Incontinentia Pigmenti, a rare skin disease that also predisposes to viral infections

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Incontinentia pigmenti (IP) is a rare genetic disorder, found almost exclusively in women. It is characterised by skin disorders starting in childhood, sometimes associated with neurological and ocular disorders. This disease has now been identified as a risk factor in the development of some life-threatening viral infections. In a cohort of 131 patients with IP, the laboratory of Human Genetics of Infectious Diseases recently analysed the frequency of autoantibodies neutralising type I interferons (IFN-I), the presence of which is already known to be responsible for an increased risk of life-threatening infections to influenza, SARS-CoV-2, tick-borne encephalitis, West Nile virus and yellow fever vaccine.
This work, made possible thanks in particular thanks to the support and participation of the IP France Association and the Filière Santé Maladies Rares Dermatologiques (FIMARAD), has also shown that the thymus, one of the key organs of the immune system, is affected in IP.

First reported in 1981 in a patient with severe chickenpox, IFN-I neutralizing autoantibodies have subsequently been identified in a wide variety of patients. The Human Genetics of Infectious Diseases laboratory at Institut Imagine (Inserm, AP-HP, Université Paris Cité), co-directed by Prof Jean-Laurent Casanova and Dr Laurent Abel, has shown that they are present in around 1% of the general population, with a significant increase after the age of 65 years old. For a long time, these autoantibodies were considered to be clinically silent, particularly in terms of susceptibility to viral infections. However, this perception has changed in recent years, when the team, along with other laboratories worldwide, discovered that these autoantibodies were responsible for around 15% of cases of severe pneumonia linked to SARS-CoV-2 (COVID-19), 20% of deaths from COVID-19, 25% of severe forms of COVID-19 in patients fully vaccinated against SARS-CoV-2, 25% of hospital admissions due to Middle East Respiratory Syndrome (MERS), around 5% of cases of potentially fatal influenza pneumonia, 35% of cases of serious adverse reactions following vaccination with live attenuated yellow fever vaccine, 40% of cases of encephalitis caused by West Nile virus, and 10% of cases of tick-borne encephalitis.

Among the first patients described with IFN-I neutralising autoantibodies and severe forms of COVID-19 in the first wave in 2020 was a woman with IP. IP is a rare genetic disease (1 case/10,000 - 100,000), identified almost exclusively in women, caused by loss-of-function genetic variants in the IKBKG/NEMO gene. The genetic defects was identified in 2000 by a consortium lead by a team located in the Hôpital Necker-Enfants malades. In female with IP, the disease is manifested by abnormalities of tissues derived from the ectoderm, such as the skin, eyes, teeth, hair, breasts, nails and central nervous system (CNS). Severe forms of the disease are associated with vascular lesions leading to ophthalmological and neurological complications, most often occurring in early childhood. In general, in the absence of neurological or ophthalmological sequelae, adult women with IP are in good health.

In a study recently published in Journal of Experimental Medicine, the laboratory of human genetics of infectious disease at Institut Imagine studied a cohort of 131 female IP patients from 10 different countries to assess the frequency and levels of IFN-I neutralising autoantibodies in these patients. The authors found that these autoantibodies were present in 40% of the women in the cohort, a much higher frequency than that observed in the general population.

To date, all the genetic diseases in which these autoantibodies have been found have in common an abnormality of an organ, the thymus, which is involved in educating immune cells to tolerate the self. The authors therefore analysed the thymuses of patients with these autoantibodies using magnetic resonance imaging: the IP patients had thymuses smaller than those of the control population, and the structure of the IP thymuses suggested premature senescence, although the levels of residual T lymphocyte production remained normal. These results were confirmed by the observation of thymuses from mouse models of PI, showing the same alterations in size and structure.

It therefore appears that in patients with IP, the skin, the eye and also the thymus are organs affected by the disease. In the case of the thymus, premature senescence of the organ favours the production of anti-IFN-I autoantibodies. These results establish a link between IP and increased susceptibility to certain viruses. It is therefore recommended that patients with IP should be vaccinated, in particular with the annual influenza vaccine and the anti-COVID-19 vaccine. More generally, this work highlights the importance of identifying the genetic, biological and physiological factors that could influence individual susceptibility to infection.

 

 

Reference :

Incontinentia pigmenti underlies thymic dysplasia, autoantibodies to type I IFNs, and viral diseases

J Rosain et al., JExp Med, 2024

doi: 10.1084/jem.20231152

 

Corresponding authors :

Jérémie Rosain

Jean-Laurent Casanova