Viruses, autoimmunity and cancer
Autoimmune diseases occur when our adaptive immune responses start attacking our own molecules. While many autoimmune diseases have been associated with various genetic risk factors, the environment also plays a major role. Viral infections have been speculated to be a major trigger of autoimmune diseases. The Iwasaki laboratory has been investigating the link between antiviral immunity and autoimmunity.
One example of such link was found for antibody responses to endogenous retroviruses.
Human endogenous retroviruses are genetic segments of retroviral origin that have become a part of the human genetic makeup in the last 100 million years, have persisted from generation to generation and today constitute approximately eight percent of the human genome. To study the role of endogenous retroviruses in human disease, Dr. Iwasaki and colleagues initially developed the human endogenous retrovirus map, called ERVMap, which included 3,220 pieces (or segments) of different endogenous retroviruses in the human genome to be able to map RNA sequencing reads to ERV loci. Among these 3,220 endogenous retroviral segments, the team found that over 100 segments are strongly elevated in immune cells called peripheral blood mononuclear cells of lupus patients.
The researchers further found that these elevated levels of endogenous retroviral genes are associated with higher amounts of autoantibodies and increased type I interferon levels, which are considered a main driver of lupus. Her team also showed that the immune system of lupus patients produces autoantibodies that interact with a unique endogenous retroviral protein HERV-K102. The autoantibody HERV-K102 complexes stimulate neutrophils to release NETs, which worsens inflammation in SLE. This research was published in the Journal of Experimental Medicine. These studies are further supported by our mouse genetic studies that mapped two genes, suppressor of non-ecotropic endogenous retroviruses (SNERV)-1 and SNERV-2, to the lupus susceptibility locus called Sgp-3.
The Iwasaki lab is currently studying whether similar antibodies to ERV antigens are found in long COVID patients, and whether such autoantibodies are shared with those with lupus-related autoantibodies. This work is supported by the Lupus Insight Prize from the Lupus Research Alliance. In addition, the laboratory is studying other links between virus infections and autoimmunity.
In addition to our laboratory's efforts to understand the origins of autoimmunity (including endogenous retroviruses), we also have ongoing projects to elucidate the consequences of persistent activation of antiviral signaling in autoimmunity. In particular, we are studying how type I interferons, thought to be the major driver of lupus disease, induce deleterious changes to the body's immune system resulting in characteristic organ pathology. Better knowledge of the critical cellular and molecular effectors downstream of type I interferons have the potential to inform new therapeutic approaches to lupus and other autoimmune diseases.
The immune system is a key player in how our bodies fight cancers. The early successes of immune-based cancer therapies suggest that a better understanding of how the immune system responds to cancer cells may help us develop better cancer treatments. Primary to our understanding of leveraging the immune system against cancers are adaptive immune cells, particularly cytotoxic CD8+ T cells, which are powerful killers that can identify and destroy tumor cells. Consistent with an overarching theme in the Iwasaki Lab– understanding how the innate immune system orchestrates adaptive immune responses–we are investigating the innate immune components that shape effective anti-tumor responses. Our work aims to better characterize the tumor-immune “interactome”, which we define as the entirety of immune interactions with tumor cells. To achieve this goal, we are developing non-biased synthetic tools that label and record when an immune cell encounters a tumor cell. We believe that these tools have the potential to reveal novel immune interactions in a range of tumor types that will inform the development of effective new cancer treatments.