This is a guest post written by Dr. Christine Konya, a fellow in Rheumatology at Beth Israel Deaconess Medical Center. She studies T cells in lupus.
Anyone interested in rheumatology or immunology will stumble on the findings by Paul Ehrlich, a scientist who helped to establish the field of immunology 100 years ago. He received the Nobel Prize in 1908 for his work. He is known for creating the “side-chain theory” of cells. He proposed that cells, when in danger, are able to express a variety of “side-chains” on their surfaces (now called “receptors”), which bind pathogens. He further noted that when these “side-chains” break off, they work as “magic bullets” (now called “antibodies”) which circulate through the body and bind toxins. Wasn’t he right? He was also the first to think about autoimmunity. He also discovered arsphenamie (Salvarsan), a compound to treat syphilis.
“The organism possesses certain means, of which the immunity reaction is prevented from acting against the organism’s own elements and so giving rise to auto toxins … so that one might be justified in speaking of a ‘horror autotoxicus’ of the organism. These contrivances are naturally of the highest importance for the existence of the individual.” –Paul Ehrlich [1].
With “horror autotoxicus,” Dr. Ehrlich described the body’s fear of self-destruction. This is why our immune system has several control mechanisms to kill self-reactive T and B cells by inducing apoptosis. However, despite these complex mechanisms, autoimmunity does develop. Tolerance can be broken, and failure of these control mechanisms can lead to disease. One of the most dramatic manifestations of autoimmunity is seen in systemic lupus erythematosus.
The chief of our rheumatology division recently sent me an interesting article from Annals of Internal Medicine, published in 1952. The article describes five young women, seen at the Cleveland Clinic in the 1940s, in whom false positive serologic test for syphilis was observed, without any signs of infection. After several years, these patients developed lupus.
“A 25 year old woman who was first seen at the Cleveland Clinic July 6, 1943, because of a history of positive serologic test for syphilis since 1941… from 1942 until 1943 she received 14 injections of bismuth and 27 injections of neoarsphenamine…General health remained good until 1946, when the patient developed a persistent cough. A roentgenogram of the chest was interpreted as chronic bronchitis. Wassermann reaction was 2 plus. A persistently low hemoglobin was noted which did not respond to iron therapy. The patient became weaker, noticed fever and abdominal cramping and developed icterus…Urine analysis revealed 3 plus albuminuria and microscopic hematuria. She was discharged and died at home one month later with pericarditis and pleural effusion.” [2]
At that time, testing for syphilis was performed with the “Wassermann test,” an older version of the VDRL. Patients with syphilis develop an antibody called reagin [3]. Reagin binds cardiolipin, a phospholipid found on the inner mitochondrial membrane of cells. Similarly, lupus patients can also develop anticadiolipin antibodies, and as a result, many were misdiagnosed.
Despite lingering evidence, the link between the false-positive syphilis test, the presence of anticardiolipin antibodies, and their correlation with lupus was not described until the 1980s, when Graham Hughes published his research on anticardiolipin antibodies and correlated them with increased incidence of thrombosis. We now know that the anticardiolipin antibodies in lupus are similar, but not identical, to the ones seen in syphilis. They can be easily distinguished with a modern ELISA test.
The five women described in the article had a severe form of lupus and antiphospholipid syndrome, but were misdiagnosed as having syphilis. In these women, the false-positive syphilis testing was found when they attempted to donate blood or with routine blood testing prior to marriage. I cannot imagine the impact that this test must have had on their lives. One of the women postponed her wedding due to the positive test and became severely depressed.
Fortunately, our knowledge has progressed, and our ability to diagnose and treat lupus has significantly improved. We now realize that autoantibodies in autoimmune diseases, such as the anticardiolipin antibodies described above, are formed years before the onset of clinical symptoms.
My thoughts drifted back to Paul Ehrlich, and I ask myself what he would say about our current understanding of immunology, lupus, and autoimmunity, all of which is based on his visions. What would he think about monoclonal antibodies, our “magic bullets” which we use for the treatment of many diseases?
I am certain that he would be very content with our advances in diagnosis and treatment of these diseases. For the future, I found this quote inspiring and worth aiming for:
“I see a world where no one ever dies from an adverse drug reaction; where physicians have an entire range of medicines to choose from to treat a deadly disease; where medications target tumors like smart bombs and leave surrounding tissues unharmed; where genetic susceptibility to disease can be determined in childhood, and possibly even prevented” Tim Downs, in his book Chop Shop.
Christine Konya, MD
Fellow in Rheumatology
Beth Israel Deaconess Medical Center
Follow me on Twitter @RheumatologyMD
References:
1. The Collected Papers of Paul Ehrlich. Yale J Biol Med. Jun 1957; 29(6): 628. PMCID: PMC2603738.
2. Systemic Lupus Erythematosus preceded by false-positive serologic tests for syphilis: Presentation of five cases. John R. Haserick and Roland Long, Ann Intern Med. 1952;37(3):559-565. doi:10.7326/0003-4819-37-3-559
3. The 100th anniversary of Wassermann-Neisser-Bruck reaction. Bialynicki-Birula. Clin Dermatol.2008 Jan-Feb;26(1):79-88. doi: 10.1016/j.clindermatol.2007.09.020.
