{"id":21200,"date":"2022-03-08T16:13:02","date_gmt":"2022-03-08T15:13:02","guid":{"rendered":"https:\/\/www.resist-cluster.de\/?page_id=21200"},"modified":"2024-12-05T15:55:27","modified_gmt":"2024-12-05T14:55:27","slug":"project-a5","status":"publish","type":"page","link":"https:\/\/www.resist-cluster.de\/en\/research\/project-area-a\/project-a5\/","title":{"rendered":"Project A5"},"content":{"rendered":"

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What genetic changes predispose people to infections?<\/h1><\/div>

Prof. Proietti<\/a><\/p><\/h2><\/div>

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What is this research project about?<\/h1><\/div>
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Diagramm of the immunogentetic plattform Gemma<\/p>\n<\/div>

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What is this research project about?<\/h1><\/div>

We aim to understand why the immune system of some individuals is unable to fight infections or control inflammation as the one of most of the people does. We are in particular interest in understanding how genetic could explain this variability.<\/p>\n

For our research work, we use the immunogenetic platform Gemma – a database in which resources and research data are stored. It can be used, for example, to automatically generate genetic research reports and to harmonise and accelerate the collection of clinical metadata.<\/p>\n<\/div>

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What’s the current status?<\/h1><\/div>
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When suspecting Inborn Errors of Immunity, the genetic diagnosis is often negative or ambiguous and clear disease-causing mutations cannot be detected. We assume that this is due to both the technical limitations of current sequencing platforms and a lack of knowledge.<\/p>\n

The figure illustrates the relationship between the number of people who receive a clinical diagnosis and the number of people for whom a genetic diagnosis is possible.<\/p>\n<\/div>

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Example of genetic data queried from Gemma<\/p>\n<\/div>

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What are the project goals?<\/h1><\/div>

We want to identify genetic alterations that predispose people to infections and immune-mediated diseases. The long-term goal is to ensure that all patients with congenital immunodeficiency around the world have an equal chance of genetic diagnosis.<\/p>\n<\/div><\/div><\/div>

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How do we get there?<\/h1><\/div>
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The genetic architecture of complex human diseases, which include Inborn Errors of Immunity, is likely to be influenced by several components. Among them are common and rare genetic variants, structural variants and gene-gene and gene-environment interactions. As a result, we need to expand the list of possible candidates on the one hand, while revising our assumptions about monogenic or oligogenic causality in many situations on the other.<\/p>\n

In order to improve technology (e.g. optical genome mapping) and knowledge (clinical, genetic and molecular expertise as well as data) related to congenital immune disorders, we are currently establishing a joint “Freiburg-Hannover ImmunoGenetics Research Unit” (FH-IGRU). In this unit, we are combining the expertise and resources of the Institute of Human Genetics and the Department of Rheumatology and Immunology of the MHH with those of the Genetics and Genomics Unit of the CCI \/ IFI at the University Hospital of Freiburg.<\/p>\n

In order to be able to efficiently analyse the large amount of genetic data, we have developed the immunogenetics platform GemmaDB. In addition, a subset of publicly available data has been made available on the internet in a satellite project (www.GeniaDB.net<\/a>). Unlike other databases, which are mainly composed of computerised and linked information, GeniaDB will ensure that synthesized and evolving information is included – clinical and genetic paradigms and pitfalls, as well as new concepts and considerations specific to each patient situation, gene and disease. GenIA will also be a practical tool for healthcare providers to help them improve their genetic and functional testing strategies, interpretation of genetic test results and\/or patient counselling.<\/p>\n

Finally, we have developed the SHaReD platform. This is an an advanced data management and research platform that offers RESIST scientists access to a comprehensive and growing collection of data from RESIST cohorts. Designed to interconnect diverse datasets and data types, SHaReD enhances data storage, management, and accessibility. We believe that SHaReD will change how researchers manage cohort and project data, making analysis and sharing more efficient, ultimately speeding up data-driven discoveries. At its core, SHaReD utilizes a relational database with a subject-centered model, organizing various data types\u2014genetic, clinical, immunophenotyping, and more\u2014into interconnected tables. Inspired by “Gemma” and “GenIA,” platforms developed by Prof. Proietti and Dr. Andr\u00e9s Caballero-Oteyza. Currently exclusive to RESIST researchers, SHaReD is set to expand its reach to a broader audience at MHH and outsied, fostering collaborative research efforts.<\/p>\n<\/div>

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Homepage of the web based platform GenIA<\/p>\n<\/div>

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Projectleader<\/h1><\/div>

Project title: Genetics of Immundysregulation<\/h4><\/div>
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Prof. Dr. Michele Proietti<\/h3><\/div>

Project: A5<\/a><\/h3><\/div>
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CV & Contact<\/span><\/a><\/div>
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Project A5 Publications<\/h1><\/div>
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Publications 2024<\/strong><\/p>\n

OTULIN-related conditions: Report of a new case and review of the literature using GenIA.<\/strong><\/a> Caballero-Oteyza A, Crisponi L, Peng XP, Wang H, Mrovecova P, Olla S, Siguri C, Marnissi F, Jouhadi Z, Aksentijevich I, Grimbacher B, Proietti Clin Immunol. 2024 Jun 22;265:110292. Epub ahead of print.<\/p>\n

37 Oral microbiome’s impact on mucositis and locoregional tumor control in HNSCC patients undergoing radiotherapy.<\/strong> <\/a>A R\u00fchle, EBM Ordonez, M Krausz, AR Thomsen, D Schnell, T Sprave, …Radiotherapy and Oncology 192, S75-S77<\/p>\n

GenIA, the Genetic Immunology Advisor database for inborn errors of immunity<\/strong><\/a> A Caballero-Oteyza, L Crisponi, XP Peng, K Yauy, S Volpi, S Giardino, …Journal of Allergy and Clinical Immunology 153 (3), 831-843<\/p>\n

Diagnostic evaluation of paediatric autoimmune lymphoproliferative immunodeficiencies (ALPID): a prospective cohort study.<\/strong><\/a> H\u00e4gele P, Staus P, Scheible R, Uhlmann A, Heeg M, Klemann C, Maccari ME, Ritterbusch H, Armstrong M, Cutcutache I, Elliott KS, von Bernuth H, Leahy TR, Leyh J, Holzinger D, Lehmberg K, Svec P, Masjosthusmann K, Hambleton S, Jakob M, Sparber-Sauer M, Kager L, Puzik A, Wolkewitz M, Lorenz MR, Schwarz K, Speckmann C, Rensing-Ehl A, Ehl S; ALPID study group.\u00a0 Lancet Haematol. 2024 Feb;11(2):e114-e126. Erratum in: Lancet Haematol. 2024 Apr;11(4):e248.<\/p>\n

A 14-Day Double-Blind, Randomized, Controlled Crossover Intervention Study with Anti-Bacterial Benzyl Isothiocyanate from Nasturtium (Tropaeolum majus) on Human Gut Microbiome and Host Defense.<\/strong> <\/a>Pf\u00e4ffle SP, Herz C, Brombacher E, Proietti M, Gigl M, Hofstetter CK, Mittermeier-Kle\u00dfinger VK, Cla\u00dfen S, Tran HTT, Dawid C, Kreutz C, G\u00fcnther S, Lamy E. Nutrients. 2024 Jan 26;16(3):373.<\/p>\n

Lipocalin-2 expression identifies an intestinal regulatory neutrophil population during acute graft-versus-host disease.<\/a> <\/strong>Czech M, Schneider S, Peltokangas N, El Khawanky N, Ghimire S, Andrieux G, H\u00fclsd\u00fcnker J, Krausz M, Proietti M, Braun LM, R\u00fcckert T, Langenbach M, Schmidt D, Martin I, Wenger V, de Vega E, Haring E, Pourjam M, Pfeifer D, Schmitt-Graeff A, Grimbacher B, Aumann K, Kircher B, Tilg H, Raffatellu M, Thiele Orberg E, H\u00e4cker G, Duyster J, K\u00f6hler N, Holler E, Nachbaur D, Boerries M, Gerner RR, Gr\u00fcn D, Zeiser R. Sci Transl Med. 2024 Feb 21;16(735):eadi1501. Epub 2024 Feb 21.<\/p>\n

ADA2 is a lysosomal deoxyadenosine deaminase acting on DNA involved in regulating TLR9-mediated immune sensing of DNA<\/strong><\/a>O. K. Greiner-Tollersrud, M. Krausz, V. Boehler, A. Polyzou, M. Seidl, A. Spahiu, et al.<\/p>\n

A Novel Transmembrane CXCR4 Variant That Expands the WHIM Genotype-Phenotype Paradigm<\/a>. <\/strong>Zmajkovicova K, Pawar S, Sharapova SO, Geier CB, Wiest I, Nguyen C, Monticelli H, Maier-Munsa S, Chen K, Sleasman JW, Aleshkevich S, Polyakova E, Sakovich I, Warnatz K, Grimbacher B, Proietti M, Sondheimer N, Ujhazi B, Gordon S, Ellison M, Yilmaz M, Walter JE, Badarau A, Taveras AG, Neff JL, Bledsoe JR, Tarrant TK.\u00a0 Blood Adv. 2024 May 20:bloodadvances.2023011875. Epub ahead of print.<\/p>\n

Publications 2023<\/strong><\/p>\n

Clinical, immunological and molecular findings of 8 patients with typical and atypical severe combined immunodeficiency: identification of 7 novel mutations by whole exome sequencing.<\/strong> <\/a>Alizadeh Z, Fazlollahi MR, Mazinani M, Badalzadeh M, Heydarlou H, Carapito R, Molitor A, de Oteyza ACG, Proietti M, Bavani MS, Shariat M, Fallahpour M, Movahedi M, Moradi L, Grimbacher B, Bahram S, Pourpak Z. Genes Immun. 2023 Aug;24(4):207-214. Epub 2023 Jul 29.<\/p>\n

Fecal Immunoglobulin Levels as a Modifier of the Gut Microbiome in Patients with Common Variable Immunodeficiency. J Clin Immunol.<\/strong> <\/a>N\u00f6ltner C, Bulashevska A, H\u00fcbscher K, Haberstroh H, Grimbacher B, Proietti M.\u00a0 2023 Aug;43(6):1208-1220.\u00a0 Epub 2023 Mar 24.<\/p>\n

ARPC5 deficiency leads to severe early-onset systemic inflammation and mortality.<\/strong><\/a> Sindram E, Caballero-Oteyza A, Kogata N, Chor Mei Huang S, Alizadeh Z, G\u00e1mez-D\u00edaz L, Fazlollhi MR, Peng X, Grimbacher B, Way M, Proietti M. Dis Model Mech. 2023 Jul 1;16(7):dmm050145. Epub 2023 Jul 20.<\/p>\n

Interferon-Driven Immune Dysregulation in Common Variable Immunodeficiency-Associated Villous Atrophy and Norovirus Infection.<\/strong><\/a> Strohmeier V, Andrieux G, Unger S, Pascual-Reguant A, Klocperk A, Seidl M, Marques OC, Eckert M, Gr\u00e4we K, Shabani M, von Spee-Mayer C, Friedmann D, Harder I, Gutenberger S, Keller B, Proietti M, Bulashevska A, Grimbacher B, Provaznik J, Benes V, Goldacker S, Schell C, Hauser AE, Boerries M, Hasselblatt P, Warnatz K.\u00a0 J Clin Immunol. 2023 Feb;43(2):371-390. Epub 2022 Oct 25.<\/p>\n

Telomere biology disorders may manifest as common variable immunodeficiency (CVID). <\/strong><\/a>Rolles B, Caballero-Oteyza A, Proietti M, Goldacker S, Warnatz K, Camacho-Ordonez N, Prader S, Schmid JP, Vieri M, Isfort S, Meyer R, Kirschner M, Br\u00fcmmendorf TH, Beier F, Grimbacher B. Clin Immunol. 2023 Dec;257:109837. Epub 2023 Nov 8.<\/p>\n

Makrozyt\u00e4re An\u00e4mie und Polychondritis: VEXAS-Syndrom [Macrocytic anemia and polychondritis: VEXAS syndrome]. <\/strong><\/a>Zeisbrich M, Schindler V, Krausz M, Proietti M, Mrovecova P, Voll RE, Glaser C, R\u00f6ther F, Warnatz K, Venhoff N.\u00a0 Z Rheumatol. 2024 Apr;83(3):229-233. German. Epub 2023 Feb 3.<\/p>\n

CVID-Associated B Cell Activating Factor Receptor Variants Change Receptor Oligomerization, Ligand Binding, and Signaling Responses. <\/strong><\/a>Block V, Sevdali E, Recher M, Abolhassani H, Hammarstrom L, Smulski CR, Baronio M, Plebani A, Proietti M, Speletas M, Warnatz K, Voll RE, Lougaris V, Schneider P, Eibel H.\u00a0 J Clin Immunol. 2023 Feb;43(2): 391-405. Epub 2022 Oct 29.<\/p>\n

Publications 2022<\/strong><\/p>\n

Copy Number Analysis in a Large Cohort Suggestive of Inborn Errors of Immunity Indicates a Wide Spectrum of Relevant Chromosomal Losses and Gains.<\/strong><\/a> Wan R, Schieck M, Caballero-Oteyza A, Hofmann W, Cochino AV, Shcherbina A, Sherkat R, Wache-Mainier C, Fernandez A, Sultan M, Illig T, Grimbacher B, Proietti M, Steinemann D.\u00a0 J Clin Immunol. 2022 Jul;42(5):1083-1092. Epub 2022 Apr 29.<\/p>\n

Clinical, Immunological and Molecular Findings of Patients with Severe Combined Immunodeficiency: Introducing of 7 Novel Mutations in 7 Genes<\/strong>.<\/a> Z Alizadeh, MR Fazlollahi, M Mazinani, M Badalzadeh, H Heydarlou, …<\/p>\n

Interferon-Driven Immune Dysregulation in Common Variable Immunodeficiency-Associated Villous Atrophy and Norovirus Infection. <\/strong><\/a>Strohmeier V, Andrieux G, Unger S, Pascual-Reguant A, Klocperk A, Seidl M, Marques OC, Eckert M, Gr\u00e4we K, Shabani M, von Spee-Mayer C, Friedmann D, Harder I, Gutenberger S, Keller B, Proietti M, Bulashevska A, Grimbacher B, Provaznik J, Benes V, Goldacker S, Schell C, Hauser AE, Boerries M, Hasselblatt P, Warnatz K. J Clin Immunol. 2023 Feb;43(2):371-390. Epub 2022 Oct 25.<\/p>\n

Multi-omics analysis of na\u00efve B cells of patients harboring the C104R mutation in TACI.<\/a> <\/strong>Ramirez N, Posadas-Cantera S, Langer N, de Oteyza ACG, Proietti M, Keller B, Zhao F, Gernedl V, Pecoraro M, Eibel H, Warnatz K, Ballestar E, Geiger R, Bossen C, Grimbacher B.\u00a0 Front Immunol. 2022 Aug 16;13:938240.<\/p>\n

Evaluation of Laboratory and Sonographic Parameters for Detection of Portal Hypertension in Patients with Common Variable Immunodeficiency.<\/a>\u00a0 <\/strong>Globig AM, Strohmeier V, Surabattula R, Leeming DJ, Karsdal MA, Heeg M, Kindle G, Goldacker S, von Spee-Mayer C, Proietti M, Bausch B, Bettinger D, Schulthei\u00df M, Thimme R, Schuppan D, Warnatz K.\u00a0 J Clin Immunol. 2022 Nov;42(8):1626-1637. Epub 2022 Jul 11.<\/p>\n

Author Correction: Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice. <\/strong><\/a>Wang L, Aschenbrenner D, Zeng Z, Cao X, Mayr D, Mehta M, Capitani M, Warner N, Pan J, Wang L, Li Q, Zuo T, Cohen-Kedar S, Lu J, Ardy RC, Mulder DJ, Dissanayake D, Peng K, Huang Z, Li X, Wang Y, Wang X, Li S, Bullers S, Gammage AN, Warnatz K, Schiefer AI, Krivan G, Goda V, Kahr WHA, Lemaire M; Genomics England Research Consortium; Lu CY, Siddiqui I, Surette MG, Kotlarz D, Engelhardt KR, Griffin HR, Rottapel R, Decaluwe H, Laxer RM, Proietti M, Hambleton S, Elcombe S, Guo CH, Grimbacher B, Dotan I, Ng SC, Freeman SA, Snapper SB, Klein C, Boztug K, Huang Y, Li D, Uhlig HH, Muise AM. Nat Genet. 2022 Feb;54(2):213. Erratum for: Nat Genet. 2021 Apr;53(4): 500-510.<\/p>\n

Therapeutic targeting of endoplasmic reticulum stress in acute graft-versus<\/i>-host disease.<\/a> <\/strong>Haring E, Andrieux G, Uhl FM, Krausz M, Proietti M, Sauer B, Esser PR, Martin SF, Pfeifer D, Schmitt-Graeff A, Duyster J, K\u00f6hler N, Grimbacher B, Boerries M, Aumann K, Zeiser R, Apostolova P. \u00a0Haematologica. 2022 Jul 1;107(7):1538-1554.<\/p>\n

Publications 2021<\/strong><\/p>\n

Multiple Immunostainings with Different Epitope Retrievals-The FOLGAS Protocol<\/a>.<\/strong> von Schoenfeld A, Bronsert P, Poc M, Fuller A, Filby A, Kraft S, Kurowski K, S\u00f6rensen K, Huber J, Pfeiffer J, Proietti M, Stehl V, Werner M, Seidl M. Int J Mol Sci. 2021 Dec 25;23(1):223.<\/p>\n

Establishing the Molecular Diagnoses in a Cohort of 291 Patients With Predominantly Antibody Deficiency by Targeted Next-Generation Sequencing: Experience From a Monocentric Study<\/strong><\/a>. Rojas-Restrepo J, Caballero-Oteyza A, Huebscher K, Haberstroh H, Fliegauf M, Keller B, Kobbe R, Warnatz K, Ehl S, Proietti M *, Grimbacher B *. Front Immunol. 2021 Dec 17;12:786516.<\/p>\n

Genetic Analysis of a Cohort of 275 Patients with Hyper-IgE Syndromes and\/or Chronic Mucocutaneous Candidiasis<\/a>.<\/strong> Frede N, Rojas-Restrepo J, Caballero Garcia de Oteyza A, Buchta M, H\u00fcbscher K, G\u00e1mez-D\u00edaz L, Proietti M, Saghafi S, Chavoshzadeh Z, Soler-Palacin P, Galal N, Adeli M, Aldave-Becerra JC, Al-Ddafari MS, Ardenyz \u00d6, Atkinson TP, Kut FB, \u00c7elmeli F, Rees H, Kilic SS, Kirovski I, Klein C, Kobbe R, Korganow AS, Lilic D, Lunt P, Makwana N, Metin A, \u00d6zg\u00fcr TT, Karakas AA, Seneviratne S, Sherkat R, Sousa AB, Unal E, Patiroglu T, Wahn V, von Bernuth H, Whiteford M, Doffinger R, Jouhadi Z, Grimbacher B. J Clin Immunol. 2021 Nov;41(8):1804-1838.<\/p>\n

Altered Spectrum of Lymphoid Neoplasms in a Single-Center Cohort of Common Variable Immunodeficiency with Immune Dysregulation.<\/strong> <\/a>Wehr C, Houet L, Unger S, Kindle G, Goldacker S, Grimbacher B, Caballero Garcia de Oteyza A, Marks R, Pfeifer D, Nieters A, Proietti M, Warnatz K, Schmitt-Graeff A. J Clin Immunol. 2021 Aug;41(6):1250-1265. Epub 2021 Apr 19.<\/p>\n

Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice<\/strong><\/a>. Wang L, Aschenbrenner D, Zeng Z, Cao X, Mayr D, Mehta M, Capitani M, Warner N, Pan J, Wang L, Li Q, Zuo T, Cohen-Kedar S, Lu J, Ardy RC, Mulder DJ,
\nDissanayake D, Peng K, Huang Z, Li X, Wang Y, Wang X, Li S, Bullers S, Gammage AN, Warnatz K, Schiefer AI, Krivan G, Goda V, Kahr WHA, Lemaire M; Genomics England Research Consortium, Lu CY, Siddiqui I, Surette MG, Kotlarz D, Engelhardt KR, Griffin HR, Rottapel R, Decaluwe H, Laxer RM, Proietti M,
\nHambleton S, Elcombe S, Guo CH, Grimbacher B, Dotan I, Ng SC, Freeman SA, Snapper SB, Klein C, Boztug K, Huang Y, Li D, Uhlig HH, Muise AM. Nat Genet. 2021 Apr;53(4):500-510. Epub 2021 Mar 29. Erratum in: Nat Genet. 2022 Feb;54(2):213.<\/p>\n

Agammaglobulinemia with normal B-cell numbers in a patient lacking Bob1.<\/strong><\/a> J Allergy Clin Immunol. 2021 May;147(5):1977-1980. Kury P, Staniek J, Wegehaupt O, Janowska I, Eckenweiler M, Korinthenberg R, Japaridze N, Pendziwiat M, Helbig I, Verhoeyen E, Jung J, Garcia de Oteyza AC, Proietti M, Phirtskhalaishvili T, Rtskhiladze I, Nielsen PJ, Ehl S, Speckmann C, Rizzi M. \u00a0Epub 2021 Feb 9.<\/p>\n

Bile acids regulate intestinal antigen presentation and reduce graft-versus-host disease without impairing the graft-versus-leukemia effect.<\/strong><\/a> Haring E, Uhl FM, Andrieux G, Proietti M, Bulashevska A, Sauer B, Braun LM, de Vega Gomez E, Esser PR, Martin SF, Pfeifer D, Follo M, Schmitt-Graeff A, Buescher J, Duyster J, Grimbacher B, Boerries M, Pearce EL, Zeiser R, Apostolova P. Haematologica. 2021 Aug 1;106(8):2131-2146.<\/p>\n<\/div>\n<\/div>

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Publications of the Project A5<\/h1><\/div>
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