Factor H also plays a role in age-regulated macular degeneration, a chronic inflammatory disease. It’s caused by a defective regulation of the alternative complement pathway, which is continuously active in these patients. Certain variants in the Factor H gene increase risk for AMD, he said.7
Interferons in Lupus
What are the possible outcomes of a microbial infection? Resolution, peaceful coexistence or disease, said Mary K. Crow, MD, physician in chief, chair of the Department of Medicine, and chief of the Division of Rheumatology at Hospital for Special Surgery in New York.
An effective immune system rapidly destroys a microbe. But the microbe can persist in some hosts in a state of détente, in which the microbe and the immune system get along and coexist for a time. When can that situation go awry, leading to disease that could even be lethal?
“In autoimmune disease, maybe, the immune system starts to kill the host, destroying tissue and causing severe disease. So much depends on genetic variation,” said Dr. Crow.
Type-1 interferon is a central pathogenic mediator in SLE, she said.8 Genetic factors and pathways lead to a sustained expression of type-1 interferon in these patients. Type-1 interferon is a complex family of cytokines with diverse effects on the immune system. It binds to IFNAR, its receptor, and signals through the STAT-JAK pathway, she said.
Therapy with recombinant IFNα can induce lupus autoantibodies and clinical lupus. Lupus serum induces IFN production, and IFN gene expression signature is found in lupus blood, said Dr. Crow. A high IFN-type 1 test score is associated with increased disease activity. Interferon scores can fluctuate in the disease activity measures SLEDAI and BILAG.
In SLE, the type-1 interferon response just doesn’t shut down as it should, she said. In healthy people, there is rapid production of IFN-type 1, followed by diminishing viral load. In lupus, there is a sustained, prolonged and pathogenic immune response. Infection with the influenza virus leads to transient expression of IFN-induced genes in lung tissue.9 It’s a tightly regulated response to this viral infection, she said.
“Sustained production of type-1 interferon in a chronic virus infection is detrimental,” said Dr. Crow. “What happens here? The virus infection both drives and, in most cases, resolves the type-1 interferon response. What turns off the interferon response? It’s the virus. The virus inhibits induction of interferon. Proteins are made that inhibit the response to interferon.”
Viruses tend to actively mutate. For example, host-encoded and virus-encoded proteins have co-evolved in response to lentivirus infection, leading to long-term coexistence. But in lupus, it’s not caused by exogenous microbial infection. Host nucleic acid drivers of immune activation don’t encode inhibitors of viral restriction factors.
