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1.
Nat Commun ; 15(1): 6443, 2024 Jul 31.
Article in English | MEDLINE | ID: mdl-39085199

ABSTRACT

Birdshot chorioretinopathy is an inflammatory eye condition strongly associated with MHC-I allele HLA-A29. The striking association with MHC-I suggests involvement of T cells, whereas natural killer (NK) cell involvement remains largely unstudied. Here we show that HLA-A29-positive birdshot chorioretinopathy patients have a skewed NK cell pool containing expanded CD16 positive NK cells which produce more proinflammatory cytokines. These NK cells contain populations that express CD8A which is involved in MHC-I recognition on target cells, display gene signatures indicative of high cytotoxic activity (GZMB, PRF1 and ISG15), and signaling through NK cell receptor CD244 (SH2D1B). Long-term monitoring of a cohort of birdshot chorioretinopathy patients with active disease identifies a population of CD8bright CD244bright NK cells, which rapidly declines to normal levels upon clinical remission following successful treatment. Collectively, these studies implicate CD8bright CD244bright NK cells in birdshot chorioretinopathy.


Subject(s)
Birdshot Chorioretinopathy , HLA-A Antigens , Killer Cells, Natural , Signaling Lymphocytic Activation Molecule Family , Single-Cell Analysis , Humans , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Birdshot Chorioretinopathy/immunology , Birdshot Chorioretinopathy/metabolism , HLA-A Antigens/genetics , HLA-A Antigens/metabolism , HLA-A Antigens/immunology , Single-Cell Analysis/methods , Signaling Lymphocytic Activation Molecule Family/metabolism , Signaling Lymphocytic Activation Molecule Family/genetics , CD8 Antigens/metabolism , CD8 Antigens/genetics , Chorioretinitis/immunology , Chorioretinitis/genetics , Female , Receptors, IgG/metabolism , Receptors, IgG/genetics , Male , Cytokines/metabolism , Adult , GPI-Linked Proteins/metabolism , GPI-Linked Proteins/genetics , Middle Aged , Perforin
2.
Sci Rep ; 11(1): 8604, 2021 04 21.
Article in English | MEDLINE | ID: mdl-33883633

ABSTRACT

Birdshot Retinochoroiditis (BSRC) is a progressive non-infectious intraocular inflammation that affects choroid and retina. Inflammatory processes have adverse effects on vision by affecting photoreceptor-bearing cells that do not regenerate. This study aimed at characterizing inflammatory CD4+ and CD8+ T cell subsets in the peripheral blood of active and inactive BSRCs. Furthermore, we correlated phenotypical and functional immunological analyses with clinical data. We observed a slight increase of terminally differentiated effector memory CD8+ T cells expressing CD45RA (TEMRA) in blood of inactive, compared to active BSRCs. Moreover, we identified a trend for a decreased population of TH2 cells and increased TH1 frequencies in active BSRCs, a typical sign of ongoing autoimmune processes. Functional assays demonstrated severe and overall impairment of effector function of both, CD4+ and CD8+ inflammatory T cells, which might reflect T cell exhaustion. Although the eye is the main site of inflammation in BSRC, we observed altered T cell subset compositions in the peripheral blood, dependent on the disease status. Our results indicate that T cells may play a major role in BSRC pathology, although our cohort size is too limited for definitve conclusions. Future studies with larger BSRCs have to be performed.


Subject(s)
Birdshot Chorioretinopathy/immunology , T-Lymphocyte Subsets/immunology , Adult , Aged , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Female , Humans , Immunologic Memory/immunology , Lymphocyte Activation/immunology , Male , Middle Aged , Pilot Projects
3.
Front Immunol ; 12: 634441, 2021.
Article in English | MEDLINE | ID: mdl-33717175

ABSTRACT

Birdshot Uveitis (BU) is a blinding inflammatory eye condition that only affects HLA-A29-positive individuals. Genetic association studies linked ERAP2 with BU, an aminopeptidase which trims peptides before their presentation by HLA class I at the cell surface, which suggests that ERAP2-dependent peptide presentation by HLA-A29 drives the pathogenesis of BU. However, it remains poorly understood whether the effects of ERAP2 on the HLA-A29 peptidome are distinct from its effect on other HLA allotypes. To address this, we focused on the effects of ERAP2 on the immunopeptidome in patient-derived antigen presenting cells. Using complementary HLA-A29-based and pan-class I immunopurifications, isotope-labeled naturally processed and presented HLA-bound peptides were sequenced by mass spectrometry. We show that the effects of ERAP2 on the N-terminus of ligands of HLA-A29 are shared across endogenous HLA allotypes, but discover and replicate that one peptide motif generated in the presence of ERAP2 is specifically bound by HLA-A29. This motif can be found in the amino acid sequence of putative autoantigens. We further show evidence for internal sequence specificity for ERAP2 imprinted in the immunopeptidome. These results reveal that ERAP2 can generate an HLA-A29-specific antigen repertoire, which supports that antigen presentation is a key disease pathway in BU.


Subject(s)
Aminopeptidases/metabolism , Antigen-Presenting Cells/enzymology , Autoantigens/metabolism , Autoimmunity , Birdshot Chorioretinopathy/enzymology , HLA-A Antigens/metabolism , Aged, 80 and over , Amino Acid Motifs , Aminopeptidases/genetics , Antigen-Presenting Cells/immunology , Autoantigens/genetics , Autoantigens/immunology , Birdshot Chorioretinopathy/diagnosis , Birdshot Chorioretinopathy/genetics , Birdshot Chorioretinopathy/immunology , Cell Line , Female , HLA-A Antigens/genetics , HLA-A Antigens/immunology , Humans
4.
Int J Mol Sci ; 21(24)2020 Dec 17.
Article in English | MEDLINE | ID: mdl-33348540

ABSTRACT

The strong association with the Major Histocompatibility Complex (MHC) class I genes represents a shared trait for a group of autoimmune/autoinflammatory disorders having in common immunopathogenetic basis as well as clinical features. Accordingly, the main risk factors for Ankylosing Spondylitis (AS), prototype of the Spondyloarthropathies (SpA), the Behçet's disease (BD), the Psoriasis (Ps) and the Birdshot Chorioretinopathy (BSCR) are HLA-B*27, HLA-B*51, HLA-C*06:02 and HLA-A*29:02, respectively. Despite the strength of the association, the HLA pathogenetic role in these diseases is far from being thoroughly understood. Furthermore, Genome-Wide Association Studies (GWAS) have highlighted other important susceptibility factors such as Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and, less frequently, ERAP2 that refine the peptidome presented by HLA class I molecules to CD8+ T cells. Mass spectrometry analysis provided considerable knowledge of HLA-B*27, HLA-B*51, HLA-C*06:02 and HLA-A*29:02 immunopeptidome. However, the combined effect of several ERAP1 and ERAP2 allelic variants could generate an altered pool of peptides accounting for the "mis-immunopeptidome" that ranges from suboptimal to pathogenetic/harmful peptides able to induce non-canonical or autoreactive CD8+ T responses, activation of NK cells and/or garbling the classical functions of the HLA class I molecules. This review will focus on this class of epitopes as possible elicitors of atypical/harmful immune responses which can contribute to the pathogenesis of chronic inflammatory diseases.


Subject(s)
Aminopeptidases/genetics , Behcet Syndrome/immunology , Birdshot Chorioretinopathy/immunology , Genes, MHC Class I , Histocompatibility Antigens Class I/genetics , Immunity/genetics , Minor Histocompatibility Antigens/genetics , Psoriasis/immunology , Spondylitis, Ankylosing/immunology , Alleles , CD8-Positive T-Lymphocytes/immunology , Humans , Polymorphism, Single Nucleotide
5.
P R Health Sci J ; 39(3): 249-253, 2020 09.
Article in English | MEDLINE | ID: mdl-33031692

ABSTRACT

OBJECTIVE: To describe the characteristics, upon presentation, of a cohort of Hispanic patients with birdshot retinochoroidopathy. METHODS: A retrospective chart review of Hispanic patients with birdshot retinochoroidopathy of was performed. The demographic and clinical characteristics were analyzed. RESULTS: Nine patients who met the research criteria for a diagnosis of birdshot retinochoroidopathy were identified and included in the analysis, all of whom were HLA-A29 positive. The median age of the cohort upon presentation was 52 years; 89% of the patients were female, and all were Hispanics. Ninety-four percent of the eyes had an initial visual acuity of 20/50 or better, while 72% had measured 20/25 or better. Sixty-one percent of the eyes had retinal vasculitis, which was bilateral in 83% of the cases. Thirty-three percent of the patients had, upon presentation, evidence of cystoid macular edema, which was always bilateral. All the eyes had the typical birdshot lesions, at presentation. CONCLUSION: Birdshot retinochoroidopathy can be found in Hispanic patients. Our study suggests that the characteristics upon presentation in Hispanics may be similar to those of Caucasian cohorts.


Subject(s)
Birdshot Chorioretinopathy/diagnosis , Hispanic or Latino , Adult , Birdshot Chorioretinopathy/ethnology , Birdshot Chorioretinopathy/immunology , Cohort Studies , Female , Fundus Oculi , HLA-A Antigens , Humans , Macular Edema/diagnosis , Macular Edema/ethnology , Male , Middle Aged , Puerto Rico , Retinal Vasculitis/diagnosis , Retinal Vasculitis/ethnology , Retrospective Studies , Symptom Assessment , Visual Acuity
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