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Anti-Idiotypic Antibodies Against a Human Multiple Organ- Reactive Autoantibody

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Anti-Idiotypic Antibodies Against a Human Multiple Organ- Reactive Autoantibody Anti-idiotypic antibodies against a human multiple organ- reactive autoantibody. Detection of idiotopes in normal individuals and patients with autoimmune diseases. K Essani, … , P R McClintock, A L Notkins J Clin Invest. 1985;76(4):1649-1656. https://doi.org/10.1172/JCI112150. Research Article We have recently isolated and characterized a human monoclonal autoantibody, MOR-h1 (multiple organ-reactive human 1), that reacts with antigens in multiple organs and have shown that this antibody binds to human growth hormone and a 35,000-mol wt protein. In the present study we generated three monoclonal anti-idiotypic antibodies (4E6, 3E5, and 3F6) against MOR-h1. These anti-idiotypic antibodies specifically reacted with MOR-h1 and not with 26 other multiple organ- reactive monoclonal IgM autoantibodies nor with pooled human IgM (myeloma proteins). The binding of the anti-idiotypic antibodies to MOR-h1 was inhibited by both human growth hormone and the 35,000-mol wt protein, which strongly suggests that these antibodies react with epitopes at or near the paratope on MOR-h1. The results of competitive binding experiments revealed that the epitope recognized by 4E6 is distinct from that recognized by 3E5 and 3F6. Using these anti-idiotypic antibodies, lymphocytes and sera from normal individuals were tested for the presence of the 4E6 and 3E5/3F6 idiotopes. By indirect immunofluorescence, the 4E6 idiotope was detected on an average of 1.1% of normal circulating B lymphocytes, and by enzyme-linked immunosorbent assays, the 4E6 and to a lesser extent the 3E5/3F6 idiotopes were found on IgG molecules in sera of normal individuals. In spite of the expression of idiotopes known to be present on MOR-h1, no MOR-h1-like antibody activity was detected in […] Find the latest version: https://jci.me/112150/pdf Anti-idiotypic Antibodies against a Human Multiple Organ-reactive Autoantibody Detection of Idiotopes in Normal Individuals and Patients with Autoimmune Diseases Karim Essani, Jo Satoh, Bellur S. Prabhakar, Patrick R. McClintock, and Abner Louis Notkins Laboratory of Oral Medicine, National Institute ofDental Research, National Institutes ofHealth, Bethesda, Maryland 20205 Abstract (7). If this turns out to be the case, then anti-idiotypic antibodies may serve as useful probes to quantitate the level of expression We have recently isolated and characterized a human monoclonal of idiotopes in both normal individuals and patients. autoantibody, MOR-hl (multiple organ-reactive human 1), that Recently we prepared a hybridoma secreting a human reacts with antigens in multiple organs and have shown that this monoclonal autoantibody, designated MOR-h 1 (multiple organ- antibody binds to human growth hormone and a 35,000-mol wt reactive human 1)' (8). This antibody (IgM-K) reacts with antigens protein. In the present study we generated three monoclonal anti- in several different organs including the pituitary, thyroid, pan- idiotypic antibodies (4E6, 3E5, and 3F6) against MOR-hl. These creas, and stomach. Using an MOR-h 1 immunoaffinity column anti-idiotypic antibodies specifically reacted with MOR-hl and we have isolated the autoantigens (i.e., 35,000 and 21,000-mol not with 26 other multiple organ-reactive monoclonal IgM au- wt proteins) with which this autoantibody reacts. The 35,000- toantibodies nor with pooled human IgM (myeloma proteins). molwt protein is present in the pituitary, thyroid, and stomach; The binding of the anti-idiotypic antibodies to MOR-hl was and the 21,000-mol wt protein, which was shown to be human inhibited by both human growth hormone and the 35,000-mol growth hormone (hGH), is found only in the pituitary. We now wt protein, which strongly suggests that these antibodies react report the preparation and characterization ofthree monoclonal with epitopes at or near the paratope on MOR-hl. The results antibodies directed against idiotypic determinants at or near the of competitive binding experiments revealed that the epitope paratope of MOR-h 1. Using these anti-idiotypic antibodies we recognized by 4E6 is distinct from that recognized by 3E5 and have studied the expression of the corresponding idiotopes on 3F6. Using these anti-idiotypic antibodies, lymphocytes and sera immunoglobulins in the sera of normal individuals and patients from normal individuals were tested for the presence of the 4E6 with autoimmune diseases. and 3E5/3F6 idiotopes. By indirect immunofluorescence, the 4E6 idiotope was detected on an average of 1.1% of normal circulating B lymphocytes, and by enzyme-linked immunosorbent assays, Methods the 4E6 and to a lesser extent the 3E5/3F6 idiotopes were found on IgG molecules in sera of normal individuals. In spite of the Human monoclonal autoantibodies. The procedure for the preparation of 1 26 other human no MOR-h and monoclonal multiple organ-reactive expression of idiotopes known to be present on MOR-li, (MOR) antibodies has already been described (8-9). All of these auto- MOR-hl-like antibody activity was detected in normal sera. Ex- antibodies are of the IgM class. Some of these antibodies were prepared amination of sera from patients with several autoimmune diseases by fusing human peripheral B lymphocytes with either human or mouse failed to show an increased expression of the 4E6 idiotope as myeloma cells (8). Others were prepared by immortalizing peripheral B compared with normal controls. These data suggest that anti- lymphocytes with Epstein-Barr virus (9). idiotypic antibody 4E6 recognizes a public idiotope, the expres- Purification of MOR-hi. MOR-hI was purified using an immu- sion of which is not restricted to autoimmune disease. noaffinity column, which was prepared by coupling the IgG fraction of sheep anti-human IgM to CNBr-activated Sepharose4B (Pharmacia Fine Chemicals, Piscataway, NJ) as previously described (10). The adsorbed Introduction MOR-h 1 was eluted with 0.1 M glycine-HCl (pH 2.5); the pH of the eluate was adjusted to 7.5 before exhaustive dialysis against deionized Idiotypic determinants on antibodies and cells and their rec- water, and the material was lyophilized. The purity of MOR-hl was ognition by anti-idiotypic antibodies have been given a promi- tested by SDS-polyacrylamide gel electrophoresis, and only two bands nent role in current theories of The having the apparent molecular weights of u- and K-chains were detected. immunoregulation (1-4). 1 are interest The purified MOR-h was also checked for immunological reactivity idiotopes expressed on autoantibodies of particular with synthetic hGH (kindly provided by Genentech, Inc., South San since it has been suggested that autoantibodies may represent Francisco, CA) and a 35,000-mol wt polypeptide (from human gastric failures of, or gaps in, the immunoregulatory network. Recent mucosa) by employing an enzyme-linked immunosorbent assay (ELISA) studies in mice (5) and in humans (6) suggested that certain as described earlier (10). idiotypes are closely associated with particular autoimmune dis- Preparation, screening, and purification ofmonoclonal anti-idiotypic orders. It also has been speculated that a limited number of antibodies. Balb/c AnN mice received five weekly, intraperitoneal in- families of immunoglobulins may be involved in autoimmunity jections of 100 Ag of affinity-purified MOR-hl . 3 d after the last injection, splenic lymphocytes were fused with P3653 Ag8 myeloma cells using Dr. Satoh's present address is The Third Department of Internal Med- icine, Tohoku University School of Medicine, 1-1 Seiryo-machi, Sendai, 1. Abbreviations used in this paper: ELISA, enzyme-linked immunosor- Miyagi 980, Japan. bent assay; FITC, fluorescein isothiocyanate; hGH, human growth hor- Receivedfor publication 25 February 1985. mone; IDDM, insulin-dependent diabetes mellitus; MOR, multiple or- gan-reactive; MOR-h 1, multiple organ-reactive human 1 autoantibody; The Journal of Clinical Investigation, Inc. RIA, radioimmunoassay; SLE, systemic lupus erythematosus; TRITC, Volume 76, October 1985, 1649-1656 tetramethylrhodamine isothiocyanate. Idiotype Expression in Normal and Autoimmune Sera 1649 50%o polyethylene glycol at neutral pH, essentially as described by Kohler fluorescein isothiocyanate (FITC)-conjugated F(ab&)2 fragment of sheep and Milstein (I 1). The fused cells were plated in 96-well tissue culture anti-mouse IgG (that did not cross react with human IgG) for 30 min plates and incubated at 370C. Supernatants from cultures grown to con- on ice. The cells were washed and fixed with 1% paraformaldehyde in fluency were initially screened for anti-MOR-hl and anti-human IgM PBS overnight at 4VC, and then viewed with an epifluorescence micro- antibody by ELISA in which Immulon II plates (Dynatech Laboratories, scope. The cells stained with TRITC (i.e., surface Ig-positive B lympho- Alexandria, VA) were coated with either MOR-hl or pooled human cytes) or the cells stained with both TRITC and FITC (i.e., 4E6-reacting myeloma IgM. The bound monoclonal IgG was detected using peroxi- B lymphocytes) were counted under rhodamine and fluorescein filters, dase-labeled goat anti-mouse -y-chain-specific antibodies. The positive respectively. At least 500 surface Ig-positive cells were counted, and the wells showing reactivity with MOR-h 1, but not with pooled human IgM, percentage of 4E6-reacting B lymphocytes out of the total B lymphocytes were cloned using the end point dilution method (12). The three hybri- was calculated. Neither MOPC-2 1 nor the FITC-labeled sheep anti-mouse domas thus obtained were designated 4E6, 3E5, and 3F6. IgG by itself stained B lymphocytes. Immunoreagents. All antiimmunoglobulin reagents, including per- Detection by ELISA of4E6, 3E5, and 3F6 idiotopes in human sera. oxidase conjugates and fluorescently labeled immunoglobulins or frag- Human sera diluted to 1:10 with PBS containing 2% BSA and 0.05% ments, and pooled human myeloma IgM were obtained from Cooper Tween-20 were added to wells that had been coated with I Mg/well of Biomedical, Malvern, PA. affinity-purified 4E6, 3E5, 3F6, or MOPC-21, and the plates were in- ELISA.
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