Antibodies against the voltage-dependent anion channel (VDAC) and its protective ligand hexokinase-I in children with autism

Gonzalez-Gronow, Mario; Cuchacovich, Miguel; Francos, Rina; Cuchacovich, Stephanie; Fernández, María del Pilar; Blanco, Angel; Bowers, Edith V.; Kaczowka, Steven J.; Pizzo, Salvatore V.

doi:10.1016/j.jneuroim.2010.06.001

Cited by 28 publications

(17 citation statements)

References 42 publications

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“…Therefore, newly identified autoantibodies, such as anti-KLHL12 and anti-HK1, could be important biomarkers for differentiating PBC from other autoimmune diseases. Despite the reported presence of anti-KLHL12 antibody in Sj€ ogren's syndrome (28) and anti-HK1 antibody in the sera of children with autism (29), the specificity of both anti-KLHL12 and anti-HK1 antibodies in PBC was very high (≥95%). A small percentage of clinically proven PBC are AMA negative (30).…”

Section: Discussionmentioning

confidence: 85%

Anti‐kelch‐like 12 and anti‐hexokinase 1: novel autoantibodies in primary biliary cirrhosis

Norman

Yang

Ostendorff

et al. 2014

Liver International

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Background Using high-density human recombinant protein microarrays, we identified two potential biomarkers, kelch-like 12 (KLHL12) and hexokinase-1 (HK1), in primary biliary cirrhosis (PBC). The objective of this study was to determine the diagnostic value of anti-KLHL12/HK1 autoantibodies in PBC. Aims Initial discovery used sera from 22 patients with PBC and 62 non-PBC controls. KLHL12 and HK1 proteins were then analyzed for immunoglobulin reactivity by immunoblot and enzyme-linked immunosorbent assay (ELISA) in two independent cohorts of PBC and disease/healthy control patients. Methods Serum samples from 100 patients with PBC and 165 non-PBC disease controls were analyzed by immunoblot and samples from 366 patients with PBC, 174 disease controls, and 80 healthy donors were tested by ELISA. Results Anti-KLHL12 and anti-HK1 antibodies were each detected more frequently in PBC compared with non-PBC disease controls (p < 0.001). Not only are both markers highly specific for PBC (≥ 95%), but they also yielded higher sensitivity than anti-gp210 and anti-sp100 antibodies. Combining anti-HK1 and anti-KLHL12 with available markers (MIT3, gp210 and sp100) increased the diagnostic sensitivity for PBC. Most importantly, anti-KLHL12 and anti-HK1 antibodies were present in 10~35% of AMA-negative PBC patients and adding these two biomarkers to conventional PBC assays dramatically improved the serological sensitivity in AMA-negative PBC from 55% to 75% in immunoblot and 48.3% to 68.5% in ELISA. Conclusions The addition of tests for highly specific anti-KLHL12 and anti-HK1 antibodies to AMA and ANA serological assays significantly improves efficacy in the clinical detection and diagnosis of PBC, especially for AMA-negative subjects.

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Section: Discussionmentioning

confidence: 85%

Anti‐kelch‐like 12 and anti‐hexokinase 1: novel autoantibodies in primary biliary cirrhosis

Norman

Yang

Ostendorff

et al. 2014

Liver International

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“…Indeed, the signal intensities of these two isoforms were highly correlated. Additionally, the HK1 has been identified as an autoantigen associated with autistic children, and anti-HK1 autoantibodies were shown to impair growth and induce apoptosis in cultured human neuroblastoma cells (97). It would be interesting to determine whether HK1-positive patients also suffer from similar nervous system-associated impairments.…”

Section: New Pbc Biomarkers By Human Proteome Microarraysmentioning

confidence: 99%

Identification of New Autoantigens for Primary Biliary Cirrhosis Using Human Proteome Microarrays

Song

Huang

et al. 2012

Molecular & Cellular Proteomics

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Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of unknown etiology and is considered to be an autoimmune disease. Autoantibodies are important tools for accurate diagnosis of PBC. Here, we employed serum profiling analysis using a human proteome microarray composed of about 17,000 full-length unique proteins and identified 23 proteins that correlated with PBC. To validate these results, we fabricated a PBC-focused microarray with 21 of these newly identified candidates and nine additional known PBC antigens. By screening the PBC microarrays with additional cohorts of 191 PBC patients and 321 controls (43 autoimmune hepatitis, 55 hepatitis B virus, 31 hepatitis C virus, 48 rheumatoid arthritis, 45 systematic lupus erythematosus, 49 systemic sclerosis, and 50 healthy), six proteins were confirmed as novel PBC autoantigens with high sensitivities and specificities, including hexokinase-1 (isoforms I and II), Kelch-like protein 7, Kelch-like protein 12, zinc finger and BTB domain-containing protein 2, and eukaryotic translation initiation factor 2C, subunit 1. To facilitate clinical diagnosis, we developed ELISA for Kelch-like protein 12 and zinc finger and BTB domain-containing protein 2 and tested large cohorts (297 PBC and 637 control sera) to confirm the sensitivities and specificities observed in the microarray-based assays. In conclusion, our research showed that a strategy using high content protein microarray combined with a smaller but more focused protein microarray can effectively identify and validate novel PBC-specific autoantigens and has the capacity to be translated to clinical diagnosis by means of an ELISAbased method. Molecular & Cellular

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“…Because t-PA activity is enhanced by VDAC (7) and because both t-PA and Pg activation are affected by the interaction of these ligands with either VDAC or GRP78, we hypothesized a functional cell surface interaction between these four components in the brain. For these studies, we used the human neuroblastoma cell line SK-N-SH as an in vitro model because these cells express VDAC on the cell surface (19). We investigated the expression of GRP78 in these cells and found that GRP78 co-localizes with VDAC on the cell surface.…”

mentioning

confidence: 99%

Binding of Tissue-type Plasminogen Activator to the Glucose-regulated Protein 78 (GRP78) Modulates Plasminogen Activation and Promotes Human Neuroblastoma Cell Proliferation in Vitro

Gonzalez-Gronow

Gomez

Ridder

et al. 2014

Journal of Biological Chemistry

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Background: Glucose-regulated protein 78 (GRP78) is a plasminogen (Pg) and tissue-type plasminogen activator (t-PA) receptor on the cell surface. Results: Binding of t-PA to GRP78 stimulates its amidolytic activity, activation of Pg, and cell proliferation in vitro. Conclusion: Cell surface GRP78 enhances Pg activation by t-PA and mediates cell proliferation via binding to t-PA and microplasminogen. Significance: This complex may play a significant role in brain physiology.

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Antibodies against the voltage-dependent anion channel (VDAC) and its protective ligand hexokinase-I in children with autism

Cited by 28 publications

References 42 publications

Anti‐kelch‐like 12 and anti‐hexokinase 1: novel autoantibodies in primary biliary cirrhosis

Anti‐kelch‐like 12 and anti‐hexokinase 1: novel autoantibodies in primary biliary cirrhosis

Identification of New Autoantigens for Primary Biliary Cirrhosis Using Human Proteome Microarrays

Binding of Tissue-type Plasminogen Activator to the Glucose-regulated Protein 78 (GRP78) Modulates Plasminogen Activation and Promotes Human Neuroblastoma Cell Proliferation in Vitro

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