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H Tighe

Publications and source records attributed to H Tighe.

35 records · Page 2Linked to original sources
PubMed1993

Function of B cells expressing a human immunoglobulin M rheumatoid factor autoantibody in transgenic mice.

We have generated transgenic mice that express the immunoglobulin (Ig)M heavy chain and kappa light chain genes coding for a human IgM rheumatoid factor (RF), Les. Transgenic B cells expressing human IgM RF show striking similarities to their counterparts in normal humans. They comprise a significant proportion of the adult B cell population, but secrete only low levels of RF into the serum. The RF transgene-expressing B cells localize to primary B cell follicles and the mantle zone regions of secondary follicles in the spleen. Using these mice we have been able to show that one of the central functions of normal RF-expressing B cells may be to act as highly efficient antigen-presenting cells for low concentrations of immune-complexed antigen. High levels of secretion of IgM RF can not be induced under normal circumstances, although RF-expressing B cells proliferate well in vitro to both aggregated human IgG and anti-human IgM antibodies. However, these mice are not intrinsically secretion deficient. By crossing the RF transgenic mice with the autoimmune MRL/lpr background, we find a dramatic increase, > 200-fold, in levels of serum RF. The results strongly suggest that a major function of normal resting RF B cells is unrelated to antibody secretion. Rather, the RF B cells in the follicles may play a role in antigen presentation and regulation of immune responses to antibody-bound nonself-, and possibly self-antigens. This physiologic role of RF B cells may be disrupted in RF-associated autoimmune disease.

Animals↗
PubMed1992

Generation and characterization of two monoclonal self-associating IgG rheumatoid factors from a rheumatoid synovium.

OBJECTIVE: To study IgG rheumatoid factor (RF) from rheumatoid synovium. METHODS: We fused the K6H6/B5 human-mouse heterohybridoma with unstimulated rheumatoid synovial B cells to generate IgG-RF-secreting hybridomas. RESULTS: The RFs from 2 such hybridomas bound specifically to the Fc fragment of human IgG and self-associated to form immune complexes. Such immune complexes are a major characteristic of the pathogenic IgG-RFs in rheumatoid synovium. CONCLUSION: IgG-RF-secreting hybridomas have been obtained. Analyses may reveal the underlying mechanisms of the induction of IgG-RF.

Animals↗
PubMed1990

Human monoclonal rheumatoid factors derived from the polyclonal repertoire of rheumatoid synovial tissue: incidence of cross-reactive idiotopes and expression of VH and V kappa subgroups.

A panel of 14 human monoclonal and monoreactive IgM rheumatoid factors (RF) derived from the synovial tissue of rheumatoid arthritis (RA) patients was studied for the expression of cross-reactive idiotopes (CRI) and variable heavy (VH) and variable kappa (V kappa) subgroups. Four of the twelve kappa RF expressed light chains of the V kappa III subgroup. Three of these were characterized as belonging to the V kappa IIIb sub-subgroup, and expressed the V kappa IIIb associated CRI, 17.109. None of the RF expressed the V kappa IIIa-associated CRI, 6B6.6. One of the fourteen RF expressed the VH-associated CRI, G6, and five expressed either or both the VHIII-associated CRI, B6 and D12. Seven RF bound to protein A (SpA), which indicates the expression of VHIII subgroup V regions. Together the data indicated that 9/11 RF express VHIII regions and 2/11 express VHI regions. There was no obvious correlation between V region usage or CRI expression and fine specificity of the RF for human IgG subclasses. These data indicate a difference in V gene usage by RF derived from RA patients compared with RF paraproteins derived from non-RA patients. There is not a bias towards variable chains of the V kappa III subgroup, but a marked preference for variable heavy chains of the VHIII subgroup is seen. Further studies may elucidate the pathological significance of these findings in RA.

Animals↗
PubMed1990

Autoantibody production by severe combined immunodeficient mice reconstituted with synovial cells from rheumatoid arthritis patients.

In an attempt to characterize the heterogeneity of the human autoantibody response, mice with severe combined immunodeficiency were reconstituted with synovial or blood lymphocytes from patients with rheumatoid arthritis (RA). Mononuclear cells extracted from synovial fluid or tissue (SMC) were a greatly enriched source of IgM rheumatoid factor (RF)-producing cells compared to the peripheral blood mononuclear cells (PBMC) of rheumatoid arthritis patients or normal donors. Six to nine weeks after reconstitution of mice with synovial mononuclear cells, 0%-39.3% (mean = 11.4%) of total IgM consisted of IgM RF compared to 0%-0.15% (mean = 0.02%) in mice given RA PBMC and 0%-1.2% (mean = 0.34%) in mice given normal PBMC. Detectable levels of IgM RF were maintained in some mice for as long as 20 weeks after transfer. Mice reconstituted with synovial membrane or synovial fluid lymphocytes produced a heterogeneous mixture of immunoglobulins. These included other autoantibodies, such as anti-nuclear and anti-cytoplasmic antibodies, and antibodies to exogenous antigens such as the Epstein-Barr virus nuclear antigen-1 (EBNA-1). This heterogeneity is further illustrated by the demonstration that the sera from mice given synovial cells also contained IgG antibodies possessing all three major VH families (VH1, VH3 and VH4) and the four major V kappa families (V kappa 1 to V kappa 4). Autoantibody production gradually decreased with time even under circumstances where total immunoglobulin levels increased, and elevated production could not be induced by antigenic stimulation. These findings describe a new model for the analysis of human autoantibody production.

Animals↗
PubMed1989

CD59, an LY-6-like protein expressed in human lymphoid cells, regulates the action of the complement membrane attack complex on homologous cells.

A novel cell surface antigen has been identified on a wide range of lymphoid cells and erythrocytes. A mAb YTH 53.1 (CD59) against this antigen enhanced the lysis of human red cells and lymphocytes by homologous complement. Studies of reactive lysis using different species of C56, and of whole serum used as a source of C7-9, indicated that the inhibitory activity of the CD59 antigen is directed towards the homologous membrane attack complex. CD59 antigen was purified from human urine and erythrocyte stroma by affinity chromatography using the mAb YTH 53.1 immobilized on Sepharose, and, following transient expression of a human T cell cDNA library in COS cells, the corresponding cDNA also identified using the antibody. It was found that the CD59 antigen is a small protein (approximately 20 kD as judged by SDS-PAGE, 11.5 kD predicted from the isolated cDNA) sometimes associated with larger components (45 and 80 kD) in urine. The sequence of CD59 antigen is unlike that of other complement components or regulatory proteins, but shows 26% identity with that of the murine LY-6 antigen. CD59 antigen was released from the surface of transfected COS cells by phosphatidylinositol-specific phospholipase C, demonstrating that it is attached to the cell membrane by means of a glycolipid anchor; it is therefore likely to be absent from the surface of affected erythrocytes in the disease paroxysmal nocturnal hemoglobinuria.

Antibodies, Monoclonal↗
PubMed1989

Beneficial effect of monoclonal antibody to interleukin 2 receptor on activated T cells in rheumatoid arthritis.

Campath 6, a rat IgG2b monoclonal antibody to the interleukin 2 receptor on activated T cells, was used to treat three patients with active rheumatoid arthritis unresponsive to conventional treatment. Two patients had an excellent response for about three months. There were no significant side effects. The results suggest that activated T cells are of importance in the pathogenesis of rheumatoid arthritis. Although infusions of rat monoclonal antibodies could not be repeated because of the risk of sensitisation, the development of humanised monoclonal antibodies targeted against specific T cell sets would allow repeated courses of treatment to be given.

Adult↗
PubMed1987

CD4 monoclonal antibody pairs for immunosuppression and tolerance induction.

A pair of rat anti-mouse CD4 monoclonal antibodies (mAb) have been selected which bind to different epitopes of the molecule. Both the mAb are rat IgG2b and show clear synergistic activity in complement lysis in vitro. When injected together in vivo, they exhibit an improved immunosuppressive effect, compared to each antibody alone, on allogeneic graft rejection, humoral responses and on tolerance induction. Limiting dilution analysis indicates that the in vivo depletion of interleukin 2-producing cells is improved using both mAb by 2-3-fold over that obtained with the individual antibodies. As little as 60 ng per mouse of the CD4 antibody pair was sufficient to allow the induction of tolerance to human gamma-globulin, even without elimination of the CD4+ cells. The results suggest that appropriate antibody pairs may be good candidates for effective immunosuppressive serotherapy in man.

Animals↗
PubMed1987

Blocking of cytotoxic T cell function by monoclonal antibodies against the CD45 antigen (T200/leukocyte-common antigen).

Cytotoxic T cells are important effectors in graft rejection and antiviral immunity. A full identification of the functional surface molecules used by these cells may help in determining the best strategies for the therapeutic control of rejection responses. Many T cell surface molecules have been implicated in cytotoxic function through the ability of specific monoclonal antibodies to inhibit T cell activity in vitro. Such measures of "inhibition" must be affected by the avidity of interaction of antibody with the particular surface molecule, as well as the avidity of that surface molecule for any physiological ligand. We show that the introduction of an antiglobulin step substantially amplifies the inhibitory effects of certain CD3 and CD8 monoclonal antibodies, presumably by conferring multivalency. In addition the "antiglobulin" approach has permitted, for the first time, the demonstration that monoclonal antibodies to the "common" determinants of the leukocyte-common antigen family (CD45/LCA/T200) prevent cytotoxic T cell function.

Animals↗
PubMedDate not supplied

T-cell control of Epstein-Barr virus-infected B cells is lost during P. falciparum malaria.

Endemic Burkitt's lymphoma, a tumour of children in which B lymphocytes are infected with Epstein-Barr virus (EBV), is common in areas of Africa where malaria is holoendemic. The tumour is characterized by chromosome translocations; usually the terminal portion of chromosome 8 containing the c-myc gene is translocated to chromosome 14, near the enhancer of the immunoglobulin heavy-chain locus. Less frequent are translocations of chromosome 8 to the kappa light-chain locus of chromosome 2 or to the lambda light-chain locus of chromosome 22. In vitro, EBV induces B cells to proliferate and secrete immunoglobulin and antibody. However, in vivo the infected B lymphocytes are under immunological control, so that abnormal proliferation is found only in immunosuppressed patients. Such patients are subsequently liable to develop lymphomas. Burkitt believed that the tumour he had described resulted from interaction between a virus(es) and a "reticuloendothelial system altered by chronic and heavy infection by malarial or other parasites". We report here that during an attack of Plasmodium falciparum malaria, T-cell subpopulations are radically altered so that, in vitro, B lymphocytes infected with EBV proliferate abnormally to secrete large amounts of immunoglobulin and antibody. This phenomenon offers some explanation for the increased incidence of Burkitt's tumour and the high levels of immunoglobulin found in people living in areas where P. falciparum malaria is common.

Adolescent↗
PubMedDate not supplied

Inhibition of IgE antibody formation by plasmid DNA immunization is mediated by both CD4+ and CD8+ T cells.

BACKGROUND: We previously showed that immunization of mice with plasmid DNA (pDNA) encoding the Escherichia coli beta-galactosidase gene (pCMV-LacZ) induces a Th1 response, whereas beta-galactosidase (beta-gal) in saline or alum induces a Th2 response. Furthermore, the Th1 response dominates over the Th2 response and downregulates preexisiting IgE antibody formation. Here, we determined by passive transfer of CD4+ or CD8+ lymphocytes and by immunizing beta2-microglobulin knockout (beta2-M KO) mice whether CD4+ and/or CD8+ cells from pDNA-immunized mice suppress IgE antibody production. METHODS: BALB/c mice were injected with either CD4+ or CD8+ lymphocytes from naive beta-gal-in-alum or pCMV-LacZ-immunized mice, then immunized with beta-gal in alum, and the IgE antibody formation was determined. Second, C57BL/6 wild-type (WT) or beta2-M KO mice were immunized with beta-gal orpCMV-LacZ, and the IgE antibody production was assessed. RESULTS: Passive transfer of both CD4+ and CD8+ lymphocytes from pDNA-immunized mice suppressed the IgE antibody response by 90% compared to transfer of CD4+ T cells from naive or beta-galin-alum immunized mice. beta2-M KO mice produced 3 times more IgE than the WT control mice both in the primary and secondary response. CONCLUSION: Both CD4+ and CD8+ subsets of T cells from pDNA-immunized mice can suppress IgE antibody production by affecting the primary response and/or by propagating the Th1 memory response in a passive cell transfer system. Immunization with pDNA-encoding allergens may be an effective new form of immunotherapy for atopic diseases.

Animals↗
PubMedDate not supplied

Probing of the rheumatoid factor (RF) V gene repertoire in rheumatoid arthritis (RA) by hybridoma clones.

Twenty human monoclonal antibodies with rheumatoid factor (RF) specificity were produced from fusions using B lymphocytes derived from the synovial tissue of two patients with rheumatoid arthritis (RA) and one with the polyarticular form of juvenile rheumatoid arthritis (JRA) (1). All the 20 monoclonal antibodies were IgM. Fourteen of these were classical RFs with specificity restricted to IgG, and included 12 kappa and 2 lambda proteins. When the fine specificity for IgG Fc determinants were investigated most of them showed the Ga specificity. In addition, 5 lambda and 1 kappa monoclonal RF antibodies showed polyreactivity and also reacted with various other antigens than IgG (1). The 14 monoreactive RFs were further studied for the expression of RF-related cross-reactive idiotypes (CRI) and variable heavy (VH) and light chain (VL) subgroups. Only four of the twelve kappa RFs expressed the V kappa III subgroup. Three of them belong to the V kappa IIIb sub-subgroup and expressed the CRI 17.109. One of these 3 clones in addition expressed the VH I associated CRI G6. Five other monoreactive RFs expressed either or both of the VH III associated CRI B6 and D12 (2). Using staphylococcal protein A (SPA) binding as well as Northern blotting techniques (2), studies indicated that 10 out of the 12 RFs studied expressed the VH III regions and 2 expressed the VH I region. These data, both for the heavy and light chains, indicated a different V gene usage by the RF derived from RA patients than by the RF M-components derived from patients with mixed cryoglobulinemia and Waldenström's macroglobulinemia but without RA.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMedDate not supplied

Regulation of rheumatoid factor synthesis.

Rheumatoid arthritis is associated with high titers of IgM and IgG autoantibodies against IgG (rheumatoid factors, RF) and is prevalent in individuals with the HLA haplotypes Dw4, Dw14 and DR1. Our investigations have aimed to determine the molecular genetic basis for RF autoantibody synthesis in people, in an effort to understand eventually how RF production may become improperly regulated in rheumatoid patients. The results have defined several cross-reactive idiotypes on the heavy and light chains of RFs that are serologic markers for specific immunoglobulin variable region genes. These autoantibody associated genes are highly conserved in human populations and are preferentially rearranged and expressed during early B cell development, and in certain lymphoproliferative diseases. They may be associated with a B cell subpopulation that is important for the processing and presentation to T cells of protein antigens trapped in immune complexes. These RF-associated idiotypes are eventually lost during the T cell dependent antibody diversification that accompanies rheumatoid arthritis. The stimuli for the diversification have not been clearly established. However, the rheumatoid arthritis disease susceptibility determinant on the beta-1 chain of individuals with the HLA Dw4, Dw14 or DR1 haplotypes is reproduced by the gp110 protein of the Epstein-Barr virus, and is a potent stimulus for T cell proliferation. Moreover, anti-gp110 antibodies are abundant in rheumatoid arthritis patients. Thus, it is possible that their continual binding and processing of gp110-IgG immune complexes by RF precursor B cells in the joints and other extravascular sites may lead to the emergence of self-reactive T cells that can trigger anti-IgG autoantibody synthesis in the absence of an external antigen.

Arthritis, Rheumatoid↗