IL‐6‐specific autoantibodies (aAb‐IL‐6) have been reported in diseased and healthy individuals. We recently established a model for aAb‐IL‐6 in different mouse strains, based on vaccination with immunogenic IL‐6 analogues, in which titers of aAb‐IL‐6 above 1,000 resulted in an in vivo IL‐6 deficiency. Here, we examined aAb‐IL‐6 in 4,230 blood donors. Stable low titers of aAb‐IL‐6 were found in 9% of the donors, while 1% had titers ranging from 64 to greater than 10,000. Such aAb‐IL‐6‐positive donors appeared normal with no overt signs of pathology. Natural and recombinant forms of IL‐6 bound avidly to their IgG, and their plasma strongly neutralized IL‐6 in vitro. Slightly elevated concentrations of IL‐6 exclusively in the form of IL‐6‐IgG complexes were present in their circulation. The complexes did not contain soluble IL‐6 receptors. Titers of 0.1% of the blood donors were as positive as the vaccination‐induced IL‐6‐deficient mice. Such donors might be IL‐6 deficient, and if so, IL‐6 seems be dispensable for several months in otherwise healthy individuals. Such highly positive donors also explain why normal human IgG for pharmaceutical use may contain high anti‐IL‐6 activity. Finally, transfusion of plasma with a high titer of aAb‐IL‐6 might, temporally, render a recipient IL‐6 deficient.

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Inappropriate expression of IL-6 plays a role in various inflammatory conditions, degenerative diseases, and cancers. Several model systems have been developed that can specifically block IL-6-receptor interactions. Here we present a simple and highly effective approach based on vaccination with a pool of specifically mutated IL-6 analogues to induce a neutralizing IL-6 antibody response in mice. Judged by the ability of the analogues to bind to heterologous anti-IL-6 antibodies and cellular IL-6 receptors the IL-6 analogues seemed to have a three-dimensional structure comparable to that of wild-type IL-6. Injection of them broke self-tolerance and induced an immune response to IL-6, presumably because of the amino acid differences between the analogues and wild-type IL-6. This resulted in a longlasting anti-IL-6 antibody-mediated IL-6 deficiency that blocked experimentally induced IL-6-mediated pathology.

Interleukin-6 (IL6) is critically involved in inflammation and metabolism. About 1% of people produce IL6 autoantibodies (aAb-IL6) that impair IL6 signaling in vivo. We tested the hypothesis that the prevalence of such aAb-IL6 is increased in type 2 diabetic patients and that aAb-IL6 plays a direct role in causing hyperglycemia. In humans, the prevalence of circulating high-affinity neutralizing aAb-IL6 was 2 . 5% in the type 2 diabetic patients and 1% in the controls (odds ratio 2 . 5, 95% confidence interval 1 . 2-4 . 9, PZ0 . 01). To test for the role of aAb-IL6 in causing hyperglycemia, such aAb-IL6 were induced in mice by a validated vaccination procedure.Mice with plasma levels of aAb-IL6 similar to the 2 . 5% type 2 diabetic patients developed obesity and impaired glucose tolerance (area under the curve (AUC) glucose, 2056G62 vs 1793G62, PZ0 . 05) as compared with shamvaccinated mice, when challenged with a high-fat diet. Mice with very high plasma levels of aAb-IL6 developed elevated fasting plasma glucose (mM, 4 . 8G0 . 4 vs 3 . 3G0 . 1, P!0 . 001) and impaired glucose tolerance (AUC glucose, 1340G38 vs 916G25, P!0 . 001) as compared with shamcontrol mice on normal chow. In conclusion, the prevalence of plasma aAb-IL6 at levels known to impair IL6 signaling in vivo is increased 2 . 5-fold in people with type 2 diabetes.In mice, matching levels of aAb-IL6 cause obesity and hyperglycemia. These data suggest that a small subset of type 2 diabetes may in part evolve from an autoimmune attack against IL6.

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Injury initiates recruitment of macrophages to support tissue repair; however, excessive macrophage activity may exacerbate tissue damage causing further destruction and subsequent delay in wound repair. Here we show that the peroxisome proliferation–activated receptor-γ agonist, rosiglitazone (Rosi), a medication recently reintroduced as a drug to treat diabetes and with known anti-inflammatory properties, paradoxically generates pro-inflammatory macrophages. This is observed in both IL-6-deficient mice and control wild-type mice experimentally induced to produce high titers of auto-antibodies against IL-6, mimicking IL-6 deficiency in human diseases. IL-6 deficiency when combined with Rosi-mediated upregulation of suppressor of cytokine signaling 3 leads to an altered ratio of nuclear signal transducer and activator of transcription 3/NF-κB that allows hyper-induction of inducible nitric oxide synthase (iNOS). Macrophages activated in this manner cause de novo tissue destruction, recapitulating human chronic wounds, and can be reversed in vivo by recombinant IL-6, blocking macrophage infiltration, or neutralizing iNOS. This study provides insight into an unanticipated paradoxical role of Rosi in mediating hyper-inflammatory macrophage activation significant for diseases associated with IL-6 deficiency.

SUMMARYWe previously demonstrated that high levels of IL-6/sIL-6R complexes are present in sera of patients with systemic juvenile idiopathic arthritis (s-JIA) and that the amount of IL-6 estimated in the IL-6/sIL-6R complexes is markedly higher than that measured by the B9 assay. Here, we show that two additional bioassays, employing human myeloma XG-1 cells and human hepatoma Hep3B cells, detected serum IL-6 levels similar to those measured by the B9 assay and approximately 10-fold lower than the IL-6 levels estimated to be present in the IL-6/sIL-6R complex. Using an assay for the measurement of the amount of circulating IL-6 complexed with the sIL-6R and available for binding to gp130 (gp130 binding activity), we show that the IL-6/gp130 binding activity is similar to that detected by the bioassays and again significantly lower than that estimated to be present in the IL-6/sIL-6R complex. Addition of recombinant human IL-6 (rhIL-6) to sera of patients or controls results in a markedly lower increase in the gp130 binding activity in patients than in controls. Moreover, sera from s-JIA patients inhibited in a dose dependent manner the gp130 binding activity assay. These results show that sera from patients with s-JIA contain a factor, or factors, that inhibit(s) the binding of the IL-6/sIL-6R complex to gp130. This inhibitory activity does not appear to be due to soluble gp130, C-reactive protein or autoantibodies to IL-6.