Circulating Natural Autoantibodies to HER2-Derived Peptides Performed Antitumor Effects on Oral Squamous Cell Carcinoma

Natural autoantibodies play a crucial role in destruction of malignant tumors due to immune surveillance function. Epidermal growth factor receptor 2 (HER2) has been found to be highly expressed in a variety of epithelial tumors including oral squamous cell carcinoma (OSCC). The present study was thus undertaken to investigate the effect of anti-HER2 natural autoantibodies on OSCC. Compared with cancer-adjacent tissues, cancer tissues from OSCC patients exhibited higher HER2 expression especially in those with middle & advanced stage OSCC. Plasma anti-HER2 IgG levels examined with an enzyme-linked immunosorbent assay (ELISA) developed in-house showed differences between control subjects, individuals with oral benign tumor and patients with OSCC. In addition, anti-HER2 IgG-abundant plasma was screened from healthy donors to treat OSCC cells and to prepare for anti-HER2 intravenous immunoglobulin (IVIg). Both anti-HER2 IgG-abundant plasma and anti-HER2 IVIg could significantly inhibit proliferation and invasion of OSCC cells by inducing the apoptosis, and also regulate apoptosis-associated factors and epithelial-mesenchymal transition (EMT), respectively. Besides, the complement-dependent cytotoxicity (CDC) pathway was likely to contribute to the anti-HER2 IgG mediated inhibition of OSCC cells. After the HER2 gene was knocked down with HER2-specific siRNAs, the inhibitory effects on OSCC cell proliferation and apoptotic induction faded away. In conclusion, human plasma IgG, or IVIg against HER2 may be a promising agent for anti-OSCC therapy.

Biphasic Production of Anti-ApoB100 Autoantibodies in Obese Humans and Mice

Obesity is associated with autoimmunity, a phenomenon considered as harmful. Here we show that obese mice and humans produce IgG-type autoantibodies that specifically recognize apolipoprotein B-100 (ApoB100), its native epitope p210, and the synthetic p210 mimotope pB1. By contrast, antibodies against epitopes p45 and p240, which have been associated with atherosclerosis, were not detected in either the humans or mice. In a longitudinal analysis of high fat diet-fed mice, autoantibody production rose with increasing body weight, then decreased and plateaued at morbid obesity. Likewise, in a cross-sectional analysis of sera from 148 human volunteers spanning a wide BMI range and free of comorbidities, the immunoreactivity increased and then decreased with increasing BMI. Thus, the obesity-related ApoB100-specific natural autoantibodies characteristically showed the same epitope recognition, IgG-type, and biphasic serum levels in humans and mice. We previously reported that a pB1-based vaccine induces similar antibodies and can prevent obesity in mice. Therefore, our present results suggest that autoantibodies directed against native ApoB100 may mitigate obesity, and that the vaccination approach may be effective in humans.

Inhibitory Effects of Circulating Natural Autoantibodies to CD47-derived Peptides on Oral Squamous Cell Carcinoma Cells

Natural autoantibodies serve as an important anti-tumorigenic system due to its immune surveillance function. The present study aims to investigate whether circulating natural IgG autoantibodies against cluster of differentiation 47 (CD47) could suppress the proliferation of oral squamous cell carcinoma (OSCC) cells. Three OSCC cell lines were used for this study. The expression of fourteen tumor related genes including CD47 were tested. OSCC cells were grown, respectively, with 20% human plasma positive and negative for anti-CD47 IgG. Cell proliferation, apoptosis and invasion/metastasis were examined. The results showed that CD47 presented highest expression among all 14 genes detected in OSCC cells. Plasma anti-CD47 IgG significantly inhibited the viability of all three OSCC cell lines. The proportions of apoptotic cells were remarkably higher in OSCC cells treated with anti-CD47 IgG-positive plasma than those treated with IgG-negative plasma. Furthermore, the cell invasion/metastasis was attenuated evidently with the attribution of plasma anti-CD47 IgG. In conclusion, natural autoantibodies against CD47 may be a potential target for OSCC immunotherapy.

Inhibitory Effects of Circulating Natural Autoantibodies to CD47-derived Peptides on Oral Squamous Cell Carcinoma Cells

Background Natural autoantibodies serve as an important anti-tumorigenic system due to its immune surveillance function. The present study aims to investigate whether circulating natural IgG autoantibodies against cluster of differentiation 47 (CD47) could inhibit the proliferation of oral squamous cell carcinoma (OSCC) cells. Methods The expression of 14 tumor-targeted genes in three OSCC cell lines was analyzed with quantitative real-time PCR. The in-house enzyme-linked immunosorbent assay (ELISA) was then performed to detect plasma IgG antibodies against CD47. Three OSCC cell lines were treated with 20% human plasma positive and negative for anti-CD47 IgG, respectively, followed by analysis of cell proliferation, apoptosis and invasion/metastasis. Results CD 47 showed highest expression among all 14 genes detected in three OSCC cell lines. Plasma anti-CD47 IgG significantly inhibited the viability of all three OSCC cell lines. The proportions of apoptotic cells were remarkably higher in OSCC cells treated with anti-CD47 IgG-positive plasma than those treated with IgG-negative plasma. Furthermore, the cell invasion/metastasis was attenuated evidently with the attribution of plasma anti-CD47 IgG. Conclusions Natural autoantibodies against CD47 may be a potential target for OSCC immunotherapy.

The Functional Roles and Applications of Immunoglobulins in Neurodegenerative Disease

Natural autoantibodies, immunoglobulins (Igs) that target self-proteins, are common in the plasma of healthy individuals; some of the autoantibodies play pathogenic roles in systemic or tissue-specific autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Recently, the field of autoantibody-associated diseases has expanded to encompass neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), with related studies examining the functions of Igs in the central nervous system (CNS). Recent evidence suggests that Igs have various effects in the CNS; these effects are associated with the prevention of neurodegeneration, as well as induction. Here, we summarize the functional roles of Igs with respect to neurodegenerative disease (AD and PD), focusing on the target antigens and effector cell types. In addition, we review the current knowledge about the roles of these antibodies as diagnostic markers and immunotherapies.

Natural Autoantibodies in Chronic Pulmonary Diseases

In autoantibody-mediated autoimmune diseases, pathogenic autoantibodies generated by a failure of central or peripheral tolerance, have different effects mediated by a variety of mechanisms. Interestingly, even non-autoimmune chronic diseases have a set of disease-specific natural autoantibodies that are maintained for a long time. Because most of these natural autoantibodies target intracellular proteins or long non-coding RNAs, they are speculated to be non-pathological and have some important as yet unrecognized physiological functions such as debris clearance. Recently, we revealed a set of disease-specific natural autoantibodies of chronic pulmonary diseases with unknown etiology by protein arrays that enable detection of specific autoantibodies against >8000 targets. Surprisingly, some of the targeted antigens of disease-specific autoantibodies were subsequently reported by other laboratories as strongly associated with the disease, suggesting that these antigens reflect the pathology of each disease. Furthermore, some of these autoantibodies that target extracellular antigens might modify the original course of each disease. Here, we review the disease-specific natural autoantibodies of chronic pulmonary diseases, including chronic fibrosing idiopathic interstitial pneumonias, sarcoidosis, and autoimmune pulmonary alveolar proteinosis, and discuss their utility and effects.

Antagonistic Autoantibodies to Insulin-Like Growth Factor-1 Receptor Associate with Poor Physical Strength

Natural autoantibodies to the IGF1 receptor (IGF1R-aAb) have been described in relation to Graves’ ophthalmopathy. Other physiological roles of natural IGF1R-aAb are not known. We hypothesized that IGF1R-aAb may be related to muscle development. Serum samples (n = 408) from young overweight subjects (n = 143) were collected during a lifestyle intervention study. Anthropometric parameters, along with leptin, IGF1 and IGF1R-aAb concentrations, were analyzed, and the subjects were categorized into positive or negative for IGF1R-aAb. Eleven out of 143 subjects (7.7%) were positive for IGF1R-aAb. Identified IGF1R-aAb were molecularly characterized and showed antagonistic activity in vitro impairing IGF1-mediated IGF1R activation. Mean body weight, height or age were similar between IGF1R-aAb-positive and -negative subjects, but IGF1 concentrations differed. Jumping ability, as well as right and left handgrip strengths, were lower in the IGF1R-aAb-positive as compared to the IGF1R-aAb-negative subjects. We conclude that natural IGF1R-aAb are detectable in apparently healthy subjects and are capable of antagonizing IGF1-dependent IGF1R activation. Moreover, the presence of IGF1R-aAb is associated with poor physical strength. Although the causality of this association is unclear, the data imply a potential influence of IGF1R autoimmunity on muscle development.