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)
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Icahn School of Medicine at Mount Sinai
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Gutzeit, Cindy; Chen, Kang; Cerutti, Andrea (2018) The enigmatic function of IgD: some answers at last. Eur J Immunol 48:1101-1113
Gies, Vincent; Schickel, Jean-Nicolas; Jung, Sophie et al. (2018) Impaired TLR9 responses in B cells from patients with systemic lupus erythematosus. JCI Insight 3:
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Smith, Tukisa D; Cunningham-Rundles, Charlotte (2018) Detection of anti-glutamic acid decarboxylase antibodies in immunoglobulin products. J Allergy Clin Immunol Pract 6:260-261
Petersheim, Daniel; Massaad, Michel J; Lee, Saetbyul et al. (2018) Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency. J Allergy Clin Immunol 141:1060-1073.e3
Bucciol, Giorgia; Moens, Leen; Bosch, Barbara et al. (2018) Lessons learned from the study of human inborn errors of innate immunity. J Allergy Clin Immunol :

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