HLA class I Upregulation and Antiviral Immune Responses in Graves’ disease

Abstract Context The origin of Graves’ disease (GD) remains elusive. However, evidence of an association between GD and viral infections is emerging. Human leukocyte antigen (HLA) class I presents viral antigens to circulating immune cells and plays a crucial role in the defense against viral infections. Objective To investigate HLA class I expression, enterovirus presence and the viral immune response proteins signal transducer and activation of transcription 1 (STAT1) and protein kinase R (PKR) in thyroid tissue from GD patients. Design and patients We collected thyroid tissue from core needle biopsies or surgical specimens from 48 GD patients and 24 controls. Standard immunohistochemistry was used to detect HLA class I and enteroviral capsid protein 1 (VP1) on formalin-fixed and paraffin-embedded tissue. STAT1 and PKR were examined by combined immunofluorescence staining. Main Outcome Measures HLA class I expression score. Results The HLA class I expression score, which takes both proportion and intensity of immunostaining into account, was significantly higher in GDs (3.1±3.3) than in controls (0.5±0.9) (p<0.001). Significantly more VP1 positive thyroid cells were found GD samples (50.1± 30.5%) than in controls (14.9±10.5%) (p<0.001). STAT1 and HLA class I was found within the same thyroid cells and PKR and VP1 were also colocalized within thyroid cells. Conclusion HLA class I is upregulated in GD and enterovirus protein is prevalent in thyroid tissue. The colocalization of HLA class I with STAT1 and VP1 with PKR indicates an antiviral tissue response. These findings support the concept of a link between viral infections and GD.

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Impact of HLA class I allele-level mismatch on viral infection within 100 days after cord blood transplantation

Scientific Reports ◽

10.1038/s41598-020-78259-5 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Tomoki Iemura ◽

Yasuyuki Arai ◽

Junya Kanda ◽

Toshio Kitawaki ◽

Masakatsu Hishizawa ◽

...

Keyword(s):

Viral Infection ◽

Cord Blood ◽

Viral Infections ◽

Cord Blood Transplantation ◽

Significant Risk ◽

Human Leukocyte ◽

Hla Class I ◽

Class I ◽

Cytotoxic T Cell ◽

Blood Transplantation

AbstractViral infection is more frequently reported in cord blood transplantation (CBT) than in transplantation of other stem cell sources, but its precise mechanism related to antiviral host defenses has not been elucidated yet. To evaluate the effect of human leukocyte antigen (HLA) class I allele-level incompatibility on viral infection in CBT, we conducted a single-center retrospective study. Total 94 patients were included, and viral infections were detected in 32 patients (34%) within 100 days after CBT. HLA-C mismatches in graft-versus-host direction showed a significantly higher incidence of viral infection (hazard ratio (HR), 3.67; p = 0.01), while mismatches in HLA-A, -B, or -DRB1 were not significant. Overall HLA class I mismatch was also a significant risk factor and the predictor of post-CBT viral infection (≥ 3 mismatches, HR 2.38, p = 0.02), probably due to the insufficient cytotoxic T cell recognition and dendritic cell priming. Patients with viral infection had significantly worse overall survival (52.7% vs. 72.1%; p = 0.02), and higher non-relapse mortality (29.3% vs. 9.8%; p = 0.01) at 5 years. Our findings suggest that appropriate graft selection as well as prophylaxis and early intervention for viral infection in such high-risk patients with ≥ 3 HLA class I allele-level mismatches, including HLA-C, may improve CBT outcomes.

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Association of HLA Class I Genotypes With Severity of Coronavirus Disease-19

Frontiers in Immunology ◽

10.3389/fimmu.2021.641900 ◽

2021 ◽

Vol 12 ◽

Author(s):

Maxim Shkurnikov ◽

Stepan Nersisyan ◽

Tatjana Jankevic ◽

Alexei Galatenko ◽

Ivan Gordeev ◽

...

Keyword(s):

Immune Response ◽

Viral Infections ◽

Characteristic Curve ◽

Human Leukocyte ◽

Hla Class I ◽

Specific Immune Response ◽

Class I ◽

Leukocyte Antigen ◽

Hla Class I Molecules ◽

Severity Of The Disease

Human leukocyte antigen (HLA) class I molecules play a crucial role in the development of a specific immune response to viral infections by presenting viral peptides at the cell surface where they will be further recognized by T cells. In the present manuscript, we explored whether HLA class I genotypes can be associated with the critical course of Coronavirus Disease-19 by searching possible connections between genotypes of deceased patients and their age at death. HLA-A, HLA-B, and HLA-C genotypes of n = 111 deceased patients with COVID-19 (Moscow, Russia) and n = 428 volunteers were identified with next-generation sequencing. Deceased patients were split into two groups according to age at the time of death: n = 26 adult patients aged below 60 and n = 85 elderly patients over 60. With the use of HLA class I genotypes, we developed a risk score (RS) which was associated with the ability to present severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) peptides by the HLA class I molecule set of an individual. The resulting RS was significantly higher in the group of deceased adults compared to elderly adults [p = 0.00348, area under the receiver operating characteristic curve (AUC ROC = 0.68)]. In particular, presence of HLA-A*01:01 allele was associated with high risk, while HLA-A*02:01 and HLA-A*03:01 mainly contributed to low risk. The analysis of patients with homozygosity strongly highlighted these results: homozygosity by HLA-A*01:01 accompanied early deaths, while only one HLA-A*02:01 homozygote died before 60 years of age. Application of the constructed RS model to an independent Spanish patients cohort (n = 45) revealed that the score was also associated with the severity of the disease. The obtained results suggest the important role of HLA class I peptide presentation in the development of a specific immune response to COVID-19.

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Upregulation of HLA class I and antiviral immune responses in graves’ disease

Endocrine Abstracts ◽

10.1530/endoabs.70.ep425 ◽

2020 ◽

Author(s):

Therese Weider ◽

Sarah Richardson ◽

Noel G. Morgan ◽

Trond H. Paulsen ◽

Knut Dahl-Jørgensen ◽

...

Keyword(s):

Immune Responses ◽

Hla Class I ◽

Class I ◽

Graves Disease

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Multiple sclerosis: disease modifying therapy and the human leukocyte antigen

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20180103 ◽

2018 ◽

Vol 76 (10) ◽

pp. 697-704 ◽

Cited By ~ 2

Author(s):

Lineu Cesar Werneck ◽

Paulo José Lorenzoni ◽

Cláudia Suemi Kamoi Kay ◽

Rosana Herminia Scola

Keyword(s):

Multiple Sclerosis ◽

Human Leukocyte Antigen ◽

Human Leukocyte ◽

Hla Class I ◽

Class I ◽

Interferon Β ◽

Leukocyte Antigen ◽

Specific Subset ◽

Hla Type ◽

Disease Modifying

ABSTRACT Objective: To investigate the potential relationship between the human leukocyte antigen (HLA) type (class I and II) and the response to several disease-modifying therapies (DMTs) in patients with multiple sclerosis (MS). Methods: We analyzed clinical data of 87 patients with MS at the beginning and end of each type of DMT including the disease duration, Expanded Disability Status Scale and Multiple Sclerosis Severity Score (MSSS). Genotyping of HLA-DRB1, HLA-DPB1, HLA-DQB1, HLA-A, HLA-B and HLA-C alleles were identified using high-resolution techniques. Statistical correlation between the HLA type and response to DMTs was done using the initial and final MSSS. Results: Statistical relationships (p < 0.05) were found for only 15 of 245 alleles tested. There was a reduction in the MSSS for patients treated with corticosteroids (DRB1*15:01, DPB1*04:01, DQB1*02:01 and DQB1*03:01), azathioprine (DRB1*03:01, DPB1*04:01, DQB1*03:02, DQB1*06:02, HLA-C*07:02), interferon β-1a 22 mcg (DRB1*11:04, DQB1*03:01 and DQB1*03:02), interferon β-1a 30 mcg (DPB1*02:01, HLA-C*05:01) and interferon β-1b (DQB1*02:01). Conclusion: These findings suggest a few relationships between the HLA and response to DMTs in the disability for some types of HLA class I and II alleles in a specific subset of MS patients.

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Human Leukocyte Antigen (HLA) Class I Defects in Head and Neck Cancer: Molecular Mechanisms and Clinical Significance

Immunologic Research ◽

10.1385/ir:33:2:113 ◽

2005 ◽

Vol 33 (2) ◽

pp. 113-134 ◽

Cited By ~ 73

Author(s):

Robert L. Ferris ◽

Jennifer L. Hunt ◽

Soldano Ferrone

Keyword(s):

Head And Neck Cancer ◽

Human Leukocyte Antigen ◽

Head And Neck ◽

Clinical Significance ◽

Neck Cancer ◽

Molecular Mechanisms ◽

Human Leukocyte ◽

Hla Class I ◽

Class I ◽

Leukocyte Antigen

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The effects of cytokines, antithyroidal drugs and glucocorticoids on phagocytosis by thyroid cells

Acta Endocrinologica ◽

10.1530/acta.0.1190413 ◽

1988 ◽

Vol 119 (3) ◽

pp. 413-419 ◽

Cited By ~ 5

Author(s):

Mayumi Matsunaga ◽

Katsumi Eguchi ◽

Takaaki Fukuda ◽

Hiroshi Tezuka ◽

Yukitaka Ueki ◽

...

Keyword(s):

Phagocytic Activity ◽

Interleukin 1 ◽

Thyroid Tissue ◽

Interferon Α ◽

Graves Disease ◽

Dependent Manner ◽

Normal Thyroid Tissue ◽

Thyroid Cells ◽

Latex Beads ◽

Thyroid Glands

Abstract. The present study was undertaken to examine whether thyrocytes possess phagocytic activity and whether the phagocytic activity is influenced by cytokines, such as interleukin 1, 2 (IL 1, IL 2) and interferon-α, -β, and -γ (IFN-α, β, and γ), and drugs, such as methimazole and dexamethasone. Thyroid glands were obtained from patients with Graves' disease. Thyrocytes were prepared by collagenase digestion. Thyrocytes were pre-incubated in the presence or absence of cytokines and drugs at 37°C for 20 h and were further incubated with fluoresceinated latex beads at 37°C for 60 min. The number of phagocytic thyrocytes was determined by FACS IV. Phagocytosis of latex beads was indeed seen within thyrocytes and gradually increased in a time-dependent manner. The rate of phagocytosis in thyrocytes was extremely slow as compared with that in macrophages. Phagocytic activity was detected in thyrocytes from patients with Graves' disease and from normal thyroid tissue adjacent to thyroid cancer. Phagocytosis was inhibited by IL 1, but was enhanced by IL 2. Although the enhanced phagocytosis with IFN-β was consistently seen, little effect was detected with IFN-α and -γ. Both methimazole and dexamethasone markedly inhibited phagocytosis. These results indicated that thyrocytes had phagocytic properties and that their phagocytic activity was modulated by cytokines, antithyroidal drugs and dexamethasone.

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Characteristics allelic of Human Leukocyte Antigen class I genotype and association with viral load and CD4 cell count in HIV-1 infected patients, Hanoi 2014 – 2016

Tạp chí Y học Dự phòng ◽

10.51403/0868-2836/2021/335 ◽

2021 ◽

Vol 31 (4) ◽

pp. 43-50

Author(s):

Tran Thi Minh Tam ◽

Nguyen Thuy Linh ◽

Phan Ha My ◽

Nguyen Thi Lan Anh

Keyword(s):

Viral Load ◽

Human Leukocyte ◽

Hla Class I ◽

Class I ◽

Cd4 Cell Count ◽

Leukocyte Antigen ◽

Cell Counts ◽

Cd4 Cell Counts ◽

Cd4 Cell ◽

Hiv 1

Human Leukocyte Antigen (HLA) class I plays a regulatory role in cellular immune response to HIV-1 infection. The role of HLA alleles in HIV progression via viral load and CD4 cell count is well known. HLA class I is polymorphic and distributed differently by nation. This descriptive cross-sectional study was performed on 303 HIV-1 infected patients in 2014 - 2016, with aims to (i) characterize HLA class I genotype with 4-digit nomenclature and (ii) identify specifc alleles in correlate with CD4 cell counts and HIV viral load. 117 allele genotypes have been identifed, including 28 HLA-A alleles, 54 HLA-B alleles and 35 HLA-C alleles. The results showed that the most prevalent alleles in the population include A*11:01 (30.7%), B*15:02 (15.2%) and C*08:01 (17.1%). The frequency of haplotype created from these alleles is 8.4%. A*02:03, B*46:01 related to gender and ethnicity respectively. In conclusion, the study provided detailed pattern of HLA class I expression in a study population of HIV-1 infected patients and reported for the frst time the associated B*51:01, C*14:02 alleles associated to an increase in CD4 cell counts.

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Results of a randomized, double-blind phase II clinical trial of NY-ESO-1 vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in participants with high-risk resected melanoma

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2019-000410 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000410

Author(s):

Jonathan S Cebon ◽

Martin Gore ◽

John F Thompson ◽

Ian D Davis ◽

Grant A McArthur ◽

...

Keyword(s):

New York ◽

High Risk ◽

Phase Ii ◽

Immune Escape ◽

Human Leukocyte ◽

Hla Class I ◽

Class I ◽

Double Positive ◽

Double Blind ◽

Hla Class I Molecules

BackgroundTo compare the clinical efficacy of New York Esophageal squamous cell carcinoma-1 (NY-ESO-1) vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in a randomized, double-blind phase II study in participants with fully resected melanoma at high risk of recurrence.MethodsParticipants with resected stage IIc, IIIb, IIIc and IV melanoma expressing NY-ESO-1 were randomized to treatment with three doses of NY-ESO-1/ISCOMATRIX or ISCOMATRIX adjuvant administered intramuscularly at 4-week intervals, followed by a further dose at 6 months. Primary endpoint was the proportion free of relapse at 18 months in the intention-to-treat (ITT) population and two per-protocol populations. Secondary endpoints included relapse-free survival (RFS) and overall survival (OS), safety and NY-ESO-1 immunity.ResultsThe ITT population comprised 110 participants, with 56 randomized to NY-ESO-1/ISCOMATRIX and 54 to ISCOMATRIX alone. No significant toxicities were observed. There were no differences between the study arms in relapses at 18 months or for median time to relapse; 139 vs 176 days (p=0.296), or relapse rate, 27 (48.2%) vs 26 (48.1%) (HR 0.913; 95% CI 0.402 to 2.231), respectively. RFS and OS were similar between the study arms. Vaccine recipients developed strong positive antibody responses to NY-ESO-1 (p≤0.0001) and NY-ESO-1-specific CD4+and CD8+responses. Biopsies following relapse did not demonstrate differences in NY-ESO-1 expression between the study populations although an exploratory study demonstrated reduced (NY-ESO-1)+/Human Leukocyte Antigen (HLA) class I+double-positive cells in biopsies from vaccine recipients performed on relapse in 19 participants.ConclusionsThe vaccine was well tolerated, however, despite inducing antigen-specific immunity, it did not affect survival endpoints. Immune escape through the downregulation of NY-ESO-1 and/or HLA class I molecules on tumor may have contributed to relapse.

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Peptide-Dependent Recognition of HLA-B*57:01 by KIR3DS1

Journal of Virology ◽

10.1128/jvi.03586-14 ◽

2015 ◽

Vol 89 (10) ◽

pp. 5213-5221 ◽

Cited By ~ 44

Author(s):

Geraldine M. O'Connor ◽

Julian P. Vivian ◽

Emma Gostick ◽

Phillip Pymm ◽

Bernard A. P. Lafont ◽

...

Keyword(s):

Hiv Infection ◽

Nk Cells ◽

Natural Killer ◽

Molecular Mechanisms ◽

Viral Infections ◽

Hla Class I ◽

Class I ◽

Disease Outcome ◽

Immune Control ◽

Peptide Epitopes

ABSTRACTKiller cell immunoglobulin-like receptors (KIRs) play an important role in the activation of natural killer (NK) cells, which in turn contribute to the effective immune control of many viral infections. In the context of HIV infection, the closely related KIR3DL1 and KIR3DS1 molecules, in particular, have been associated with disease outcome. Inhibitory signals via KIR3DL1 are disrupted by downregulation of HLA class I ligands on the infected cell surface and can also be impacted by changes in the presented peptide repertoire. In contrast, the activatory ligands for KIR3DS1 remain obscure. We used a structure-driven approach to define the characteristics of HLA class I-restricted peptides that interact with KIR3DL1 and KIR3DS1. In the case of HLA-B*57:01, we used this knowledge to identify bona fide HIV-derived peptide epitopes with similar properties. Two such peptides facilitated productive interactions between HLA-B*57:01 and KIR3DS1. These data reveal the presence of KIR3DS1 ligands within the HIV-specific peptide repertoire presented by a protective HLA class I allotype, thereby enhancing our mechanistic understanding of the processes that enable NK cells to impact disease outcome.IMPORTANCENatural killer (NK) cells are implicated as determinants of immune control in many viral infections, but the precise molecular mechanisms that initiate and control these responses are unclear. The activating receptor KIR3DS1 in combination with HLA-Bw4 has been associated with better outcomes in HIV infection. However, evidence of a direct interaction between these molecules is lacking. In this study, we demonstrate that KIR3DS1 recognition of HLA-Bw4 is peptide dependent. We also identify HIV-derived peptide epitopes presented by the protective HLA-B*57:01 allotype that facilitate productive interactions with KIR3DS1. Collectively, these findings suggest a mechanism whereby changes in the peptide repertoire associated with viral infection provide a trigger for KIR3DS1 engagement and NK cell activation.

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