Transcriptomic and proteomic analysis of iris tissue and aqueous humor in juvenile idiopathic arthritis-associated uveitis

Wildschütz, Lena; Ackermann, Doreen; Witten, Anika; Kasper, Maren; Busch, Martin; Glander, Shirin; Melkonyan, Harutyun; Walscheid, Karoline; Tappeiner, Christoph; Thanos, Solon; Barysenka, Andrei; Koch, Jörg; Heinz, Carsten; Laffer, Björn; Bauer, Dirk; Stoll, Monika; König, Simone; Heiligenhaus, Arnd

doi:10.1016/j.jaut.2019.03.004

Cited by 42 publications

(20 citation statements)

References 63 publications

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“…Also, SpA patients (with or without AAU) mostly do not benefit from treatment with the anti-CD20 antibody rituximab 57 . In fact, AqH of AAU patients showed reduced levels of the B-cell factors BAFF and APRIL compared to patients with juvenile idiopathic arthritis-associated anterior uveitis 58 . It is notable, that naive B-cells expressing higher levels of autoimmune related CLEC16A 41 , and plasma cells, expressing several SpA risk genes, were preferentially enriched in B27+AAU.…”

Section: Discussionmentioning

confidence: 90%

Intra-ocular dendritic cells are increased in HLA-B27 associated acute anterior uveitis

Kasper

Heming

Schafflick

et al. 2021

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Uveitis describes a heterogeneous group of inflammatory eye diseases characterized by infiltration of leukocytes into the uveal tissues. HLA-B27-associated Uveitis is a common subtype of uveitis and a prototypical ocular autoimmune disease. Local immune mechanisms driving human uveitis are poorly characterized mainly due to the limited available biomaterial and subsequent technical limitations. Here, we provide the first high-resolution characterization of intraocular leukocytes in HLA-B27 positive and negative AU and an infectious endophthalmitis control by combining single cell RNA sequencing (scRNA-seq) with flow cytometry and low-input proteomics. Ocular cell infiltrates consisted primarily of lymphocytes in uveitis and of myeloid cells in infectious endophthalmitis. HLA-B27 positive uveitis exclusively featured an plasmacytoid and classical dendritic cells (cDC) infiltrate, and of plasma cells. Moreover, cDCs were central in predicted local cell-cell communication. The data suggests a unique pattern of ocular leukocyte infiltration in HLA-B27 positive uveitis with relevance of particular dendritic cells.

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Section: Discussionmentioning

confidence: 90%

Intra-ocular dendritic cells are increased in HLA-B27 associated acute anterior uveitis

Kasper

Heming

Schafflick

et al. 2021

Preprint

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“…In contrast, collagen-induced arthritis (CIA) could be passively transferred to healthy recipient animals by injecting immunoglobulin concentrates of immune serum or anti-collagen antibodies systemically (48, 49). A crucial role of autoantibodies in JIAU is supported by studies that demonstrate B and plasma cells to be dominant cell types in the ocular inflammatory infiltrate, a high prevalence of ANA, and rituximab to be effective in the treatment of JIAU patients (3, 8, 14, 16, 50, 51). Furthermore, it was reported that anti-H3 histone serum antibodies and serum antibodies against different ocular antigens such as low-molecular-weight iris antigen or retinal S antigen correlated with uveitis occurrence (52, 53).…”

Section: Discussionmentioning

confidence: 98%

“…Although inflammatory autoimmune reactions involving adaptive and innate immune cells interacting in a versatile network are suspected (12), the precise mechanisms underlying JIAU pathogenesis are not well-understood. There is increasing evidence indicating that B and plasma cells, representing the predominant cellular infiltrate, play a crucial role in the disease (13–16). This hypothesis is supported by the observation that 80% of JIAU patients are positive for serum anti-nuclear antibodies (ANA), which represent an important risk factor for uveitis occurrence in JIA patients (6, 8).…”

Section: Introductionmentioning

confidence: 99%

Identification of Ocular Autoantigens Associated With Juvenile Idiopathic Arthritis-Associated Uveitis

et al. 2019

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The purpose of the current study was to analyze the binding patterns of serum autoantibodies from juvenile idiopathic arthritis (JIA) and JIA-associated uveitis (JIAU) patients to proteomes from different ocular tissues and to identify potential ocular autoantigens in JIAU. Proteomes from porcine iris, ciliary body, or retina tissue were isolated, separated using 2D-gel electrophoresis, and transferred to a blotting membrane. The binding pattern of serum antibodies from JIA or JIAU patients or healthy controls to ocular proteins was visualized by using anti-human IgG secondary antibodies and chemiluminescence reaction. Selected protein spots were excised from silver-stained 2D gels and subjected to mass spectrometry. Serum antibodies binding to ocular proteins were detected in all patient groups and healthy controls. Irrespective of the patient groups, serum antibodies bound to 49 different protein spots of the retina proteome, to 53 of the ciliary body proteome, and to 44 of the iris proteome. The relative binding frequency of sera to these iris protein spots was significantly higher in JIAU than in JIA patients or healthy controls. Particularly in JIAU patients, cluster analyses indicated a broad range of serum antibodies directed against ocular antigens, mostly in the iris proteome. Iris proteins frequently bound by serum antibodies in all groups were identified as tubulin beta chain, vimentin, ATP synthase subunit beta, actin, and L-lactate dehydrogenase B chain. Iris proteins exclusively bound by JIAU serum antibodies were heat shock cognate 71 kDa protein and keratin. Although serum autoantibody binding to ocular antigens was not disease-specific, a significant diversity of autoantibodies against a broad range of antigens, particularly from the iris tissue, was detected in JIAU patients. As the iris is a major site of inflammation in JIAU, the present data give further evidence that autoantibodies may be involved in JIAU immunopathology.

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“…In fact, plasma cells and CD20 + B cells outnumbered other immune cells in enucleated eyes and iridectomy specimens (10,11). A more recent study performed transcriptomic and proteomic analysis of iris tissue in three JIA-U+ and three primary open-angle glaucoma patients and detected increased expression for immunoglobulin genes and B cell-associated proteins in JIA-U+ (39). None of the upregulated B-cell associated genes identified in this study were found to be different between the disease groups in our study.…”

Section: Discussionmentioning

confidence: 99%

Whole Transcriptome Analysis Reveals Heterogeneity in B Cell Memory Populations in Patients With Juvenile Idiopathic Arthritis-Associated Uveitis

et al. 2020

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Purpose: Patients with juvenile idiopathic arthritis (JIA) are prone to developing chronic anterior uveitis (JIA-U+). Although several risk factors for JIA-U+ have been identified, the underlying etiology is poorly understood. Histopathological studies demonstrate B cell infiltrates in eye tissues of patients with JIA-U+. Methods: We performed transcriptome profiling of peripheral blood CD19-positive B cells taken from 14 cases with JIA-U+, 13 JIA cases without uveitis (JIA-U−), and five healthy controls. Deconvolution-based estimation was used to determine the immune cell fractions for each sample. Results: Deconvolution results revealed that naive B cells made up on average 71% of the CD19-positive cell fractions analyzed. Differential expression analysis identified 614 differentially expressed genes (DEGs) between the groups at nominal significance and six genes at a false discovery rate of 5% (FDR < 0.05). Head-to-head comparison of all JIA-U− versus JIA-U+ revealed no DEGs in the CD19+ B cell pool (FDR < 0.05). However, principal component analysis based on a panel of key genes for B cell subsets revealed that JIA-U+ cases bifurcate into distinct clusters, characterized by markedly disparate expression for genes associated with specific memory B cell populations. CIBERSORT analysis of the overall transcriptome of the new uveitis cluster identified an increased proportion of memory B cells. Conclusion: These data show that JIA-U− and JIA-U+ have a globally similar transcriptome considering the global peripheral CD19-positive B cell pool. However, heterogeneity in B cell memory genes among cases with uveitis suggests a role for specific memory B cell subsets in the etiology of JIA-U+.

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Transcriptomic and proteomic analysis of iris tissue and aqueous humor in juvenile idiopathic arthritis-associated uveitis

Cited by 42 publications

References 63 publications

Intra-ocular dendritic cells are increased in HLA-B27 associated acute anterior uveitis

Intra-ocular dendritic cells are increased in HLA-B27 associated acute anterior uveitis

Identification of Ocular Autoantigens Associated With Juvenile Idiopathic Arthritis-Associated Uveitis

Whole Transcriptome Analysis Reveals Heterogeneity in B Cell Memory Populations in Patients With Juvenile Idiopathic Arthritis-Associated Uveitis

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