Mechanism of Mitochondrial Transcription Factor A Attenuation of CpG-Induced Antibody Production

• Published in: PloS one 2016-06, Vol.11 (6), p.e0157157-e0157157
• Main Authors: Malarkey, Christopher S, Gustafson, Claire E, Saifee, Jessica F, Torres, Raul M, Churchill, Mair E A, Janoff, Edward N
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - pharmacology; Antibodies; Antibody Formation; Attenuation; Autoimmune diseases; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Binding; Biochemistry; Biology; Biology and Life Sciences; CpG islands; Cytokines; Damage patterns; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - metabolism; Deoxyribonucleic acid; DNA; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - immunology; DNA-Binding Proteins - metabolism; Humans; Immune response; Immunity, Innate - drug effects; Immunity, Innate - immunology; Immunoglobulin G - biosynthesis; Immunology; Influence; Innate immunity; Lymphocytes B; Medicine; Medicine and Health Sciences; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins - antagonists & inhibitors; Mitochondrial Proteins - immunology; Mitochondrial Proteins - metabolism; Molecular chains; Oligodeoxyribonucleotides - pharmacology; Oligonucleotides; Pharmacology; Phosphorothioate; Physical Sciences; Pregnancy; Proteins; Research and Analysis Methods; Sequestering; Signal Transduction; Stimulation; T cell receptors; Transcription factors; Transcription Factors - antagonists & inhibitors; Transcription Factors - immunology; Transcription Factors - metabolism; Vaccines
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0157157

Mitochondrial transcription factor A (TFAM) had previously been shown to act as a damage associated molecular pattern with the ability to enhance CpG-A phosphorothioate oligodeoxynucleotide (ODN)-mediated stimulation of IFNα production from human plasmacytoid dendritic cells. Examination of the mechanism by which TFAM might influence CpG ODN mediated innate immune responses revealed that TFAM binds directly, tightly and selectively to the structurally related CpG-A, -B, and -C ODN. TFAM also modulated the ability of the CpG-B or -C to stimulate the production of antibodies from human B cells. TFAM showed a dose-dependent modulation of CpG-B, and -C -induced antibody production from human B cells in vitro, with enhancement of high dose and inhibition of low doses of CpG stimulation. This effect was linked to the ability of TFAM to directly inhibit the binding of CpG ODNs to B cells, in a manner consistent with the relative binding affinities of TFAM for the ODNs. These data suggest that TFAM alters the free concentration of the CpG available to stimulate B cells by sequestering this ODN in a TFAM-CpG complex. Thus, TFAM has the potential to decrease the pathogenic consequences of exposure to natural CpG-like hypomethylated DNA in vivo, as well as such as that found in traumatic injury, infection, autoimmune disease and during pregnancy.