Unravelling the secrets of cancer points the way to understanding the secrets of lupus, and vice versa. Here’s what recent research has discovered.
By Dona Suri
Lupus is not a common disease; it affects only 0.44 percent of America’s approximately 332 million people. It’s not surprising that only a few people have ever heard its name, and fewer yet know anything about the disease or its symptoms. Unless you are one of the few people who have it or are likely to get it, why should you want to know about it?
Cancer will kill about 6 million Americans this year; it is Number Two (after heart disease) in the cause-of-death list. If there were some astonishing advance in cancer treatment, you would definitely want to know about it.
There is a reason we are mentioning cancer.
Day by day, medical researchers are finding out more and more about the way cancer works and what cellular processes have to be targeted to halt its progression. Similarly, day by day, researchers are finding out more and more about the way lupus works. Guess what ! When you get way down to the cellular level, unravelling the secrets of cancer points the way to understanding the secrets of lupus, and vice versa.
But let’s start at the beginning. You know what cancer is, now learn something about lupus.
When your body’s immune system attacks your own tissues and organs, you have an autoimmune disease. Lupus is one such autoimmune condition.
It’s a disease that even doctors have trouble recognizing. Typically, a person experiences symptoms and goes to a doctor who prescribes something, but then the symptoms continue so another doctor is consulted and then another and another. On average, it takes nearly six years for people with lupus to be diagnosed, from the time they first notice their symptoms. It’s not entirely the doctors’ fault. Lupus symptoms come and go, the symptoms change, or appear to be symptoms of some other condition. Even a blood test can be inconclusive. The best bet for figuring out if you’ve got lupus or something else is to see a doctor specializing in rheumatology.
[ A rheumatologist deals with ailments whose common feature is inflammation in the bones, muscles, joints, and internal organs. This includes musclo-skeletal and autoimmune conditions.]
Lupus is painful and it saps its victims of energy. It causes inflammation anywhere in the body: joints, skin, kidneys, blood cells, brain, heart and lungs. At present, lupus can be managed but not cured.
If it is not diagnosed, not treated, not managed, it causes lots of serious trouble. But… few people die from lupus. They die from lupus complications. These include:
- Kidney failure is the leading cause of death among people with lupus.
- Brain and central nervous system damage happens when lupus attacks the brain. It starts out with memory problems and difficulty expressing thoughts, shows up in headaches, dizziness, behavior changes, vision problems. And then come potentially fatal seizures and strokes.
- Anemia (deficiency of healthy red blood cells) is a common complication of lupus. Sufferers have increased risk of both bleeding and blood clots and their blood vessels can become inflamed.
- Lupus inflames the lining of the chest cavity lining with the result that breathing becomes painful. The next stage is bleeding into lungs. Pneumonia is another outcome.
- Cardiovascular disease and heart attacks are associated with lupus. It causes inflammation of the heart muscle, arteries and heart membrane.
Can lupus sufferers reach a ripe old age?
Yes, IF they are diagnosed and treated. Fortunately, diagnostic methods are improving and medical research has zeroed in on effective ways to manage the condition.
Doctors are not yet entirely sure what causes lupus. Environmental, genetic, and hormonal factors … all seem to be involved. Overwhelmingly, it is a woman’s disease. Ninety percent of people living with lupus are women. It strikes them during the childbearing years (between the ages of 15 and 45). Of these lupus patients, about a third of them will have other autoimmune diseases in addition to lupus.
To date, there have been no nationwide database examinations of the socio-demographics of adult systemic lupus prevalence or incidence. That leaves us in the dark about exact figures about who is most likely to suffer. Based on data from smaller studies the picture that emerges shows systemic lupus in terms of ethnicity in this order (most susceptible to least susceptible):
Native American
Black
Asian and Pacific Islander
Hispanic
White
Curiously, Hispanic and Asian patients have the lowest annual death rates.
The rate is highest among Native Americans, Blacks, and Whites, in that order.
You notice we are referring to systemic lupus. Lupus takes four different forms:
- Systemic lupus: Accounts for approximately 70 percent of all cases. It’s called “systemic” because it attacks some major “system” – an organ or tissue of the body – heart, lungs, kidneys, or brain.
- Cutaneous lupus: Accounts for approximately 10 percent of all cases. It affects the skin
- Drug-induced lupus: Accounts for approximately 10 percent of all cases. It is caused by high doses of certain medications. Symptoms are similar to systemic lupus but it goes away when the medications are discontinued.
- Neonatal lupus: Rare condition and temporary, disappearing completely after six months with no lasting effects. At birth, the baby may have a skin rash, liver problems, or low blood cell counts because the fetus has reacted to the mother’s antibodies.
Genes have something to do with who gets lupus and how severely they are affected. About 20 percent of people with lupus will have a parent or sibling who already has lupus. About 5 percent of children born to mothers with lupus will develop the illness. One of three patients have another autoimmune disease in addition to lupus, and almost half have a relative with lupus.
But people with no family history of lupus can get it too.
The risk of developing lupus increases when certain environmental factors are added to genetic predisposition. The main environmental factor is exposure to strong sunlight. Having an infection can initiate lupus or cause a relapse in some people. We have already mentioned drug-induced lupus. The medications involved are antibiotics, anti-seizure medications and drugs that control blood pressure.
In terms of what is going on in the body, systemic lupus clearly involves B cells (a type of white blood cell that makes infection-fighting proteins called antibodies) and B lymphocyte stimulator (BLyS). These two components are responsible for mediating normal immunity and auto-antibody production.
Systemic lupus is mainly treated with drugs that inhibit the activity of the immune system. Hydroxychloroquine and corticosteroids (e.g. prednisone) are often used. In 2011 the FDA approved belimumab. This drug binds with BLyS so that it cannot interact with its three receptors and indirectly decreases B-cell survival and production of auto-antibodies. The National Institutes of Health monitored the results of six months of treatment with belimumab and announced that eight out of ten of patients showed a 20 percent improvement in overall disease activity and four out of ten patients improved at least 50 percent.
You’ve heard of T cells and B cells? Both are lymphocytes, a type of white blood cell.
T cells start in the bone marrow but migrate to the thymus to be ripened and trained. Their job is to activate cell-mediated immunity. There are several types of T cells; The most common and well-known Ts are the CD4+ Ts, also known as Helper Ts and the CD8+ Ts, also known as Cytotoxic Ts, or Killer Ts.
B cells also start out in the bone marrow but they migrate to the spleen where they mature and become different kinds of specialized Bs. Following their release into the blood and lymph, they patrol the body looking for antigens. An antigen is a trouble-maker protein. When a fresher B cell finds an antigen it divides into two different kinds of B: a memory B and an effector B.
Using the B Cell Receptors on their surface, the effector Bs grab the antigen cells. Then they produce antibodies that neutralize the antigen and prevent it from harming the body. B cells are committed to wiping out antigens down to the last enemy cell no matter how long it takes – days, weeks, months. Meanwhile, the memory Bs are doing a different job. These remember the enemy antigen forever so that if it ever shows up again there will be no time lost in putting it down.
B cells deal in humoural immunity, meaning that they protect against infection through antibodies.
T cells deal in cell-mediated immunity.
They attack antigens with cytokines and then eat them up with macrophages (large, specialized cells that recognize, engulf and destroy target cells.)
The goal of both the Army and the Marines is to protect the nation from enemies, but they do it in different ways. We need both of them. Think of your T cells and B cells as the Army and the Marines.
This background is important for understanding research advances that are resulting in new lines of treatment for both lupus and certain cancers.
Let’s start in the Jackson Laboratory, tucked away in scenic Bar Harbor, Maine. In a quiet corner, Dr Chih-Hao “Lucas” Chang is piecing together the precise ways in which the immune system and metabolism interact … how they interact when they are healthy and how they interact when something is wrong. He has pinpointed where immunology and metabolism overlap and where the mechanisms of cancer mesh with the mechanisms of auto-immune diseases such as lupus.
Specifically, he is mapping out the metabolic pathway that converts glucose into pyruvate (a 3 carbon sugar) formed during the first stage of respiration (glycolysis). This pyruvate powers the biochemical process called the Krebs Cycle (Step 2 in cellular aerobic respiration) in which nutrients are broken down to produce energy (stored in the form of ATP) and release waste products.
Thanks to his research, it is now known how glycolysis influences cytokines. (Remember those Killer Ts mentioned earlier?)
He’s also on to what’s going on with the B cells. It all comes down to how the body processes glucose, along with how the immune cells utilize glucose after it’s broken down. At cellular level, glycolysis involves specific subsets of B cells (Remember them? The ones that produce antibodies.)
In the case of lupus, B cells are highly sensitive. This is where metabolic dysfunction is localized. When glucose metabolism is inhibited in lupus-causing cells, the lupus symptoms go away and organs and tissues start behaving normally again.
Chang has cracked the riddle of how lupus-related cells act differently from normal immune cells. This opens the door to new therapies that target only the problematic immune cells. Ultimately, he believes that he will be able to repurpose existing cancer-fighting drugs to treat lupus.
Chang is not the only knowledge-warrior out there on the front line.
At the University of Erlangen-Nürnberg, in Germany, immunologist Dr Georg Schett is tackling the lupus problem from another angle. He isolates T cells from a patient’s blood, genetically modifies them, then puts the engineered cells back into the patient.
Oh! But that’s old hat! The treatment was developed more than a decade ago to treat certain leukemias and lymphomas. The modified T cells target B cells that have turned cancerous. It’s called CAR-T therapy.
Well, right you are, but …
When B cells mess up in one way, it’s cancer; when they mess up in a different way, it’s lupus. Dr Schett has tweaked the process so that it works on lupus. Before he worked it out, doctors were apprehensive that using modified Killer Ts against an auto-immune disease, would make the condition worse.
Here’s what Dr Schett did:
He took six lupus patients. Before giving them the modified T cells, he gave them chemotherapy. This wiped out their immune cells, thereby giving the transplanted cells more room to multiply and preventing preexisting immune cells from extinguishing them. Then he injected the modified T cells. In the months that followed, new B cells were gradually born but these B cells didn’t behave like the previous ones. They were NOT attacking the body’s own tissues. No lupus.
If the body were a computer, you might say that Dr Schett’s treatment successfully achieved “restore to default settings”.
Medical researchers do not normally gamble but Dr Schett did … and won. Rather than making the condition worse, the treatment ended the lupus symptoms. Now he’s watching his patients carefully to see if there is any sign of a relapse. The big victory will be permanent cure because the treatment is too costly and too risky for a patient to take more than once.
Dr Schett’s work also shows how understanding of the lupus-B cell relationship inevitably sheds light on the cancer-B cell relationship.
Cancer treatment involves supporting immune cells capable of fighting cancer by activating them through immunotherapies, while also targeting the hijacked immune cells that cancer uses to shield itself from antibodies and cytokines.
Auto-immune disease treatment involves reducing immune cell responses … but this leaves patients vulnerable to infection and cancer.
The problem is to get at just those cells that are dysfunctional while sparing the ones that are working the way they are supposed to.
Thanks to researchers like Chang and Schett, medical science is getting closer and closer to solving that problem – which means that the door opens to therapies that effectively tackle both cancer and auto-immune diseases like lupus.