Published on 07.04.2022
Research Acceleration
In patients with severe combined immunodeficiency [1], the immune system is deficient and cannot help fight against the multiple microbial attacks coming from our environment. Alain Fischer, a founding member of Institut Imagine located at the Necker-Enfants malades AP-HP hospital, is familiar with these patients, whom he has followed for more than 30 years. "To treat these people, an allogeneic bone marrow transplant [2[ must be performed, sometimes with pre-transplant chemotherapy to avoid rejection of the graft," summarizes the physician and immunologist. This process allows us to cure patients, to restore their immune system, but we had never studied in detail what happens in the nasal mucosa. Indeed, the machinery of the immune response is very complex and involves a large number of actors: the actors of the innate immune response, which act at the level of the mucous membranes of the intestine, the lungs and the nose in particular, and those of the adaptive response, circulating in the blood and lymph.
In order to better understand how the innate immune system was regulated, James Di Santo, head of the Innate Immunity Unit (Institut Pasteur/Inserm), proposed to compare the immune systems of immunocompromised patients after transplantation with those of healthy patients from the Indoor Environment cohort [3]. "We had already collected nasopharyngeal samples from some 1,000 subjects using a simple nasal swab and were able to study the immune response with them," explains the researcher. The idea was to perform the same type of sampling in immunodeficient patients, coupled with a blood test, to observe the differences.
Very quickly, the researchers were able to observe notable differences in some patients. While in healthy subjects and the majority of immunodeficient patients, the entire nasopharyngeal sphere is usually in battle order in the face of aggression, with the formation of protective mucus, the production of large quantities of antibodies (especially IgA) and immune cells, and the maintenance of the microbiota, the nasal mucosa is disrupted in a certain number of patients after transplantation. In fact, in patients with partial immune deficiency and limited pre-transplant chemotherapy, the nasopharyngeal sphere has less mucus, fewer IgA antibodies and cytokines [4] and a predominance of pathogenic bacteria. In other words, these individuals have a less active mucosal immune system in the face of daily pathogen attacks. In addition, their blood work reveals a selective deficiency of certain circulating immune cells.
"It is known that immune cells in the blood produce cytokines that stimulate the production of antibodies, which are responsible for neutralizing pathogenic bacteria. When the immune cells in the blood are absent, a real chain reaction takes place and ultimately leads to an imbalance in the microbiota, which we call dysbiosis," says James Di Santo. For the first time, researchers have been able to observe, in humans, the mechanisms of innate immunity at work in the nasal mucosa. This discovery could also lead doctors to adjust their transplant protocol.
Patients whose ability to produce IgA antibodies is not restored are potentially more vulnerable to respiratory infections. This can be compensated for by antibody replacement therapy, but the results of this new study also suggest that pre-transplant chemotherapy should be used more systematically to allow complete reconstitution of their immunity - Pr Alain Fischer
(1) Not all severe combined immunodeficiencies or SCIDs have the same genetic origin, nor the same immunological profile. SCIDs are very rare diseases: the most common form affects only about one in 200,000 births each year.
(2) Graft from someone else.
(3) Milieu Intérieur (LabeX) Lluis Quintana-Murci - Darragh Duffy - Milieu Intérieur [LabEx] - Research - Institut Pasteur
(4) Soluble messengers that ensure communication between the cells of the immune system.
Source
Defects in mucosal immunity and nasopharyngeal dysbiosis in HSC transplanted SCID patients with IL2RG/JAK3 deficiency, Blood, 14 février 2022
Pedro Goncalves1, Jean-Marc Doisne1, Toshiki Eri1, Bruno Charbit2, Vincent Bondet3, Celine Posseme3, Alba Llibre3, Milieu Intérieur Consortium†, Armanda Casrouge1, Christelle Lenoir4,5, Benedicte Neven4,5,6 Darragh Duffy3, Alain Fischer4,5,6,7 and James P. Di Santo1,*
1Institut Pasteur, Université de Paris, Inserm U1223, Innate Immunity Unit, F-75015, Paris, France
2Institut Pasteur, Université de Paris, Center for Translational Science, F-75015 Paris, France
3Institut Pasteur, Université de Paris, Translational Immunology Unit, F-75015 Paris, France
4Inserm UMR 1163, F-75015 Paris, France.
5Université de Paris Descartes Sorbonne Paris Cité, Imagine Institut, F-75015 Paris, France.
6Department of Pediatric Immunology, Hematology and Rheumatology, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), F-75015 Paris, France.
7Collège de France, F-75231 Paris, France
doi: 10.1182/blood.2021014654.