Anti-AICDA monoclonal antibody, clone nBJE-3

Sterile alpha motif and histidine-aspartic acid domain-containing protein 1 (SAMHD1), adNTPtriphosphohydrolase, regulates the levels of cellulardNTPs through their hydrolysis.SAMHD1 protects cells from invading viruses that depend ondNTPs to replicate and is frequently mutated in cancers and Aicardi-Goutieres syndrome, a hereditary autoimmune encephalopathy. We discovered thatSAMHD1 localizes at the immunoglobulin (Ig) switch region, and serves as a novelDNArepair regulator of Ig class switch recombination (CSR). Depletion ofSAMHD1 impaired not onlyCSRbut alsoIgH/c-Myctranslocation. Consistently, we could inhibit these two processes by elevating the cellular nucleotide pool. A high frequency of nucleotide insertion at the break-point junctions is a notable feature inSAMHD1 deficiency during activation-induced cytidine deaminase-mediated genomic instability. Interestingly,CSRinduced by staggered but not blunt, double-strandedDNAbreaks was impaired bySAMHD1 depletion, which was accompanied by enhanced nucleotide insertions at recombination junctions. We propose thatSAMHD1-mediateddNTPbalance regulatesdNTP-sensitiveDNAend-processing enzyme and promotesCSRand aberrant genomic rearrangements by suppressing the insertionalDNArepair pathway.

Background: It is incompletely understood how cigarette smoke (CS) exposure affects lung mucosal immune responses during viral respiratory infections. B cell activating factor belonging to the tumor necrosis factor family (BAFF) plays an important role in the induction of secretory immunoglobulin A (S-IgA) which is the main effector of the mucosal immune system. We therefore investigated the effects of CS exposure on BAFF expression and S-IgA responses in the lung during influenza virus infection. Methods: Mice were exposed to CS and/or infected with influenza virus. Bronchoalveolar lavage fluid and lung compartments were analyzed for BAFF expression, influenza-specific S-IgA level and histological changes. Lung B cells were isolated and the activation-induced cytidine deaminase (Aicda) expression was determined. BEAS-2B cells were treated with CS extract (CSE), influenza virus, interferon beta or N-acetylcysteine and BAFF expression was measured. Results: CS inhibited BAFF expression in the lung, particularly after long-term exposure. BAFF and S-IgA levels were increased during influenza virus infection. Three-month CS exposure prior to influenza virus infection resulted in reduced BAFF and S-IgA levels in the lung as well as augmented pulmonary inflammation on day 7 after infection. Prior CS exposure also caused decreased Aicda expression in lung B cells during infection. Neutralization of BAFF in the lung resulted in reduced S-IgA levels during influenza virus infection. CSE inhibited virus-mediated BAFF induction in a dose-dependent manner in BEAS-2B cells, while this inhibition of BAFF by CSE was prevented by pretreatment with the antioxidant N-acetylcysteine. Conclusions: Our findings indicate that CS may hinder early mucosal IgA responses in the lung during influenza virus infection through oxidative inhibition of BAFF, which might contribute to the increased incidence and severity of viral infections in smokers.