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While genetic errors are more common in younger patients, autoantibodies against type I interferons appear mainly in older patients.
Vall d'Hebron has participated in an international research that points to new genetic and immunological defects as a cause of severe or critical COVID-19. The study, led by The Rockefeller University in New York and the Necker-Enfants Malades Hospital in Paris, has counted with the participation of the Vall d'Hebron University Hospital and the Vall d'Hebron Institute of Research (VHIR) and has resulted in two publications in the journal Science Immunology. The two studies focus on the role of the TLR7 gene and autoantibodies against type I interferons.
TLR7 gene mutations and the risk of severe COVID-19 in young people
The first of the studies establishes that patients with mutations or deficiencies in the TLR7 gene are more likely to be diagnosed with severe or critical COVID-19, especially in men under 60 years of age. TLR7 is an immune system gene that contributes to the production of type I interferons (IFN-I), which are key to building an essential immune response against SARS-CoV-2. Thus, defects in TLR7 increase the likelihood of a serious diagnosis. "We have seen that these genetic errors appear mainly in younger patients, under 60 years old", says Dr. Pere Soler-Palacín, head of the Paediatric Infectious Diseases and Immunodeficiencies Unit at Vall d'Hebron University Hospital and of the Research Group on Infection in Immunocompromised Paediatric Patients at VHIR.
On the other hand, TLR7 is a gene located on the X chromosome and therefore plays a role in males and only occasionally in females. This may help to explain the poorer prognosis of COVID-19 in men compared to women. In the case of females, people have two X chromosomes and therefore the risk of having complications from this cause is lower.
Of the 1,202 people studied during the research, 20 of the patients between the ages of 7 and 71 were deficient in TLR7. Also, these individuals had no previous diagnoses or serious illnesses. Furthermore, none of the asymptomatic or mildly ill patients were affected.
The presence of autoantibodies against type I interferons and the risk of COVID-19 in older people
Since the beginning of the pandemic, age has been shown to be the main risk factor for COVID-19. In particular, the risk of hospitalisation and death from pneumonia doubles every 5 years. The second of the papers presented here confirms that this increased risk is explained, at least in part, by the presence of autoantibodies against type I IFN or, in other words, by the development of an autoimmune response against one's own type I interferons. This study has attempted to demonstrate the neutralising capacity of these autoantibodies against concentrations similar to those circulating in the human body, in contrast to previous studies.
The results show that, overall, 13.6% of patients with COVID-19 have these kind of autoantibodies. The percentage rises to 20% in patients older than 80 years with this condition. "These autoantibodies may explain the increased risk for severe COVID-19 and we show that they do so especially in the elderly", explains Dr. Roger Colobran, head of the Diagnostic Immunology Research Group at VHIR.
It should be noted that these autoantibodies are a cause and not a consequence of SARS-CoV-2 infection, and that they are also found in the general population and increase with age. In those under 70 years of age, between 0.17 and 1.1% of individuals have autoantibodies and, in those over 70 years of age, they are found in between 1.4% and 4.4%. Between 80 and 85 years of age, an increase of up to 4.2 to 7.1 per cent is observed. "With age, the immune system ages: this is known as immunosenescence. This makes it more likely that autoimmunity phenomena like this one will appear", says Dr. Soler.
For this analysis, the researchers studied blood samples from 3,595 patients hospitalised with critical COVID-19, 623 critically ill patients, 1,639 patients with mild or asymptomatic infection and 34,159 healthy individuals to study whether they had this type of autoantibody.
The authors of the study stress the importance of understanding the factors that influence the response to SARS-CoV-2 and hope that it will open the door to targeted therapies based on each patient's profile.
COVID Human Genetic Effort: a consortium for COVID-19 research
The COVID Human Genetic Effort (COVIDHGE) is an international consortium led by The Rockefeller University in New York and Necker-Enfants Malades Hospital in Paris that includes hundreds of hospitals worldwide and participants of various nationalities from Asia, Europe, Latin America and the Middle East. COVIDHGE is working to find new genetic variants that influence the immune response to COVID-19.
From VHIR, the studies published in Science Immunology have been led by the Infection in Immunocompromised Paediatric Patients and Diagnostic Immunology research groups, with the participation of the Shock, Organ Dysfunction and Resuscitation (SODIR) research group of VHIR and the Intensive Care Medicine Service of Vall d'Hebron University Hospital.
At the national level, the Bellvitge Biomedical Research Institute (IDIBELL), the August Pi i Sunyer Biomedical Research Institute (IDIBAPS), the Biomedical Research Institute of Barcelona-CSIC, the Sant Joan de Déu Research Institute, the IrsiCaixa, the Germans Trias i Pujol Research Institute (IGTP), the University of Vic-Central University of Catalonia (UVic-UCC), the MútuaTerrassa University Hospital, the National Centre for Genomic Analysis (CNAG-CRG), Infanta Leonor University Hospital (Madrid), Gran Canaria Doctor Negrín University Hospital (Las Palmas), Institute of Health Carlos III, Center for Biomedical Research of La Rioja, Donostia University Hospital, Fernando Pessoa-Canarias University, Research Institute Hospital 12 de Octubre, Complutense University of Madrid, Institute of Technology and Renewable Energies (ITER), Ntra. Sra. de Candelaria University Hospital (Santa Cruz de Tenerife), University Institute of Biomedical Technologies (Canary Islands) and the Hospital La Paz Institute for Health Research.
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