Project Summary/Abstract
Inborn errors of immunity (IEI) are genetic disorders of the immune system that can present with a wide diversity
of signs and symptoms. Specific antibody deficiency (SAD) is among the most common classes of IEI and occurs
when patients have normal levels of serum immunoglobulins but are unable to form specific responses to
antigens. Despite its high prevalence, the pathogenesis of SAD remains poorly understood. Here, we investigate
a family that presented with a specific antibody deficiency with an autosomal dominant inheritance pattern.
Although whole exome sequencing did not reveal any variants in known IEI-associated genes, whole genome
sequencing uncovered a heterozygous tandem duplication on chromosome 14 that intersects the
immunoglobulin heavy chain (IgH) locus. All affected individuals also had a selective memory (CD27+ CD38
Lo/Int) B cell deficiency in peripheral blood. CD27- B cells were hyperproliferative in response to T-dependent
and T-independent stimuli yet showed diminished differentiation to plasmablasts when stimulated with CD40L
and IL-21. Intriguingly, one of the duplicated genes, JAG2 was upregulated more than 100-fold at baseline when
measured by bulk RNA-seq. CITE-seq revealed that JAG2 is uniquely overexpressed in patient B cells but not
in other immune cells. Given the diminished differentiation and B-cell-specific overexpression of JAG2 seen in
these patients, we hypothesize that the duplication has transposed JAG2 under the transcriptional control of the
IgH locus, a phenomenon known as ‘enhancer hijacking’, resulting in its increased expression only in B cells.
We further hypothesize that the sustained expression of JAG2 upon stimulation results in diminished
differentiation, leading to the clinical phenotype of SAD. Throughout this project, we will investigate the effects
of JAG2 on B cell differentiation and explore the genetic mechanism of JAG2 overexpression using a number of
cutting-edge techniques and novel models, including tonsil organoids and measles-pseudotyped lentivirus to
manipulate the expression of JAG2 in human B cells and assess its effects on B cell differentiation. Previous
studies of IEI have primarily focused on single nucleotide variants causing altered protein function or abundance.
Here, we propose a structural variant is causing altered enhancer interactions between JAG2 and the
IgH locus, resulting in SAD. This represents a novel genetic mechanism of IEI and would alter the way we
approach the genetic diagnosis of IEI.