# Human Genetic Dissection of Antibody Response to Pneumococcal Glycans

> **NIH NIH P01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $453,068

## Abstract

Project Summary/Abstract
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
immunodeficiencies. 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
patients. Most patients carry mutations in NEMO and NFKBIA, which respectively underlie X-linked recessive
(XR) and autosomal dominant (AD) forms. Patients with SPAD/IgG2D display a much more selective
impairment of Ab response to glycans, which also leads to IPD. It is rarely caused by mutations in IgG2.
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 consequences. It is rarely caused by bi-
allelic mutations in ICOS, TACI, BAFF-R, CD81, CD19, CD20, or LRBA or mono-allelic
mutations in NFKB2, CTLA4, PIK3CD, NFKB1, or IRF2BP2. 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 CVID, and the first inborn errors of the linear ubiquitination complex (LUBAC), with
mutations in HOIL1 and HOIP 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 PIDs, and our development of powerful prediction software. 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 ar...

## Key facts

- **NIH application ID:** 9984945
- **Project number:** 5P01AI061093-16
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Jean-Laurent Casanova
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $453,068
- **Award type:** 5
- **Project period:** 2004-07-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984945

## Citation

> US National Institutes of Health, RePORTER application 9984945, Human Genetic Dissection of Antibody Response to Pneumococcal Glycans (5P01AI061093-16). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9984945. Licensed CC0.

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