanogoh and Kikutani 2004). Triggering CD100 with mAb has been shown to result in costimulation of T cells in response to CD3 or CD2. Association of CD100 with CD45 results in increased T cell homotypic adhesion induced by a CD45 mAb. Interaction of CD100 cytoplasmic domain with a serine-threonine kinase activity in T and NK cells suggests a potential role of CD72/CD100 signaling in activation of T cells and NK cells (Kikutani and Kumanogoh 2003; Kumanogoh and Kikutani 2004). Association of CD100 with tyrosine phosphatase activities in B lymphocytes, its promotion of homotypic adhesion as well as increase in survival of B cells provide evidence for the functional role for CD100/CD72 in B cell function (Kikutani and Kumanogoh 2003; Kumanogoh and Kikutani 2004). Aberrations in the expression and/or function of either of these molecules are likely to result in deregulation of the B and T cell homeostasis leading to autoimmune functions (Kumanogoh et al. 2005). A role for CD72 in CD100-mediated T cell costimulation remains to be explored further.
Investigation of the expression of CD100 on lymphocytes revealed disease associated increase in CD100 on T lymphocytes and shedding from the membrane of activated T cells in multiple sclerosis (MS). MS was also associated with a decrease of CD72 receptor expression by B lymphocytes suggesting a possible contribution of CD100 to the disease development via the direct effects in the CNS and the immunomodulatory effect on B cell activity regulation (Kuklina et al. 2014). Modulation of B cell regulatory molecules CD22 and CD72 in myasthenia gravis (MG) and MS has been reported by Lu et al. (2013). Compared to normal healthy controls, CD72 expression was aberrant on B cells in myasthenia gravis and multiple sclerosis patients. In accordance with other studies linking changes in CD72 expression to autoimmunity, CD72 expression was negatively correlated with anti-acetylcholine receptor antibody levels in MG. The expression of CD72 mRNA in immune thrombocytopenia (ITP) patients with active disease was found to be significantly lower than that in patients in remission suggesting a role for CD72 in the pathophysiological process of the ITP disease by enhancing B-cell receptor signals (Zhou et al. 2012).
Aberrant CD72/CD100 interaction in mature B cell signaling events could potentially contribute to hitherto unidentified lymphoproliferative disorders. Deaglio et al. have described a potential role for CD100/CD72 network in chronic lymphocytic leukemia (CLL) (Deaglio et al. 2005). CD38/CD31 interaction triggers relocalization of BCR/CD19 to the CD38/CD31 contact areas, increased cell survival and proliferation of CLL B cells. This is associated with upregulation of CD100, mainly in proliferating cells, and a concomitant decrease in CD72, low-affinity CD100 ligand (Deaglio et al. 2005). Nurse-like cells from B-CLL patients express CD31 and plexin-B1, a high-affinity ligand for CD100, which deliver growth and survival signals to CD38+/CD100+ B-CLL as well as downregulation of CD72 (Deaglio et al. 2005). Simultaneous cross-linking of CD72 has been shown to inhibit BCR-mediated apoptosis in Burkitt’s lymphoma cells, but enhanced CD20-mediated apoptosis suggesting receptor dependent positive and negative regulatory roles for CD72 in leukemia and lymphoma (Mimori et al. 2003). Consistent with a role for CD72 in B cell malignancies, CLL and mantle cell lymphoma cells have been shown to proliferate in response to CD72 activation exhibiting CD40 like costimulatory effects. CD5 and/or CD72 engagement also has been shown to deliver critical costimulatory signals in B-1a, B-2, and B cells from CLL patients, but with different requirements and patterns (Planken et al. 1998). Interestingly CD72 is reported to be present at high levels in B-lineage acute lymphoblastic leukemias (ALL) and has also been shown to serve as an effective target for therapy with anti-CD72 immunotoxin for refractory ALL in vitro and in vivo animal models (Myers and Uckun 1995). High level expression of CD72 in a wide range of B cell malignancies including precursor B-cell lymphomas, Burkitt’s lymphomas, germinal center lymphomas, chronic lymphocytic leukemias, and hairy cell leukemia (Schwarting et al. 1992) warrants further exploration and development of CD72 and CD100 targeted therapeutic agents. CD72 was also shown to be expressed in acute myelogenous leukemia (AML). Engagement by an agonistic antibody or by natural ligand CD100 suppressed the proliferation of Kasumi-1, an AML cell line with gain of function KIT mutation. This growth inhibition was associated with the phosphorylation of CD72, the formation of the CD72 – SHP-1 complex and dephosphorylation of src family kinases and JNK culminating in enhanced cell death (Kataoka et al. 2013). More examples of AML cells expressing CD72 need to be studied to determine if CD72 can be a therapeutic target.
Recently, changes in CD100 expression on CD8+ T cells have been implicated to be involved in immune cell responses during human immunodeficiency virus and hantaan virus infection, suggesting viral infection might also modulate CD100 expression and related immune responses (Eriksson et al. 2012; Liu et al. 2013; Liu et al. 2015). In general loss of CD100 was associated with decreased function of CD8+ T cells. This finding has been further extended by He et al. who reported that hepatitis C virus (HCV) infection and IFNα therapy could upregulate CD100 expression on B cells, which returned to the normal levels in HCV patients who achieved sustained virological response. The IFN-α-induced CD100 expression on B cells was negatively correlated with the HCV RNA level, suggesting that enhanced CD100 expression might be associated with the control of HCV infection (He et al. 2014).
CD72 and its ligand, the immune semaphorin play critical roles in many physiological and pathological processes, including autoimmunity, B cell growth and differentiation, diverse hematological malignancies, and infectious diseases. The CD72 and CD100 receptors as therapeutic targets in controlling autoimmunity, cancers, and infectious diseases have promise.
CD72 is a B cell surface molecule with ability to modulate B cell receptor derived signals. CD100, a member of semaphorin family, is the physiological ligand for CD72. CD72 is a type II transmembrane protein with two immunoreceptor inhibitory motifs in the cytoplasmic domain. CD72 has been shown to associate with SHP-1 and Grb2 which play a role in its positive and negative regulatory effects. Increased susceptibility of Asian populations to lupus with a FcRγIIb polymorphism is dependent on the presence of a polymorphism in CD72. In the mouse model one specific allele of CD72 is associated with autoimmunity. CD72 is also expressed in a variety of B cell malignancies and could be a therapeutic target. Mast cells and natural killer cells also express CD72 where it may negatively regulate their ability to degranulate and secrete γ-interferon respectively CD100 expression is altered in infections with viruses suggesting a role for CD72-CD100 interactions in generating an effective immune response.
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