CD 40

Ancell (BE1), Biodesign (BL-C4), Caltag Laboratories (BLB40), Coulter/Immunotech (MAB89), Cymbus Bioscience (B-B20), Immunotech (MAB89), Pharmingen (5C3), Sanbio/Monosan (BL-C4), Sanbio/Monosan/Accurate (BLC4) and Serotec (B-B20).

The antigen is resistant to formalin fixation and immunostaining can be performed on cryostat sections and cytological preparations.

CD 40 is a 48 kD integral membrane protein expressed by B lymphocytes, dendritic cells, monocytes, epithelial cells, endothelial cells and tumor cells including carcinomas, B-cell lymphomas/leukemias and Reed-Sternberg cells of Hodgkin's disease. It has been clustered as a member of the nerve growth factor (NGF)/tumor necrosis factor (TNF) receptor superfamily. Its corresponding counterstructure, the CD 40 ligand (CD 40L) being mainly expressed by activated CD 4+ T cells and also some activated CD 8+ T cells, basophils, eosinophils, mast cells and stromal cells. CD 40L shares significant amino acid homology with TNF particularly in its extracellular domain, and is therefore viewed as a member of the TNF, ligand superfamily. The recent flurry of publications relating to CD 40 suggest that this receptor may have a pivotal role in the function of B lymphocytes and their survival (Klaus et al, 1997; Van Kooten & Banchereau, 1997; Liu & Arpin, 1997; Lipsky et al, 1997; Gulbranson-Judge et al, 1997). Binding of CD 40L+ T cells to CD 40+ B-cells is thought to play a major role in the T cell-dependent B-cell activation, B-cell proliferation, Ig isotype switching, memory B-cell formation and rescue of B-cells from apoptotic death in germinal centers (Gruss et al, 1997). Mutations of the CD 40L gene have been associated with the X-linked hyper-IgM immunodeficiency syndrome, indicating the critical role of the CD 40/CD 40L interaction in the T-cell B cell-interplay. Accordingly, expression of CD 40 has been found in most of the B-cell neoplasms, Reed-Sternberg cells of Hodgkin's disease and some carcinomas. In contrast, functional CD 40/CD 40L interactions appear to be critical for cellular activation signals during immune responses and neoplastic tumor cell growth. Lack of this important interaction results in greatly reduced activation of CD 4+ T cells (Gray et al 1997), while successful interaction of these molecules results in full activation of T-cell effector functions such as help for B-cell differentiation and class switch, activation of monocytes and macrophages to produce lymphokines and to kill intracellular pathogens and activation of autoreactive T-cells to mount an autoimmune response (Klaus et al, 1997; Grewal & Flavell, 1997a, b).

The intense research interest in CD 40 and its ligand has yet to be translated into diagnostic applications. Current uses of CD 40 have mostly been for the immunodetection and identification of tumor cells in all subtypes of Hodgkin's disease. As many as 100% of Hodgkin's disease cases have displayed positivity for CD 40, irrespective of their antigenic phenotype (Carbone et al, 1995). In contrast, CD 40 was immunodetected in only one-third of anaplastic large cell lymphomas, whereas almost 83% of B-cell non-Hodgkin's lymphomas were positive (Carbone et al, 1995). In vitro engagement of CD 40 by its soluble ligand CD 40L enhanced both clonogenic capacity and colony cell survival of Hodgkin's disease cell lines. Recombinant CD 40L induced interleukin-8 secretion and enhanced IL-6, TNF and lymphotoxin-a release from cultured Reed-Sternberg cells. These cytokines play a significant role in the clinical presentation and pathology of Hodgkin's disease, a tumor of cytokine-producing cells. CD 40L has pleiotropic biologic activities on Reed-Sternberg cells and the CD 40-CD 40L interaction might be a critical element in the deregulated cytokine network and cell contact-dependent activation cascade typical of Hodgkin's disease (Gruss et al, 1994; Carbone et al, 1995).

CD 40 shows distinctive immunolocalization to the cell membrane and as a paranuclear dot similar to that of CD 30 and CD 15.

•Carbone A, Gloghini A, Gruss HJ, Pinto A 1995. CD 40 ligand is constitutively expressed in a subset of T-cell lymphomas and on the microenvironmental reactive T cells of follicular lymphomas and Hodgkin's disease. American Journal of Pathology 147: 912-922.

•Gray D, Bergthorsdottir S, Van Essen D 1997. Observations on memory B-cell development. Seminars in Immunology 9: 249-254.

•Grewal IS, Flavell RA 1997a. The role of CD 40 ligand in co-stimulation and T-cell activation. Immunology Reviews 153: 85-106.

•Grewal IS, Flavell RA 1997b. The CD 40 ligand. At the center of the immune universe? Immunology Reviews 16: 59-70.

•Gruss HJ, Hirschstein D, Wright B et al 1994. Expression and function of CD 40 on Hodgkin and Reed-Sternberg cells and the possible relevance for Hodgkin's disease. Blood 84: 2305-2314.

•Gruss H, Hermann F, Gatlei V et al 1997. CD 40/CD 40 ligand interactions in normal, reactive and malignant lympho-hemopoietic tissues. Leukemia and Lymphorma 24: 393-422.

•Gulbranson-Judge A, Casamayor-Palleja M, MacLennan IC 1997. Mutually dependent T and B cell responses in germinal centers. Annals of the New York Academy of Sciences 815: 199-210.

•Klaus GG, Choi MS, Lam EW et al 1997. CD 40: a pivotal receptor in the determination of life/death decisions in B lymphocytes. International Reviews in Immunology 15: 5-31.

•Lipsky PE, Attrep JF, Grammer AC et al 1997. Analysis of CD 40-CD 40 ligand interactions in the regulation of human B cell function. Annals of the New York Academy of Science 815: 372-383.

•Liu YJ, Arpin C 1997. Germinal center development. Immunology Reviews 156:111-126.

•Van Kooten C, Banchereau J 1997. Functional role of CD 40 and its ligand. Archives of Allergy and Immunology 113: 393-399.

Manual of diagnostic antibodies for immunohistology / Anthony S.-Y. Leong, Kumarasen Cooper, F. Joel W.-M. Leong.