What's New and Important in Lupus Research

Lupus research around the world is increasing, in terms of the number of studies, the quality of the work, and the support it receives, and dramatic advances have been made. Here at the Hospital for Special Surgery (HSS), we recently received an $8 million gift to open the Kirkland Center for basic and clinical research, with a special interest in neurocognitive abnormalities. Finding the cause and cure of lupus will have positive applications for many other autoimmune and inflammatory disorders, even heart disease.

Immunology and Lupus

To understand what goes wrong in lupus, you have to start by understanding how our immune systems function. The immune system is designed to prevent invaders, such as viruses or bacteria, from damaging our bodies. The system has multiple "troops" in our blood with different tasks (such as the Army, the Marines, and Special Forces), and has an armamentarium ranging from bullets to cruise missiles. It is primarily set to prevent infections. If a cold virus invades, for example, you have two to three days of sniffles and a runny nose, but within a few days, you're better because these troops have done their job.

Antigens are what trigger the immune system into action. Antigens are any proteins that the body sees as foreign - the invaders.

Macrophages are cells that eat antigens and present them to T cells. They are the sentinel at the front gates, preventing invaders doing damage by eating them, chopping the antigen into small pieces, and then presenting a part of it to the T lymphocyte.

T lymphocytes are the prime immune movers - the traffic cops. They also have memory, so they know what invader they are dealing with. T lymphocytes decide whether to bring in other battalions. One of the cell types that T lymphocytes often stimulate to action are B lymphocytes.

B lymphocytes are instructed to produce antibodies that attach to the invader.

Antibodies are proteins that battle the invaders. When antibodies lock on to the invading proteins, they destroy them. In lupus, some antibodies also are not friendly to "self" - proteins that are not invaders but rather part of your own body. So while the general job of antibodies is to take out invaders, they also may form antinuclear antibodies that react with the nucleus of your own cells (the part that contains DNA) and damage them.

Complement is another group of proteins in our blood that kills invaders or causes inflammation. It can lead to inflammatory damage when it forms complexes with antinuclear antibodies.

The immune system is always on patrol, keeping us healthy. But, in lupus, the immune system overreacts and forms antibodies against cells in our joints, skin, or other parts of the body. Why does this happen, and what are we doing about it? Here are the clues and research underway.

Genetics - In infectious disease, we know which antibiotics work against which bacteria; we know which weapon to choose based on cultures or blood tests that identify the enemy. We need to develop that same paradigm for lupus, so that we know which therapies will help which patients - and a key factor will be genetics. Some people have hair loss, others arthritis, others skin problems, and others kidney disease. There are probably 10 to 15 genes that interact to cause lupus and to cause the particular, individual type of lupus each person has. We are working on ways to correlate people's individual genetics with their disease - so we can profile them in the same way that we do infectious disease and can prognosticate about a given patient, as well as develop cures based on genetics and other issues.

Immune Abnormalities - In lupus, the T lymphocytes stimulate the B lymphocytes to produce autoantibodies that attack the self. We are looking for ways to suppress the production of those abnormal antibodies without tamping down the rest of the immune system that we need to protect us against and fight infection. Such targeted immune system suppression would not cause many of the infectious risks that currently blanket immune suppression causes

Blood Vessel Problems and Atherosclerosis - The endothelial cells that line blood vessels determine when something in the blood gets out into tissues to fight invaders or cause damage. Thus, they help define whether you get inflammation and atherosclerosis, which occurs earlier in people who have lupus. The major question is why such premature atherosclerosis (and subsequent heart attacks and strokes) hit people with lupus. One hypothesis is that it's due to the same risk factors as everyone else (i.e. elevated cholesterol, diabetes, hypertension). Our hypothesis, now supported by an NIH study here at HSS, is that it's also due to the inflammatory process itself in people with lupus, who have a heightened immune response going on. Proteins called cytokines are involved in the inflammatory process and can irritate endothelial cells and cause atherosclerosis. So, for people with lupus, we try to avoid all the traditional atherosclerosis risk factors (such as smoking, high cholesterol levels, sedentary lifestyle, etc.) as well as reduce the inflammatory process.

Clotting Disorder - A clotting disorder called the antiphospholipid syndrome (APS) can develop all by itself or in association with lupus. It may cause miscarriages or clotting problems leading to heart attacks and strokes. APS is treated with blood thinners (anticoagulants) to help prevent blood clots. Depending on its severity, this may include aspirin, warfarin (brand named Coumadin), and heparin. Jane Salmon, MD, of HSS, presented recent research, at the American College of Rheumatology's 2001 meetings, in which she has been able to halt the pregnancy loss of APS by using a safe medication to block complement. While this was an animal study, she is now developing the first multicenter study of this approach in humans.

Genes: Function and Importance

The nucleus of every cell in our body contains DNA - the information that makes each of us an individual. It is the DNA in our genes that predispose us to particular diseases, such as lupus, but it is our interaction with our environment that yields the final result of who we are. Once we unlock what's going on in the genes to cause lupus, we may be able to alter the negative impact of those harmful genes and stop them from leading to such a self-perpetuating illness. Understanding gene function shows why that's important.

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On the cell surface, a receptor may be triggered by an internal protein or environmental factor. For example, a signal from a virus or a cytokine may tickle the cell, sending a signal from the receptor into DNA in the nucleus. The signal says, "Produce a protein to stop that invader from getting in." In response, the DNA produces messenger RNA, which goes back out into cytoplasm that surrounds the nucleus. That messenger RNA stimulates production of a protein, which is then excreted from the cell and has some activity in the body. That protein could be an enzyme, a cytokine or collagen. That protein can act in a good way or a bad way. For example, it can form a substance that helps you, like an antibody, or a harmful cytokine that causes inflammation. Learning to manipulate the gene can affect the resulting action.

Immune Cell Interactions and New Therapies

As discussed earlier, when a virus or other antigen enters the body, it attaches to the surface of a macrophage (also called an antigen-presenting cell). The antigen is then chopped up and presented to the T lymphocyte. This may stimulate B lymphocytes to produce an autoantibody, as in lupus.

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So the interaction between these cells is a very important and complicated balance. If you wipe out the production of antibodies, you might control the lupus but predispose the patient to infection. We need a careful balance in order to reset this thermostat and turn off lupus but avoid infection risk. How might we do that? There are multiple possibilities.

• Take out the T lymphocytes, but then you may win the battle but lose the war to infection.
• Anti-CD40 ligand - This is an antibody that modifies the reaction between the T and B lymphocyte to reduce overall B lymphocyte activity. The goal is a reduction in autoantibody production. Two companies have been conducting clinical trials in lupus. One was shown to have certain clotting problems, and the other is ongoing. Peggy Crow, MD, the Director of Rheumatology Research at HSS, is very interested in this approach, and studies are underway here with two products.
• BlyS inhibitors - BlyS is a cytokine that stimulates B lymphocytes to produce autoantibodies. We are one of 20 centers in the country studying how to inhibit the action of BlyS.
• Rituximab is a drug used to treat B cell leukemias and lymphomas. It is a monoclonal antibody (an antibody created in a test tube) that destroys B lymphocytes - not all of them, just enough to help control lupus. It has shown promise in early clinical trials with small groups of lupus patients in a few centers, but we need to better evaluate potential side effects. The level of side effects that might be acceptable for short-term treatment of cancer is different from what might be acceptable for long-term treatment of lupus.
• Complement inhibitors - Researchers are seeking ways to block the formation of tissue-damaging immune complexes by complement and autoantibodies. This could help prevent inflammatory damage and pregnancy loss in the APS. Studies in humans are just beginning.
• TNF inhibitors - TNF is another cytokine, although it plays a stronger role in rheumatoid arthritis than other forms of arthritis. Nonetheless, we are evaluating some new TNF-inhibiting drugs, already approved for rheumatoid arthritis, to see how well they might work in sarcoidosis, uveitis, and inflammatory bowel disease. The chemical balance in lupus is different than in those diseases and, thus, these drugs are is not used, presently, in patients with lupus. But studies are underway to determine whether the TNF inhibitors may benefit a particular subset of lupus patients or could give us excellent guidance in the choice of similar types of treatments in lupus.

We are excited about all of these approaches. But the longer term goal, as mentioned earlier, is to understand how each of us is genetically different and which cells and cytokines are activated in lupus in order to target therapy individually. We are profiling people's genes now - determining which genes are turned on and which are turned off in people with lupus. Within four to five years, we hope to find out what genes are involved in inflammation. Eventually, we will all be gene-assessed and be immunized to stop lupus and other serious diseases.

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