Masato Ogishi

All Publications

• Tuberculosis in otherwise healthy adults with inherited TNF deficiency. Nature Arias, A. A., Neehus, A. L., Ogishi, M., Meynier, V., Krebs, A., Lazarov, T., Lee, A. M., Arango-Franco, C. A., Yang, R., Orrego, J., Corcini Berndt, M., Rojas, J., Li, H., Rinchai, D., Erazo-Borrás, L., Han, J. E., Pillay, B., Ponsin, K., Chaldebas, M., Philippot, Q., Bohlen, J., Rosain, J., Le Voyer, T., Janotte, T., Amarajeeva, K., Soudée, C., Brollo, M., Wiegmann, K., Marquant, Q., Seeleuthner, Y., Lee, D., Lainé, C., Kloos, D., Bailey, R., Bastard, P., Keating, N., Rapaport, F., Khan, T., Moncada-Vélez, M., Carmona, M. C., Obando, C., Alvarez, J., Cataño, J. C., Martínez-Rosado, L. L., Sanchez, J. P., Tejada-Giraldo, M., L'Honneur, A. S., Agudelo, M. L., Perez-Zapata, L. J., Arboleda, D. M., Alzate, J. F., Cabarcas, F., Zuluaga, A., Pelham, S. J., Ensser, A., Schmidt, M., Velásquez-Lopera, M. M., Jouanguy, E., Puel, A., Krönke, M., Ghirardello, S., Borghesi, A., Pahari, S., Boisson, B., Pittaluga, S., Ma, C. S., Emile, J. F., Notarangelo, L. D., Tangye, S. G., Marr, N., Lachmann, N., Salvator, H., Schlesinger, L. S., Zhang, P., Glickman, M. S., Nathan, C. F., Geissmann, F., Abel, L., Franco, J. L., Bustamante, J., Casanova, J. L., Boisson-Dupuis, S. 2024

  Abstract

  Severe defects in human IFNγ immunity predispose individuals to both Bacillus Calmette-Guérin disease and tuberculosis, whereas milder defects predispose only to tuberculosis1. Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant. Neither has any other clinical phenotype and both mount normal clinical and biological inflammatory responses. Their leukocytes, including monocytes and monocyte-derived macrophages (MDMs) do not produce TNF, even after stimulation with IFNγ. Blood leukocyte subset development is normal in these patients. However, an impairment in the respiratory burst was observed in granulocyte-macrophage colony-stimulating factor (GM-CSF)-matured MDMs and alveolar macrophage-like (AML) cells2 from both patients with TNF deficiency, TNF- or TNFR1-deficient induced pluripotent stem (iPS)-cell-derived GM-CSF-matured macrophages, and healthy control MDMs and AML cells differentiated with TNF blockers in vitro, and in lung macrophages treated with TNF blockers ex vivo. The stimulation of TNF-deficient iPS-cell-derived macrophages with TNF rescued the respiratory burst. These findings contrast with those for patients with inherited complete deficiency of the respiratory burst across all phagocytes, who are prone to multiple infections, including both Bacillus Calmette-Guérin disease and tuberculosis3. Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and many other infectious agents.

  View details for DOI 10.1038/s41586-024-07866-3

  View details for PubMedID 39198650

  View details for PubMedCentralID 11099312

• Human inherited PD-L1 deficiency is clinically and immunologically less severe than PD-1 deficiency. The Journal of experimental medicine Johnson, M. B., Ogishi, M., Domingo-Vila, C., De Franco, E., Wakeling, M. N., Imane, Z., Resnick, B., Williams, E., Galao, R. P., Caswell, R., Russ-Silsby, J., Seeleuthner, Y., Rinchai, D., Fagniez, I., Benson, B., Dufort, M. J., Speake, C., Smithmyer, M. E., Hudson, M., Dobbs, R., EXE-T1D consortium, Quandt, Z., Hattersley, A. T., Zhang, P., Boisson-Dupuis, S., Anderson, M. S., Casanova, J., Tree, T. I., Oram, R. A., Weedon, M. N., Roep, B. O., Hagopian, W. 2024; 221 (6)

  Abstract

  We previously reported two siblings with inherited PD-1 deficiency who died from autoimmune pneumonitis at 3 and 11 years of age after developing other autoimmune manifestations, including type 1 diabetes (T1D). We report here two siblings, aged 10 and 11 years, with neonatal-onset T1D (diagnosed at the ages of 1 day and 7 wk), who are homozygous for a splice-site variant of CD274 (encoding PD-L1). This variant results in the exclusive expression of an alternative, loss-of-function PD-L1 protein isoform in overexpression experiments and in the patients' primary leukocytes. Surprisingly, cytometric immunophenotyping and single-cell RNA sequencing analysis on blood leukocytes showed largely normal development and transcriptional profiles across lymphoid and myeloid subsets in the PD-L1-deficient siblings, contrasting with the extensive dysregulation of both lymphoid and myeloid leukocyte compartments in PD-1 deficiency. Our findings suggest that PD-1 and PD-L1 are essential for preventing early-onset T1D but that, unlike PD-1 deficiency, PD-L1 deficiency does not lead to fatal autoimmunity with extensive leukocytic dysregulation.

  View details for DOI 10.1084/jem.20231704

  View details for PubMedID 38634869

• FLT3L governs the development of partially overlapping hematopoietic lineages in humans and mice. Cell Momenilandi, M., Levy, R., Sobrino, S., Li, J., Lagresle-Peyrou, C., Esmaeilzadeh, H., Fayand, A., Le Floc'h, C., Guerin, A., Mina, E. D., Shearer, D., Delmonte, O. M., Yatim, A., Mulder, K., Mancini, M., Rinchai, D., Denis, A., Neehus, A., Balogh, K., Brendle, S., Rokni-Zadeh, H., Changi-Ashtiani, M., Seeleuthner, Y., Deswarte, C., Bessot, B., Cremades, C., Materna, M., Cederholm, A., Ogishi, M., Philippot, Q., Beganovic, O., Ackermann, M., Wuyts, M., Khan, T., Fouere, S., Herms, F., Chanal, J., Palterer, B., Bruneau, J., Molina, T. J., Leclerc-Mercier, S., Pretet, J., Youssefian, L., Vahidnezhad, H., Parvaneh, N., Claeys, K. G., Schrijvers, R., Luka, M., Perot, P., Fourgeaud, J., Nourrisson, C., Poirier, P., Jouanguy, E., Boisson-Dupuis, S., Bustamante, J., Notarangelo, L. D., Christensen, N., Landegren, N., Abel, L., Marr, N., Six, E., Langlais, D., Waterboer, T., Ginhoux, F., Ma, C. S., Tangye, S. G., Meyts, I., Lachmann, N., Hu, J., Shahrooei, M., Bossuyt, X., Casanova, J., Beziat, V. 2024; 187 (11): 2817

  Abstract

  FMS-related tyrosine kinase 3 ligand (FLT3L), encoded by FLT3LG, is a hematopoietic factor essential for the development of natural killer (NK) cells, B cells, and dendritic cells (DCs) in mice. We describe three humans homozygous for a loss-of-function FLT3LG variant with a history of various recurrent infections, including severe cutaneous warts. The patients' bone marrow (BM) was hypoplastic, with low levels of hematopoietic progenitors, particularly myeloid and B cell precursors. Counts of B cells, monocytes, and DCs were low in the patients' blood, whereas the other blood subsets, including NK cells, were affected only moderately, if at all. The patients had normal counts of Langerhans cells (LCs) and dermal macrophages in the skin but lacked dermal DCs. Thus, FLT3L is required for B cell and DC development in mice and humans. However, unlike its murine counterpart, human FLT3L is required for the development of monocytes but not NK cells.

  View details for DOI 10.1016/j.cell.2024.04.009

  View details for PubMedID 38701783

• Helper T cell immunity in humans with inherited CD4 deficiency. The Journal of experimental medicine Guerin, A., Moncada-Velez, M., Jackson, K., Ogishi, M., Rosain, J., Mancini, M., Langlais, D., Nunez, A., Webster, S., Goyette, J., Khan, T., Marr, N., Avery, D. T., Rao, G., Waterboer, T., Michels, B., Neves, E., Iracema Morais, C., London, J., Mestrallet, S., Quartier Dit Maire, P., Neven, B., Rapaport, F., Seeleuthner, Y., Lev, A., Simon, A. J., Montoya, J., Barel, O., Gomez-Rodriguez, J., Orrego, J. C., L'Honneur, A., Soudee, C., Rojas, J., Velez, A. C., Sereti, I., Terrier, B., Marin, N., Garcia, L. F., Abel, L., Boisson-Dupuis, S., Reis, J., Marinho, A., Lisco, A., Faria, E., Goodnow, C. C., Vasconcelos, J., Beziat, V., Ma, C. S., Somech, R., Casanova, J., Bustamante, J., Franco, J. L., Tangye, S. G. 2024; 221 (5)

  Abstract

  CD4+ T cells are vital for host defense and immune regulation. However, the fundamental role of CD4 itself remains enigmatic. We report seven patients aged 5-61 years from five families of four ancestries with autosomal recessive CD4 deficiency and a range of infections, including recalcitrant warts and Whipple's disease. All patients are homozygous for rare deleterious CD4 variants impacting expression of the canonical CD4 isoform. A shorter expressed isoform that interacts with LCK, but not HLA class II, is affected by only one variant. All patients lack CD4+ T cells and have increased numbers of TCRalphabeta+CD4-CD8- T cells, which phenotypically and transcriptionally resemble conventional Th cells. Finally, patient CD4-CD8- alphabeta T cells exhibit intact responses to HLA class II-restricted antigens and promote B cell differentiation in vitro. Thus, compensatory development of Th cells enables patients with inherited CD4 deficiency to acquire effective cellular and humoral immunity against an unexpectedly large range of pathogens. Nevertheless, CD4 is indispensable for protective immunity against at least human papillomaviruses and Trophyrema whipplei.

  View details for DOI 10.1084/jem.20231044

  View details for PubMedID 38557723

• Neutralizing IFN-γ autoantibodies are rare and in HLA-DRB1*15:02 or 16:02 individuals JOURNAL OF CLINICAL INVESTIGATION Peel, J. N., Yang, R., Le Voyer, T., Gervais, A., Rosain, J., Bastard, P., Behere, A., Cederholm, A., Bodansky, A., Seeleuthner, Y., Conil, C., Ding, J., Lei, W., Bizien, L., Soudee, C., Migaud, M., Ogishi, M., Yatim, A., Lee, D., Bohlen, J., Perpoint, T., Perez, L., Messina, F., Genet, R., Karkowski, L., Blot, M., Lafont, E., Toullec, L., Goulvestre, C., Mehlal-Sedkaoui, S., Sallette, J., Martin, F., Puel, A., Jouanguy, E., Anderson, M. S., Landegren, N., Tiberghien, P., Abel, L., Boisson-Dupuis, S., Bustamante, J., Ku, C., Casanova, J., CONSTANCES Cohort, 3C-Dijon Study, Etab Sang Study Grp 2024; 134 (8)

  Abstract

  BACKGROUNDWeakly virulent environmental mycobacteria (EM) can cause severe disease in HLA-DRB1*15:02 or 16:02 adults harboring neutralizing anti-IFN-γ autoantibodies (nAIGAs). The overall prevalence of nAIGAs in the general population is unknown, as are the penetrance of nAIGAs in HLA-DRB1*15:02 or 16:02 individuals and the proportion of patients with unexplained, adult-onset EM infections carrying nAIGAs.METHODSThis study analyzed the detection and neutralization of anti-IFN-γ autoantibodies (auto-Abs) from 8,430 healthy individuals of the general population, 257 HLA-DRB1*15:02 or 16:02 carriers, 1,063 patients with autoimmune disease, and 497 patients with unexplained severe disease due to EM.RESULTSWe found that anti-IFN-γ auto-Abs detected in 4,148 of 8,430 healthy individuals (49.2%) from the general population of an unknown HLA-DRB1 genotype were not neutralizing. Moreover, we did not find nAIGAs in 257 individuals carrying HLA-DRB1* 15:02 or 16:02. Additionally, nAIGAs were absent in 1,063 patients with an autoimmune disease. Finally, 7 of 497 patients (1.4%) with unexplained severe disease due to EM harbored nAIGAs.CONCLUSIONThese findings suggest that nAIGAs are isolated and that their penetrance in HLA-DRB1*15:02 or 16:02 individuals is low, implying that they may be triggered by rare germline or somatic variants. In contrast, the risk of mycobacterial disease in patients with nAIGAs is high, confirming that these nAIGAs are the cause of EM disease.FUNDINGThe Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI095983 and U19AIN1625568), the National Center for Advancing Translational Sciences (NCATS), the NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), the French National Research Agency (ANR) under the "Investments for the Future" program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), ANR-GENMSMD (ANR-16-CE17-0005-01), ANR-MAFMACRO (ANR-22-CE92-0008), ANRSECTZ170784, the French Foundation for Medical Research (FRM) (EQU201903007798), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), and ANR AI2D (ANR-22-CE15-0046) projects, the ANR-RHU program (ANR-21-RHUS-08-COVIFERON), the European Union's Horizon 2020 research and innovation program under grant agreement no. 824110 (EASI-genomics), the Square Foundation, Grandir - Fonds de solidarité pour l'enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the Battersea & Bowery Advisory Group, William E. Ford, General Atlantic's Chairman and Chief Executive Officer, Gabriel Caillaux, General Atlantic's Co-President, Managing Director, and Head of business in EMEA, and the General Atlantic Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM) and of Paris Cité University. JR was supported by the INSERM PhD program for doctors of pharmacy (poste d'accueil INSERM). JR and TLV were supported by the Bettencourt-Schueller Foundation and the MD-PhD program of the Imagine Institute. MO was supported by the David Rockefeller Graduate Program, the Funai Foundation for Information Technology (FFIT), the Honjo International Scholarship Foundation (HISF), and the New York Hideyo Noguchi Memorial Society (HNMS).

  View details for DOI 10.1172/JCI178263

  View details for Web of Science ID 001208946600026

  View details for PubMedID 38470480

  View details for PubMedCentralID PMC11014650

• Human MCTS1-dependent translation of JAK2 is essential for IFN-g immunity to mycobacteria CELL Bohlen, J., Zhou, Q., Philippot, Q., Ogishi, M., Rinchai, D., Nieminen, T., Seyedpour, S., Parvaneh, N., Rezaei, N., Yazdanpanah, N., Momenilandi, M., Conil, C., Neehus, A., Schmidt, C., Arango-Franco, C. A., Le Voyer, T., Khan, T., Yang, R., Puchan, J., Erazo, L., Roiuk, M., Vatovec, T., Janda, Z., Bagaric, I., Materna, M., Gervais, A., Li, H., Rosain, J., Peel, J. N., Seeleuthner, Y., Han, J., L'Honneur, A., Moncada-Velez, M., Martin-Fernandez, M., Horesh, M. E., Kochetkov, T., Schmidt, M., Alshehri, M. A., Salo, E., Saxen, H., ElGhazali, G., Yatim, A., Soudee, C., Sallusto, F., Ensser, A., Marr, N., Zhang, P., Bogunovic, D., Cobat, A., Shahrooei, M., Beziat, V., Abel, L., Wang, X., Boisson-Dupuis, S., Teleman, A. A., Bustamante, J., Zhang, Q., Casanova, J. 2023; 186 (23): 5114-+

  Abstract

  Human inherited disorders of interferon-gamma (IFN-γ) immunity underlie severe mycobacterial diseases. We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries (from China, Finland, Iran, and Saudi Arabia). Complete deficiency of this translation re-initiation factor impairs the translation of a subset of proteins, including the kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes. JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines. Defective responses to IL-23 preferentially impair the production of IFN-γ by innate-like adaptive mucosal-associated invariant T cells (MAIT) and γδ T lymphocytes upon mycobacterial challenge. Surprisingly, the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients. These findings suggest that X-linked recessive human MCTS1 deficiency underlies isolated mycobacterial disease by impairing JAK2 translation in innate-like adaptive T lymphocytes, thereby impairing the IL-23-dependent induction of IFN-γ.

  View details for DOI 10.1016/j.cell.2023.09.024

  View details for Web of Science ID 001115514300001

  View details for PubMedID 37875108

  View details for PubMedCentralID PMC10841658

• Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency NATURE Le Voyer, T., Parent, A. V., Liu, X., Cederholm, A., Gervais, A., Rosain, J., Nguyen, T., Lorenzo, M., Rackaityte, E., Rinchai, D., Zhang, P., Bizien, L., Hancioglu, G., Ghillani-Dalbin, P., Charuel, J., Philippot, Q., Gueye, M., Renkilaraj, M., Ogishi, M., Soudee, C., Migaud, M., Rozenberg, F., Momenilandi, M., Riller, Q., Imberti, L., Delmonte, O. M., Mueller, G., Keller, B., Orrego, J., Gallego, W., Rubin, T., Emiroglu, M., Parvaneh, N., Eriksson, D., Aranda-Guillen, M., Berrios, D. I., Vong, L., Katelaris, C. H., Mustillo, P., Raedler, J., Bohlen, J., Celik, J., Astudillo, C., Winter, S., McLean, C., Guffroy, A., DeRisi, J. L., Yu, D., Miller, C., Feng, Y., Guichard, A., Beziat, V., Bustamante, J., Pan-Hammarstrom, Q., Zhang, Y., Rosen, L. B., Holland, S. M., Bosticardo, M., Kenney, H., Castagnoli, R., Slade, C. A., Boztug, K., Mahlaoui, N., Latour, S., Abraham, R. S., Lougaris, V., Hauck, F., Sediva, A., Atschekzei, F., Sogkas, G., Poli, M., Slatter, M. A., Palterer, B., Keller, M. D., Pinzon-Charry, A., Sullivan, A., Droney, L., Suan, D., Wong, M., Kane, A., Hu, H., Ma, C., Grombirikova, H., Ciznar, P., Dalal, I., Aladjidi, N., Hie, M., Lazaro, E., Franco, J., Keles, S., Malphettes, M., Pasquet, M., Maccari, M., Meinhardt, A., Ikinciogullari, A., Shahrooei, M., Celmeli, F., Frosk, P., Goodnow, C. C., Gray, P. E., Belot, A., Kuehn, H., Rosenzweig, S. D., Miyara, M., Licciardi, F., Servettaz, A., Barlogis, V., Le Guenno, G., Herrmann, V., Kuijpers, T., Ducoux, G., Sarrot-Reynauld, F., Schuetz, C., Cunningham-Rundles, C., Rieux-Laucat, F., Tangye, S. G., Sobacchi, C., Doffinger, R., Warnatz, K., Grimbacher, B., Fieschi, C., Berteloot, L., Bryant, V. L., Assant, S., Su, H., Neven, B., Abel, L., Zhang, Q., Boisson, B., Cobat, A., Jouanguy, E., Kampe, O., Bastard, P., Roifman, C. M., Landegren, N., Notarangelo, L. D., Anderson, M. S., Casanova, J., Puel, A., NF kB Consortium, COVID Human Genetic Effort 2023; 623 (7988): 803-813

  Abstract

  Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)1,2, conferring a predisposition to life-threatening COVID-19 pneumonia3. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52LOF/IκBδGOF). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF/IκBδLOF) or gain-of-function of p52 (hereafter, p52GOF/IκBδLOF). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.

  View details for DOI 10.1038/s41586-023-06717-x

  View details for Web of Science ID 001182780400001

  View details for PubMedID 37938781

  View details for PubMedCentralID PMC10665196

• Human inherited complete STAT2 deficiency underlies inflammatory viral diseases JOURNAL OF CLINICAL INVESTIGATION Bucciol, G., Moens, L., Ogishi, M., Rinchai, D., Matuozzo, D., Momenilandi, M., Kerrouche, N., Cale, C. M., Treffeisen, E. R., Al Salamah, M., Al-Saud, B. K., Lachaux, A., Duclaux-Loras, R., Meignien, M., Bousfiha, A., Benhsaien, I., Shcherbina, A., Roppelt, A., COVID Human Genetic Effort, C., Gothe, F., Houhou-Fidouh, N., Hackett, S. J., Bartnikas, L. M., Maciag, M. C., Alosaimi, M. F., Chou, J., Mohammed, R. W., Freij, B. J., Jouanguy, E., Zhang, S., Boisson-Dupuis, S., Beziat, V., Zhang, Q., Duncan, C. A., Hambleton, S., Casanova, J., Meyts, I. 2023; 133 (12)

  Abstract

  STAT2 is a transcription factor activated by type I and III IFNs. We report 23 patients with loss-of-function variants causing autosomal recessive (AR) complete STAT2 deficiency. Both cells transfected with mutant STAT2 alleles and the patients' cells displayed impaired expression of IFN-stimulated genes and impaired control of in vitro viral infections. Clinical manifestations from early childhood onward included severe adverse reaction to live attenuated viral vaccines (LAV) and severe viral infections, particularly critical influenza pneumonia, critical COVID-19 pneumonia, and herpes simplex virus type 1 (HSV-1) encephalitis. The patients displayed various types of hyperinflammation, often triggered by viral infection or after LAV administration, which probably attested to unresolved viral infection in the absence of STAT2-dependent types I and III IFN immunity. Transcriptomic analysis revealed that circulating monocytes, neutrophils, and CD8+ memory T cells contributed to this inflammation. Several patients died from viral infection or heart failure during a febrile illness with no identified etiology. Notably, the highest mortality occurred during early childhood. These findings show that AR complete STAT2 deficiency underlay severe viral diseases and substantially impacts survival.

  View details for DOI 10.1172/JCI168321

  View details for Web of Science ID 001023897600001

  View details for PubMedID 36976641

  View details for PubMedCentralID PMC10266780

• Human <i>RELA</i> dominant-negative mutations underlie type I interferonopathy with autoinflammation and autoimmunity JOURNAL OF EXPERIMENTAL MEDICINE Moriya, K., Nakano, T., Honda, Y., Tsumura, M., Ogishi, M., Sonoda, M., Nishitani-Isa, M., Uchida, T., Hbibi, M., Mizoguchi, Y., Ishimura, M., Izawa, K., Asano, T., Kakuta, F., Abukawa, D., Rinchai, D., Zhang, P., Kambe, N., Bousfiha, A., Yasumi, T., Boisson, B., Puel, A., Casanova, J., Nishikomori, R., Ohga, S., Okada, S., Sasahara, Y., Kure, S. 2023; 220 (9)

  Abstract

  Inborn errors of the NF-κB pathways underlie various clinical phenotypes in humans. Heterozygous germline loss-of-expression and loss-of-function mutations in RELA underlie RELA haploinsufficiency, which results in TNF-dependent chronic mucocutaneous ulceration and autoimmune hematological disorders. We here report six patients from five families with additional autoinflammatory and autoimmune manifestations. These patients are heterozygous for RELA mutations, all of which are in the 3' segment of the gene and create a premature stop codon. Truncated and loss-of-function RelA proteins are expressed in the patients' cells and exert a dominant-negative effect. Enhanced expression of TLR7 and MYD88 mRNA in plasmacytoid dendritic cells (pDCs) and non-pDC myeloid cells results in enhanced TLR7-driven secretion of type I/III interferons (IFNs) and interferon-stimulated gene expression in patient-derived leukocytes. Dominant-negative mutations in RELA thus underlie a novel form of type I interferonopathy with systemic autoinflammatory and autoimmune manifestations due to excessive IFN production, probably triggered by otherwise non-pathogenic TLR ligands.

  View details for DOI 10.1084/jem.20212276

  View details for Web of Science ID 001019227000001

  View details for PubMedID 37273177

  View details for PubMedCentralID PMC10242411

• Inborn errors of human transcription factors governing IFN-? antimycobacterial immunity CURRENT OPINION IN IMMUNOLOGY Ogishi, M., Yang, R., Rosain, J., Busmante, J., Casnova, J., Boisson-Dupis, S. 2023; 81: 102296

  Abstract

  Inborn errors of immunity (IEI) delineate redundant and essential defense mechanisms in humans. We review 15 autosomal-dominant (AD) or -recessive (AR) IEI involving 11 transcription factors (TFs) and impairing interferon-gamma (IFN-γ) immunity, conferring a predisposition to mycobacterial diseases. We consider three mechanism-based categories: 1) IEI mainly affecting myeloid compartment development (AD GATA2 and AR and AD IRF8 deficiencies), 2) IEI mainly affecting lymphoid compartment development (AR FOXN1, AR PAX1, AR RORγ/RORγT, AR T-bet, AR c-Rel, AD STAT3 gain-of-function (GOF), and loss-of-function (LOF) deficiencies), and 3) IEI mainly affecting myeloid and/or lymphoid function (AR and AD STAT1 LOF, AD STAT1 GOF, AR IRF1, and AD NFKB1 deficiencies). We discuss the contribution of the discovery and study of inborn errors of TFs essential for host defense against mycobacteria to molecular and cellular analyses of human IFN-γ immunity.

  View details for DOI 10.1016/j.coi.2023.102296

  View details for Web of Science ID 000957336100001

  View details for PubMedID 36867972

  View details for PubMedCentralID PMC10023504

• Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children SCIENCE Lee, D., Le Pen, J., Yatim, A., Dong, B., Aquino, Y., Ogishi, M., Pescarmona, R., Talouarn, E., Rinchai, D., Zhang, P., Perret, M., Liu, Z., Jordan, I., Bozdemir, S., Bayhan, G., Beaufils, C., Bizien, L., Bisiaux, A., Lei, W., Hasan, M., Chen, J., Gaughan, C., Asthana, A., Libri, V., Luna, J. M., Jaffre, F., Hoffmann, H., Michailidis, E., Moreews, M., Seeleuthner, Y., Bilguvar, K., Mane, S., Flores, C., Zhang, Y., Arias, A. A., Bailey, R., Schluter, A., Milisavljevic, B., Bigio, B., Le Voyer, T., Materna, M., Gervais, A., Moncada-Velez, M., Pala, F., Lazarov, T., Levy, R., Neehus, A., Rosain, J., Peel, J., Chan, Y., Morin, M., Pino-Ramirez, R., Belkaya, S., Lorenzo, L., Anton, J., Delafontaine, S., Toubiana, J., Bajolle, F., Fumado, V., DeDiego, M. L., Fidouh, N., Rozenberg, F., Perez-Tur, J., Chen, S., Evans, T., Geissmann, F., Lebon, P., Weiss, S. R., Bonnet, D., Duval, X., Pan-Hammarstrom, Q., Planas, A. M., Meyts, I., Haerynck, F., Pujol, A., Sancho-Shimizu, V., Dalgard, C. L., Bustamante, J., Puel, A., Boisson-Dupuis, S., Boisson, B., Maniatis, T., Zhang, Q., Bastard, P., Notarangelo, L., Beziat, V., de Diego, R., Rodriguez-Gallego, C., Su, H. C., Lifton, R. P., Jouanguy, E., Cobat, A., Alsina, L., Keles, S., Haddad, E., Abel, L., Belot, A., Quintana-Murci, L., Rice, C. M., Silverman, R. H., Zhang, S., Casanova, J., CoV Contact Cohort, Covid Human Genetic Effort 2023; 379 (6632): 554-+

  Abstract

  Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.

  View details for DOI 10.1126/science.abo3627

  View details for Web of Science ID 001052667200001

  View details for PubMedID 36538032

  View details for PubMedCentralID PMC10451000

• Human IRF1 governs macrophagic IFN-g immunity to mycobacteria CELL Rosain, J., Neehus, A., Manry, J., Yang, R., Le Pen, J., Daher, W., Liu, Z., Chan, Y., Tahuil, N., Turel, O., Bourgey, M., Ogishi, M., Doisne, J., Izquierdo, H. M., Shirasaki, T., Le Voyer, T., Guerin, A., Bastard, P., Moncada-Velez, M., Han, J., Khan, T., Rapaport, F., Hong, S., Cheung, A., Haake, K., Mindt, B. C., Perez, L., Philippot, Q., Lee, D., Zhang, P., Rinchai, D., Al Ali, F., Ata, M., Rahman, M., Peel, J. N., Heissel, S., Molina, H., Kendir-Demirkol, Y., Bailey, R., Zhao, S., Bohlen, J., Mancini, M., Seeleuthner, Y., Roelens, M., Lorenzo, L., Soudee, C., Paz, M., Gonzalez, M., Jeljeli, M., Soulier, J., Romana, S., L'Honneur, A., Materna, M., Martinez-Barricarte, R., Pochon, M., Oleaga-Quintas, C., Michev, A., Migaud, M., Levy, R., Alyanakian, M., Rozenberg, F., Croft, C. A., Vogt, G., Emile, J., Kremer, L., Ma, C. S., Fritz, J. H., Lemon, S. M., Spaan, A. N., Manel, N., Abel, L., MacDonald, M. R., Boisson-Dupuis, S., Marr, N., Tangye, S. G., Di Santo, J. P., Zhang, Q., Zhang, S., Rice, C. M., Beziat, V., Lachmann, N., Langlais, D., Casanova, J., Gros, P., Bustamante, J. 2023; 186 (3): 621-645.e33

  Abstract

  Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn errors of IFN-α/β-dependent intrinsic immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria and related intramacrophagic pathogens. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-α/β immunity. In leukocytes or fibroblasts stimulated in vitro, IRF1-dependent responses to IFN-γ are, both quantitatively and qualitatively, much stronger than those to IFN-α/β. Moreover, IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ. By contrast, IFN-α/β-dependent intrinsic immunity to nine viruses, including SARS-CoV-2, is almost normal in IRF1-deficient fibroblasts. Human IRF1 is essential for IFN-γ-dependent macrophagic immunity to mycobacteria, but largely redundant for IFN-α/β-dependent antiviral immunity.

  View details for DOI 10.1016/j.cell.2022.12.038

  View details for Web of Science ID 000989740000001

  View details for PubMedID 36736301

  View details for PubMedCentralID PMC9907019

• Human IL-23 is essential for IFN-y-dependent immunity to mycobacteria SCIENCE IMMUNOLOGY Philippot, Q., Ogishi, M., Bohlen, J., Puchan, J., Arias, A., Nguyen, T., Martin-Fernandez, M., Conil, C., Rinchai, D., Momenilandi, M., Mandaviani, S., Keramatipour, M., Rosain, J., Yang, R., Khan, T., Neehus, A., Materna, M., Han, J., Peel, J., Mele, F., Weisshaar, M., Jovic, S., Bastard, P., Levy, R., Le Voyer, T., Zhang, P., Renkilaraj, M., Arango-Franco, C. A., Pelham, S., Seeleuthner, Y., Pochon, M., Ata, M., Al Ali, F., Migaud, M., Soudee, C., Kochetkov, T., Molitor, A., Carapito, R., Bahram, S., Boisson, B., Fieschi, C., Mansouri, D., Marr, N., Okada, S., Shahrooei, M., Parvaneh, N., Chavoshzadeh, Z., Cobat, A., Bogunovic, D., Abel, L., Tangye, S. G., Ma, C. S., Beziat, V., Sallusto, F., Boisson-Dupuis, S., Bustamante, J., Casanova, J., Puel, A. 2023; 8 (80): eabq5204

  Abstract

  Patients with autosomal recessive (AR) IL-12p40 or IL-12Rβ1 deficiency display Mendelian susceptibility to mycobacterial disease (MSMD) due to impaired IFN-γ production and, less commonly, chronic mucocutaneous candidiasis (CMC) due to impaired IL-17A/F production. We report six patients from four kindreds with AR IL-23R deficiency. These patients are homozygous for one of four different loss-of-function IL23R variants. All six patients have a history of MSMD, but only two suffered from CMC. We show that IL-23 induces IL-17A only in MAIT cells, possibly contributing to the incomplete penetrance of CMC in patients unresponsive to IL-23. By contrast, IL-23 is required for both baseline and Mycobacterium-inducible IFN-γ immunity in both Vδ2+ γδ T and MAIT cells, probably contributing to the higher penetrance of MSMD in these patients. Human IL-23 appears to contribute to IL-17A/F-dependent immunity to Candida in a single lymphocyte subset but is required for IFN-γ-dependent immunity to Mycobacterium in at least two lymphocyte subsets.

  View details for DOI 10.1126/sciimmunoLabq5204

  View details for Web of Science ID 000964533700003

  View details for PubMedID 36763636

  View details for PubMedCentralID PMC10069949

• Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency JOURNAL OF EXPERIMENTAL MEDICINE Levy, R., Gothe, F., Momenilandi, M., Magg, T., Materna, M., Peters, P., Raedler, J., Philippot, Q., Rack-Hoch, A., Langlais, D., Bourgey, M., Lanz, A., Ogishi, M., Rosain, J., Martin, E., Latour, S., Vladikine, N., Distefano, M., Khan, T., Rapaport, F., Schulz, M. S., Holzer, U., Fasth, A., Sogkas, G., Speckmann, C., Troilo, A., Bigley, V., Roppelt, A., Dinur-Schejter, Y., Toker, O., Martinsen, K., Sherkat, R., Somekh, I., Somech, R., Shouval, D. S., Kuehl, J., Ip, W., McDermott, E. M., Cliffe, L., Ozen, A., Baris, S., Rangarajan, H. G., Jouanguy, E., Puel, A., Bustamante, J., Alyanakian, M., Fusaro, M., Wang, Y., Kong, X., Cobat, A., Boutboul, D., Castelle, M., Aguilar, C., Hermine, O., Cheminant, M., Suarez, F., Yildiran, A., Bousfiha, A., Al-Mousa, H., Alsohime, F., Cagdas, D., Abraham, R. S., Knutsen, A. P., Fevang, B., Bhattad, S., Kiykim, A., Erman, B., Arikoglu, T., Unal, E., Kumar, A., Geier, C. B., Baumann, U., Neven, B., Rohlfs, M., Walz, C., Abel, L., Malissen, B., Marr, N., Klein, C., Casanova, J., Hauck, F., Beziat, V., CARMIL2 Consortium 2022; 220 (2)

  Abstract

  Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28.

  View details for DOI 10.1084/jem.20220275

  View details for Web of Science ID 000938843500001

  View details for PubMedID 36515678

  View details for PubMedCentralID PMC9754768

• Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis JOURNAL OF EXPERIMENTAL MEDICINE Ogishi, M., Yang, R., Rodriguez, R., Golec, D. P., Martin, E., Philippot, Q., Bohlen, J., Pelham, S. J., Arias, A., Khan, T., Ata, M., Al Ali, F., Rozenberg, F., Kong, X., Chrabieh, M., Laine, C., Lei, W., Han, J., Seeleuthner, Y., Kaul, Z., Jouanguy, E., Beziat, V., Youssefian, L., Vahidnezhad, H., Rao, V., Neven, B., Fieschi, C., Mansouri, D., Shahrooei, M., Pekcan, S., Alkan, G., Emiroglu, M., Tokgoez, H., Uitto, J., Hauck, F., Bustamante, J., Abel, L., Keles, S., Parvaneh, N., Marr, N., Schwartzberg, P. L., Latour, S., Casanova, J., Boisson-Dupuis, S. 2022; 220 (1)

  Abstract

  Inborn errors of IFN-γ immunity can underlie tuberculosis (TB). We report three patients from two kindreds without EBV viremia or disease but with severe TB and inherited complete ITK deficiency, a condition associated with severe EBV disease that renders immunological studies challenging. They have CD4+ αβ T lymphocytopenia with a concomitant expansion of CD4-CD8- double-negative (DN) αβ and Vδ2- γδ T lymphocytes, both displaying a unique CD38+CD45RA+T-bet+EOMES- phenotype. Itk-deficient mice recapitulated an expansion of the γδ T and DN αβ T lymphocyte populations in the thymus and spleen, respectively. Moreover, the patients' T lymphocytes secrete small amounts of IFN-γ in response to TCR crosslinking, mitogens, or forced synapse formation with autologous B lymphocytes. Finally, the patients' total lymphocytes secrete small amounts of IFN-γ, and CD4+, CD8+, DN αβ T, Vδ2+ γδ T, and MAIT cells display impaired IFN-γ production in response to BCG. Inherited ITK deficiency undermines the development and function of various IFN-γ-producing T cell subsets, thereby underlying TB.

  View details for DOI 10.1084/jem.20220484

  View details for Web of Science ID 001062493400001

  View details for PubMedID 36326697

  View details for PubMedCentralID PMC9641312

• Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency JOURNAL OF EXPERIMENTAL MEDICINE Ogishi, M., Augusto Arias, A., Yang, R., Han, J., Zhang, P., Rinchai, D., Halpern, J., Mulwa, J., Keating, N., Chrabieh, M., Laine, C., Seeleuthner, Y., Ramirez-Alejo, N., Nekooie-Marnany, N., Guennoun, A., Muller-Fleckenstein, I., Fleckenstein, B., Kilic, S. S., Minegishi, Y., Ehl, S., Kaiser-Labusch, P., Kendir-Demirkol, Y., Rozenberg, F., Errami, A., Zhang, S., Zhang, Q., Bohlen, J., Puel, A., Jouanguy, E., Pourmoghaddas, Z., Bakhtiar, S., Willasch, A. M., Horneff, G., Llanora, G., Shek, L. P., Chai, L. A., Tay, S., Rahimi, H. H., Mahdaviani, S., Nepesov, S., Bousfiha, A. A., Erdeniz, E., Karbuz, A., Marr, N., Navarrete, C., Adeli, M., Hammarstrom, L., Abolhassani, H., Parvaneh, N., Al Muhsen, S., Alosaimi, M. F., Alsohime, F., Nourizadeh, M., Moin, M., Arnaout, R., Alshareef, S., El-Baghdadi, J., Genel, F., Sherkat, R., Kiykim, A., Yucel, E., Keles, S., Bustamante, J., Abel, L., Casanova, J., Boisson-Dupuis, S. 2022; 219 (10)

  Abstract

  Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.

  View details for DOI 10.1084/jem.20220094

  View details for Web of Science ID 000892570400001

  View details for PubMedID 36094518

  View details for PubMedCentralID PMC9472563

• Human T-bet governs the generation of a distinct subset of CD11c<SUP>high</SUP>CD21<SUP>low</SUP> B cells SCIENCE IMMUNOLOGY Yang, R., Avery, D. T., Jackson, K. L., Ogishi, M., Benhsaien, I., Du, L., Ye, X., Han, J., Rosain, J., Peel, J. N., Alyanakian, M., Neven, B., Winter, S., Puel, A., Boisson, B., Payne, K. J., Wong, M., Russell, A. J., Mizoguchi, Y., Okada, S., Uzel, G., Goodnow, C. C., Latour, S., El Bakkouri, J., Bousfiha, A., Preece, K., Gray, P. E., Keller, B., Warnatz, K., Boisson-Dupuis, S., Abel, L., Pan-Hammarstrom, Q., Bustamante, J., Ma, C. S., Casanova, J., Tangye, S. G. 2022; 7 (73): eabq3277

  Abstract

  High-level expression of the transcription factor T-bet characterizes a phenotypically distinct murine B cell population known as "age-associated B cells" (ABCs). T-bet-deficient mice have reduced ABCs and impaired humoral immunity. We describe a patient with inherited T-bet deficiency and largely normal humoral immunity including intact somatic hypermutation, affinity maturation and memory B cell formation in vivo, and B cell differentiation into Ig-producing plasmablasts in vitro. Nevertheless, the patient exhibited skewed class switching to IgG1, IgG4, and IgE, along with reduced IgG2, both in vivo and in vitro. Moreover, T-bet was required for the in vivo and in vitro development of a distinct subset of human B cells characterized by reduced expression of CD21 and the concomitantly high expression of CD19, CD20, CD11c, FCRL5, and T-bet, a phenotype that shares many features with murine ABCs. Mechanistically, human T-bet governed CD21loCD11chi B cell differentiation by controlling the chromatin accessibility of lineage-defining genes in these cells: FAS, IL21R, SEC61B, DUSP4, DAPP1, SOX5, CD79B, and CXCR4. Thus, human T-bet is largely redundant for long-lived protective humoral immunity but is essential for the development of a distinct subset of human CD11chiCD21lo B cells.

  View details for DOI 10.1126/sciimmunol.abq3277

  View details for Web of Science ID 000852639600008

  View details for PubMedID 35867801

  View details for PubMedCentralID PMC9413977

• Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin SCIENCE Spaan, A. N., Neehus, A., Laplantine, E., Staels, F., Ogishi, M., Seeleuthner, Y., Rapaport, F., Lacey, K. A., Van Nieuwenhove, E., Chrabieh, M., Hum, D., Migaud, M., Izmiryan, A., Lorenzo, L., Kochetkov, T., Heesterbeek, D. C., Bardoel, B. W., DuMont, A. L., Dobbs, K., Chardonnet, S., Heissel, S., Baslan, T., Zhang, P., Yang, R., Bogunovic, D., Wunderink, H. F., Haas, P. A., Molina, H., Van Buggenhout, G., Lyonnet, S., Notarangelo, L. D., Seppanen, M. J., Weil, R., Seminario, G., Gomez-Tello, H., Wouters, C., Mesdaghi, M., Shahrooei, M., Bossuyt, X., Sag, E., Topaloglu, R., Ozen, S., Leavis, H. L., van Eijk, M. J., Bezrodnik, L., Galicia, L., Hovnanian, A., Nassif, A., Bader-Meunier, B., Neven, B., Meyts, I., Schrijvers, R., Puel, A., Bustamante, J., Aksentijevich, I., Kastner, D. L., Torres, V. J., Humblet-Baron, S., Liston, A., Abel, L., Boisson, B., Casanova, J. 2022; 376 (6599): 1285-+

  Abstract

  The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor-mediated nuclear factor κB signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor α-toxin. Naturally elicited antibodies against α-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to α-toxin in nonleukocytic cells.

  View details for DOI 10.1126/science.abm6380

  View details for Web of Science ID 000815052900037

  View details for PubMedID 35587511

  View details for PubMedCentralID PMC9233084

• Human genetic and immunological determinants of critical COVID-19 pneumonia NATURE Zhang, Q., Bastard, P., Cobat, A., Casanova, J., COVID Human Genetic Effort 2022; 603 (7902): 587-598

  Abstract

  SARS-CoV-2 infection is benign in most individuals but, in around 10% of cases, it triggers hypoxaemic COVID-19 pneumonia, which leads to critical illness in around 3% of cases. The ensuing risk of death (approximately 1% across age and gender) doubles every five years from childhood onwards and is around 1.5 times greater in men than in women. Here we review the molecular and cellular determinants of critical COVID-19 pneumonia. Inborn errors of type I interferons (IFNs), including autosomal TLR3 and X-chromosome-linked TLR7 deficiencies, are found in around 1-5% of patients with critical pneumonia under 60 years old, and a lower proportion in older patients. Pre-existing auto-antibodies neutralizing IFNα, IFNβ and/or IFNω, which are more common in men than in women, are found in approximately 15-20% of patients with critical pneumonia over 70 years old, and a lower proportion in younger patients. Thus, at least 15% of cases of critical COVID-19 pneumonia can be explained. The TLR3- and TLR7-dependent production of type I IFNs by respiratory epithelial cells and plasmacytoid dendritic cells, respectively, is essential for host defence against SARS-CoV-2. In ways that can depend on age and sex, insufficient type I IFN immunity in the respiratory tract during the first few days of infection may account for the spread of the virus, leading to pulmonary and systemic inflammation.

  View details for DOI 10.1038/s41586-022-04447-0

  View details for Web of Science ID 000769826700001

  View details for PubMedID 35090163

  View details for PubMedCentralID PMC8957595

• Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child. Nature medicine Ogishi, M., Yang, R., Aytekin, C., Langlais, D., Bourgey, M., Khan, T., Ali, F. A., Rahman, M., Delmonte, O. M., Chrabieh, M., Zhang, P., Gruber, C., Pelham, S. J., Spaan, A. N., Rosain, J., Lei, W. T., Drutman, S., Hellmann, M. D., Callahan, M. K., Adamow, M., Wong, P., Wolchok, J. D., Rao, G., Ma, C. S., Nakajima, Y., Yaguchi, T., Chamoto, K., Williams, S. C., Emile, J. F., Rozenberg, F., Glickman, M. S., Rapaport, F., Kerner, G., Allington, G., Tezcan, I., Cagdas, D., Hosnut, F. O., Dogu, F., Ikinciogullari, A., Rao, V. K., Kainulainen, L., Béziat, V., Bustamante, J., Vilarinho, S., Lifton, R. P., Boisson, B., Abel, L., Bogunovic, D., Marr, N., Notarangelo, L. D., Tangye, S. G., Honjo, T., Gros, P., Boisson-Dupuis, S., Casanova, J. L. 2021; 27 (9): 1646-1654

  Abstract

  The pathophysiology of adverse events following programmed cell death protein 1 (PD-1) blockade, including tuberculosis (TB) and autoimmunity, remains poorly characterized. We studied a patient with inherited PD-1 deficiency and TB who died of pulmonary autoimmunity. The patient's leukocytes did not express PD-1 or respond to PD-1-mediated suppression. The patient's lymphocytes produced only small amounts of interferon (IFN)-γ upon mycobacterial stimuli, similarly to patients with inborn errors of IFN-γ production who are vulnerable to TB. This phenotype resulted from a combined depletion of Vδ2+ γδ T, mucosal-associated invariant T and CD56bright natural killer lymphocytes and dysfunction of other T lymphocyte subsets. Moreover, the patient displayed hepatosplenomegaly and an expansion of total, activated and RORγT+ CD4-CD8- double-negative αβ T cells, similar to patients with STAT3 gain-of-function mutations who display lymphoproliferative autoimmunity. This phenotype resulted from excessive amounts of STAT3-activating cytokines interleukin (IL)-6 and IL-23 produced by activated T lymphocytes and monocytes, and the STAT3-dependent expression of RORγT by activated T lymphocytes. Our work highlights the indispensable role of human PD-1 in governing both antimycobacterial immunity and self-tolerance, while identifying potentially actionable molecular targets for the diagnostic and therapeutic management of TB and autoimmunity in patients on PD-1 blockade.

  View details for DOI 10.1038/s41591-021-01388-5

  View details for PubMedID 34183838

  View details for PubMedCentralID PMC8446316

• X-linked recessive TLR7 deficiency in ∼1% of men under 60 years old with life-threatening COVID-19 SCIENCE IMMUNOLOGY Asano, T., Boisson, B., Onodi, F., Matuozzo, D., Moncada-Velez, M., Renkilaraj, M., Zhang, P., Meertens, L., Bolze, A., Materna, M., Korniotis, S., Gervais, A., Talouarn, E., Bigio, B., Seeleuthner, Y., Bilguvar, K., Zhang, Y., Neehus, A., Ogishi, M., Pelham, S. J., Le Voyer, T., Rosain, J., Philippot, Q., Soler-Palacin, P., Colobran, R., Martin-Nalda, A., Riviere, J. G., Tandjaoui-Lambiotte, Y., Chaibi, K., Shahrooei, M., Darazam, I., Olyaei, N., Mansouri, D., Palabiyik, F., Ozcelik, T., Novelli, G., Novelli, A., Casari, G., Aiuti, A., Carrera, P., Bondesan, S., Barzaghi, F., Rovere-Querini, P., Tresoldi, C., Franco, J., Rojas, J., Reyes, L., Bustos, I. G., Arias, A., Morelle, G., Kyheng, C., Troya, J., Planas-Serra, L., Schluter, A., Gut, M., Pujol, A., Allende, L. M., Rodriguez-Gallego, C., Flores, C., Cabrera-Marante, O., Pleguezuelo, D. E., de Diego, R., Keles, S., Aytekin, G., Akcan, O., Bryceson, Y. T., Bergman, P., Brodin, P., Smole, D., Smith, C., Norlin, A., Campbell, T. M., Covill, L. E., Hammarstrom, L., Pan-Hammarstrom, Q., Abolhassani, H., Mane, S., Marr, N., Ata, M., Al Ali, F., Khan, T., Spaan, A. N., Dalgard, C. L., Bonfanti, P., Biondi, A., Tubiana, S., Burdet, C., Nussbaum, R., Kahn-Kirby, A., Snow, A. L., Bustamante, J., Puel, A., Boisson-Dupuis, S., Zhang, S., Beziat, V., Lifton, R. P., Bastard, P., Notarangelo, L. D., Abel, L., Su, H. C., Jouanguy, E., Amara, A., Soumelis, V., Cobat, A., Zhang, Q., Casanova, J., COVID Human Genetic Efft, COVID-STORM Cliniciano, COVID Clinicians, Imagine COVID Grp, French COVID Cohort Study Grp, Cov-Contact Cohort, Amsterdam UMC Covid-19 Biobank, NIAID-USUHS Covid Study Grp 2021; 6 (62)

  Abstract

  Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 × 10-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10-4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.

  View details for DOI 10.1126/sciimmunol.abl4348

  View details for Web of Science ID 000695969700003

  View details for PubMedID 34413140

  View details for PubMedCentralID PMC8532080

• Inherited deficiency of stress granule ZNFX1 in patients with monocytosis and mycobacterial disease PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Voyer, T., Neehus, A., Yang, R., Ogishi, M., Rosain, J., Alroqi, F., Alshalan, M., Blumental, S., Al Ali, F., Khan, T., Ata, M., Rozen, L., Demulder, A., Bastard, P., Gruber, C., Roynard, M., Seeleuthener, Y., Rapaport, F., Bigio, B., Chrabieh, M., Sng, D., Berteloot, L., Boddaert, N., Rozenberg, F., Al-Muhsen, S., Bertoli-Avella, A., Abel, L., Bogunovic, D., Marr, N., Mansouri, D., Al Mutairi, F., Beziat, V., Weil, D., Mahdaviani, S., Ferster, A., Zhang, S., Reversade, B., Boisson-Dupuis, S., Casanova, J., Bustamante, J. 2021; 118 (15)

  Abstract

  Human inborn errors of IFN-γ underlie mycobacterial disease, due to insufficient IFN-γ production by lymphoid cells, impaired myeloid cell responses to this cytokine, or both. We report four patients from two unrelated kindreds with intermittent monocytosis and mycobacterial disease, including bacillus Calmette-Guérin-osis and disseminated tuberculosis, and without any known inborn error of IFN-γ. The patients are homozygous for ZNFX1 variants (p.S959* and p.E1606Rfs*10) predicted to be loss of function (pLOF). There are no subjects homozygous for pLOF variants in public databases. ZNFX1 is a conserved and broadly expressed helicase, but its biology remains largely unknown. It is thought to act as a viral double-stranded RNA sensor in mice, but these patients do not suffer from severe viral illnesses. We analyze its subcellular localization upon overexpression in A549 and HeLa cell lines and upon stimulation of THP1 and fibroblastic cell lines. We find that this cytoplasmic protein can be recruited to or even induce stress granules. The endogenous ZNFX1 protein in cell lines of the patient homozygous for the p.E1606Rfs*10 variant is truncated, whereas ZNFX1 expression is abolished in cell lines from the patients with the p.S959* variant. Lymphocyte subsets are present at normal frequencies in these patients and produce IFN-γ normally. The hematopoietic and nonhematopoietic cells of the patients tested respond normally to IFN-γ. Our results indicate that human ZNFX1 is associated with stress granules and essential for both monocyte homeostasis and protective immunity to mycobacteria.

  View details for DOI 10.1073/pnas.2102804118

  View details for Web of Science ID 000640381300015

  View details for PubMedID 33876776

  View details for PubMedCentralID PMC8053974

• Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents JOURNAL OF CLINICAL INVESTIGATION Levy, R., Langlais, D., Beziat, V., Rapaport, F., Rao, G., Lazarov, T., Bourgey, M., Zhou, Y. J., Briand, C., Moriya, K., Ailal, F., Avery, D. T., Markle, J., Lim, A., Ogishi, M., Yang, R., Pelham, S., Emam, M., Migaud, M., Deswarte, C., Habib, T., Saraiva, L. R., Moussa, E. A., Guennoun, A., Boisson, B., Belkaya, S., Martinez-Barricarte, R., Rosain, J., Belkadi, A., Breton, S., Payne, K., Benhsaien, I., Plebani, A., Lougaris, V., Di Santo, J. P., Neven, B., Abel, L., Ma, C. S., Bousfiha, A., Marr, N., Bustamante, J., Liu, K., Gros, P., Geissmann, F., Tangye, S. G., Casanova, J., Puel, A. 2021; 131 (17)

  Abstract

  We studied a child with severe viral, bacterial, fungal, and parasitic diseases, who was homozygous for a loss-of-function mutation of REL, encoding c-Rel, which is selectively expressed in lymphoid and myeloid cells. The patient had low frequencies of NK, effector memory cells reexpressing CD45RA (Temra) CD8+ T cells, memory CD4+ T cells, including Th1 and Th1*, Tregs, and memory B cells, whereas the counts and proportions of other leukocyte subsets were normal. Functional deficits of myeloid cells included the abolition of IL-12 and IL-23 production by conventional DC1s (cDC1s) and monocytes, but not cDC2s. c-Rel was also required for induction of CD86 expression on, and thus antigen-presenting cell function of, cDCs. Functional deficits of lymphoid cells included reduced IL-2 production by naive T cells, correlating with low proliferation and survival rates and poor production of Th1, Th2, and Th17 cytokines by memory CD4+ T cells. In naive CD4+ T cells, c-Rel is dispensable for early IL2 induction but contributes to later phases of IL2 expression. The patient's naive B cells displayed impaired MYC and BCL2L1 induction, compromising B cell survival and proliferation and preventing their differentiation into Ig-secreting plasmablasts. Inherited c-Rel deficiency disrupts the development and function of multiple myeloid and lymphoid cells, compromising innate and adaptive immunity to multiple infectious agents.

  View details for DOI 10.1172/JCI150143

  View details for Web of Science ID 000755619500016

  View details for PubMedID 34623332

  View details for PubMedCentralID PMC8409595

• Multibatch Cytometry Data Integration for Optimal Immunophenotyping JOURNAL OF IMMUNOLOGY Ogishi, M., Yang, R., Gruber, C., Zhang, P., Pelham, S. J., Spaan, A. N., Rosain, J., Chbihi, M., Han, J., Rao, V., Kainulainen, L., Bustamante, J., Boisson, B., Bogunovic, D., Boisson-Dupuis, S., Casanova, J. 2021; 206 (1): 206-+

  Abstract

  High-dimensional cytometry is a powerful technique for deciphering the immunopathological factors common to multiple individuals. However, rational comparisons of multiple batches of experiments performed on different occasions or at different sites are challenging because of batch effects. In this study, we describe the integration of multibatch cytometry datasets (iMUBAC), a flexible, scalable, and robust computational framework for unsupervised cell-type identification across multiple batches of high-dimensional cytometry datasets, even without technical replicates. After overlaying cells from multiple healthy controls across batches, iMUBAC learns batch-specific cell-type classification boundaries and identifies aberrant immunophenotypes in patient samples from multiple batches in a unified manner. We illustrate unbiased and streamlined immunophenotyping using both public and in-house mass cytometry and spectral flow cytometry datasets. The method is available as the R package iMUBAC (https://github.com/casanova-lab/iMUBAC).

  View details for DOI 10.4049/jimmunol.2000854

  View details for Web of Science ID 000601307900019

  View details for PubMedID 33229441

  View details for PubMedCentralID PMC7855665

• Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria CELL Yang, R., Mele, F., Worley, L., Langlais, D., Rosain, J., Benhsaien, I., Elarabi, H., Croft, C. A., Doisne, J., Zhang, P., Weisshaar, M., Jarrossay, D., Latorre, D., Shen, Y., Han, J., Ogishi, M., Gruber, C., Markle, J., Al Ali, F., Rahman, M., Khan, T., Seeleuthner, Y., Kerner, G., Husquin, L. T., Maclsaac, J. L., Jeljeli, M., Errami, A., Ailal, F., Kobor, M. S., Oleaga-Quintas, C., Roynard, M., Bourgey, M., El Baghdadi, J., Boisson-Dupuis, S., Puel, A., Batteux, F., Rozenberg, F., Marr, N., Pan-Hammarstrom, Q., Bogunovic, D., Quintana-Murci, L., Carroll, T., Ma, C. S., Abel, L., Bousfiha, A., Di Santo, J. P., Glimcher, L. H., Gros, P., Tangye, S. G., Sallusto, F., Bustamante, J., Casanova, J. 2020; 183 (7): 1826-+

  Abstract

  Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes, and of Mycobacterium-non reactive classic TH1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8+ αβ T and non-classic CD4+ αβ TH1∗ lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2+ γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8+ αβ T, and CD4+ αβ TH1∗ cells unable to compensate for this deficit.

  View details for DOI 10.1016/j.cell.2020.10.046

  View details for Web of Science ID 000602900800009

  View details for PubMedID 33296702

  View details for PubMedCentralID PMC7770098

• Autoantibodies against type I IFNs in patients with life-threatening COVID-19 SCIENCE Bastard, P., Rosen, L. B., Zhang, Q., Michailidis, E., Hoffmann, H., Zhang, Y., Dorgham, K., Philippot, Q., Rosain, J., Beziat, V., Manry, J., Shaw, E., Haljasmagi, L., Peterson, P., Lorenzo, L., Bizien, L., Trouillet-Assant, S., Dobbs, K., de Jesus, A., Belot, A., Kallaste, A., Catherinot, E., Tandjaoui-Lambiotte, Y., Le Pen, J., Kerner, G., Bigio, B., Seeleuthner, Y., Yang, R., Bolze, A., Spaan, A. N., Delmonte, O. M., Abers, M. S., Aiuti, A., Casari, G., Lampasona, V., Piemonti, L., Ciceri, F., Bilguvar, K., Lifton, R. P., Vasse, M., Smadja, D. M., Migaud, M., Hadjadj, J., Terrier, B., Duffy, D., Quintana-Murci, L., van de Beek, D., Roussel, L., Vinh, D. C., Tangye, S. G., Haerynck, F., Dalmau, D., Martinez-Picado, J., Brodin, P., Nussenzweig, M. C., Boisson-Dupuis, S., Rodriguez-Gallego, C., Vogt, G., Mogensen, T. H., Oler, A. J., Gu, J., Burbelo, P. D., Cohen, J. I., Biondi, A., Bettini, L., D'Angio, M., Bonfanti, P., Rossignol, P., Mayaux, J., Rieux-Laucat, F., Husebye, E. S., Fusco, F., Ursini, M., Imberti, L., Sottini, A., Paghera, S., Quiros-Roldan, E., Rossi, C., Castagnoli, R., Montagna, D., Licari, A., Marseglia, G., Duval, X., Ghosn, J., Tsang, J. S., Goldbach-Mansky, R., Kisand, K., Lionakis, M. S., Puel, A., Zhang, S., Holland, S. M., Gorochov, G., Jouanguy, E., Rice, C. M., Cobat, A., Notarangelo, L. D., Abel, L., Su, H. C., Casanova, J., HGID Lab, NIAID-USUHS Immune Response COVID, COVID Clinicians, COVID-STORM Clinicians, Imagine COVID Grp, French COVID Cohort Study Grp, Milieu Interieur Consortium, CoV-Contact Cohort, Amsterdam UMC Covid-19 Biobank, COVID Human Genetic Effort 2020; 370 (6515): 423-+

  Abstract

  Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

  View details for DOI 10.1126/science.abd4585

  View details for Web of Science ID 000581077200035

  View details for PubMedID 32972996

  View details for PubMedCentralID PMC7857397

• Inborn errors of type I IFN immunity in patients with life-threatening COVID-19 SCIENCE Zhang, Q., Bastard, P., Liu, Z., Le Pen, J., Moncada-Velez, M., Chen, J., Ogishi, M., Sabli, I. D., Hodeib, S., Korol, C., Rosain, J., Bilguvar, K., Ye, J., Bolze, A., Bigio, B., Yang, R., Arias, A., Zhou, Q., Zhang, Y., Onodi, F., Korniotis, S., Karpf, L., Philippot, Q., Chbihi, M., Bonnet-Madin, L., Dorgham, K., Smith, N., Schneider, W. M., Razooky, B. S., Hoffmann, H., Michailidis, E., Moens, L., Han, J., Lorenzo, L., Bizien, L., Meade, P., Neehus, A., Ugurbil, A., Corneau, A., Kerner, G., Zhang, P., Rapaport, F., Seeleuthner, Y., Manry, J., Masson, C., Schmitt, Y., Schlueter, A., Le Voyer, T., Khan, T., Li, J., Fellay, J., Roussel, L., Shahrooei, M., Alosaimi, M. F., Mansouri, D., Al-Saud, H., Al-Mulla, F., Almourfi, F., Al-Muhsen, S., Alsohime, F., Al Turki, S., Hasanato, R., van de Beek, D., Biondi, A., Bettini, L., D'Angio, M., Bonfanti, P., Imberti, L., Sottini, A., Paghera, S., Quiros-Roldan, E., Rossi, C., Oler, A. J., Tompkins, M. F., Alba, C., Vandernoot, I., Goffard, J., Smits, G., Migeotte, I., Haerynck, F., Soler-Palacin, P., Martin-Nalda, A., Colobran, R., Morange, P., Keles, S., Colkesen, F., Ozcelik, T., Yasar, K., Senoglu, S., Karabela, S., Rodriguez-Gallego, C., Novelli, G., Hraiech, S., Tandjaoui-Lambiotte, Y., Duval, X., Laouenan, C., Snow, A. L., Dalgard, C. L., Milner, J. D., Vinh, D. C., Mogensen, T. H., Marr, N., Spaan, A. N., Boisson, B., Boisson-Dupuis, S., Bustamante, J., Puel, A., Ciancanelli, M. J., Meyts, I., Maniatis, T., Soumelis, V., Amara, A., Nussenzweig, M., Garcia-Sastre, A., Krammer, F., Pujol, A., Duffy, D., Lifton, R. P., Zhang, S., Gorochov, G., Beziat, V., Jouanguy, E., Sancho-Shimizu, V., Rice, C. M., Abel, L., Notarangelo, L. D., Cobat, A., Su, H. C., Casanova, J., COVID-STORM Clinicians, COVID Clinicians, Imagine COVID Grp, French COVID Cohort Study Grp, CoV-Contact Cohort, Amsterdam UMC Covid-19 Biobank, COVID Human Genetic Effort, NIAID-USUHS, TAGC COVID Immunity Grp 2020; 370 (6515)

  Abstract

  Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

  View details for DOI 10.1126/science.abd4570

  View details for Web of Science ID 000581077200034

  View details for PubMedID 32972995

  View details for PubMedCentralID PMC7857407

• Comparison of the Clinical Features of Hepatitis A in People Living with HIV between Pandemics in 1999-2000 and 2017-2018 in the Metropolitan Area of Japan JAPANESE JOURNAL OF INFECTIOUS DISEASES Koga, M., Lim, L., Ogishi, M., Satoh, H., Kikuchi, T., Adachi, E., Sugiyama, R., Kiyohara, T., Suzuki, R., Muramatsu, M., Koibuchi, T., Tsutsumi, T., Yotsuyanagi, H. 2020; 73 (2): 89-95

  Abstract

  Since 2017, hepatitis A virus (HAV) infection has been an epidemic among men who have sex with men (MSM) in Japan. We have come across 11 MSM patients with hepatitis A who were also infected with HIV. In 1999-2000, we came across 5 HIV-infected patients with hepatitis A. Since the conditions of current HIV-infected patients have changed owing to the recent progress in anti-HIV therapies, we compared clinical features of hepatitis A between patients in 2017-2018 and those in 1999-2000. By comparing the background characteristics of the patients, we found that the CD4/CD8 ratio was significantly higher in the 2017-2018 group. After the onset of hepatitis, peak levels of hepatic transaminases were found to be higher in the 2017-2018 group, suggesting severe hepatocellular damage. In contrast, neither the peak level of total bilirubin nor the nadir of prothrombin time was significantly different among the 2 groups. We also analyzed the HAV genome derived from some of the recently infected patients, and found that the HAV strains were almost the same among these patients; slight differences were observed from the previously identified strain. Thus, we concluded that the recovery of immunity by recent anti-HIV therapies may result in more severe hepatocellular damages and differences in clinical features.

  View details for DOI 10.7883/yoken.JJID.2019.275

  View details for Web of Science ID 000606606800001

  View details for PubMedID 31666497

• Homozygosity for <i>TYK2</i> P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Kerner, G., Ramirez-Alejo, N., Seeleuthner, Y., Yang, R., Ogishi, M., Cobat, A., Patin, E., Quintana-Murci, L., Boisson-Dupuis, S., Casanova, J., Abel, L. 2019; 116 (21): 10430-10434

  Abstract

  The human genetic basis of tuberculosis (TB) has long remained elusive. We recently reported a high level of enrichment in homozygosity for the common TYK2 P1104A variant in a heterogeneous cohort of patients with TB from non-European countries in which TB is endemic. This variant is homozygous in ∼1/600 Europeans and ∼1/5,000 people from other countries outside East Asia and sub-Saharan Africa. We report a study of this variant in the UK Biobank cohort. The frequency of P1104A homozygotes was much higher in patients with TB (6/620, 1%) than in controls (228/114,473, 0.2%), with an odds ratio (OR) adjusted for ancestry of 5.0 [95% confidence interval (CI): 1.96-10.31, P = 2 × 10-3]. Conversely, we did not observe enrichment for P1104A heterozygosity, or for TYK2 I684S or V362F homozygosity or heterozygosity. Moreover, it is unlikely that more than 10% of controls were infected with Mycobacterium tuberculosis, as 97% were of European genetic ancestry, born between 1939 and 1970, and resided in the United Kingdom. Had all of them been infected, the OR for developing TB upon infection would be higher. These findings suggest that homozygosity for TYK2 P1104A may account for ∼1% of TB cases in Europeans.

  View details for DOI 10.1073/pnas.1903561116

  View details for Web of Science ID 000468403400043

  View details for PubMedID 31068474

  View details for PubMedCentralID PMC6534977

• Quantitative Prediction of the Landscape of T Cell Epitope Immunogenicity in Sequence Space FRONTIERS IN IMMUNOLOGY Ogishi, M., Yotsuyanagi, H. 2019; 10: 827

  Abstract

  Immunodominant T cell epitopes preferentially targeted in multiple individuals are the critical element of successful vaccines and targeted immunotherapies. However, the underlying principles of this "convergence" of adaptive immunity among different individuals remain poorly understood. To quantitatively describe epitope immunogenicity, here we propose a supervised machine learning framework generating probabilistic estimates of immunogenicity, termed "immunogenicity scores," based on the numerical features computed through sequence-based simulation approximating the molecular scanning process of peptides presented onto major histocompatibility complex (MHC) by the human T cell receptor (TCR) repertoire. Notably, overlapping sets of intermolecular interaction parameters were commonly utilized in MHC-I and MHC-II prediction. Moreover, a similar simulation of individual TCR-peptide interaction using the same set of interaction parameters yielded correlates of TCR affinity. Pathogen-derived epitopes and tumor-associated epitopes with positive T cell reactivity generally had higher immunogenicity scores than non-immunogenic counterparts, whereas thymically expressed self-epitopes were assigned relatively low scores regardless of their immunogenicity annotation. Immunogenicity score dynamics among single amino acid mutants delineated the landscape of position- and residue-specific mutational impacts. Simulation of position-specific immunogenicity score dynamics detected residues with high escape potential in multiple epitopes, consistent with known escape mutations in the literature. This study indicates that targeting of epitopes by human adaptive immunity is to some extent directed by defined thermodynamic principles. The proposed framework also has a practical implication in that it may enable to more efficiently prioritize epitope candidates highly prone to T cell recognition in multiple individuals, warranting prospective validation across different cohorts.

  View details for DOI 10.3389/fimmu.2019.00827

  View details for Web of Science ID 000464588900001

  View details for PubMedID 31057550

  View details for PubMedCentralID PMC6477061

• Prediction of HIV-associated neurocognitive disorder (HAND) from three genetic features of envelope gp120 glycoprotein RETROVIROLOGY Ogishi, M., Yotsuyanagi, H. 2018; 15: 12

  Abstract

  HIV-associated neurocognitive disorder (HAND) remains an important and yet potentially underdiagnosed manifestation despite the fact that the modern combination antiretroviral therapy (cART) has achieved effective viral suppression and greatly reduced the incidence of life-threatening events. Although HIV neurotoxicity is thought to play a central role, the potential of viral genetic signature as diagnostic and/or prognostic biomarker has yet to be fully explored.Using a manually curated sequence metadataset (80 specimens, 2349 sequences), we demonstrated that only three genetic features are sufficient to predict HAND status regardless of sampling tissues; the accuracy reached 100 and 94% in the hold-out testing subdataset and the entire dataset, respectively. The three genetic features stratified HAND into four distinct clusters. Extrapolating the classification to the 1619 specimens registered in the Los Alamos HIV Sequence Database, the global HAND prevalence was estimated to be 46%, with significant regional variations (30-71%). The R package HANDPrediction was implemented to ensure public availability of key codes.Our analysis revealed three amino acid positions in gp120 glycoprotein, providing the basis of the development of novel cART regimens specifically optimized for HAND-associated quasispecies. Moreover, the classifier can readily be translated into a diagnostic biomarker, warranting prospective validation.

  View details for DOI 10.1186/s12977-018-0401-x

  View details for Web of Science ID 000423440000001

  View details for PubMedID 29374475

  View details for PubMedCentralID PMC5787250

• Delineation of autoantibody repertoire through differential proteogenomics in hepatitis C virus-induced cryoglobulinemia SCIENTIFIC REPORTS Ogishi, M., Yotsuyanagi, H., Moriya, K., Koike, K. 2016; 6: 29532

  Abstract

  Antibodies cross-reactive to pathogens and autoantigens are considered pivotal in both infection control and accompanying autoimmunity. However, the pathogenic roles of autoantibodies largely remain elusive without a priori knowledge of disease-specific autoantigens. Here, through a novel quantitative proteogenomics approach, we demonstrated a successful identification of immunoglobulin variable heavy chain (VH) sequences highly enriched in pathological immune complex from clinical specimens obtained from a patient with hepatitis C virus-induced cryoglobulinemia (HCV-CG). Reconstructed single-domain antibodies were reactive to both HCV antigens and potentially liver-derived human proteins. Moreover, over the course of antiviral therapy, a substantial "de-evolution" of a distinct sub-repertoire was discovered, to which proteomically identified cryoprecipitation-prone autoantibodies belonged. This sub-repertoire was characterized by IGHJ6*03-derived, long, hydrophobic complementarity determining region (CDR-H3). This study provides a proof-of-concept of de novo mining of autoantibodies and corresponding autoantigen candidates in a disease-specific context in human, thus facilitating future reverse-translational research for the discovery of novel biomarkers and the development of antigen-specific immunotherapy against various autoantibody-related disorders.

  View details for DOI 10.1038/srep29532

  View details for Web of Science ID 000379389300004

  View details for PubMedID 27403724

  View details for PubMedCentralID PMC4941579

• Deconvoluting the Composition of Low-Frequency Hepatitis C Viral Quasispecies: Comparison of Genotypes and NS3 Resistance-Associated Variants between HCV/HIV Coinfected Hemophiliacs and HCV Monoinfected Patients in Japan PLOS ONE Ogishi, M., Yotsuyanagi, H., Tsutsumi, T., Gatanaga, H., Ode, H., Sugiura, W., Moriya, K., Oka, S., Kimura, S., Koike, K. 2015; 10 (3): e0119145

  Abstract

  Pre-existing low-frequency resistance-associated variants (RAVs) may jeopardize successful sustained virological responses (SVR) to HCV treatment with direct-acting antivirals (DAAs). However, the potential impact of low-frequency (∼0.1%) mutations, concatenated mutations (haplotypes), and their association with genotypes (Gts) on the treatment outcome has not yet been elucidated, most probably owing to the difficulty in detecting pre-existing minor haplotypes with sufficient length and accuracy. Herein, we characterize a methodological framework based on Illumina MiSeq next-generation sequencing (NGS) coupled with bioinformatics of quasispecies reconstruction (QSR) to realize highly accurate variant calling and genotype-haplotype detection. The core-to-NS3 protease coding sequences in 10 HCV monoinfected patients, 5 of whom had a history of blood transfusion, and 11 HCV/HIV coinfected patients with hemophilia, were studied. Simulation experiments showed that, for minor variants constituting more than 1%, our framework achieved a positive predictive value (PPV) of 100% and sensitivities of 91.7-100% for genotyping and 80.6% for RAV screening. Genotyping analysis indicated the prevalence of dominant Gt1a infection in coinfected patients (6/11 vs 0/10, p = 0.01). For clinical samples, minor genotype overlapping infection was prevalent in HCV/HIV coinfected hemophiliacs (10/11) and patients who experienced whole-blood transfusion (4/5) but none in patients without exposure to blood (0/5). As for RAV screening, the Q80K/R and S122K/R variants were particularly prevalent among minor RAVs observed, detected in 12/21 and 6/21 cases, respectively. Q80K was detected only in coinfected patients, whereas Q80R was predominantly detected in monoinfected patients (1/11 vs 7/10, p < 0.01). Multivariate interdependence analysis revealed the previously unrecognized prevalence of Gt1b-Q80K, in HCV/HIV coinfected hemophiliacs [Odds ratio = 13.4 (3.48-51.9), p < 0.01]. Our study revealed the distinct characteristics of viral quasispecies between the subgroups specified above and the feasibility of NGS and QSR-based genetic deconvolution of pre-existing minor Gts, RAVs, and their interrelationships.

  View details for DOI 10.1371/journal.pone.0119145

  View details for Web of Science ID 000350689400049

  View details for PubMedID 25748426

  View details for PubMedCentralID PMC4351984

• Obesity-Associated Autoantibody Production Requires AIM to Retain the Immunoglobulin M Immune Complex on Follicular Dendritic Cells CELL REPORTS Arai, S., Maehara, N., Iwamura, Y., Honda, S., Nakashima, K., Kai, T., Ogishi, M., Morita, K., Kurokawa, J., Mori, M., Motoi, Y., Miyake, K., Matsuhashi, N., Yamamura, K., Ohara, O., Shibuya, A., Wakeland, E. K., Li, Q., Miyazaki, T. 2013; 3 (4): 1187-1198

  Abstract

  Natural immunoglobulin M (IgM) is reactive to autoantigens and is believed to be important for autoimmunity. Blood pentameric IgM loaded with antigens forms a large immune complex (IC) that contains various elements, including apoptosis inhibitor of macrophage (AIM). Here we demonstrate that this IgM-AIM association contributes to autoantibody production under obese conditions. In mice fed a high-fat diet, natural IgM increased through B cell TLR4 stimulation. AIM associated with IgM and protected AIM from renal excretion, increasing blood AIM levels along with the obesity-induced IgM augmentation. Meanwhile, the AIM association inhibited IgM binding to the Fcα/μ receptor on splenic follicular dendritic cells, thereby protecting the IgM IC from Fcα/μ receptor-mediated internalization. This supported IgM-dependent autoantigen presentation to B cells, stimulating IgG autoantibody production. Accordingly, in obese AIM-deficient (AIM(-/-)) mice, the increase of multiple IgG autoantibodies observed in obese wild-type mice was abrogated. Thus, the AIM-IgM association plays a critical role in the obesity-associated autoimmune process.

  View details for DOI 10.1016/j.celrep.2013.03.006

  View details for Web of Science ID 000321897100023

  View details for PubMedID 23562157