HSS has a long and distinguished record of contributing significant research advances in systemic lupus erythematosus (SLE). Since the 1960s, when HSS investigators characterized the role of products of the immune system – immune complexes – in the inflammatory disease that affects the kidneys in lupus, many important insights have come from our laboratories and from careful study of our patients. SLE is one of the most complex diseases in all of medicine. It is only through research that we have moved our understanding of SLE from recognition that it is an autoimmune disease – with cells and antibodies of the immune system targeting self-molecules – to a comprehensive view that incorporates genetics, environmental triggers and nearly all components of the immune system.
The Immune System and Lupus:
The immune system has evolved over millions of years to allow us and our predecessors to survive in a relative equilibrium with the many potentially damaging microorganisms that we encounter. Usually our immune systems do a good job of responding to and eliminating bacteria and viruses in a manner that minimizes damage to our tissues and organs.
However, in some individuals or in response to some particularly damaging microbes, infection persists for months or years, with sustained activity of cells and products of the immune system damaging healthy tissue to eliminate the microbe. Just as warfare can have the unfortunate consequence of injuring civilians, chronic mobilization of the immune system can lead to disease. We think a similar scenario occurs in SLE, but in that case the culprit is probably not a microbe.
In SLE an individual’s genetically determined set point for triggering immune system activation allows cells to respond to our own DNA or RNA – the molecules that provide the genetic code that determines how our bodies function. Instead of responding to the DNA or RNA that is a core component of a virus, lupus immune systems respond to self-DNA or RNA, with significant consequences for how the immune system functions.
Research at HSS:
Research at HSS has addressed many aspects of SLE disease – from study of variations in the genome that determine risk of developing the disease to identification of specific molecules that might be targeted by lupus therapeutics. One of the most significant observations that our laboratory has pursued is that molecules called interferon, typically produced in the setting of infection with a virus, are produced in most lupus patients over many years. Interferon can alter the function of most cells of the immune system, resulting in production of autoantibodies and generation of inflammation in tissue.
These studies have led to drug development programs with the goal of blocking the activity of interferon. What we really want to know is: what is driving the production of the interferon? We know that immune complexes have a role in stimulating its production, but are there other molecules in cells that are responsible for the sustained interferon production that we see in lupus? Studies to answer that question are in progress.
We need to learn more about the T and B cells of the immune system and how they escape their usual control mechanisms and generate damaging autoantibodies. HSS investigators are studying the signaling molecules in those cells, and some of those molecules might represent targets of potential new therapies.
We are also excited by the prospect of gaining insight into why women are so much more frequently affected by SLE than men. With a 9:1 female to male ratio, we suspect that a comparison of the molecular and immune mechanisms of both men and women with SLE, in comparison to healthy men and women, will yield important clues that might explain key mechanisms of disease. We are analyzing the molecular patterns in the blood of each of these groups of study subjects, and our results are suggesting clues to the most important mechanisms of disease.
The Importance of Research Studies:
We have learned that what is most informative and productive in our quest to understand and better treat lupus is to partner with our patients in research studies. Developing cohorts of patients who are studied over time – through the waxing and waning course of their disease – teaches us about the underlying biology that is responsible for disease flares and for the periods when the disease is relatively quiet. We use molecular tools to characterize the different molecular pathways that are associated with disease activity. One goal is to define those immune mechanisms that are a feature of most patients with SLE – those that might represent productive targets for new therapies – as well as those mechanisms that might be less common and a feature of individual patients.
Of course we aspire to identify the most precise and effective treatments for every individual patient. First we need to continue our quest to understand the genetic factors that confer risk of disease, the immune functions that account for the autoimmunity and inflammation, and the precise molecular mechanisms that are responsible for those immune functions. With availability of new therapies – with many currently in the pipeline – the next step will be to design clever approaches to combine therapies in a manner that will most effectively control the lupus immune system and restore its function to health.
Dr. Mary K. Crow is Physician-in-Chief and Chair of the Department of Medicine at HSS. She is also the Director of the Autoimmunity and Inflammation Research Program and Co-Director of the Mary Kirkland Center for Lupus Research at HSS. Dr. Crow’s academic and research career has focused on unraveling the cellular and molecular mechanisms that underlie the systemic autoimmune diseases, with a particular focus on systemic lupus erythematosus and rheumatoid arthritis.
