Antibody (Ab)-mediated opsonization is essential for protective immunity to pneumococcus in humans, as attested by the frequent occurrence of invasive pneumococcal disease (IPD) in patients with B cell immunodeficiencies1,2. We are interested in deciphering the molecular genetic basis of three otherwise distinct primary immunodeficiencies (PIDs) sharing an impaired Ab response to glycans and predisposition to IPD, (i) common variable immunodeficiency (CVID), (ii) specific antibody deficiency (SPAD) and IgG2 deficiency (IgG2D), and (iii) anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). EDA-ID is a rare syndromic PID that manifests in multiple ways, yet underlies IPD and impaired Ab response to glycans in most, if not all patients3,4. Most patients carry mutations in NEMO and NFKBIA, which respectively underlie X-linked recessive (XR) and autosomal dominant (AD) forms5,6. Patients with SPAD/IgG2D display a much more selective impairment of Ab response to glycans, which also leads to IPD7,8. It is rarely caused by mutations in IgG29-12. CVID is more common and heterogeneous, of later onset, and results in a global decrease of IgG levels, underlying impaired Ab response to glycans and IPD among other consequences13-16. It is rarely caused by bi- allelic mutations in ICOS17, TACI18,19, BAFF-R20, CD8121, CD1922, CD2023, or LRBA24-26 or mono-allelic mutations in NFKB227, CTLA428, PIK3CD29,30, NFKB131, or IRF2BP232. We hypothesize that patients with genetically unexplained CVID, SPAD/IgG2D, or EDA-ID may suffer from novel inborn errors of immunity. We thus aim to decipher novel IPD-predisposing single-gene inborn errors of B cell- and Ab-mediated immunity to glycans in patients with these conditions. In the last four years, we discovered AD IKAROS deficiency as a novel genetic etiology of CVID33, and the first inborn errors of the linear ubiquitination complex (LUBAC), with mutations in HOIL1 and HOIP34,35 in patients with amylopectinosis and immunodeficiency (AM-ID), which is related to EDA-ID. To discover new genetic etiologies of these three related B cell deficiencies, we will rely on a unique recruitment of patients (including CVID from team 1), the recent advent of next-generation sequencing (NGS), including whole-exome (WES) and -genome sequencing (WGS), which have been pioneered in the lab for PIDs36-38, and our development of powerful prediction software39-41. The immunological consequences of the mutant alleles will be studied in collaboration with the other PPG teams. Our preliminary data are exciting, as we have identified genetic etiologies of CVID (mutations in LIG1), SPAD/IgG2D (mutations in TIFA), and EDA- ID (the first mutation impacting quantitatively the four transcripts of NEMO). This project will discover new causes of CVID, SPAD/IgG2D, and EDA-ID/AM-ID. The immunological implications of this study are important, as it will shed new light onto the genetic control of human Ab responses to glycans and protective immunity to pneumococcus. The clinical implications are equally important, as our results will improve the management of affected families and facilitate the investigation of the genetic basis of other PIDs.

Public Health Relevance

Patients with IPD, including septicemia or meningitis, often display impaired Ab responses to pneumococcus. This defect can be genetic, but there are only few known underlying PIDs. We intend to decipher novel genetic basis of three related PIDs associated with impaired Ab response to pneumococcus and IPD.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
New York
United States
Zip Code
Casanova, Jean-Laurent; Abel, Laurent (2017) Human genetics of infectious diseases: Unique insights into immunological redundancy. Semin Immunol :
Boisson, Bertrand; Puel, Anne; Picard, Capucine et al. (2017) Human I?B? Gain of Function: a Severe and Syndromic Immunodeficiency. J Clin Immunol 37:397-412
Gernez, Yael; Freeman, Alexandra F; Holland, Steven M et al. (2017) Autosomal Dominant Hyper-IgE Syndrome in the USIDNET Registry. J Allergy Clin Immunol Pract :
Schickel, Jean-Nicolas; Glauzy, Salomé; Ng, Yen-Shing et al. (2017) Self-reactive VH4-34-expressing IgG B cells recognize commensal bacteria. J Exp Med 214:1991-2003
Perkins, Tiffany; Rosenberg, Jacob M; Le Coz, Carole et al. (2017) Smith-Magenis Syndrome Patients Often Display Antibody Deficiency but Not Other Immune Pathologies. J Allergy Clin Immunol Pract 5:1344-1350.e3
Ma, Chi A; Stinson, Jeffrey R; Zhang, Yuan et al. (2017) Germline hypomorphic CARD11 mutations in severe atopic disease. Nat Genet 49:1192-1201
Magri, Giuliana; Comerma, Laura; Pybus, Marc et al. (2017) Human Secretory IgM Emerges from Plasma Cells Clonally Related to Gut Memory B Cells and Targets Highly Diverse Commensals. Immunity 47:118-134.e8
Albin-Leeds, Stephanie; Ochoa, Juliana; Mehta, Harshna et al. (2017) Idiopathic T cell lymphopenia identified in New York State Newborn Screening. Clin Immunol 183:36-40
Di Niro, R; Snir, O; Kaukinen, K et al. (2016) Responsive population dynamics and wide seeding into the duodenal lamina propria of transglutaminase-2-specific plasma cells in celiac disease. Mucosal Immunol 9:254-64
Scott, Eric M; Halees, Anason; Itan, Yuval et al. (2016) Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery. Nat Genet 48:1071-6

Showing the most recent 10 out of 153 publications