A large part of the population carries human papillomaviruses (HPVs), and in particular cutaneous papillomaviruses, which generally cause warts or local and benign lesions. However, very rare patients in the world develop severe forms of these viral diseases, including “man-tree” syndrome. This very disabling disease is manifested by an uncontrolled outbreak of cutaneous horns for which surgery is not effective. As part of an international collaboration, researchers from Inserm and teacher-researchers from the University of Paris and doctors from the AP-HP grouped together at the Imagine Institute (In serm / University of Paris, AP-HP )located in the Necker-Enfants Malades hospital AP-HP have demonstrated for the first time a genetic cause of this syndrome. This work was carried out by Vivien Béziat, under the supervision of Prof. Jean-Laurent Casanova and Laurent Abel, who run an associated laboratory between Paris and Rockefeller University in New York  . It is the subject of a publication on 1 st July 2021 in the journal Cell.
There are over 200 papillomaviruses (HPVs). Some cause benign skin lesions such as common or plantar warts, others can lead to cervical cancer. The Human Genetics of Infectious Diseases laboratory has focused on cutaneous HPVs, and has been working for several years to understand why a few very rare cases develop a severe form of these infections, which are generally not serious.
Genetic mutation makes skin papillomavirus more susceptible
In a publication in the journal Cell , the team of Vivien Béziat, Inserm researcher in the Human Genetics of Infectious Diseases laboratory studied the genetic characteristics of an Iranian patient suffering from man-tree syndrome, and two members of his family who have a severe form of cutaneous HPV infection with a large number of warts on the hands and feet, but without having developed this syndrome. A common point was found in these three patients: a mutation of the CD28 gene. This normally plays a major role in the activation of T lymphocytes, immune cells which destroy cells infected by a virus.
In these patients, the mutation of the CD28 gene prevents the immune system from recognizing the virus and triggering an appropriate response. The virus then proliferates in the keratinocytes, the cells which constitute the epidermis of the skin, and causes an uncontrolled multiplication of warts and / or cutaneous horns. This is the first time that a genetic cause of the “tree man” syndrome has come to light.
The CD28 gene, central for resistance to certain skin papillomaviruses, but not for the immune system
But by analyzing the CD28 mutation, it is another discovery that was made by these researchers. The CD28 gene, so far considered a mainstay in the functioning of the immune system and the response of T lymphocytes, does not seem to play such a major role. In fact, the three patients studied were exposed in their medical history to several types of HPVs and to a large number of other pathogens. However, they only developed severe reactions to HPV2 for the patient with man-tree syndrome, and to HPV4 for the two members of the family.
“These patients only showed abnormally high sensitivity to certain papillomaviruses of the gamma-HPV and alpha-HPV genus. On the basis of the work carried out over the past thirty years, we believed on the contrary that a dysfunction of the CD28 gene would make patients susceptible to many infectious agents. However, even if their immune response is weakened, patients defend themselves well against other pathogens, ” explains Vivien Béziat, researcher at Inserm and first author of the study.
This discovery therefore brings both new perspectives on the understanding of genetic susceptibility to HPVs, and calls into question the dogmas of immune response by T lymphocytes.
“Today, no treatment has shown efficacy against ‘man-tree’ syndrome. A hematopoietic stem cell transplant to replace the patient’s immune system is considered. This cumbersome and costly treatment is not, however, easily accessible to populations living in less developed countries and who will develop into very severe forms, in particular due to a lack of access to care. By advancing research, the team hopes to accelerate access to treatment for these patients.
 The Human Genetics of Infectious Diseases laboratory is headed by Jean-Laurent Casanova and Laurent Abel is located at the Imagine Institute in Paris and at Rockefeller University in New York. Jean-Laurent Casanova heads genetics and experimental immunology in the two branches (Paris and New York), while Laurent Abel heads genetics and mathematical epidemiology in both branches.
Featured image: Papillomavirus. © Inserm / U190
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