International Immunology, Vol. 15, No. 8, pp. 903-913,
August 2003
© 2003 Japanese Society for Immunology
Spontaneous production of anti-IFN-
and anti-IL-12 autoantibodies by thymoma cells from myasthenia gravis patients suggests autoimmunization in the tumor
1 Neuroscience Group, Weatherall Institute for Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK 2 National Institute of Arthritis, Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892, USA 3 Immunobiology, National Institute of Biological Standards and Control, Potters Bar, Hertfordshire EN6 3QG, UK 4 Present address: Department of Thoracic Surgery, Osaka University Graduate School of Medicine,E12-2 Yamadaoka, Suita, Osaka 565-0871, Japan 5 Present address: FIRS laboratories, Llanishen, Cardiff CF14 5DU, UK 6 Present address: Department of Clinical Neurology, People’s Hospital, Laizhou, 261400, Shandong, China
The first two authors contributed equally to this workCorrespondence to: N. Willcox; E-mail: nick.willcox{at}imm.ox.ac.uk
Transmitting editor: D. T. Fearon
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-
, 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- 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- (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-. The diverse V genes clearly showed ongoing antigen-driven selection. These results imply pre-activation in situ by native IFN-/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.
Keywords: anti-cytokine autoantibody, dendritic cell, human anti-IFN- antibody, human anti-IL-12 antibody, paraneoplastic autoimmunity, tumor immunity
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