Disease relevance of SEMA4D

• To investigate which mechanisms operate in these crosstalks and whether they are malignancy-related or reproduce the mechanisms used by normal B cells we have studied the expression and functional role of semaphorin CD100 (now called Sema4D) in chronic lymphocytic leukemia (CLL) cells and normal CD5+ B cells [1].
• Thus, our results show that CD100 is a new important element in the deleterious T cell-neural cell cross talk during neuroinflammation and suggest its role in demyelination or absence of remyelination in neuroinflammatory diseases including multiple sclerosis and human T lymphotropic virus type 1-associated myelopathy [2].
• In contrast, all five cases of high-grade, small non-cleaved (Burkitt-like) B-cell lymphoma were immunoreactive for CD100 expression, as were 18 of 20 cases (90%) of malignant T cell neoplasms [3].
• The neoplastic cells in 3 of 11 cases of predominantly large-cell-type follicular lymphoma did express CD100 [3].
• We tested the hypothesis that CD100 plays a pathogenetic role in experimental immune complex glomerulonephritis [4].

High impact information on SEMA4D

• Expression cloning revealed that the CD100 receptor on lymphocytes is CD72, a negative regulator of B cell responsiveness [5].
• CD100 stimulation significantly enhanced the effects of CD40 on B cell responses [5].
• Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100: a novel mechanism for regulating B cell signaling [5].
• We have identified the lymphocyte semaphorin CD100/Sema4D as a CD40-inducible molecule by subtractive cDNA cloning [5].
• Administration of soluble CD100 markedly accelerated in vivo antigen-specific antibody responses [5].

Biological context of SEMA4D

• In the present study, we showed that activation of peripheral blood or tonsillar B lymphocytes induced the expression of CD100 in CD38(+)CD138(-) cell populations, including in CD148(+) subpopulations, thus expressing a memory B-cell-like phenotype [6].
• 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 [7].
• By expressing a CD100 molecule mutated at cysteine 674 into a COS cell system, we additionally demonstrate that this particular residue in the extracellular domain of the molecule is required for dimerization [8].
• Together these results demonstrate that membrane CD100 is cleaved by a metalloprotease-dependent process, which is probably regulated by phosphorylation [8].
• Biological activity of soluble CD100. II. Soluble CD100, similarly to H-SemaIII, inhibits immune cell migration [9].

Anatomical context of SEMA4D

• CD100 is a 150-kDa human surface glycoprotein implicated in T cell activation [10].
• CD100, in particular, has been shown to influence monocyte migration, T-cell activation, B-cell survival as well as T/B and T/dendritic cell cooperation [11].
• Human soluble CD100 also induces monocyte paralysis and the arrest of its spontaneous and chemokine-induced migration by signaling through an as yet unknown receptor that is different from PlexinB1 and CD72 [11].
• Thus, these results suggest that semaphorins as exemplified by CD100 also play a functional role in the immune system [12].
• Human CD100, a novel leukocyte semaphorin that promotes B-cell aggregation and differentiation [12].

Associations of SEMA4D with chemical compounds

• The human membrane-bound CD100 engagement triggers costimulatory signals to T cells through its interaction with membrane protein tyrosine phosphatase CD45 and an intracellular serine kinase [11].
• Switch in the protein tyrosine phosphatase associated with human CD100 semaphorin at terminal B-cell differentiation stage [6].
• The RU-486 structure was solved in several different crystal forms, two with helix 12 intact (GR1 and GR3) and one with a protease-digested C terminus (GR2) [13].
• Sequential immunoprecipitation studies with GR3, GR4 and integrin antibodies confirmed that GR3 is directed against the alpha 3 integrin chain, whereas GR4 is directed against the beta 1 chain [14].
• It has to be noted that perturbation of the same 150 kDa surface molecule with BB18 mAb exerts no effect on CD2 and CD3 induced proliferations, while inducing a strong lymphocyte proliferation in the presence of submitogenic concentrations of phorbol myristate acetate [15].

Physical interactions of SEMA4D

• We then show that proteolytic conversion of plexin-B1 into a heterodimeric receptor greatly increases the binding and the functional response to its specific ligand semaphorin 4D/CD100 [16].

Regulatory relationships of SEMA4D

• Furthermore, we show that the association is increased during T cell activation and that triggering CD45 molecules through discrete epitopes induces the down-modulation of CD100 molecules at the cell surface [10].

Other interactions of SEMA4D

• A second event is the up-modulation of the survival receptor CD100, restricted to proliferating cells, and a concomitant decrease of CD72 (low-affinity CD100 ligand and negative regulator of immune responses) [17].
• CD38 and CD100 lead a network of surface receptors relaying positive signals for B-CLL growth and survival [17].
• We show in this study that CD100 is associated with CD45 and that this association has functional significance [10].
• Conversely, triggering the CD100 molecule through the BD16-defined epitope only exerts an effect on CD2- and CD3-induced PBMC proliferation [10].
• We have also observed that the semaphorin CD100, a ligand for plexin-B1, stimulates the interaction between plexin-B1 and active Rac [18].

Analytical, diagnostic and therapeutic context of SEMA4D

• Immunodepletion and Western blotting experiments demonstrated that CD45 was the PTP associated with CD100 in cell lines displaying pre-B, activated B, and pre-plasma cell phenotypes [6].
• This proliferative response require E+ cells and accessory cells, and this even after immobilization of BB18 mAb [19].
• In addition, both CD100 and H-SemaIII were recognized by two CD100 mAbs in an ELISA, and one of these mAb abolished the inhibitory effect of each of these semaphorins [9].
• Mouse CD100 plays a crucial role in both humoral and cellular immunity through ligation of the lymphocyte receptor, CD72 [20].
• Northern blot analysis of CD100 expression correlated with immunohistochemical findings [3].

References