Role of nucleic acid sensing in the pathogenesis of type 1 diabetes

Table 1 Nucleic acid sensors involved in various autoimmune diseases including type 1 diabetes

No.	Nucleic acid sensor	Downstream signaling molecule	Autoimmune disease	Ref.
1	TLR9	Myd88/ IRF3/7	SLE	[73,74]
2	TLR7	Myd88	T1D	[27]
3	TLR3	TRIF	T1D	[25,75]
4	RLR	IRF3	Singleton-Merton Syndrome,	[76,77]
			AGS and T1D	[34,78]
5	cGAS-STING	cGMP	SLE and AGS	[79,80]
6	NLR	Inflammasome activation	T1D and SLE	[58,81]
7	AIM		SLE	[81]
8	IFI16	Inflammasome	Primary Sjogren’s Syndrome	[82]
		Activation	Rheumatoid Arthritis	[83]
9	CTL	Bcl10/CARD9	Multiple Sclerosis	[84]

AIM: Absent-in-melanoma; cGAS-STING: Cyclic GMP-AMP synthase-stimulator of interferon genes; CTL: C-type lectin; NLR: Nucleotide-binding and oligomerization domain-like receptor; RLR: Retinoic acid inducible gene-I-like receptors; TLR: Toll-like receptor; TRIF: TIR-domain-containing adapter-inducing IFN-β.

Table 2 Studies and trials with antagonists/inhibitors of nucleic acid sensors and their signaling mediators in various autoimmune diseases

No.	Inhibitor	Disease	Target	Phase (Preclinical/Clinical-trial ID)	Ref.
1	Hydroxychloroquine	Rheumatoid arthritis and SLE	TLR7, TLR9, cGAS-STING	NCT0380218 (Ongoing Trial)	[139]
2	SM934	SLE	TLR7 and TLR9	NCT03951259 (Phase II)	[125]
3	Amlexanox	T2D	TBK1 and IKKε	NCT01975935 (Phase II)	[140]
4	TJ-M2010-6	T1D	Myd88	Preclinical	[129]
5	ST-2825	SLE	IRAK1 and IRAK4	Preclinical	[126]
6	Aspirin	AGS	cGAS	Preclinical	[141]
7	ODN-1411	Rheumatoid Arthritis	TLR8	Preclinical	[142]
8	INH-ODNs	SLE	TLR3 and TLR9	Preclinical	[143]
9	X6	Autoimmune myocarditis	cGAS	Preclinical	[144]
10	PF-06650833	Rheumatoid Arthritis	IRAK4	NCT02996500 (Phase II)	[127]
11	Compound II	SLE and AGS	TBK1	Preclinical	[128]
12	Sifalimumab (MEDI-545)	SLE	IFN-α	NCT00979654 (Phase II)	[145]
13	AGS-009	SLE and Rheumatoid Arthritis	IFN-α	NCT00960362 (Phase I)	[132]
14	IMO-8400	Plaque Psoriasis	TLR-7, 8, and 9	NCT01899729 (Phase IIa)	[122]
15	CpG-52364	SLE	TLR-7, 8, and 9	NCT00547014 (Phase I)	[116]

SLE: Systemic lupus erythematosus; T2D: Type 2 diabetes; TID: Type 1 diabetes.