Immunologic and Genetic Analysis to Understand the Pathogenesis of Primary Selective IgM Immunodeficiency (sIgMID)

• Applicant: Dr. Anna B. Stittrich
• Subject Area: Immunology ; Human Genetics
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 397650460

Patients with primary selective immunoglobulin (Ig) M immunodeficiency (sIgMID) have an isolated IgM deficiency in serum and typically suffer from recurrent infections that can be severe or even life-threatening. Common clinical presentations include upper and lower respiratory tract infections, urinary tract infections and gastroenteritis. During adulthood, some sIgMID patients develop autoimmune diseases. It is not clear how IgM deficiency causes these symptoms. Previous studies indicate that B cell-intrinsic defects and defects in T cell function may contribute to sIgMID. Also genetic abnormalities have been described, but overall the pathogenesis of sIgMID remains poorly understood.I hypothesize that sIgMID is a heterogeneous disease and that stratification is key to understand the pathogenesis. For the first time, we will analyze a large cohort of ~50 sIgMID patients with the objective to stratify the disease by a comprehensive immunological and genetic analysis. This study has three specific aims: (i) We want to perform a comprehensive immunological phenotyping of sIgMID patients that comprises the analysis of B and T cell subset distribution, the characterization of B cell subsets according activation status, survival, apoptosis, maturation and migration, the analysis of IgM expression, as well as in vitro stimulation including cross-stimulation with patient B cells and healthy donor T cells and vice versa.(ii) We want to perform whole-exome sequencing (and whole-genome sequencing, respectively) of sIgMID patients and their unaffected family members to identify single nucleotide variants and/or copy number variants that may cause or predispose for sIgMID. For this analysis, patients shall be grouped according to subtypes emerging from aim (i).(iii) To validate the newly identified candidate variants and assess their biological impact, we want to generate lymphoblastoid cell lines (LCLs) from the patients B cells and use CRISPR/Cas9 gene editing to correct the variants back to reference. Then we will compare the original and corrected LCLs according to their capacity to expand and to produce IgM. The results from this study will make it possible to relate different clinical sIgMID phenotypes to specific immunological defects and/or certain genetic variants. Such disease stratification will facilitate diagnosis and could improve therapy. Furthermore, I see sIgMID as a model disease and understanding sIgMID pathogenesis could not only shed light on other immune deficiencies but it will also provide insight into general immune mechanisms such as regulation of immunoglobulin production, T cell - B cell interaction and B cell maturation and differentiation.

• DFG Programme: Research Grants