Dusan Bogunovic, PhD

Malle L, Patel RS, Martin-Fernandez M, Stewart OJ, Philippot Q, Buta S, Richardson A, Barcessat V, Taft J, Bastard P, Samuels J, Mircher C, Rebillat AS, Maillebouis L, Vilaire-Meunier M, Tuballes K, Rosenberg BR, Trachtman R, Casanova JL, Notarangelo LD, Gnjatic S, Bush D, Bogunovic D. Autoimmunity in Down's syndrome via cytokines, CD4 T cells and CD11c+ B cells. Nature. 2023 Mar;615(7951):305-314. doi: 10.1038/s41586-023-05736-y. Epub 2023 Feb 22. PMID: 36813963; PMCID: PMC9945839. Down syndrome (DS) presents with cardiac, neurocognitive and growth impairments. Individuals with DS are prone to severe infections and autoimmune disorders including thyroiditis, type 1 diabetes, coeliac disease, and alopecia areata. Mapped soluble and cellular immune landscape of individuals with DS. Found persistent elevation of as many as 22 cytokines at steady state (at levels often exceeding those during acute infection) and detected basal cellular activation: chronic IL-6 signaling in CD4 T cells and a high proportion of plasmablasts and CD11c+TbethighCD21low B cells. These data point to an autoimmunity-prone state in DS, in which a steady-state cytokinopathy, hyperactivated CD4 T cells, and ongoing B cell activation contribute to a breach in immune tolerance.

Taft J, Markson M, Legarda D, Patel R, Chan M, Malle L, Richardson A, Gruber C, Martín-Fernández M, Mancini GMS, van Laar JAM, van Pelt P, Buta S, Wokke BHA, Sabli IKD, Sancho-Shimizu V, Chavan PP, Schnappauf O, Khubchandani R, Cüceo?lu MK, Özen S, Kastner DL, Ting AT, Aksentijevich I, Hollink IHIM, Bogunovic D. Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death. Cell. 2021Aug 19;184(17):4447-4463.e20. doi: 10.1016/j.cell.2021.07.026. Epub 2021 Aug 6. PMID: 34363755; PMCID: PMC8380741. TANK binding kinase 1 (TBK1) regulates IFN-I, NF-κB, and TNF-induced RIPK1-dependent cell death (RCD). In mice, biallelic loss of TBK1 is embryonically lethal. We discovered four humans, inclusive of two individuals in their 20s, from three unrelated consanguineous families homozygous for loss-of-function mutations in TBK1. All suffer from chronic and systemic autoinflammation, but not severe viral infections. Demonstrated that TBK1 loss results in hypomorphic but sufficient IFN-I induction via RIG-I/MDA5, while the system retains near intact IL-6 induction through NF-κB. Documented that complete loss-of-expression of TBK1 is less detrimental to IFN-I production, as compared to expressed, but kinase dead TBK1, as it leaves physical room for IKKe to phosphorylate IRF3. Autoinflammation is driven by TNF-induced RCD as patient-derived fibroblasts experienced higher rates of RIPK1 mediated necroptosis in vitro, and CC3 was elevated in peripheral blood ex vivo. Treatment with anti-TNF dampened the baseline circulating inflammatory profile and ameliorated the clinical condition in vivo. These findings highlight the plasticity of the IFN-I response and underscore the role of TBK1 in the regulation of RCD.

Gruber CN, Patel RS, Trachtman R, Lepow L, Amanat F, Krammer F, Wilson KM, Onel K, Geanon D, Tuballes K, Patel M, Mouskas K, O'Donnell T, Merritt E, Simons NW, Barcessat V, Del Valle DM, Udondem S, Kang G, Gangadharan S, Ofori-Amanfo G, Laserson U, Rahman A, Kim-Schulze S, Charney AW, Gnjatic S, Gelb BD, Merad M, Bogunovic D. Mapping systemic inflammation and antibody responses in multisystem inflammatory syndrome in children (MIS-C). Cell. 2020 Nov 12;183(4):982-995.e14. doi: 10.1016/j.cell.2020.09.034. Epub 2020 Sep 14. PMID: 32991843; PMCID: PMC7489877. A month into the COVID-19 pandemic, a novel multisystem inflammatory syndrome in children (MIS-C) emerged. We reported on the immune profiles of children with MIS-C. All had evidence of prior SARS-CoV-2 exposure, mounting an antibody response with intact neutralization capability. Cytokine profiling identified elevated signatures of inflammation (IL-18 and IL-6), lymphocytic and myeloid chemotaxis and activation (CCL3, CCL4, and CDCP1), and mucosal immune dysregulation (IL-17A, CCL20, and CCL28). Immunophenotyping of peripheral blood revealed reductions of non-classical monocytes, and subsets of NK and T lymphocytes, suggesting extravasation to affected tissues. Finally, profiling autoantigen reactivity of MIS-C plasma revealed both known disease-associated autoantibodies (anti-La) and novel candidates that recognize endothelial, gastrointestinal, and immune-cell antigens. Patients treated with anti-IL-6R antibody and/or IVIG led to rapid disease resolution.

Gruber CN, Calis JJA, Buta S, Evrony G, Martin JC, Uhl SA, Caron R, Jarchin L, Dunkin D, Phelps R, Webb BD, Saland JM, Merad M, Orange JS, Mace EM, Rosenberg BR, Gelb BD, Bogunovic D*. Complex autoinflammatory syndrome unveils fundamental principles of JAK1 kinase transcriptional and biochemical function. Immunity. 2020 Sep 15;53(3):672-684.e11. doi: 10.1016/j.immuni.2020.07.006. Epub 2020 Aug 3. PMID: 32750333; PMCID: PMC7398039 Documented monogenic, heterozygous, mosaic gain-of-function mutation in pseudokinase domain of JAK1 as cause of severe autoinflammatory disease which resolved with JAK1 inhibition. Using custom based single cell RNA sequencing, monoallelic expression of JAK1 in immune cells was first documented. Given mosaicism of a heterozygous mutation, we expected to observe some cells (i.e., homozygous WT JAK1) containing only WT JAK1 transcripts and others (i.e., heterozygous S703I JAK1) containing both WT and S703I JAK1 transcripts. These findings present a departure from the classic genetic interpretation of heterozygosity and allow for a shift in understanding genetic penetrance of disease.

Alsohime F, Martin-Fernandez M, Temsah MH, Alabdulhafid M, Le Voyer T, Alghamdi M, Qiu X, Alotaibi N, Alkahtani A, Buta S, Jouanguy E, Al-Eyadhy A, Gruber C, Hasan GM, Bashiri FA, Halwani R, Hassan HH, Al-Muhsen S, Alkhamis N, Alsum Z, Casanova JL, Bustamante J, Bogunovic D*, Alangari AA*. JAK inhibitor therapy in a child with inherited USP18 deficiency. N Engl J Med. 2020 Jan 16;382(3):256-265. doi: 10.1056/NEJMoa1905633. PMID: 31940699; PMCID: PMC7155173. *co-senior and co-corresponding Deficiency of ubiquitin-specific peptidase 18 (USP18) is a severe type I interferonopathy. USP18 down- regulates type I interferon signaling by blocking access of Janus-associated kinase 1 (JAK1) to e type I interferon receptor. Absence of USP18 results in unmitigated interferon-mediated inflammation and is lethal during the perinatal period. We described a neonate with hydrocephalus, necrotizing cellulitis, systemic inflammation, and respiratory failure. Exome sequencing identified homozygous mutation at essential splice site on USP18, which resulted in exon 10 skipping. The encoded protein was expressed but devoid of negative regulatory ability. Treatment with ruxolitinib was followed by prompt and sustained recovery.