FRI0013 Anti-IL-6 autoantibody inhibited elevation of serum C-reactive protein level in two patients with severe bacterial infection

Background C-reactive protein (CRP) is an acute phase reactant, of which serum level is generally elevated in patients with bacterial infection and is useful in determining severity of infection and effectiveness of treatment with antibiotics. IL-6 is a major cytokine to induce production of CRP from hepatocytes. IL-6 is engaged by IL-6 receptor and IL-6 signal transducer/gp130, and then dimer of the trimers is formed as signaling-competent hexamer. Objectives We experienced two patients who suffered from severe bacterial infection without elevation of serum CRP. In these patients, we examined the presence and characteristics of autoantibody against IL-6. Methods Serum anti-IL-6 autoantibody was detected by ELISA and western blotting. Inhibition of IL-6 bioactivity by sera from the patients was examined using IL-6-dependent TF-1 cells. Epitope mapping of anti-IL-6 autoantibody was carried out using 15-mer peptides overlapping by 10 amino acids from human IL-6 amino acid sequence. Results Patient 1 was a 67-year-old man, who developed thoracic empyema by infection with Escherichia coli and Streptococcus intermedius. His serum CRP level was negative despite the severe infection. Although he was treated with antibiotics, bronchopleural fistula developed and died of respiratory failure. Patient 2 was a 56-year-old woman with rheumatoid arthritis. She developed systemic multiple subcutaneous abscesses by infection with Staphylococcus aureus. Serum CRP level was also negative. Treatment with antibiotics was effective for her. In these patients with severe bacterial infection, lack of IL-6 function was postulated since serum CRP level was not raised. Anti-IL-6 autoantibody was detected in the sera from both patients using ELISA. Isotypes of the autoantibodies were IgG4 and IgG1, respectively. Anti-IL-6 autoantibody was also detected by western blotting. These sera inhibited proliferation of TF-1 cell in the presence of recombinant IL-6. Epitope mapping analysis revealed that both sera strongly bound to a peptide, LTKLQAQNQWLQDMT, which includes binding site of IL-6 and IL-6 signal transducer to form the hexamer by dimerization of the trimmers of IL-6, IL-6 receptor and IL-6 signal transducer. Antibodies against IL-6 receptor and IL-6 signal transducer were not detected in the sera. Although we analyzed the presence of serum anti-IL-6 autoantibody in 100 healthy controls and 120 patients with rheumatic diseases, anti-IL-6 autoantibody was not detected in these 220