This is the first of three blog posts I intend to create relating to recent research on autoimmune diseases, Lupus in particular, the links between autoimmune diseases and lymphoma cancers, and such cancers themselves. This Part I post is focused on recent research regarding one particular autoimmune disease, Lupus erythematosus, its genetic causes and new therapies intended to address it. The Part II post will be concerned with the association between Lupus and other autoimmune diseases with lymphoma and what this association is telling us. The final Part III post will review some recent research on lymphomas and emerging treatments for them.
An autoimmune disease is “An illness that occurs when the body tissues are attacked by its own immune system(ref).” Autoimmune diseases, including Lupus erythematosus , Crohns Disease, Graves’ Disease, Rheumatoid arthritis, Scleroderma, Pulmonary Fibrosis, and Sjogren’s Syndrome affect hundreds of millions of people worldwide, are the cause of untold suffering, and are the subjects of intense research from multiple viewpoints. Well over 70 autoimmune diseases and conditions have been discovered, some of which are close cousins of one another. Many patients have symptoms of multiple autoimmune diseases. In fact there is a category known as “mixed connective tissue disease.” “It has been estimated that autoimmune diseases are among the ten leading causes of death among women in all age groups up to 65 years(ref).” Moreover, as I will discuss in a next blog post, patients with autoimmune diseases have a significant susceptibility to developing lymphoma cancers.
Systemic Lupus erythemetosus (SLE)
Patients with SLE are subject to severe inflammatory conditions that can occur in Lupus flares and that can possibly affect many different body systems including blood cells, joints, skin, kidneys, heart, and lungs. About 1.5 million people in the US and at least 5 million worldwide are affected by lupus(ref). The majority of those affected by SLE are women, perhaps 90% of the patients, and blacks and Latinos are significantly more susceptible than whites. . When the disease first strikes, the victims are usually in their 30s and 40s. The manifestations of SLE and how and when they will emerge vary widely from patient to patient. External symptoms can include fatigue, Raynaud’s syndrome, fever, joint pain, stiffness and swelling, rashes, arthritic attacks, skin lesions, chest pain, and mouth sores. A patient may go many years in a relatively benign condition between inflammatory flares. On the other hand SLE can attack many internal organs, leading to death. In case of a flare the disease is usually treated aggressively with a strong anti-inflammatory drug, particularly Prednisone. Otherwise a low-level of the disease may be treated with a more benign anti-inflammatory drug like Plaquinil.
A common feature shared by SLE patients is the presence of antibodies that can be identified by tests, like ANA and anti-dsDNA(ref). These antibody tests, clinical manifestations and other blood tests like sedimentation-rate are used in diagnosis of lupus. Lupus comes in multiple manifestations and is sometimes confused or compounded with other autoimmune diseases.
How does SLE work?
Basically, SLE involves immune cells attacking normal body cells. But what are the underlying genetic/bimolecular mechanisms? On a general level, SLE appears to be a disease of faulty B-cell signaling(ref). “Although the cause of SLE remains unsolved, the research accumulated thus far points to numerous aberrations in antigen-receptor mediated signaling events exhibited by SLE B cells and highlights signaling defects that presumably play a central role in the pathogenesis of the disease. Abnormal B cell signaling certainly plays a significant role in the breakdown of B cell tolerance and subsequently the pathogenesis of SLE.”
There are several interesting possibilities undergoing research investigation relating to the basic processes underlying SLE. For example:
- I discussed an underlying genetic conditions thought to be important to SLE in a blog post earlier this month: A Fascinating dance of death and life – Fas, FasL and diseases. I said: “Defects in the Gene encoding Fas is correlated with systemic lupus erythematosus (SLE). “In the murine MRL/Ipr-Ipr model of systemic lupus erythematosus (SLE), the lymphoproliferation (lpr) mutation results in defective transcription of the gene that codes for the Fas protein.” – “Interest in the importance of Fas in SLE has risen with the observation that 60% of human subjects with lupus have elevated levels of the soluble Fas receptor in their serum and that the abnormal presence of this molecule may protect lymphocytes from undergoing apoptosis(ref).” The link of FAS to autoimmune diseases goes back over a decade, considering the 1998 paper Human autoimmune lymphoproliferative syndrome, a defect in the apoptosis-inducing Fas receptor: a lesson from the mouse model.
- Abnormal editing of gene-produced messages in T cells may be a causal factor in Lupus(ref). “Dama Laxminarayana, Ph.D., assistant professor of internal medicine and senior author, said that in systemic lupus erythematosus, the normal editing process goes awry, causing a shift in the balance of proteins that results in impaired functions in T cells, a type of white blood cell involved in the regulation of immune functions.” — “150-kDa ADAR1, one of the three enzymes involved in editing gene messages, is higher in the T cells of lupus patients compared to those without lupus. ADARs are adenosine deaminases that act on RNA(ref).”
Aberrant differentiation of T helper cells into T follicular helper cells (Tfh cells) under the influence of Bc16 (a gene and transcription factor B-cell lymphoma 6), a might play a role in the manifestation of SLE as well as B-cell lymphomas. “Tfh cells and germinal centers have been implicated in antibody-mediated autoimmune diseases such as lupus and rheumatoid arthritis, Dong noted. In these diseases, the germinal centers are likely producing the wrong type of antibody at great volume(ref).”
- Variations in the TREX1 gene may be related to susceptibility to SLE, according to a study reported in 2007(ref). “The study involved 417 lupus patients from the United Kingdom and Germany. Mutations were found in nine patients with lupus and were absent in 1,712 people without lupus. “Our data identify a stronger risk for developing lupus in patients that carry variants of the gene,” said Lee-Kirsch.” – “The gene manufactures a protein, also known as TREX1, whose function is to “disassemble” or “unravel” DNA, the strand of genetic material that controls processes within cells. The “unraveling” occurs during the natural process of cells dying and being replaced by new cells. If a cell’s DNA isn’t degraded or unraveled during cell death, the body develops antibodies against it. “If the TREX1 protein isn’t working to disassemble the DNA, you make antibodies to your own DNA and can end up with a disease like lupus,” said Perrino(ref).”
- Lupus gene-discovery results are being reported more and more frequently. For example, see New Batch of Lupus Genes Discovered. A January 2008 review study analyzes the Significance And Limitations Of New Lupus Gene Expression Research.
- Finally, Lupus research is surfacing some interesting curiosities, such as revealed in the report Sex-Dependent Effect of Melatonin on Systemic Erythematosus Lupus Developed in Mrl/Mpj-Faslpr Mice: It Ameliorates the Disease Course in Females, whereas It Exacerbates It in Males. Clearly, SLE appears to be sex-hormone linked.
New therapeutic approaches are being investigated for SLE. For example:
- In 2004, “researchers at the Department of Health and Human Services’ National Institutes of Health (NIH) launched a five-year study to see whether a therapy using transplantation of hematopoietic stem cells, blood stem cells found in bone marrow, can produce long-term remission for patients with severe, treatment-resistant systemic lupus erythematosus(ref).” The study was extended for another two years and no results have yet been published. The approach uses powerful immunosuppressive drugs to wipe out patients’ immune system cells, an approach that is potentially quite dangerous because for a week or two a patient undergoing the treatment has no operational immune system. However, the treatment approach might-well work. The idea is that autologous hematopoietic stem cells may have the same genes as mature immune system cells in a given individual, but that they might not have the epigenetic experience that leads to manifestation of SLE. So, it may well be possible to reset an individual’s immune system to an earlier state, before development of SLE. Besides showing that the technique works, the study could provide important information since it was designed with an intent to investigate how B and T cells function in the immune systems of lupus patients. The results of this study will not be known for a couple of years although the results of other studies using the same approach are likely to be known earlier.
- Treatment with Rituximab is another semi-experimental approach for dealing with SLE, particularly in episodes of severe inflammation where more conventional treatments like prednisone are not doing the job(ref). Rituximab is a chimeric monoclonal antibody that wipes out B cells by targeting the pan-B-cell surface marker CD20. The results of this approach appears to be a mixed bag. A 2005 report indicates that for Lupus “A total of 100 rituximab-treated patients with severe disease, refractory to major immunosuppressive treatment, have been reported so far. Within a median follow-up period of 12 months rituximab was well tolerated, which is compatible with the experience accumulated from its use in more than 500 000 lymphoma patients. About 80% of patients achieved marked and rapid reductions in global disease activity. Because of the clinical heterogeneity, dosing differences, and concomitant treatments, including cyclophosphamide in 35% of patients, a proper evaluation of the clinical efficacy or rituximab is difficult. Variable degrees of clinical benefit have been reported for all clinical systemic lupus erythematosus manifestations, including active proliferative nephritis.” – “The findings reviewed point to a growing optimism for targeting B cells in the treatment of systemic lupus erythematosus; therefore double-blind studies comparing rituximab with existing immunosuppressive therapies are needed.” Many studies have involved only one or a few patients, such as described in this report. A 2007 report on a study involving 2000 patients is headlined Over One-third of Refractory Lupus Patients Remain Stable After Receiving B-cell Depletion Therapy. A March 2009 report indicates that a Phase III clinical trial was discontinued because the therapy that included rituximab for lupus nephritis was ineffective. “March 11, 2009 – Genentech, Inc. (NYSE: DNA) and Biogen Idec (Nasdaq: BIIB) announced today that a Phase III study of Rituxan® (rituximab) plus mycophenolate mofetil (MMF) and corticosteroids in patients with lupus nephritis did not meet its primary endpoint of significantly reducing disease activity at 52 weeks.” That conclusion seems to be in conflict with this study report released about the same time suggesting that rituximab may indeed be a useful treatment for patients with severe lupus nephritis. Of course, the treatment protocols were not the same. Finally, rituximab treatment may have serious side effects, some of which are life-threatening(ref).
- Therapy involving mycophenolate mofetil may be useful for reducing the frequency of lupus flares, according to a 2007 study(ref). “The research team evaluated mycophenolate mofetil (MMF) to see if it would reduce the number of flares in SLE, which is both chronic and relapsing. In the retrospective study, researchers studied 88 patients treated with MMF at Mayo Clinic over a two-year period. They also studied patient histories and data on lupus flares going back two years. The patients, whose average age was 44, had lupus for an average of 10 years. The majority of participants were women. Before the MMF, lupus flares in the group totaled 155 compared to 99 after treatment. For severe flares, the improvement was even more dramatic, from 98 to 54.” – “”Our findings show this therapy reduces lupus flares overall and is especially effective in reducing severe flares by roughly half,” says Mayo rheumatologist Kevin Moder, M.D., who led the research(ref).”
- Laboratory experiments reported in May 2009(ref) suggest that class R inhibitory oligonucleotides may be useful for controlling inflamation in patients experiencing a lupus flare. The idea is to suppress lupus-related inflammation without generally suppressing the entire immune system. “Using human cell lines and isolated mouse cells, Lenert and his colleagues showed that the DNA-like compounds were able to selectively reduce the activity of two types of immune cells called autoreactive B cells and dendritic cells. When given to mice with lupus, the compounds delayed death and reduced kidney damage, proving their effectiveness.” – “”With further testing, we hope that class R inhibitory oligonucleotides may become another weapon in the fight against lupus,” Lenert said(ref).”
- Finally, the big recent news in the world press was interim success in a Phase III clinical trial of Benlysta, a new drug for lupus created by Human Genome Sciences(ref). “Belimumab is a monoclonal antibody which targets and inhibits the activity of BLyS (B cell lymphocyte stimulator). BLyS is a naturally occurring protein which is normally involved in the survival of antibody producing B cells. When present in excess it can lead to the development of autoimmune diseases like lupus(ref).” The drug may not turn out to be a blockbuster for lupus, but the announcement tripled the price of HGSI stock(ref). That says something about the world’s hunger for an effective new treatment for SLE.
This has been a sampling of what is known about SLE and some emerging treatments for it. The next post in this series will look more deeply at SLE and inflammation, and the relationship of SLE to lymphomas. It is Summer and I am on a slowed-down work schedule so this next post may be a few days in coming.
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