Monogenic Autoimmune Diseases

Dae Chul Jeong

doi:10.4078/jrd.2018.25.4.213

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Jeong: Monogenic Autoimmune Diseases

Review Article

J Rheum Dis 2018;25(4):213-220.

Published online: 31 October 2018

DOI: https://doi.org/10.4078/jrd.2018.25.4.213

Monogenic Autoimmune Diseases

Dae Chul Jeong

Division of Pediatric Rheumatology and Clinical Immunology, Department of Pediatrics, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

Corresponding to: Dae Chul Jeong http://orcid.org/0000-0003-0934-817X Division of Pediatric Rheumatology and Clinical Immunology, Department of Pediatrics, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea. E-mail: dcjeong@catholic.ac.kr

Received 13 March 201813 June 2018 Accepted 28 June 2018

This is a Open Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Monogenic autoimmune diseases (AD) present as lupus-like clinical manifestations with recurrent fever or various vasculopathies. Recurrent fever with an elevation of acute phase reactants and various skin lesions are similar in monogenic AD and autoinflammatory disease. The molecular pathogenesis of adult systemic erythematosus can be understood through monogenic AD based on gene defects: complement, apoptosis, interferonopathy via nucleic acid sensing, tolerance, raso-pathies, and others. Skin vasculopathy with chilblains and livedo reticularis, interstitial lung disease, and panniculitis are common occurrences in type I interferonopathy. Some syndromes have been reported to present with autoimmune inflammation and the general clinical findings, including cerebral calcification. Various clinical manifestations in monogenic AD present in accordance with the gene loss- or gain-of-function mutations involved. The monogenic AD for the early onset of more severe lupus-like symptoms or vasculopathy needs to be considered. Furthermore, clinical trials were conducted via targeted therapy for related molecular pathways, because conventional treatments were not effective in managing monogenic AD.

Keywords: Autoimmune diseases, Genes, Systemic lupus erythematosus, Interferon

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Figure 1.

Type 1 interferon signaling and type 1 interferonopathies as currently assigned. This figure is adapted from Rodero et al. J Exp Med 2016;213:2527-38 [28]. ADAR1: adenosine deaminase RNA specific 1, ACP5: acid phosphatase 5, C1q: complement 1q, cGAS: GMP-AMP synthetase, IFN /: interferon /, IFNAR1: interferon alpha and beta receptor subunit 1, IFNAR2: interferon alpha and beta receptor subunit 2, JAK1: Janus kinase 1, IRF3: interferon regulatory factor 3, IRF9: interferon regulatory factor 9, ISGs: interferon-stimulating genes, ISG15: interferon-stimulating gene 15, MDA5: melanoma differentiation-associated gene 5, MAVS: mitochondrial antiviral signaling 5, POLA1: DNA polymerase 1, PSMB4: proteasome subunit beta 4, PSMB8: proteasome subunit beta 8, PSMA3: proteasome subunit beta 3, RNASEH2A: ribonuclease H2A, RNASEH2B: ribonuclease H2B, RNASEH2C: ribonuclease H2C, RIG-1: retinoic acid inducible gene-1, SAMHD1: SAM domain and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1, SKIV2L: superkiller viralicidic activity 2-like RNA helicase, STAT1: signal transducers and activators of transcription 1, STAT2: signal transducers and activators of transcription 2, TYK2: tyrosine kinase 2.

Table 1.

The monogenic autoimmune diseases with corresponding pathogenesis and phenotype

Pathogenesis	Gene	Proteins	Inheritance	Phenotype
Complement/immune clearance	C1QA/C1QB/C1QC	C1q	AR	SLE with rashes, GN, CNS, ani-dsDNA often negative, recurrent infection
	C1R	C1r	AR	SLE with rashes, GN, recurrent infection
	C1S	C1s	AR	SLE with rashes, GN, recurrent infection
	C2	C2	AR	SLE with arthritis, rashes, autoantibodies often negative, recurrent infection
	C4A, C4B	C4	AR	SLE with variable phenotype, rashes, proliferative GN, recurrent infection
Apoptosis	TNFRSF6	Fas	AD	Autoimmune lymphoproliferative syndrome (ALPS), autoimmune cytopenias
	FASL	FasL	AD	ALPS, SLE with lymphadenopathy
Immune clearance	DNASE1	DNase1	AD	SLE: high titer anti-nucleosomal antigens
	DNASE1L3	DNase1L3	AD	Anti-dsDNA antibodies, low C3/C4, GN and positive ANCA: very young age of onset
Nucleic acid sensing/Type I IFN	TREX1	TREX1	AR/AD	AGS: FCL: SLE with severe CNS disease
	SAMHD1	SAMHD1	AR	AGS: FCL
	ADAR1	ADAR1	AR/AD	AGS
Nucleic acid sensing/Type I IFN	IFIH1	IFHI1, MDA5	AD	AGS
	RNASEH (2A, 2B, 2C)	RNaseH2 complex	AR	AGS
	NEIL3	NEIL3	AR	Recurrent infection; autoimmune cytopenias
	ACP5	TRAP	AR	Spndyloenchondrodysplasia, autoimmune cytopenia; recurrent infection
Apoptosis/Tolerance	PRKCD	PKCδ	AR	SLE
Tolerance	RAG2	RAG2	AR/AD	Leaky SCID; Omenn syndrome: autoimmune cytopenia; granuloma
Ras/MAPK	SHOC2	Shoc2	AD	Noonan syndrome; SLE with polyarthritis
	KRAS	K-Ras	AD	Noonan syndrome; SLE
Collagen degradation	PEPD	PEPD	AR	Polidase deficiency; sever leg ulcers; SLE

AR: autosomal recessive, AD: autosomal dominant, GN: glomerulonephritis, CNS: central nervous system disease, AGS: Aicardi-Goutieres syndrome, FCL: familial chilblain lupus, SCID: severe combined immunodeficiency. This table is modified and adapted from Lo, Curr Rheumatol Rep 2016;18:71 [10].

Table 2.

Differences in clinical manifestations of IL-1 and IFN-mediated autoinflammatory diseases

Organ	IL-1 mediated diseases	IFN-mediated diseases (CANDLE, SAVI, AGS)
Systemic	CRP closely correlates with disease activity	CRP only elevated in severe disease
	Granulocytosis with flares	Lymphopenia, leucopenia with flares
CNS	Aseptic neutrophilic meningitis	Mild lymphocyte meningitis
	Arachnoid adhesion (Severe disease)	Basal ganglion calcifications, CNS vasculopathy, white matter disease
Skin/Vessel	Neutrophilic dermatitis (urticaria-like with	Panniculitis (“immature” neutrophhils), lipoatrophy, a mature neutrophilic infiltrate)
		Vasculitis (chilblain-like lesion) microthrombotic disease
Lung/Heart	Serositis, pericarditis	Pulmonary fibrosis/Interstitial lung disease
		Hypertension, pulmonary hypertension
MSK	Osteomyelitis, bony overgrowth, fasciitis, arthralgia	Myositis, non-erosive arthritis, arthralgia
ENT	Hearing loss (inflammatory)	None
Eyes	Conjunctivitis, anterior uveitis	Glaucoma, episcleritis
Serology	40% lupus anticoagulant positive	40%∼50% lupus anticoagulant positive in CANDLE/SAVI,
	Other autoantibodies uncommon	Some with other variable/transient autoantibodies

IL-1: interleukin-1, IFN: interferon, CANDLE: Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature, SAVI: STING associated vasculopathy with onset in Infancy, AGS: Aicardi-Goutieres syndrome, CRP: C-reactive protein, CNS: central nervous system, MSK: musculoskeletal system, ENT: ear, nose, throat. This table is adapted from Kim et al. J Mol Med (Berl) 2016;94:1111-27 [13].

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