A Patient with Type 3 Autoimmune Polyglandular Syndrome who Developed Systemic Lupus Erythematosus 8 years after the Diagnosis of Autoimmune Hepatitis

Eight years prior to her present admission, a 61-year-old Japanese woman was diagnosed with autoimmune hepatitis, slowly progressive insulin-dependent diabetes mellitus, and chronic thyroiditis; she had been treated with oral prednisolone (PSL). After she suddenly discontinued PSL, she newly developed systemic lupus erythematosus. A combination therapy of oral PSL and intravenous cyclophosphamide resulted in remission. She was finally diagnosed with autoimmune polyglandular syndrome (APS) type 3 (3A ,3B, 3D), complicated with four different autoimmune diseases. Since patients with type 3 APS may present many manifestations over a long period of time, they should be carefully monitored

Differential Regulation of Caspase-1 Activation, Pyroptosis, and Autophagy via Ipaf and ASC in Shigella-Infected Macrophages

Shigella infection, the cause of bacillary dysentery, induces caspase-1 activation and cell death in macrophages, but the precise mechanisms of this activation remain poorly understood. We demonstrate here that caspase-1 activation and IL-1β processing induced by Shigella are mediated through Ipaf, a cytosolic pattern-recognition receptor of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, and the adaptor protein apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC). We also show that Ipaf was critical for pyroptosis, a specialized form of caspase-1-dependent cell death induced in macrophages by bacterial infection, whereas ASC was dispensable. Unlike that observed in Salmonella and Legionella, caspase-1 activation induced by Shigella infection was independent of flagellin. Notably, infection of macrophages with Shigella induced autophagy, which was dramatically increased by the absence of caspase-1 or Ipaf, but not ASC. Autophagy induced by Shigella required an intact bacterial type III secretion system but not VirG protein, a bacterial factor required for autophagy in epithelial-infected cells. Treatment of macrophages with 3-methyladenine, an inhibitor of autophagy, enhanced pyroptosis induced by Shigella infection, suggesting that autophagy protects infected macrophages from pyroptosis. Thus, Ipaf plays a critical role in caspase-1 activation induced by Shigella independently of flagellin. Furthermore, the absence of Ipaf or caspase-1, but not ASC, regulates pyroptosis and the induction of autophagy in Shigella-infected macrophages, providing a novel function for NLR proteins in bacterial–host interactions

Differential Regulation of <i>Shigella</i>-Induced Autophagy by Ipaf and ASC

<div><p>GFP-LC3-expressing Ipaf-deficient or ASC-deficient BMMs were infected with <i>Shigella</i> WT or TTSS mutant.</p><p>(A) At 30 min after infection, the infected cells were immunostainted with Cy5-labeled anti-<i>Shigella</i> LPS antibody (colored red) and examined using a confocal microscope. The merged image with Cy5 bacteria and GFP fluorescence, and differential interference contrast (DIC) were also shown. Scale bars = 10 μm.</p><p>(B) GFP-LC3-associated intracellular bacteria were quantified. Error bars represent mean ± SD.</p></div

Ipaf and ASC Are Required for <i>Shigella</i>-Induced Caspase-1 and IL-1β Processing

<p>Wild-type, caspase-1-deficient, Ipaf-deficient, or ASC-deficient BMMs were infected with <i>Shigella</i> WT. Immunoblot for caspase-1 p10 (A, C, and E) and for IL-1β (B, D, and F). Blots are representative of three experiments.</p