Insights into the genetic basis of systemic sclerosis: immunity in human disease and in mouse models

Figures & data

Table 1 Established susceptibility alleles in MHC region from SSc GWASs and/or Immunochip study

Gene	Phenotype	GWAS (P-value^Table Footnote**)	Immunochip (P-value^Table Footnote**)	References
HLA-DQB1	ACA+	2.61×10−^54	1.94×10−^17	8–10,14
HLA-DQA1^Table Footnote*	SSc	1.47×10−^11	1.12×10−^25	8–10,14
	ATA+		4.46×10−^23
	ACA+
HLA-DPB1^Table Footnote*	SSc	4.64×10−^8	3.21×10−^23	8–10,14
	ATA+	2.42×10−^20
HLA-DRBI^Table Footnote*	ACA+	NA	1.79×10−^39	9,14
	ATA+	1.47×10−^11	3.55×10−^22
NOTCH4	SSc	6.82×10−^12	NA	8–10
	ACA+	8.84×10−^21
	ATA+	1.14×10−^8
TAP2	SSc	NA	5.87×10−^62	14
	ACA+		2.74×10−^11
MICA	SSc	7.18×10−^9	NA	8
MICB	SSc	5.68×10−^9	NA	8

Notes:

* Variant at amino acid part of the binding pocket of the molecule;

** P-value of the most highly associated SNP for the SSc phenotype.

Abbreviations: ACA, anti-centromere antibody; ATA, anti-topoisomerase antibody; GWAS, genome-wide association study; MHC, major histocompatibility complex; NA, not associated; SSc, systemic sclerosis; SNP, single-nucleotide polymorphism.

Table 2 Selected relevant susceptibility alleles in the non-MHC region found with GWAS, Immunochip, and meta-analysis in SSc

Gene	Phenotype	GWAS (P-value*)	Immunochip (P-value*)	Meta-analysis (P-value*)	References
IRF5	SSc	3.84×10−^14	1.01×10−^10	7.53×10−^20	8–0,4,34
	IcSSc	1.64×10−^10		9.63×10−^14
	DcSSc			4.38×10−^15
	ACA+			4.06×10−^11
	ATA+			6.05×10−^17
IRF8	IcSSc	2.32×10−^12	3.32×10−^3	NA	9,4
CD247	SSc	3.39×10−^9	NA	4.26×10−^1	8–0
	IcSSc	2.66×10−^6
STAT4	SSc	1.90×10−^10	2.94×10−^12	2.26×10−^13	8–0,25
	IcSSc	7.70×10−^8	NA
TNIPI	SSc	4.68×10−^9		3.26×10−^5	0,14,17
	IcSSc			1.23×10−^3
	dcSSc			5.57×10−^4
	ATA+		NA	1.31×10−^5
	ACA+		2.33×10−^3	2.27×10−^3
DNASEIL3	SSc	NA	5.95×10−^10	3.36×10−^16	4
	IcSSc		1.36×10−^11	1.28×10−^20
	ACA+		7.50×10−^8	4.25×10−^31
SCHIPI-ILI2A	SSc	NA	9.74×10−^8	1.22×10−^11	4
	IcSSc		1.05×10−^6	1.53×10−^11
	ACA+		1.53×10−^5	2.40×10−^8
IL12RB2	SSc	4.74×10−^6		2.82×10−^9	9,11,14
	ACA+		3.72×10−^5
TNFSF4	SSc		NA	1×10−^5	9,69
	IcSSc	7.70×10−^4		7.70×10−^4
	ACA+			1.62×10−^2
	ATA+			9.05×10−^3
BANK1	DcSSc	1.03×10−^2	2.47×10−^3	1.03×10−^2	9
BLK	DcSSc		2.60×10−^5	1.39×10−^3	9,14
	IcSSc			1.54×10−^4
	ACA+	1.45×10−^4		1.45×10−^4
TNFAIP3	SSc	NA		1.16×0−^7	14,70
	ACA+		8.78×10−^4
	DcSSc			5.2×10−^9
	Fibrosing alveolitis			2.5×10−^6
	Pulmonary hypertention			1.3×10−^5
PTPN22	ATA+	NA	7.10×10−^3	2.20×10−^16	4,53
CSK	SSc	7.9×10−^7	NA	5.04×10−^12	69
PPARG	SSc	1.64×10−^6	NA	5.0×10−^7	0,3
MECP2	DcSSc	NA	NA	5.26×10−^4	6
IRAKI	DcSSc	NA	NA	1.56×10−^4	5
	ATA+			1.07×10−^6
	SSc-related fibrosing alveolitis			9.05×10−^4
	Pulmonary fibrosis			3.90×10−^2

Note: *P-value of the most highly associated SNP for SSc phenotype.

Abbreviations: ACA, anti-centromere antibody; ATA, anti-topoisomerase antibody; DcSSc, diffuse cutaneous systemic sclerosis; GWAS, genome-wide association study; lcSSc, limited cutaneous systemic sclerosis; MHC, major histocompatibility complex; NA, not associated; SSc, systemic sclerosis; SNP, single-nucleotide polymorphism.

Table 3 Interferon pathway genes associated with human SSc

Gene	Expression cells	Function
STAT4	Macrophages, DCs, Thl cells, NK cells	• Required for most IL-12 biological responses including IFN-γ production • Thl differentiation (Kaplan et al^Citation27)
IRF5	B-cells, splenic cells, DCs	• Regulate TLR signaling pathway proinflammatory cytokine genes-Type I IFNs, IL-6, TNF-α, IL-12 et al (Tamura et al^Citation22)
IRF8	B-cells, T-cells, macrophages, CD11b-negative DCs	• Required for TLR9 signaling • Promote Type I IFN production in DCs • Stimulate IFN-γ and PAMP-inducible genes-IL-12, iNOS, FeγRI (Tamura et al^Citation22)

Abbreviations: DCs, dendritic cells; IFN, interferon; IL, interleukin; NK, natural killer; PAMP, pathogen-associated microbial pattern; SSc, systemic sclerosis; Th1, T helper 1; TLR, toll-like receptor; TNF, tumor necrosis factor.

Table 4 Overview of general mouse models in SSc

Model	Features	Innate immunity	Additive immunity	Autoantibodies	IFN signature	References
Bleomycin-induced mouse model	Skin inflammation; fibrosis	Yes	Yes	No	Yes	71
TSK1 mouse	Skin subcutaneous fibrosis; lung emphysema	Yes	Yes	Yes	No	72
TSK2 mouse	Skin inflammation; fibrosis	Yes	Yes	Yes	Not evaluated	73
GVHD mouse	Skin, lung and kidney inflammation; fibrosis	Yes	Yes	Yes	Yes	74

Abbreviations: GVHD, graft-versus-host disease; IFN, interferon; SSc, systemic sclerosis; TSK, tight skin.

Table 5 Interferon pathway gene knockout in mouse model

Model	Deletion location	Features	References
STAT4 deficient	Exon of the STAT4 gene	• Reduced IFN-γ production; reduced IL-12 response; Impaired Thl cell development and propensity towards to Th2 cells; abrogated NK cells cytotoxicity; mice are viable, fertile • Protected against bleomycin-induced skin fibrosis; do not abrogate skin fibrosis in TSK1 model by cross-breeding mice	27,28
IRF5 deficient	Exons 2–9 of the IRF5 gene	• Normal IFN-α induction; reduced IL-2, IL-6, TNF-α induction in DCs; deficiency in Th1 response; mice developed normally; normal hematopoietic cell population • Not yet confirmed in SSc animal models	36
IRF8 deficient	Exon 2 of the IRF8 gene; BXH2 mutation in IRF8 gene	• Abnormal populations of B-cells, T-cells, granulocytes and macrophages; mice are viable and fertile as young animals • Not yet confirmed in SSc animal models	41

Abbreviations: DCs, dendritic cells; IFN, interferon; IL, interleukin; NK, natural killer; SSc, systemic sclerosis; Th1, T helper 1; Th2, T helper 2; TLR, toll-like receptor; TNF, tumor necrosis factor; TSK1, tight skin 1.

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