Day after day, the human immune system has to work hard. It protects – most of the time successfully – against viral and bacterial intruders. But if this process gets out of control, the body attacks its own tissue and destroys it. One of those autoimmune diseases is the systemic lupus erythematodes (SLE), just in Germany we are talking about an estimated 40,000 patients.
Familiar and yet so strange
Until today, physicians cannot explain where the disease comes from. In addition to genetic factors, environmental influences like UV-radiation or infections with viruses are taken into consideration as potential causes. They lead to a controlled cell death, i. e. apoptosis, and thus to the release of genetic material and proteins. Prof. Dr. Veit Hornung at the Bonn University explains: “Free DNA in the cytoplasma of a cell most of the times origins from pathogens, i. e. bacteria“. His working group has discovered a molecular switch functioning as an alarm system in the body. Once it’s activated by free genetic molecules, messenger substances like interleukins attract the body-own defense troops – the cells of the immune system. Hornung thinks it is possible that SLE can be triggered due to a misdirection of this switch – the immune system interprets body owned components as threatening and starts fighting them. If we could influence hyperactive regulators targeted, we would be able to contain the wrong positive reaction.
Dying cells also release nucleosomes, i. e. DNA-protein-packages. There and then, the molecule HMGB1 attaches itself and activates the immune system. Not really a surprise: Here as well, we observe the release of messenger substances, particularly cytokines, and the inflammation blazes up – thus the discovery of a working group at the University of Erlangen-Nürnberg around PD Dr. Reinhard Voll.
Researchers at the Wilhelms-University Münster/Germany got wise to another molecular-biological mechanism. They discovered a connection between calcium-binding proteins and T-cells, i. e. important species of the immune system. In SLE-patients, the body produces these special proteins abundantly. When they dock to binding sites of the T-cells, the body-own messenger substance interleukin-17 is being produced and the destruction of the tissue gets started.
Caught in the net
It’s long known that lupus erythematodes might end deadly due to a failure of the kidneys. Researchers at the Max Planck-Institute for infection biology and the Erlangen University now discovered how it happens: leukocytes send out a net during an infection phase to catch pathogens and finally inactivate them. If the infection has been fought against successfully, the enzyme DNase-1 sees to a fast removal of the structures. But not in SLE-patients: They are missing the enzyme or it is blocked. Eventually body-own antibodies connect to the net and the resulting complexes deposit in the tissue. Medium-term, the kidneys quit their job.
Discrimination of women
Prof. Dr. Oliver Werz, University of Tübingen, and his team focused on the question, why SLE and other autoimmune diseases occur nine times more in women than in men. The researchers got on the track of leukotrienes, small molecules with several double bonds built in leukocytes. The crucial point: An enzyme essential for synthesis is distributed differently between the genders. The researcher group from Tübingen was able to prove that the effect of an activation of signal pathways completely different is based on male sexual hormones.
Sledgehammer – or selective therapy?
Lupus erythematodes has many faces – symptoms range from photosensitivity and skin rashes to joint- and muscle pains all the way to fever and chronic fatigue. The disease gets really dangerous mainly due to a potential multi-organ-failure: Once the inflammation gets to the heart, the lungs, the kidneys or the brain, it’s high time to intervene. The problem here: SLE often shows episodic symptoms. After a phase of disease, the patient feels better but not as good as prior to the phase. Solely this continuous exacerbation makes a therapeutic intervention extremely important.
Here the treatment complies with the severity level of the inflammation. In mild cases, non-steroidal antirheumatics (NSAR) are applied. In cases of a more severe autoimmune disease physicians apply immunosuppressive drugs, often in a combination with cortisone. However, those drugs have a significant disadvantage: They suppress the body-own immune response regardless of the consequences. Researchers at the University Hospital in Tübingen made a great step forward, their finding: The key enzyme with the cryptic name PI3K-gamma with its various sub-units is capable of controlling completely different processes in leukocytes. Now it’s the target to find active substances inhibiting an exuberant reaction of the immune system without a complete suppression of the immune response against intruders.
The return of the classic
Hardly any other drug has such a varied history as Thalidomid (Contergan ®). Due to its teratogenis effect once fallen into contempt, researcher have been able to prove a therapeutic potential in cases of multiple myeloma during the past few years. But studies also showed an anti-inflammatory effect helpful against autoimmune diseases. The reliable conception control prior to and during the treatment is mandatory.
Good antibodies, bad antibodies
Once a protein has no more business in a cell, for example if it’s damaged, the proteasome has its big appearance: A molecular shredder shredding proteins into small reusable pieces. The inhibitor bortezomib can stop this process, as scientists at the University of Erlangen-Nürnberg discovered. Originally applied for multiple myeloma, bortezomib provides valuable services in cases of SLE: This molecular clamp turns off the tab especially for the protein-hungry but otherwise therapeutically hard to reach plasma cells. Once the supplies of basic material are missing, they stop producing antibodies. At least in animal experiments, the number of antibodies as well as the protein concentration in urine is decreased. And the durable plasma cells, otherwise hardly open to any therapy, were completely eliminated.
A human, monoclonal antibody caused a stir in the run up of its approval. The two companies Human Genome Sciences and GlaxoSmithKline have applied for approval of a therapeutic agent named Belimumab (Benlysta ®) against SLE. Belimumab inhibits the genesis of a protein responsible for the maturing processes of immune cells. In the end, this creates less aggressive antibodies possibly turning against the own body. The researchers achieved positive results in two clinical studies phase III with a total of 1,684 SLE-patients.
Now it’s supposed to progress fast: The Food and Drug Administration (FDA) approved for Belimumab the so-called ”priority review designation“. Experts consider the reasons for this accelerated process mainly in the essential progress for treatment of SLE as well as the currently missing of alternative adequate therapies. Approval was applied for with the European Medication Agency (EMA). The decision of the FDA is expected as early as December 9, 2010.