Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.23 (beta-galactosidase)
 14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antigen-stimulated B lymphocytes either differentiate into IgM-secreting plasma cells or into memory B cells that secrete other immunoglobulin isotypes upon antigen restimulation. The mechanisms that generate and maintain memory B cells are poorly understood. Previously, we described a severe B lymphocyte deficiency in adult strain A/WySnJ mice compared to subline A/J. Here we show that the single, autosomal co-dominant locus responsible for the deficiency also diminishes IgG-secreting B cell formation without interfering with IgM-secreting plasma cell differentiation. A/WySnJ secondary IgG1 responses to the protein antigens hemocyanin, bovine gamma-globulin, ovalbumin, lysozyme and beta-galactosidase were 6- to 50-fold lower than A/J responses. The defect also decreased secondary IgG2a and IgG3 responses, and primary IgG1 and IgG2a responses. The reduced A/WySnJ secondary IgG1 response was not due to differential response kinetics or dose responsiveness, and could not be augmented to A/J levels by repeated immunizations. Serum IgG1, IgG2a and IgG3 levels from nonimmune A/WySnJ mice were similarly reduced. The secondary IgG1 response and splenic B cell percentage showed significant positive correlation (r = 0.72) in F2 mice, suggesting that a single locus controlled both traits. In contrast, A/WySnJ mice made good primary IgM responses to hemocyanin, beta-galactosidase, and the thymus-independent antigen trinitrophenyl-Ficoll. The A/WySnJ splenic adherent cells were competent in antigen-presenting function, and A/WySnJ immune T cells proliferated in response to antigen and provided the requisite B cell stimulatory signals for an IgG1 response. Together, our results suggest that A/WySnJ mice have a genetic lesion that causes a selective IgG immune response dysfunction. The absence of IgG-secreting cell precursors or a defect in precursor activation or differentiation are two possible mechanisms which could precipitate a selective IgG response dysfunction. We propose that the defective A/WySnJ and normal A/J strain pair offer the opportunity to use a natural genetic variation as a tool to investigate B lymphocyte development and function.
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PMID:A single autosomal gene defect severely limits IgG but not IgM responses in B lymphocyte-deficient A/WySnJ mice. 153 37

A transgenic mouse line was produced which allowed the expression of E. coli beta-galactosidase (beta-Gal) under the regulatory elements of the immunoglobulin heavy chain locus. Expression of the transgene is found in spleen and bone marrow. Upon immunization of the transgenic mice with beta-Gal, a reduced but clearly detectable antibody response was obtained. Affinity purification with sera from immunized transgenic mice suggests that they contain lower affinity antibodies as compared to normal littermates. Transgenic and nontransgenic mice immunized with bovine serum albumin (BSA) alone or as a mixture with beta-Gal gave comparable anti-BSA responses. Immunization with a chemically cross-linked (Gal-BSA)-protein, however, showed a 10- to 30-fold difference in the anti-BSA response. Partial unresponsiveness to beta-Gal in the transgenic mice is best explained by a dominant, peripheral suppression mechanism linked to the antigen-presenting potential of B cells.
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PMID:Partial tolerance in beta-galactosidase-transgenic mice. 211 98

Anti-Sm and anti-ribosomal P protein antibodies show a high degree of specificity for the disease SLE. To determine whether a relationship between these two autoantibodies existed, the frequency of anti-P was determined in sera with and without anti-Sm activity. Of sera from lupus patients with anti-Sm 18/65 (28%), and 6/55 (11%) of sera without anti-Sm had anti-P as determined by an ELISA using a recombinant P2-beta-galactosidase fusion protein as Ag (p less than 0.05). The levels of anti-P were significantly higher in sera containing anti-Sm (0.37 +/- 0.45) than in sera without anti-Sm antibodies (0.18 +/- 0.20) (p less than 0.01). Similarly, a significantly higher proportion of anti-P positivity was found in autoimmune MRL/Mp-lpr/lpr mice positive for anti-Sm (11/53 = 21%) compared to age- and sex-matched mice without anti-Sm (3/53 = 6%) (p less than 0.05). The IgG subclass distributions for anti-Sm and anti-P antibodies were similar in the MRL mice (IgG2a greater than IgG2b greater than IgG3 greater than IgG1). The association did not reflect polyclonal B cell activation in a proportion of MRL mice because no significant differences were observed in anti-DNA, antichromatin or total serum IgG levels in mice with and without anti-Sm or, in mice positive for both anti-P and anti-Sm compared to mice positive for anti-Sm alone. Cross-inhibition experiments excluded the possibility that the Sm and P protein Ag shared a common epitope. Longitudinal measurement of anti-P and anti-Sm antibody levels by ELISA in three mice indicated that both antibodies first appeared at about 3 to 4 mo of age and fluctuated two- to threefold over 3 to 8 mo with independent peaks of activity. Recent observations regarding a relationship between anti-Sm and autoantibodies to other ribosomal proteins suggest that the association may be explained by an immune response to epitopes coassociated on the ribosome.
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PMID:Association between anti-Sm and anti-ribosomal P protein autoantibodies in human systemic lupus erythematosus and MRL/lpr mice. 276 Apr 62

The p40 subunit of interleukin 12 (IL-12p40) has been known to act as an IL-12 antagonist in vitro. We here describe the immunosuppressive effect of IL-12p40 in vivo. A murine myoblast cell line, C2C12, was transduced with retro-virus vectors carrying the lacZ gene as a marker and the IL-12p40 gene. IL-12p40 secreted from the transfectant inhibited the IL-12-induced interferon gamma (IFN-gamma) production by splenocytes in vitro. Survival of C2C12 transplanted into allogeneic recipients was substantially prolonged when transduced with IL-12p40. Cytokine (IL-2 and IFN-gamma) production and cytotoxic T lymphocyte induction against allogeneic C2C12 were impaired in the recipients transplanted with the IL-12p40 transfectant. Delayed-type hypersensitivity response against C2C12 was also diminished in the IL-12p40 recipients. Furthermore, serum antibodies against beta-galactosidase of the T-helper 1-dependent isotypes (IgG2 and IgG3) were decreased in the IL-12p40 recipients. These results indicate that locally produced IL-12p40 exerts a potent immunosuppressive effect on T-helper 1-mediated immune responses that lead to allograft rejection. Therefore, IL-12p40 gene transduction would be useful for preventing the rejection of allografts and genetically modified own cells that are transduced with potentially antigenic molecules in gene therapy.
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PMID:Local production of the p40 subunit of interleukin 12 suppresses T-helper 1-mediated immune responses and prevents allogeneic myoblast rejection. 879 58

MRL/Mp-lpr/lpr (MRL/lpr) mice suffer from a generalized autoimmune disease that includes autoantibody production and glomerulonephritis and develop massive lymphadenopathy characterized by an expanded population of CD4- CD8- B220+ T cells that is derived from autoreactive T cells in the periphery. Some of us previously reported that these atypical T cells overexpressed a gene for tyrosine kinase p59fyn (Fyn). To define the role of Fyn in the renal disease and lymphadenopathy in MRL/lpr mice, we have generated Fyn-deficient MRL/lpr mice whose fyn gene is replaced by the gene for beta-galactosidase. Fyn-deficient MRL/lpr mice developed markedly limited disease and lived more than twice as long as the conventional MRL/lpr mice. In the mutant mice, the production of IgG3 anti-DNA autoantibody was significantly (p < 0.005%) reduced, and glomerular deposits of IgG3 and C3 were remarkably diminished. Ag receptor-mediated proliferative responses of Fyn-deficient splenic T cells were markedly impaired. The mutant mice showed delayed accumulation of the atypical CD4- CD8- B220+ T cells that exhibited a significantly lower activity of ZAP-70 compared with those in the conventional MRL/lpr mice. These data demonstrated that Fyn is involved as a positive regulator in the disease of MRL/lpr mice. Fyn provides a signal for both the expansion of autoreactive T cells and the production of IgG3 anti-DNA autoantibody by B cells. Thus, manipulation of Fyn may improve systemic autoimmune disease in humans.
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PMID:Suppression of autoimmune disease and of massive lymphadenopathy in MRL/Mp-lpr/lpr mice lacking tyrosine kinase Fyn (p59fyn). 927 47

Clostridium difficile toxin A binds nonspecifically to a mouse monoclonal antibody (MAb) immunoglobulin G3 lambda chain [IgG3(lambda)], through the Fab component. This binding, which is retained even after boiling the MAb, is temperature dependent, with more toxin bound at 4 than 37 degrees C (P = 0.0024). The nonspecific binding was decreased by incubation of the IgG3 lambda MAb with alpha- or beta-galactosidase (P = 0.0001 and 0.029, respectively), indicating that toxin A binds to a carbohydrate moiety on the Fab. However, binding was not blocked by the Bandeiraea simplicifolia lectin BS-1, indicating that a terminal alpha-galactose may not be involved. Binding was also not affected by competitive assays with Lewis X antigen. The dependence on carbohydrate moieties in nonspecific binding was also shown for two other MAbs, IgA(kappa) and IgM(lambda), with demonstration of a significant reduction in binding with alpha-galactosidase (P = 0.0001 and 0.0002, respectively) but not beta-galactosidase (P = 0.27 and 0.25, respectively).
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PMID:Nonspecific binding of Clostridium difficile toxin A to murine immunoglobulins occurs via the fab component. 957 79

Using a yeast two-hybrid system to search for proteins interacting with Ro52 autoantigen, we identified a novel protein-protein interaction. Two different cDNA clones, which interacted with Ro52 in the yeast two-hybrid system, were identified and isolated from a human B-cell library. Surprisingly, both clones encoded the heavy chain of human IgG1. The expression of both HIS3 and beta-galactosidase reporter genes in yeast suggested that the interaction between Ro52 and IgG occurred in vivo. In vitro studies utilizing recombinant Ro52 and purified immunoglobulins indicated that the interaction was immunoglobulin class and subclass specific. Ro52 interacted with IgG1 and IgG4, but not with IgG2, IgG3, IgA or IgM. Ro52 could also precipitate IgG directly from serum. The identified cDNA clones did not include the variable region of IgG, which suggested a non-classical interaction independent of antibody specificity. We further mapped the domain of Ro52 responsible for this interaction to the C-terminus rfp-like region. In conclusion, our data support an unusual interaction between native Ro52 and IgG. The potential biological significance of this unusual protein-protein interaction is discussed.
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PMID:Protein-protein interactions between native Ro52 and immunoglobulin G heavy chain. 1035 73

We evaluated whether immune responses stimulated by Salmonella vaccine carriers can be modulated by using different promoters to drive antigen expression. Mice were orally immunized with strains transfected with plasmids carrying beta-galactosidase (beta-gal) under the control of either a constitutive or an in vivo-activated promoter. While alpha-gal-reactive IgG1, IgG2a, IgG2b and IgG3 were detected in sera of mice immunized with Salmonella expressing constitutively beta-gal, higher titers dominated by IgG2a and IgG2b were detected in sera when the in vivo-activated promoter was used. beta-gal-specific proliferative responses of spleen-derived CD4+ T lymphocytes were similar in both groups. However, CD4+ T lymphocytes from mice immunized with the constitutive promoter secreted IL-4, IL-5, IL-6, IL-10 and IFN-gamma (Th1/Th2 pattern), whereas CD4+ cells mainly secreted IFN-gamma (Th1 pattern) when the second construct was used. The spleens of all immunized mice contained beta-gal-reactive CD8+ CTL precursors. The vaccine prototypes were tested for their capacity to control seeding and/or development within the lung of an intravenously delivered aggressive fibrosarcoma transfected with beta-gal. Reduced metastasis and significantly increased mean survival times were observed in all vaccinated mice. However, protection was improved when the carrier expressed beta-gal upon infection (80 % versus 50% survival, p < 0.05).
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PMID:Modulation of host immune responses stimulated by Salmonella vaccine carrier strains by using different promoters to drive the expression of the recombinant antigen. 1074 91

We have developed an antibody fusion protein (anti-rat TfR IgG3-Av) with the ability to deliver different molecules into cancer cells. It consists of avidin genetically fused to the C(H)3 region of a human IgG3 specific for the rat transferrin receptor. It forms strong, noncovalent interactions with biotinylated molecules such as glucose oxidase and beta-galactosidase, and delivers them into the rat myeloma cell line Y3-Ag1.2.3 through receptor-mediated endocytosis. Importantly, the beta-galactosidase retains activity after internalization. Furthermore, we have unexpectedly discovered that anti-rat TfR IgG3-Av, but not a recombinant anti-rat TfR IgG3 or a nonspecific IgG3-Av, possesses proapoptotic activities against Y3-Ag1.2.3 and the rat T cell lymphoma cell line C58 (NT) D.1.G.OVAR.1. These activities were not observed in two rat cell lines of nonhematopoietic lineage (bladder carcinoma BC47 and gliosarcoma 9L). Anti-human TfR IgG3-Av also demonstrated proapoptotic activity against the human erythroleukemia cell line K562. Studies showed that anti-rat TfR IgG3-Av exists as a dimer, suggesting that cross-linking of the surface transferrin receptor may be responsible for the cytotoxic activity. These findings demonstrate that it is possible to transform an antibody specific for a growth factor receptor that does not exhibit inhibitory activity into a drug with significant intrinsic cytotoxic activity against selected cells by fusing it with avidin. The antitumor activity may be enhanced by delivering biotinylated therapeutics into cancer cells. Further development of this technology may lead to effective therapeutics for in vivo eradication of hematological malignancies, and ex vivo purging of cancer cells in autologous transplantation.
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PMID:An anti-transferrin receptor-avidin fusion protein exhibits both strong proapoptotic activity and the ability to deliver various molecules into cancer cells. 1214 72

Activation-induced cytidine deaminase (AID) is indispensable for immunoglobulin maturation by somatic hypermutations and class switch recombination and is supposed to deaminate cytidines in DNA, while its homolog APOBEC-1 edits apolipoprotein (apo) B mRNA by cytidine deamination. We studied the editing activity of APOBEC-1 and AID in yeast using the selectable marker Gal4 linked to its specific inhibitor protein Gal80 via an apo B cassette (Gal4-C) or via the variable region of a mouse immunoglobulin heavy chain gene (Gal4-VH). Expression of APOBEC-1 induced C to U editing in up to 15% of the Gal4-C transcripts, while AID was inactive in this reaction even in the presence of the APOBEC-1 complementation factor. After expression of APOBEC-1 as well as AID approximately 10(-3) of yeast cells survived low stringency selection and expressed beta-galactosidase. Neither AID nor APOBEC-1 mutated the VH sequence of Gal4-VH, and consequently the yeast colonies did not escape high stringent selection. AID, however, induced frequent plasmid recombinations that were only rarely observed with APOBEC-1. In conclusion, AID cannot substitute APOBEC-1 to edit the apo B mRNA, and the expression of AID in yeast is not sufficient for the generation of point mutations in a highly transcribed Gal4-VH sequence. Cofactors for AID induced somatic hypermutations of immunoglobulin variable regions, that are present in B cells and a variety of non-B cells, appear to be missing in yeast. In contrast to APOBEC-1, AID alone does not exhibit an intrinsic specificity for its target sequences.
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PMID:The cytidine deaminases AID and APOBEC-1 exhibit distinct functional properties in a novel yeast selectable system. 1596 68


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