TABLE 1.

T1D candidate genes expressed in mononuclear phagocytes with evidence for their potential roles in T1D pathogenesis

Candidate genes		Locationa		Known roles in DCs or other mononuclear phagocytes	Known link to diabetes via mononuclear phagocytes	References
Gene symbol	Gene name	Human T1D	Mouse NOD
CCR5	Chemokine (C–C motif) receptor 5	3p21.31	chr9	Recruits DC precursor and immature DCs into inflammatory tissue via MIP/RANTES	Is reduced CCR5 on pancreatic CD8α+CD103+Langerin+ DCs in prediabetic NOD mice	[15, 16]
		IDDM22
CTLA4	Cytotoxic T lymphocyte-associated protein 4	2q33.2	chr1	Inhibits DC maturation, Ag presentation, and IL-10/IDO production by monocyte-derived hDCs	Antagonistic anti-CTLA4–treated DCs prevent insulitis in NOD mice	[17–19]
		IDDM12	Idd5.1
CYP27B1	Cytochrome P450, family 27, subfamily B, polypeptide 1	12q14.1	chr10	Regulates VitD3 activation and is predominantly expressed in monocyte-derived hDCs	CYP27B1 T1D variant may result in less active VitD3 in monocyte-derived hDCs	[20, 21]
ERBB3	Erb-B2 receptor tyrosine kinase 3	12q13.2	chr10	Is upregulated by TLR ligands; affects cross-presentation by mBM-DCs; ERBB3+ hDCs increase T cell proliferation	T1D ERBB3 SNPs increase expression in hPBMC-DCs	[22, 23]
HLA-A	MHC, class I	chr6	chr17	Cross-presents exogenous Ag or presents endogenous Ag to stimulate CD8+ T cells	NOD MHC alters autoreactive CD8+ T cell selection	[24]
HLA-B		IDDM1	Idd1
HLA-DQB1	MHC, class II	chr6	chr17	Presents exogenous Ag to stimulate CD4+ T cells	NOD MHC alters autoreactive CD4+ T cell selection	[25, 26]
HLA-DRB1		IDDM1	Idd1
IFIH1	Interferon-induced with helicase C domain 1, MDA5	2q24.2	chr2	Is a cytoplasmic dsRNA sensor in cDCs that induces type I IFN response for defense against viruses, including enteroviruses	Alleles that both increase and decrease diabetes risk have been identified; NOD mice with lower Ifih1 have less diabetes	[27, 28]
IKZF1	IKAROS family zinc finger 1 (Ikaros)	7p12.2	chr11	Ikaros deficiency results in the absence of most DCs; a hypomorphic mutation leads to a specific loss of pDCs	The minor allele (rs10272724) protects from T1D and is expressed in blood mononuclear cells	[29–31]
IL10	IL-10	1q32.1	chr1	Suppresses DC maturation and IL-12 production and results in less Th1 response	IL-10–conditioned DCs induce islet-directed immune tolerance	[32, 33]
			Idd5.4
IL2	IL-2	4q27	chr3	DC-derived IL-2 induces stimulation of NK cells and T cells, including Tregs; IL-2 inhibits DC development	For full protection from diabetes in NOD mice, the resistant IL-2 allele is needed in both APCs and T cells	[34–36]
			Idd3
IL21	IL-21	4q27	chr3	Inhibits DC activation and maturation; IL-21R deficiency in DCs fails to acquire CCR7 and MHC II	Transfer of IL-21R+ DCs restores diabetes development in IL-21 RKO NOD mice	[37]
			Idd3
IL27	IL-27	16p11.2	chr7	Modulates DCs to suppresses Th1/Th17 and increase Treg/Tr1 differentiation; inhibits HLA class I Ag presentation in immature DCs	IL-27-producing DCs induces IL-10+ T cells through anti-CD3 treatment in T1D mice	[38]
ITGB7	Integrin, β-7	12q13.13	chr15	Migratory αE (CD103)+β7+ DCs cross-present Ags to CD8+ T cells; CD103+ DCs contribute to intestinal homeostasis by Treg conversion	CD103+ DCs presentation to CD4+ T cells and CD8+ T cells in pancreatic draining LNs is essential for diabetes development	[7, 39]
SH2B3	SH2B adaptor protein 3, LNK	12q24.12	chr5	Sh2b3 deficiency in mice increases DC number and Sh2b3- DCs induce more Th1 differentiation	The disease risk variant of human LNK increases proliferation of PBMCs in patients	[40, 41, 42]
		IDDM20
STAT4	STAT4	2q32.3	chr1	Mediates IL-12-dependent IFN-γ production by activated DCs	STAT4 deficiency in NOD mice prevented the development of spontaneous diabetes	[43, 44]

hDCs, human DCs; mBM-DCs; mouse bone marrow-derived DCs; hPBMC-DCs, human peripheral blood mononuclear cells-derived DCs.

^aWhere applicable, the relevant human IDDM or mouse Idd locus is given.