myelin-basic-protein and Lymphoma--Large-B-Cell--Diffuse

The pattern-recognition pathway plays an important role in infection recognition and immune responses, and previous studies have suggested an association between genetic variation in innate immunity genes and non-Hodgkin lymphoma (NHL). We evaluated NHL risk associated with genetic variation in pattern-recognition genes using data from a case-control study of NHL conducted in Connecticut women. Single nucleotide polymorphisms (SNPs) in 27 pattern-recognition genes were genotyped in 432 Caucasian incident NHL cases and 494 frequency-matched controls. Unconditional logistic regression was used to compute odds ratios (ORs) for NHL and common NHL subtypes in relation to individual SNPs and haplotypes. A gene-based analysis that adjusted for the number of tagSNPs genotyped in each gene showed a significant association with overall NHL for the MBP gene (P = 0.028), with the diffuse large B-cell lymphoma (DLBCL) subtype for the MASP2 gene (P = 0.011), and with the follicular lymphoma (FL) subtype for DEFB126 (P = 0.041). A SNP-based analysis showed that MBP rs8094402 was associated with decreased risks of overall NHL (allele risk OR = 0.72, P-trend = 0.0018), DLBCL (allele risk OR = 0.72, P-trend = 0.036), and FL (allele risk OR = 0.67, P-trend = 0.021), while MASP2 rs12711521 was associated with a decreased risk of DLBCL (allele risk OR = 0.57, P-trend = 0.0042). We also observed an increased risk of FL for DEFB126 rs6054706 (allele risk OR = 1.39, P-trend = 0.033). Our results suggest that genetic variation in pattern-recognition genes is associated with the risk of NHL or specific NHL subtypes, but these preliminary findings require replication in larger studies.

Topics: Adult; Aged; Aged, 80 and over; beta-Defensins; Case-Control Studies; Connecticut; Female; Genetic Predisposition to Disease; Haplotypes; Humans; Immunity, Innate; Logistic Models; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Mannose-Binding Protein-Associated Serine Proteases; Middle Aged; Myelin Basic Protein; Polymorphism, Single Nucleotide; Receptors, Pattern Recognition; White People; Young Adult

Treatment of human myeloid leukemia cells with 1-beta-D-arabinofuranosylcytosine (ara-C) is associated with induction of protein kinase activity and early-response gene expression. The present studies in ara-C-treated U-937 cells extend these findings by demonstrating activation of a protein kinase that phosphorylates myelin basic protein (MBP). Purification by sequential ion-exchange chromatography and gel filtration supports the detection of a 40-kD MBP kinase. Substrate and inhibitor studies further support a pattern similar to that of protein kinase C (PKC) isozymes. Results of N-terminal amino acid sequencing and immunoblot analysis demonstrate detection of a 40-kD catalytic fragment of PKCdelta. The results also demonstrate the activation and cleavage of PKCdelta (1) is inhibited by expression of antiapoptotic proteins, and (2) is induced by camptothecin (CAM) and mitomycin C (MMC). These findings support proteolytic activation of PKCdelta in the cellular response to ara-C and other DNA-damaging agents.

Topics: Amino Acid Sequence; Apoptosis; Camptothecin; Cytarabine; DNA Damage; Endopeptidases; Enzyme Activation; Genes, jun; Humans; Intracellular Signaling Peptides and Proteins; Isoenzymes; Leukemia, Myeloid; Lymphoma, Large B-Cell, Diffuse; Membrane Proteins; Mitomycin; Molecular Sequence Data; Myelin Basic Protein; Myristoylated Alanine-Rich C Kinase Substrate; Neoplasm Proteins; Neoplastic Stem Cells; Nucleosomes; Phosphorylation; Protein Kinase C; Protein Kinase C-delta; Protein Processing, Post-Translational; Proteins; Signal Transduction; Substrate Specificity; Tumor Cells, Cultured

Calpain secreted by lymphoid (MOLT-3, M.R.) or monocytic (U-937, THP-1) cell lines activated with PMA and A23187 degraded myelin antigens. The degradative effect of enzymes released in the extracellular medium was tested on purified myelin basic protein and rat central nervous system myelin in vitro. The extent of protein degradation was determined by SDS-PAGE and densitometric analysis. Various proteinase inhibitors were used to determine to what extent protein degradation was mediated by calpain and/or other enzymes. Lysosomal and serine proteinase inhibitors inhibited 20-40% of the myelin-degradative activity found in the incubation media of cell lines, whereas the calcium chelator (EGTA), the calpain-specific inhibitor (calpastatin), and a monoclonal antibody to m calpain blocked myelin degradation by 60-80%. Since breakdown products of MBP generated by calpain may include fragments with antigenic epitopes, this enzyme may play an important role in the initiation of immune-mediated demyelination.

Topics: Animals; Antibodies, Monoclonal; Calcimycin; Calcium; Calcium-Binding Proteins; Calpain; Chelating Agents; Culture Media, Conditioned; Demyelinating Diseases; Egtazic Acid; Humans; Leukemia-Lymphoma, Adult T-Cell; Lymphoma, Large B-Cell, Diffuse; Monocytes; Myelin Basic Protein; Myelin Sheath; Neoplasm Proteins; Protease Inhibitors; Rabbits; Rats; T-Lymphocytes; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured

We measured the level of myelin basic protein (MBP) in the cerebrospinal fluid (CSF) of patients with various kinds of tumors, including malignant tumors, using radioimmunoassay. The CSF had been obtained by lumbar puncture through an Ommaya reservoir or a shunt device placed in the lateral ventricle. The level of MBP was high (> 4 ng/ml) in the patients with meningeal dissemination of malignant tumors, but in those who showed a good response to chemotherapy and/or radiation, it decreased or returned to the normal level, with improvement on the computed tomography and magnetic resonance imaging, cytological, general CSF, and neurological findings. Of seven malignant gliomas without CSF dissemination, six showed an elevated level of MBP before selective intra-arterial chemotherapy with a combination of etoposide and cisplatin administered via a microcatheter placed at A1, M1, P1-P2, and the basilar top. All CSF specimens obtained during the period of the intra-arterial chemotherapy showed an abnormally high (> 4 ng/ml) level of MBP that exceeded the prechemotherapy level. The MBP level decreased or returned to normal in the patients with a good response to chemotherapy after intra-arterial chemotherapy. In some patients with multiple metastatic brain tumors, the MBP level was elevated before treatment and returned to normal after treatment (surgical removal, chemotherapy, and/or irradiation) in all except one. Thus, there was a clear correlation between the timing of treatment and changes in imaging studies and MBP levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Astrocytoma; Biomarkers, Tumor; Brain Damage, Chronic; Brain Neoplasms; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Cranial Irradiation; Etoposide; Female; Follow-Up Studies; Glioblastoma; Humans; Infusions, Intra-Arterial; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Myelin Basic Protein; Treatment Outcome

To study how viruses interact with oligodendroglia and produce demyelination, we immunostained paraffin and epon sections of lesions from patients with progressive multifocal leukoencephalopathy (PML) with antisera to papovaviruses, oligodendroglial myelin-associated glycoprotein (MAG), and myelin basic protein (MBP) according to the peroxidase-antiperoxidase method. In paraffin sections from a rapidly progressive case of PML, hyperimmune JC virus antiserum stained single oligodendroglia which were located in white matter that appeared normal histologically and stained normally with MAG and MBP antisera. In zones surrounding areas of demyelination, virus containing oligodendroglia were most numerous and MAG staining of periaxonal regions was decreased, but there was little change in MBP staining. In demyelinated regions, both MAG and MBP staining were severely altered; also there was much less JC virus staining. In tissue from three other chronic cases, viral antiserum stained fewer oligodendrocytes and the differences in MAG and MBP staining were much less striking. In epon sections from two biopsies of central nervous system tissue, we studied the electron microscopic appearance of oligodendroglia that also had been stained by JC virus antiserum. Virions were present in all nuclei and in some cytoplasmic regions. The results suggest that changes in MAG distribution are useful indicators of early oligodendroglial abnormalities which can cause myelin breakdown.

Topics: Aged; Brain; Brain Chemistry; Female; Humans; Leukemia, Lymphoid; Leukoencephalopathy, Progressive Multifocal; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Myelin Basic Protein; Myelin P0 Protein; Myelin Proteins; Papillomaviridae; Polyomaviridae