Spontaneous production of anti-IFN-alpha and anti-IL-12 autoantibodies by thymoma cells from myasthenia gravis patients suggests autoimmunization in the tumor
| Autor: | David Beeson, Angela Vincent, W Zhang, Nicholas Willcox, Ian Matthews, Jian-Li Liu, Hiroyuki Shiono, Yat Lei Wong, G. P. Sims, Anthony Meager |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Adult
Male Thymoma Immunology Blotting Western Molecular Sequence Data Immunoglobulin Variable Region Radioimmunoassay Muscle Proteins Autoimmunity Thymus Gland Plasma cell Epitope Antibodies Immunoglobulin Fab Fragments Neutralization Tests Peptide Library Myasthenia Gravis medicine Tumor Cells Cultured Immunology and Allergy Humans Connectin Receptors Cholinergic B cell Aged Autoantibodies biology Reverse Transcriptase Polymerase Chain Reaction Autoantibody Interferon-alpha General Medicine Middle Aged medicine.disease Interleukin-12 Myasthenia gravis medicine.anatomical_structure biology.protein Interleukin 12 Female Antibody Protein Kinases |
| Zdroj: | International immunology. 15(8) |
| ISSN: | 0953-8178 |
| Popis: | Myasthenia gravis (MG) is mediated by autoantibodies to the acetylcholine receptor (AChR), expressed in muscle and rare thymic myoid cells. Most early-onset cases show thymic lymph node-type infiltrates, including pre-activated plasma cells spontaneously producing anti-AChR antibodies. Since these are not evident in the associated thymomas found in another 10% of MG patients, AChR-specific B cells must be autosensitized elsewhere. Unexpectedly, at diagnosis, >70% of MG/thymoma patients also have high-titer neutralizing autoantibodies to IFN-alpha, and >50% to IL-12; moreover, titers increase strikingly if the thymomas recur, indicating a closer tumor relationship than for anti-AChR. To investigate this, we have measured autoantibody production by cells cultured from thymomas, any available thymic remnants and blood, with or without the B cell stimulant pokeweed mitogen (PWM). To check autoantibody specificity and clonal origins, we isolated Fabs from two combinatorial libraries from producer thymus/thymoma cells. Surprisingly, thymoma cells spontaneously produced antibodies to IFN-alpha and/or IL-12 in >40% of seropositive cases, showing typical plasma cell behavior, whereas they produced anti-AChR only after PWM stimulation. We isolated 15 combinatorial Fabs to IFN-alpha (versus only one to AChR). Their strong binding in radio-immunoprecipitation and Western blots implies high affinities. The four Fabs tested neutralized anti-viral actions of IFN-alpha. The diverse V genes clearly showed ongoing antigen-driven selection. These results imply pre-activation in situ by native IFN-alpha/IL-12 expressed within a 'dangerous' tumor microenvironment. With these molecules, it should be easier to identify provoking cell type(s) that may give novel additional clues to autoimmunization against T-cell epitopes from the more complex AChR. |
| Databáze: | OpenAIRE |
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