Genetic characterization of patients with lymphoma and severe viral infections due to inborn errors of immunity

<p dir="ltr">In this thesis, we discovered rare and novel inborn errors of immunity (IEIs) that impair antiviral defense and immune surveillance. These genetic defects, including mutations in TLR7 (Toll-like receptor 7), OAS1 (2'-5'-oligoadenylate synthetase 1), and TET2 (Ten-eleven translocation 2), contribute to unexpected disease severity, including vaccine failure, lymphoproliferation, and cancer. Our findings illustrate the power of genetic diagnosis in personalizing patient care and may contribute to the development of new treatment strategies for immune-related diseases.</p><p dir="ltr">Study I describes a unique case of critical COVID-19 in a patient diagnosed with ataxia-telangiectasia (A-T) and a coexisting TLR7 deficiency. Although SARS- CoV-2 infection is typically mild in A-T patients, the TLR7 deficiency led to a severe phenotype. This underscores the necessity of broad genetic testing even when a primary IEI diagnosis is known, especially to guide prognosis and therapy. Study II explores SARS-CoV-2 breakthrough infections (BTIs) in vaccinated individuals without known immunodeficiencies. We found significant factors contributing to severe BTIs, including impaired CD8+ T cell responses and defective type 1 interferon or inflammasome signaling. A novel homozygous OAS1- p48 variant was also identified in one patient, impairing its apoptotic function and potentially explaining the severe disease despite vaccination. These findings reveal a critical role for apoptosis in antiviral immunity and support performing genetic screening in severe BTI cases. Study III presents an in-depth genomic analysis of lymphomas in IEI patients, revealing potential disease-causing germline mutations in ~60% of cases and recurring somatic mutations in genes in the DNA repair and apoptosis pathways. EBV-positive lymphomas were more frequent, and these IEI-related lymphomas showed distinct somatic mutational patterns. Our data support a two-hit model, germline IEI mutation followed by multiple somatic drivers, and advocate for integrating immunogenetic profiling in early- onset lymphomas to guide treatment. Study IV identifies a novel homozygous TET2 variant in an IEI patient with autoimmune lymphoproliferative syndrome-like features. The mutation caused DNA hypermethylation, defective class switch recombination, and B cell hyperproliferation. Functional studies confirmed the pathogenic role of this variant and suggested a mechanism for TET2 in lymphomagenesis. These insights pave the way for targeted therapies in cases where standard treatments like hematopoietic stem cell transplantation fail.</p><p dir="ltr">These studies demonstrate the diverse and profound consequences of IEI-related genetic variants on human immunity. They thus reinforce the need for personalized genomic approaches in diagnosing and managing immune dysregulation, especially in severe infections, vaccine failure, and lymphoid malignancies.</p><h3>List of scientific papers</h3><p dir="ltr">I. X-linked TLR7 deficiency underlies critical COVID-19 pneumonia in a male patient with Ataxia-Telangiectasia Abolhassani H, Vosughimotlagh A, Asano T, Landegren N, Boisson B, Delavari S, Bastard P, Aranda-Guillen M, <b>Wang Y,</b> Zuo F, Sardh F, Marcotte H, Du L, Zhang SY, Zhang Q, Rezaei N, Kämpe O, Casanova JL, Hammarström L, Pan- Hammarström Q. J Clin Immunol. 2022 Jan;42(1):1-9.<br><a href="https://doi.org/10.1007/s10875-021-01151-y" rel="noreferrer" target="_blank">https://doi.org/10.1007/s10875-021-01151-y</a><br><br></p><p dir="ltr">II. Genetic and immunological evaluation of a patient cohort with severe breakthrough SARS-CoV-2 infection identifies a case of inherited OAS1 deficiency <br><b>Wang Y,</b> Delavari S, Salami F, Zuo F, Du L, Dargahi Mal-Amir M, Nashibi R, Houshmandfar S, Marcotte H, Khoirunnisa N, Dabrowka Podolan J, Bastard P, Lee D, Zhang SY, Casanova JL, Rezaei N, Hammarström L, Abolhassani H, Pan- Hammarström Q. [Manuscript]<br><br></p><p dir="ltr">III. Genomic characterization of lymphomas in patients with inborn errors of immunity <br>Ye X*, Maglione PJ*, Wehr C*, Li X*, <b>Wang Y,</b> Abolhassani H, Deripapa E, Liu D, Borte S, Du L, Wan H, Plötner A, Giannoula Y, Ko HB, Hou Y, Zhu S, Grossman JK, Sander B, Grimbacher B, Hammarström L, Fedorova A, Rosenzweig SD, Shcherbina A, Wu K, Warnatz K, Cunningham-Rundles C, Pan-Hammarström Q. Blood Adv. 2022 Sep;6(18):5403-5414 *Shared authorship<br><a href="https://doi.org/10.1182/bloodadvances.2021006654" rel="noreferrer" target="_blank">https://doi.org/10.1182/bloodadvances.2021006654</a><br><br></p><p dir="ltr">IV. B cell lymphoproliferation and genome-wide methylation defects associated with a novel biallelic germline TET2 mutation <br><b>Wang Y,</b> Abolhassani H, Ye C, Dai Q, Behniafard N, Zuo F, Yang M, Liu M, Delavari S, Salami F, Vlachiotis S, Sun R, Du L, Kalmar D, Palmeri A, Rezaei N, Hammarström L, Wilhem M, He C, Pan-Hammarström Q. [Manuscript]</p>