Table 4.
Summary of Polymorphisms in DNA Sensors and Their Associated Syndromes
| Protein | Genetic Polymorphisms That Lead to Autoimmunity/Autoinflammation | Associated Syndrome/Pathology |
|---|---|---|
| TLR9 | 1. Loss of TLR9 leads to increased lymphocyte activation, type I IFN, and autoantibodies (Christensen et al., 2006) 2. Impaired TLR9 signaling in B cells with decreased CD19/21 (Gies et al., 2018) |
1–2. Systemic lupus erythematosus |
| TREX1 | 1. Loss-of-function mutations in TREX1 of AGS patients (Abe et al., 2014; Bailey et al., 2012; Crow, 2011; Crow et al., 2006a; Grieves et al., 2015; Lindahl et al., 2009; Namjou et al., 2011; Olivieri et al., 2013; Orebaugh et al., 2011; Uyur Yalçın et al., 2015) 2. TREX1-deficient mice have cGAMP accumulation and produce high amounts of proinflammatory cytokines (Ahn et al., 2012, 2014; Gao et al., 2015; Gray et al., 2015) 3. Missense TREX1 mutations present in systemic lupus erythematosus patients (Lee-Kirsch et al., 2007) |
1–3. Aicardi–Goutières syndrome, familial chilblain lupus, systemic lupus erythematosus |
| RNase H2 | 1. Mutations in RNASEH2A, RNASEH2B, and RNASH2C lead to nucleic acid accumulation (Chon et al., 2013; Coffin et al., 2011; Günther et al., 2015; Kind et al., 2014; Pizzi et al., 2015; Ramantani et al., 2010; Reijns et al., 2011) 2. RNase H2-deficient mice are embryonic lethal; all subunits are necessary (Hiller et al., 2012; Reijns et al., 2012) 3. Mice that are RNASEH2A-and RNASEH2B-null have increased nucleic acid accumulation and increased ISG expression (Mackenzie et al., 2016; Pokatayev et al., 2016) |
1–3. Aicardi–Goutières syndrome, lupus-like symptoms |
| SAMHD1 | 1. Over 16 missense, nonsense, and 12-nucleotide deletion mutations (e.g., AGS82, AGS92, and AGS91) have been identified in AGS patients and their families (Rice et al., 2009) 2. Mice deficient in Samhd1 lack AGS symptoms but have increased ISG expression (Maelfait et al., 2016) |
1. Aicardi–Goutières syndrome 2. Increased cGAS/STING signaling |
| STING | 1. De novo gain-of-function mutations in TMEM173 (Dobbs et al., 2015; Jeremiah et al., 2014; Konig et al., 2017; Konno et al., 2018; Liu et al., 2014, 2015a; Melki et al., 2017; Munoz et al., 2015; Picard et al., 2016; Warner et al., 2017) 2. Activation of STING via agonist leads to development of anti-STING antibodies, results in production of IFN-β in salivary gland cells (Papinska et al., 2018) |
1. SAVI, familial chilblain lupus 2. Sjögren’s syndrome |