The genetics of type I interferon in systemic lupus erythematosus

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The discovery that type I interferon (IFN)-inducible genes were strongly upregulated in peripheral blood in SLE over a decade ago sparked interest in understanding the relationship between type I IFN and SLE. Genome-wide association studies provide strong genetic evidence that type I IFNs are important for SLE risk. Of 47 genetic variants associated with SLE, over half (27/47, 57%) can be linked to type I IFN production or signaling. The recent identification of single gene mutations for disorders that share features with SLE – Aicardi–Goutières syndrome, chilblain lupus, and spondyloenchondrodysplasia – provide additional support for the hypothesis that type I IFNs are central drivers of SLE pathogenesis. These insights provide significant focus for efforts to tackle SLE therapeutically.

Highlights

► Type I IFN appears to be a central pathway dysregulated in SLE. ► Most SLE patients have a prominent IFN gene signature in blood. ► Over half of the common alleles associated with SLE map into the type I IFN pathway. ► Rare, monogenic SLE-like diseases also show activation of type I IFN.

Introduction

SLE is characterized by IgG autoantibodies to highly conserved nuclear antigens such as double-stranded DNA (dsDNA), histones and ribonuclear proteins. Immune complexes comprised of IgG and self-antigens deposit in tissues and blood vessels, including skin, kidneys, and pleura/pericardium, leading to end-organ disease. Additional autoantibodies directly target cell surface antigens, causing cytopenias and other pathologies. Similar to most autoimmune diseases, human leukocyte antigen (HLA) genes are associated with increased SLE risk, with strongest evidence for the class II HLA alleles DRB1*15:01 and DRB1*03:01 [1]. Although the survival rate for SLE has improved greatly over the years, patients are 2.5 times more likely to die than the general population [2], and there is a pressing need to develop new therapies.

Here, we review evidence from genomic, candidate gene, and genomewide association studies (GWAS), together with recent findings from monogenic SLE and SLE-related diseases, that support the hypothesis that type I interferons (IFNs) are key factors in SLE pathogenesis.

Section snippets

Pleiotropic effects of type I IFN and related pathways

Type I IFNs (13 IFN-α isotypes, IFN-β, IFN-ɛ, IFN-κ, and IFN-ω) are produced primarily by plasmacytoid dendritic cells (pDCs), and are regulated by engagement of cell membrane or endosomal receptors, such as certain toll-like receptors (TLRs) (TLR 3, 7/8, 9), that recognize nucleic acids in viruses, bacteria and protozoa. Intracellular viral RNA and DNA are recognized by a specialized set of receptors (e.g. RIG-I, IFIH1) that also trigger type I IFN production. Type I IFN binds to the

The IFN gene expression signature and IFN-α in SLE

Using microarray gene expression analysis, we generated initial data in 1999 showing that about two-thirds of adult SLE patients exhibited elevated expression of type I IFN-inducible genes in peripheral blood cells, and coined the term ‘IFN signature’ [9••]. Additional groups reported similar findings in SLE [10••, 11, 12], and subsequently the IFN signature was found to be prominent in Sjögren's syndrome, dermatomyositis, subacute cutaneous lupus and discoid lupus erythematosus [13, 14, 15, 16

Genetic risk for SLE and the type I IFN pathway

An important development over the past 5 years has been the identification of genes that associate with SLE and that map into the type I IFN pathway. An initial candidate gene study by Sigurdsson et al. [36] found an association of the transcription factor interferon regulatory factor 5 (IRF5) with SLE. Further genetic and functional studies identified a single risk haplotype for IRF5 characterized by three functional alleles [37, 38•]. The non-risk haplotypes for IRF5 contain a splice site

Single gene lupus-related disorders of the type I IFN pathway

In addition to studying sporadic SLE, it is worthwhile to examine highly penetrant phenotypes with a clinical presentation that is similar to or shared with SLE. These single-gene, or Mendelian, disorders can offer insight into therapeutic targets for SLE. However, they may not be representative of sporadic SLE.

Recent data on rare single gene variants that lead to either SLE or SLE-like disease further support the idea that inappropriate activation of type I IFN is on the causal pathway for SLE

Type I IFN as a therapeutic target in SLE

Developing novel therapeutics for SLE is particularly important because there are so few effective therapies for SLE available today. The FDA recently approved Belimumab, a human monoclonal antibody that inhibits the B-lymphocyte stimulator (BLyS), for use in non-renal SLE, and it is the first SLE therapeutic approved in over five decades. The relatively modest clinical benefits reported in the pivotal trials for Belimumab suggest the optimal patient subset for this drug has not yet been

Conclusions

In aggregate, the evidence supporting the direct involvement of type I IFNs in SLE pathogenesis is quite compelling: (a) IFN-α immunotherapy can induce lupus [98]; (b) circulating immune complexes from SLE blood can initiate type I IFN production; (c) there are prominent IFN regulated gene and cytokine signatures in SLE; (d) polymorphisms in IFN pathway genes are associated with SLE in GWAS studies; and (e) several single gene disorders cause increased type I IFN and SLE or SLE-like symptoms.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We would like to thank A. Manoharan and H. Sun for their invaluable assistance in curating the published SLE literature for genetic associations.

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