2007 Why the Lupus Immune System Reacts to Its Own DNA
2012 B Cells, Why the Lupus Immune System Reacts to Its Own DNA
Initial events in autoimmune disease
2012: The Study and What it Means to Patients
“Given lupus patients’ increased risk of non-Hodgkin’s lymphoma, we’re asking whether their fundamental causes might be similar. We’re exploring whether autoreactive B cells can multiply because of retroviruses disrupting critical control genes (as can happen in cancer). If correct, preventing lupus in susceptible individuals may be possible with anti-retroviral drugs, like those for HIV.”
The observation that patients with lupus are at higher risk of lymphoma is the basis of our hypotheses to explain how harmful autoreactive cells first arise in lupus. We propose that similar to cancer where mutations disrupt genes that control cell growth allowing cells to proliferate and spread, so too in lupus, mutations in critical control genes allow autoreactive B cells to survive and proliferate. According to our theory, these mutations are caused by retroviruses — viruses that can insert themselves into our DNA. We will test this theory by screening the DNA of B cells from lupus mice to determine whether retroviruses have inserted themselves into critical control genes.
The LRI grant is giving us the freedom to explore an entirely novel theory on the fundamental cause of lupus — if autoreactive B cells are allowed to proliferate as a result of retroviruses disrupting critical control genes.
The blueprint for what makes us each unique — DNA and RNA — is carried inside the nucleus of each of our cells. Normally, our immune systems deftly distinguish our own DNA and RNA from that of foreign invaders such as viruses and bacteria.
But in people with lupus, the immune system reacts to its own DNA and RNA as if these blueprint “chips” were the enemy that required extermination. What prompts these cases of misidentification?
For example, the body’s DNA carries remnants of ancient viruses that once infected our ancestors, but then became an integral part of the human genome. Dr. Wabl hypothesizes that these viral relics are what that the lupus immune system mistakes for virus DNA, thus triggering the attack on the body’s own DNA.
In systemic lupus erythematosus, there is a well-documented increased risk of non-Hodgkin's lymphoma. Analogously, the B/W mouse develops lupus disease and recapitulates the human disease in most clinical aspects, and also suffers from hyperproliferation of lymphocytes and, eventually, lymphoma. In mice, lymphomas are generally caused by insertional mutagenesis. Similarly, in autoimmune disease we hypothesize that immature B cells are not tolerized to self-antigen because of a retroelement insertion blocking the relevant pathway. Because a single mutation in a stem cell may jeopardize the tolerization of a larger lymphocyte population, but cancer generally requires accumulation of several mutations within the same cell, autoimmune disease will precede cancer. Because B lymphocytes of B/W mice produce large amounts of endogenous MLV, B lymphoid hyperplasia in these mice may occur by de novo proviral insertions into the genome. To identify retroviral integration sites, we will isolate genomic DNA from B/W lymphomas, and from clones of hyperproliferating (autoimmune) spleen cells. Using an anchored PCR technique, we will determine the genes affected by retroviral insertion. We will then study the effects of the mutations on B lymphocyte apoptosis and proliferation.
Past LRI-Funded Work
2010 Update: Congratulations, Dr. Wabl!
- Top Score at National Institutes of Health (NIH) Based on Ongoing LRI Work
- Abstract based on LRI work, Retroelements as Trigger of Lupus was selected for the 9th International Congress on Systemic Lupus Erythematosus
Vancouver 2010 (June)
- Top Abstract
- Present to the Congress
- Winner, Cutting Edge of LUPUS Research Travel Grant
Early onset of autoimmune disease by the retroviral integrase inhibitor raltegravir. Beck-Engeser GB, Eilat D, Harrer T, Jäck HM, Wabl M. Proc Natl Acad Sci U S A. 2009 Nov 18.
In 2010, Dr. Wabl not only won a major grant from the National Institutes of Health to continue the work first supported by the Lupus Research Institute—a 5-year R01 grant for $1.25 million—but received the highest score of all funding applications from the last three grant cycles.