asialo-gm1-ganglioside and Lymphoproliferative-Disorders

Mice with severe combined immune deficiency (C.B-17 scid/scid [SCID mice]) lack functional B and T lymphocytes and are permissive for the growth of human xenografts. However, the development of functional NK cells is not affected by the scid mutation. Mouse NK cells express the surface glycolipid asialo GM1 and are implicated in the rejection of heterotransplanted cells. In the present study, we demonstrate that SCID mice treated with rabbit anti-asialo GM anti-serum (alpha-asialo GM1), for in vivo depletion of endogenous NK cell function, develop lethal Epstein-Barr virus (EBV)-induced lymphoproliferative disorders (EBV-LPD) at lower doses od inoculated EBV-transformed lymphoblastoid B cell lines (EBV-LCL) than untreated animals. Furthermore, at any given dose of EBV-LCL inoculated, EBV-LPD developed earlier and induced lethality sooner in alpha-asialo GM1-treated animals. We also demonstrate that SCID mice treated with alpha-asialo GM1 have reduction in the number of asialo GM1-expressing splenocytes. Moreover, splenic cell suspensions derived from alpha-asialo GM1-treated SCID mice show lower cytotoxicity against the mouse NK-sensitive cell line YAC-1 and human EBV-LCL than splenocytes obtained from untreated SCID mice.

Topics: Animals; Antibodies; B-Lymphocytes; Cell Transformation, Viral; Cytotoxicity, Immunologic; G(M1) Ganglioside; Herpesvirus 4, Human; Humans; In Vitro Techniques; Killer Cells, Natural; Lymphoproliferative Disorders; Mice; Mice, SCID; Rabbits; Spleen; Transplantation, Heterologous

Although changes in surface carbohydrate expression of abnormally expanded MRL/Mp-lpr/lpr (MRL/lpr) lymph node (LN) cells have previously been described, the composition and function of glycolipids present on these cells as well as the spectrum of specificity of anti-carbohydrate antibodies reactive with these cells remains obscure. Analysis of antibodies to a panel of 22 carbohydrate structures using a liposome immune lysis assay (LILA) showed that, except for anti-asialo GM2 (GA2) antibodies, marked reduction of antiglycolipid antibody levels was observed in sera from 4-mo-old MRL/lpr mice compared with these from MRL/Mp(-)+/+ (MRL/+) mice. Absorption experiments revealed that both anti-asialo GM1 (GA1) and globoside antibodies had binding capacity to MRL/lpr LN cells. To elucidate the glycolipid profiles of MRL/lpr LN cells, glycolipids were extracted from LN cells of both MRL/lpr and MRL/+ mice and analysed. A 30-fold elevation of GM1 was found in MRL/lpr LN cells compared with MRL/+ LN cells. From the results of LILA using GA1/GM1 mixed liposomes, aberrantly expressed GM1 inhibited the classical complement pathway but did not interfere with the binding of anti-GA1 antibodies to liposomal GA1. These findings suggest that a drastic GM1 increase on MRL/lpr LN cells would inhibit the action of anti-GA1 antibodies and complement on the cell surface. This may explain the escape of these cells from an activated self directed immune response.

Topics: Animals; Antibody Specificity; Autoantibodies; Autoimmune Diseases; Carbohydrate Sequence; Complement System Proteins; G(M1) Ganglioside; Glycolipids; Liposomes; Lymph Nodes; Lymphoproliferative Disorders; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Molecular Sequence Data

Analysis of monoclonal human Ig that occur in association with lymphoproliferative diseases has provided valuable information about antibody structure and idiotypes. We analyzed 940 human sera that contained monoclonal IgM proteins for their ability to bind to four carbohydrate epitopes. Ten sera bound asialo-GM1, five of these sera also bound GM1, 10 bound to 3-fucosyllactosamine (3-FL), and one each bound to levan and galactan. Although the antibody activity in each serum was associated with a single L chain isotype, both kappa and lambda isotypes were represented among the proteins that bound to asialo-GM1 and to 3-FL. Some antibodies against asialo-GM1 were highly specific for this compound, whereas others cross-reacted with the structurally related gangliosides GM1 and GD1b. The antibodies to asialo-GM1 also varied considerably in their ability to lyse liposomes that contain asialo GM1. An association of IgM mAb against gangliosides with peripheral neuropathies has been reported recently, but only one of five patients whose antibodies reacted with GM1 ganglioside had a neuropathy. The antibodies that bound 3-FL exhibited narrower specificity, and less than 10% cross reactivity was noted with structurally related carbohydrates. The frequency of monoclonal proteins that bound 3-FL and asialo-GM1, approximately 1:100 sera for each specificity, was surprisingly high in view of the fact that both of these epitopes are expressed in human tissues. We suggest that these antibodies may be poly-specific and/or that the subset of B lymphocytes that synthesizes these anti-carbohydrate antibodies undergoes malignant transformation more frequently than other B lymphocytes.

Topics: Antibodies, Monoclonal; Antibody Specificity; G(M1) Ganglioside; Glycolipids; Glycosphingolipids; Immunoglobulin M; Lewis X Antigen; Lymphoproliferative Disorders; Oligosaccharides; Paraproteinemias