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Biology of HLA class I associated inflammatory diseases

Bordbar, Ali; Manches, Olivier; Nowatzky, Johannes
Human leukocyte antigen (HLA) class I association is a well-established feature of common and uncommon inflammatory diseases, but it is unknown whether it impacts the pathogenesis of these disorders. The "arthritogenic peptide" hypothesis proposed initially for HLA-B27-associated ankylosing spondylitis (AS) seems the most intuitive to serve as a model for other HLA class I-associated diseases, but evidence supporting it has been scarce. Recent technological advances and the discovery of epistatic relationships between disease-associated HLA class I and endoplasmic reticulum aminopeptidase (ERAP) coding variants have led to the generation of new data and conceptual approaches to the problem requiring its re-examination. Continued success in these endeavors holds promise to resolve a Gordian Knot in human immunobiology. It may ultimately benefit patients by enabling the development of new therapies and precision tools for assessing disease risk and predicting treatment responses.
PMID: 39085016
ISSN: 1532-1770
CID: 5687362

Immunopathogenesis of Behçet's disease

Al-Obeidi, Arshed F; Nowatzky, Johannes
Behçet's disease (BD) is a multi-system inflammatory disorder with vasculitic features. It does not suit any of the current pathogenesis-driven disease classifications well, a unifying concept of its pathogenesis is not unanimously conceivable at present, and its etiology is obscure. Still, evidence from immunogenetic and other studies supports the notion of a complex-polygenic disease with robust innate effector responses, reconstitution of regulatory T cells upon successful treatment, and first clues to the role of an, as of yet, underexplored adaptive immune system and its antigen recognition receptors. Without an attempt to be comprehensive, this review aims to collect and organize impactful parts of this evidence in a way that allows the reader to appreciate the work done and define the efforts needed now. The focus is on literature and notions that drove the field into new directions, whether recent or more remote.
PMCID:10484394
PMID: 37295542
ISSN: 1521-7035
CID: 5591842

EULAR study group on 'MHC-I-opathy': identifying disease-overarching mechanisms across disciplines and borders

Kuiper, Jonas Jw; Prinz, Jörg C; Stratikos, Efstratios; Kuśnierczyk, Piotr; Arakawa, Akiko; Springer, Sebastian; Mintoff, Dillon; Padjen, Ivan; Shumnalieva, Russka; Vural, Seçil; Kötter, Ina; van de Sande, Marleen G; Boyvat, Ayşe; de Boer, Joke H; Bertsias, George; de Vries, Niek; Krieckaert, Charlotte Lm; Leal, Inês; Vidovič Valentinčič, Nataša; Tugal-Tutkun, Ilknur; El Khaldi Ahanach, Hanane; Costantino, Félicie; Glatigny, Simon; Mrazovac Zimak, Danijela; Lötscher, Fabian; Kerstens, Floor G; Bakula, Marija; Viera Sousa, Elsa; Böhm, Peter; Bosman, Kees; Kenna, Tony J; Powis, Simon J; Breban, Maxime; Gul, Ahmet; Bowes, John; Lories, Rik Ju; Nowatzky, Johannes; Wolbink, Gerrit Jan; McGonagle, Dennis G; Turkstra, Franktien
The 'MHC-I (major histocompatibility complex class I)-opathy' concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet's disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.
PMID: 36987655
ISSN: 1468-2060
CID: 5463262

Inflammatory eye disease for rheumatologists

Corbitt, Kelly; Nowatzky, Johannes
PURPOSE OF REVIEW:This review provides a framework for understanding inflammatory eye disease diagnosis, differential diagnosis, and management for rheumatologists. Uveitis, scleritis, episcleritis, peripheral ulcerative keratitis, and orbital inflammation are all discussed. The goal is to facilitate the development of approaches to inflammatory eye diseases that will help rheumatologists co-manage these patients with eye care providers specializing in ocular inflammation. RECENT FINDINGS:In recent years, studies have aimed to advance biologic treatments and define standard-of-care therapy. Inflammatory eye diseases are highly heterogeneous and often rare, which poses significant challenges to their research and the interpretation of existing data. To date, glucocorticoids, mycophenolate, methotrexate, and TNF inhibitors remain the mainstay of treatment options for many of these diseases. SUMMARY:Patients with inflammatory eye diseases require multidisciplinary care for best outcomes, frequently including rheumatologists. Understanding the differentials, diagnostics, and treatment are essential to preserving vision in these patients. The diverse nature of the disease processes within this field requires focusing on specific disease phenotypes and endotypes in research and clinical practice.
PMID: 36943695
ISSN: 1531-6963
CID: 5462782

Hedgehog and PDGF Signaling Intersect During Postnatal Lung Development

Yie, Ting-An; Loomis, Cynthia A; Nowatzky, Johannes; Khodadadi-Jamayran, Alireza; Lin, Ziyan; Cammer, Michael; Barnett, Clea; Mezzano, Valeria; Alu, Mark; Novick, Jackson A; Munger, John S; Kugler, Matthias C
Normal lung development critically depends on Hedgehog (HH) and Platelet-derived growth factor (PDGF) signaling, which coordinate mesenchymal differentiation and proliferation. PDGF signaling is required for postnatal alveolar septum formation by myofibroblasts. Recently, we demonstrated a requirement for HH in postnatal lung development involving alveolar myofibroblast differentiation. Given shared features of HH and PDGF signaling and their impact/convergence on this key cell type, we sought to clarify their relationship during murine postnatal lung development. Timed experiments revealed that HH inhibition phenocopies the key lung myofibroblast phenotypes of Pdgfa and Pdgfra knockouts during secondary alveolar septation. Utilizing a dual signaling reporter, Gli1IZ;PdgfraEGFP
PMID: 36693140
ISSN: 1535-4989
CID: 5419542

Behcet's disease risk-variant HLA-B51/ERAP1-Hap10 alters human CD8 T cell immunity

Cavers, Ann; Kugler, Matthias Christian; Ozguler, Yesim; Al-Obeidi, Arshed Fahad; Hatemi, Gulen; Ueberheide, Beatrix M; Ucar, Didar; Manches, Olivier; Nowatzky, Johannes
OBJECTIVES/OBJECTIVE:, the classical risk factor for the disease. The mechanistic implications and biological consequences of this epistatic relationship are unknown. Here, we aimed to determine its biological relevance and functional impact. METHODS:LCL, analysed the HLA class I-bound peptidome for peptide length differences and assessed immunogenicity of genome-edited cells in CD8 T cell co-culture systems. RESULTS:KO cells showed peptidomes with longer peptides above 9mer and significant differences in their ability to stimulate alloreactive CD8 T cells compared with wild-type control cells. CONCLUSIONS:at the cellular level and point to an HLA-B51-restricted process. Our findings suggest that variant ERAP1-Hap10 partakes in BD pathogenesis by generating HLA-B51-restricted peptides, causing a change in immunodominance of the ensuing CD8 T cell response.
PMID: 35922122
ISSN: 1468-2060
CID: 5288102

Evidence-Based Behcet's Disease Activity Scale (EBDA) - A New Instrument with Improved Acuity for Major Organ Disease Activity and Remission Depth Assessment [Meeting Abstract]

Lagdameo, Maria Caterina; Do, Hyungrok; Nowatzky, Johannes
ISI:000744545207201
ISSN: 2326-5191
CID: 5340412

Generation of Human Regulatory T Cell Clones

Nowatzky, Johannes; Manches, Olivier
Human regulatory T cells (Treg) are notoriously difficult to isolate in high purity given the current methods of Treg enrichment. These methods are based on the identification of Treg through several activation-dependent cellular surface markers with varying expression levels in different physiologic and pathologic conditions. Populations isolated as "Treg" therefore often contain considerable numbers of non-Treg effector cells (i.e., Teff) which hamper the precise phenotypic and functional characterization of these cells, their genomic and proteomic characterization, their reliable enumeration in different states of health and disease, as well as their isolation and expansion for therapeutic purposes. The latter, in particular, remains a major hurdle, as the inadvertent expansion of effector cells homing in Treg-relevant cellular compartments (e.g., CD4+CD25+ T cells) may render Treg-based immunotherapy ineffective, or even harmful. This work presents a method that circumvents the problems associated with population-based isolation and expansion of Treg and shows that the generation of Treg candidate clones with the subsequent selection, culture, and expansion of only carefully vetted, monoclonal cells, enables the generation of an ultrapure Treg cell product that can be kept in culture for many months, enabling downstream investigation of these cells, including for possible therapeutic applications.
PMID: 32478733
ISSN: 1940-087x
CID: 4465932

ERAP1-mediated immunogenicity and immune-phenotypes in HLA-B51(+) Behcet's and Behcet's uveitis point to pathogenic CD8 T cell effector responses [Meeting Abstract]

Nowatzky, Johannes; Cavers, Ann; Ozguler, Yesim; Al-Obeidi, Arshed Fahad; Yurttas, Berna; Zhong, Hua; Xia, Yuhe; Ueberheide, Beatrix; Hatemi, Gulen; Kugler, Matthias; Manches, Olivier
ISI:000554528303086
ISSN: 0146-0404
CID: 5340352

Miscellaneous Manifestations of Behcet Syndrome

Chapter by: Nowatzky, Johannes; Fresko, Izzet
in: BEHCET SYNDROME by Yazici, Y; et al [Eds]
pp. 143-160
ISBN: 978-3-030-24131
CID: 5340342