Anti‐cytokine autoantibodies are ubiquitous in healthy individuals

Watanabe, Masato; Uchida, Kanji; Nakagaki, Kazuhide; Kanazawa, Hiroko; Trapnell, Bruce C.; Hoshino, Yoshihiko; Kagamu, Hiroshi; Yoshizawa, Hirohisa; Keicho, Naoto; Goto, Hajime; Nakata, Koh

doi:10.1016/j.febslet.2007.04.029

Cited by 97 publications

(84 citation statements)

References 19 publications

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“…Our tentative conclusion is that GM-CSF most likely drove the original antibody response. There is no evidence for B-cell tolerance or anergy for an antigen like GM-CSF that is not detectable in the plasma (31); indeed, there is evidence to the contrary (32,33). There is evidence of B-cell anergy for soluble antigens at serum concentration of >0.1 nM (34).…”

Section: Discussionmentioning

confidence: 99%

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

Wang

Thomson

Allan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The origin of pathogenic autoantibodies remains unknown. Idiopathic pulmonary alveolar proteinosis is caused by autoantibodies against granulocyte–macrophage colony-stimulating factor (GM-CSF). We generated 19 monoclonal autoantibodies against GM-CSF from six patients with idiopathic pulmonary alveolar proteinosis. The autoantibodies used multiple V genes, excluding preferred V-gene use as an etiology, and targeted at least four nonoverlapping epitopes on GM-CSF, suggesting that GM-CSF is driving the autoantibodies and not a B-cell epitope on a pathogen cross-reacting with GM-CSF. The number of somatic mutations in the autoantibodies suggests that the memory B cells have been helped by T cells and re-entered germinal centers. All autoantibodies neutralized GM-CSF bioactivity, with general correlations to affinity and off-rate. The binding of certain autoantibodies was changed by point mutations in GM-CSF that reduced binding to the GM-CSF receptor. Those monoclonal autoantibodies that potently neutralize GM-CSF may be useful in treating inflammatory disease, such as rheumatoid arthritis and multiple sclerosis, cancer, and pain.

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Section: Discussionmentioning

confidence: 99%

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

Wang

Thomson

Allan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Cytokine-targeted autoantibodies have been described in healthy human subjects (45,46); however, the implications of this reactivity remain unclear. Small but detectable populations of circulating autoreactive lymphocytes appear in healthy humans, which indicates that immune homeostasis may involve a controlled level of self-recognition…”

Section: Discussionmentioning

confidence: 99%

Protein microarray analysis reveals BAFF-binding autoantibodies in systemic lupus erythematosus

et al. 2013

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Autoantibodies against cytokines, chemokines, and growth factors inhibit normal immunity and are implicated in inflammatory autoimmune disease and diseases of immune deficiency. In an effort to evaluate serum from autoimmune and immunodeficient patients for Abs against cytokines, chemokines, and growth factors in a high-throughput and unbiased manner, we constructed a multiplex protein microarray for detection of serum factor-binding Abs and used the microarray to detect autoantibody targets in SLE. We designed a nitrocellulosesurface microarray containing human cytokines, chemokines, and other circulating proteins and demonstrated that the array permitted specific detection of serum factor-binding probes. We used the arrays to detect previously described autoantibodies against cytokines in samples from individuals with autoimmune polyendocrine syndrome type 1 and chronic mycobacterial infection. Serum profiling from individuals with SLE revealed that among several targets, elevated IgG autoantibody reactivity to B cell-activating factor (BAFF) was associated with SLE compared with control samples. BAFF reactivity correlated with the severity of disease-associated features, including IFN-α-driven SLE pathology. Our results showed that serum factor protein microarrays facilitate detection of autoantibody reactivity to serum factors in human samples and that BAFF-reactive autoantibodies may be associated with an elevated inflammatory disease state within the spectrum of SLE.

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“…Anti-OPN antibodies are produced in such pathological conditions, but OPN is a weak immunogen (0.95-15%) (16,21). Healthy individuals presented very low or absent anti-OPN reactivity levels as compared to autoimmune diseases (16,22). Similar mechanisms mediate tolerance to tumor antigens and self-antigens in order to avoid autoimmunity, and numerous autoimmune phenomena were reported in malignancies (23,24).…”

Section: Discussionmentioning

confidence: 99%

Osteopontin is a tumor autoantigen in prostate cancer patients

et al. 2010

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Abstract. Anti-tumor antibodies act as biomarkers for the early diagnosis of prostate cancer (PCa). Osteopontin (OPN) is overexpressed in PCa cells and contributes to the progression of the disease. This study aimed to evaluate whether OPN evokes a humoral immune response in PCa patients and whether the reactivity levels of anti-OPN antibodies may be used to better differentiate PCa from benign and healthy donor plasma samples. Plasma samples from biopsy-proven PCa patients (29), benign prostate hyperplasia (BPH) (18) and control healthy donors (HD) (30) were tested by immunoblots using the recombinant human OPN. The frequency of anti-OPN antibodies was significantly higher in PCa (66%) plasma samples as compared to BPH (33%) and HD controls (10%). Anti-OPN antibodies were detected in a high proportion of plasma samples from patients with a Gleason score of less than 6 (57%), prostate-specific antigen levels lower than 10 ng/ml (67%) and pT2 organ-confined disease (70%), suggesting that anti-OPN antibodies may be used as an early serum marker for PCa. To the best of our knowledge, this is the first description of OPN as a tumor autoantigen and one of the most reactive individual autoantigens described thus far. These data support the inclusion of OPN in a multiplex of tumor antigens in order to perform antibody profiling in PCa as well as in other malignancies overexpressing OPN.

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Anti‐cytokine autoantibodies are ubiquitous in healthy individuals

Cited by 97 publications

References 19 publications

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

Protein microarray analysis reveals BAFF-binding autoantibodies in systemic lupus erythematosus

Osteopontin is a tumor autoantigen in prostate cancer patients

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