The discovery of two new genes in the interferon (IFN) system associated with systemic lupus erythematosus (SLE) may ultimately help researchers solve the IFN puzzle, according to a new study presented in the American Journal of Human Genetics.1

Increased production of type I IFN and expression of IFN-inducible genes is commonly observed in SLE and may be pivotal in the molecular pathogenesis of the disease.

Genome scans using 44 single-nucleotide polymorphisms (SNPs) in 13 genes from the type I-IFN pathway revealed that the SNPs in two of the genes displayed strong signals in joint analysis of linkage and association with SLE. Specifically, the two genes displaying these signals encode tyrosine kinase 2 (TYK2) and the IFN regulatory factor 5 (IRF5); TYK2 binds to the type I-IFN receptor complex and IRF5 is a regulator of type I-IFN gene expression, the study showed.
"These genes are associated with the risk to develop SLE. They may also be connected to certain clinical manifestations, such as nephritis, because we noted a reduced frequency of nephritis in the patients with the TYK2 polymorphism ," says researcher Lars Rönnblom, MD, PhD, professor in the department of medical sciences at Uppsala University in Uppsala, Sweden. Further studies with larger patient cohorts are needed, however, to clarify this issue, he tells CIAOMed. That said, "functional studies of the TYK2 and IRF5 proteins have to be performed and we also need to determine how they work in SLE," Dr. Rönnblom says. "Our working hypothesis is that the noted polymorphisms are associated with a reduced function of the involved proteins, leading to a decreased type I interferon response." It is probable that novel drug targets will follow suit as the two newly described genes may only reflect the "tip of an iceberg" with regard to IFN-related genes in SLE. "There is still much to work out, but with new genotyping systems, it will be possible to investigate these genes," Dr. Rönnblom predicts. The current study looked at 11 of the approximately 200 genes that belong to the IFN system. Future studies will also investigate other genes within the IFN-signaling pathway.

This present study provides considerable support for the role of the type I-IFN system in SLE and "also suggests that components of the IFN system are putative drug targets," Dr. Rönnblom points out. "Our findings give us important information with regard to two possible target molecules. We are today [much] closer to an understanding of the cause of lupus. I anticipate that within 1 to 2 years the first studies in SLE patients will be performed with inhibitors of the type 1 interferon system."
The new findings may extend previous knowledge of the association of IFN in SLE. "If these differences that they have identified among individuals have functional significance, they could give us clues as to why lupus patients make more IFN or have a more active response to IFN," comments SLE researcher Mary K. Crow, MD, professor of medicine at the Hospital for Special Surgery in New York City.

"There is a lot of interest in IFN-alpha these days and the new study provides a lot of support of this pathway," Dr. Crow notes. "No one really understands why IFN-alpha may be over expressed in lupus and possibly these data may give some hints."

Asked if IFN in SLE is analogous to tumor necrosis factor (TNF) in rheumatoid arthritis (RA), Dr. Crow remarks that she thinks "IFN is made earlier in the SLE disease process than TNF is in RA. TNF is made from chronic inflammation," she adds, "but we don't know why IFN-alpha is made. It may be made early in the disease process and may not be as close to target organ damage as TNF is in RA."

"The analogy makes sense in that TNF has been targeted very successfully for many patients with RA," she continues. "Interferon alpha still remains a very good target for therapy and this data might give some clues as to why IFN may be important in lupus immune system."

In the past, Dr. Crow observes, "many biotech and pharmaceutical companies were very hesitant to embark on anything for lupus because it's so heterogeneous, but I have a lot of optimism that some groups will try to develop something that blocks interferon pathway."

Reference

1. Sigurdsson S, Nordmark G, Göring HHH, Lindroos K, Wiman A-C, Sturfelt G, et al. Polymorphisms in the Tyrosine Kinase 2 and Interferon Regulatory Factor 5 Genes Are Associated with Systemic Lupus Erythematosus. Am J Hum Genet. 2005;18:76-79.