Jehane Fadlallah1, Delphine Sterlin2, Claire Fieschi3, Christophe Parizot2, Karim Dorgham2, Hela El Kafsi2, Gaëlle Autaa2, Pascale Ghillani-Dalbin2, Catherine Juste4, Patricia Lepage4, Marion Malphettes3, Lionel Galicier3, David Boutboul3, Karine Clément5, Sébastien André6, Florian Marquet6, Christophe Tresallet7, Alexis Mathian2, Makoto Miyara2, Eric Oksenhendler3, Zahir Amoura2, Hans Yssel2, Martin Larsen8, Guy Gorochov9. 1. Sorbonne Université, INSERM, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Assistance Publique-Hôpitaux de Paris (AP-HP), Groupement Hospitalier Pitié-Salpêtrière, Département d'Immunologie, Paris, France; Université Paris Diderot Paris 7, Department of Clinical Immunology, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris (APHP), Paris, France. 2. Sorbonne Université, INSERM, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Assistance Publique-Hôpitaux de Paris (AP-HP), Groupement Hospitalier Pitié-Salpêtrière, Département d'Immunologie, Paris, France. 3. Université Paris Diderot Paris 7, Department of Clinical Immunology, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris (APHP), Paris, France. 4. Micalis Institute, INRA, AgroParisTech, Universite Paris-Saclay, 78350 Jouy-en-Josas, Paris, France. 5. Sorbonne Universite, INSERM, UMRS1166, NutriOmics team, ICAN, Paris, France; Assistance Publique Hôpitaux de Paris, Nutrition department, Pitié-Salpêtrière Hospital, Paris, France. 6. Sorbonne Universite, INSERM, UMRS1166, NutriOmics team, ICAN, Paris, France. 7. Department of Surgery, Assistance Publique Hôpitaux de Paris, Pitiè-Salpêtrière Hospital, Paris, France. 8. Sorbonne Université, INSERM, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Assistance Publique-Hôpitaux de Paris (AP-HP), Groupement Hospitalier Pitié-Salpêtrière, Département d'Immunologie, Paris, France. Electronic address: Martin.Larsen@sorbonne-universite.fr. 9. Sorbonne Université, INSERM, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Assistance Publique-Hôpitaux de Paris (AP-HP), Groupement Hospitalier Pitié-Salpêtrière, Département d'Immunologie, Paris, France. Electronic address: Guy.Gorochov@sorbonne-universite.fr.
Abstract
BACKGROUND: Commensals induce local IgA responses essential to the induction of tolerance to gut microbiota, but it remains unclear whether antimicrobiota responses remain confined to the gut. OBJECTIVE: The aim of this study was to investigate systemic and intestinal responses against the whole microbiota under homeostatic conditions and in the absence of IgA. METHODS: We analyzed blood and feces from healthy donors, patients with selective IgA deficiency (SIgAd), and patients with common variable immunodeficiency (CVID). Immunoglobulin-coated bacterial repertoires were analyzed by using combined bacterial fluorescence-activated cell sorting and 16S rRNA sequencing. Bacterial lysates were probed by using Western blot analysis with healthy donor sera. RESULTS: Although absent from the healthy gut, serum antimicrobiota IgG are present in healthy subjects and increased in patients with SIgAd. IgG converges with nonoverlapping secretory IgA specificities to target the same bacteria. Each individual subject targets a diverse microbiota repertoire with a proportion that correlates inversely with systemic inflammation. Finally, intravenous immunoglobulin preparations target CVID gut microbiota much less efficiently than healthy microbiota. CONCLUSION: Secretory IgA and systemic IgG converge to target gut microbiota at the cellular level. SIgAd-associated inflammation is inversely correlated with systemic anticommensal IgG responses, which might serve as a second line of defense. We speculate that patients with SIgAd could benefit from oral IgA supplementation. Our data also suggest that intravenous immunoglobulin preparations can be supplemented with IgG from IgA-deficient patient pools to offer better protection against gut bacterial translocations in patients with CVID.
BACKGROUND: Commensals induce local IgA responses essential to the induction of tolerance to gut microbiota, but it remains unclear whether antimicrobiota responses remain confined to the gut. OBJECTIVE: The aim of this study was to investigate systemic and intestinal responses against the whole microbiota under homeostatic conditions and in the absence of IgA. METHODS: We analyzed blood and feces from healthy donors, patients with selective IgA deficiency (SIgAd), and patients with common variable immunodeficiency (CVID). Immunoglobulin-coated bacterial repertoires were analyzed by using combined bacterial fluorescence-activated cell sorting and 16S rRNA sequencing. Bacterial lysates were probed by using Western blot analysis with healthy donor sera. RESULTS: Although absent from the healthy gut, serum antimicrobiota IgG are present in healthy subjects and increased in patients with SIgAd. IgG converges with nonoverlapping secretory IgA specificities to target the same bacteria. Each individual subject targets a diverse microbiota repertoire with a proportion that correlates inversely with systemic inflammation. Finally, intravenous immunoglobulin preparations target CVID gut microbiota much less efficiently than healthy microbiota. CONCLUSION: Secretory IgA and systemic IgG converge to target gut microbiota at the cellular level. SIgAd-associated inflammation is inversely correlated with systemic anticommensal IgG responses, which might serve as a second line of defense. We speculate that patients with SIgAd could benefit from oral IgA supplementation. Our data also suggest that intravenous immunoglobulin preparations can be supplemented with IgG from IgA-deficientpatient pools to offer better protection against gut bacterial translocations in patients with CVID.
Authors: Kristýna Fiedorová; Matěj Radvanský; Juraj Bosák; Hana Grombiříková; Eva Němcová; Pavlína Králíčková; Michaela Černochová; Iva Kotásková; Matej Lexa; Jiří Litzman; David Šmajs; Tomáš Freiberger Journal: Front Immunol Date: 2019-08-13 Impact factor: 7.561