on September 5, 2012
A study conducted in close collaboration between the IRB and the Laboratory of Molecular and Cellular Biology at the Istituto Dermopatico dell’Immacolata (IDI), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) in Rome, led to the discovery of the origins of a serious autoimmune disease, the pemphigus. The research just published in the Journal of Clinical Investigation is the work of several researchers led by Professor Antonio Lanzavecchia and Dr Giovanna Zambruno, with the help of German, Dutch and Japanese teams.
Pemphigus is a blistering autoimmune disease mediated by autoantibodies, that is caused by the presence in the blood of patients of antibodies directed against one of their own constituent of the skin, the desmogleins. The desmogleins 1 and 3 are proteins present on the surface of the epithelial cells of the skin and mucous membranes that are needed to maintain the adhesion between the cells themselves. The anti-desmoglein antibodies present in the blood of pemphigus patients reach the skin and mucous membranes where they bind to desmoglein, interfere with cell adhesion and thus leads to the formation of bubbles not only on the whole skin but also in the mouth and in other mucous membranes, such as the nose, the pharynx, the esophagus or genitals. The disease is chronic and so severe that, before the discovery of the treatment with cortisone, it caused the death of the majority of patients. Although the current cortisone- and other immunosuppressant drugs-based therapies can control the disease, these therapies are often harmful especially as they are used for long periods.
The IRB and IDI researchers have isolated different anti-desmogleins antibodies from the blood of pemphigus patients and have found that those which cause the disease are directed against a particular region of the desmogleins. Furthermore, they also found that the desmoglein itself is not at the origin of the production of the autoantibodies, rather those are primarily produced against other antigens, such as virus or a bacteria, and have become autoreactive only in response to the mutations that occur in the process of antibody maturation.
Although more studies are needed, the results obtained by the IRB and IDI researchers are an important step forward for the diagnosis and treatment of this serious disease.
These results also demonstrate the need, for a basic research institute, such as the IRB, of collaborating with clinical research centers, such as the IDI, to understand the pathophysiology of the disease through the study of patients.
These studies were funded in part by the European Community, and in part by the Italian Ministry of Health and the Swiss National Science Foundation.
The study demonstrates how the autoantibodies (in purple) can destroy the net of desmoglein (in grey), which is necessary to maintain the adhesion between the epidermal cells
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The application of a methodology used for the study of infectious diseases permits the isolation of antibodies responsible of an autoimmune disease
Prof. Lanzavecchia and Dr. Zambruno have thought of applying the methodology developed at the IRB, and successfully used to isolate antibodies against infectious agents, to study pemphigus.
Using B lymphocytes obtained from the blood of pemphigus patients collected at the IDI, Dr. Giulia Di Lullo from the IRB has managed to isolate antibodies specific for desmoglein 3. Using techniques of biochemistry, cell biology and disease models, Dr. Di Zenzo and researchers from the IDI have also characterized these antibodies, identifying some pathogens, capable of causing pemphigus.
The origin of the autoantibodies
In the course of the immune response, antibodies undergo a maturation process characterized by a series of mutations in the DNA sequence. Using modern technologies of molecular biology and bioinformatics, Dr. David Corti, together with the IRB and the IDI researchers, was able to simulate a trip back in time to obtain the antibodies produced at the beginning of the development of the immune response which leads to pemphigus. The researchers found that these “original” antibodies do not recognize the desmoglein, and that the subsequent recognition of the desmoglein is caused by mutations that undergo the antibodies while developing an immune response to another antigen, such as to a virus or to a bacteria. In other words the autoantibodies derived from the mutations that appear in the genetic code of antibodies during their maturation. This finding is an important step forward, first, to understand the mechanisms that lead to the production of autoantibodies that are responsible of the autoimmune diseases and then, to identify the most efficient and specialized treatments.
The target of the autoantibodies in pemphigus
The study of the pathogenic antibodies (i.e. the ones that induce the disease) has also allowed us to identify on the desmoglein 3 a specific region to which the antibodies bind. When the IDI researchers have used the blood of a large cohort of pemphigus patients, it has been possible to show that almost all patients have circulating autoantibodies directed against this region of the desmoglein 3. The result obtained is not only important to better understand the mechanism of formation of the bubbles in pemphigus, but also to improve the diagnosis of the disease and to better monitor its pathophysiology, for example searching for the presence of specific pathogenetic antibodies.
