scholarly journals Tristetraprolin/ZFP36 Regulates the Turnover of Autoimmune-Associated HLA-DQ mRNAs

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1570 ◽  
Author(s):  
Laura Pisapia ◽  
Russell S. Hamilton ◽  
Federica Farina ◽  
Vito D’Agostino ◽  
Pasquale Barba ◽  
...  
Keyword(s):  
T Cells ◽  
Autoimmune Diseases ◽  
Zinc Finger Protein ◽  
Class Ii ◽  
Hla Class Ii ◽  
Autoimmune Response ◽  
Risk Genes ◽  
Hla Dq ◽  
Rnp Complex ◽  
Hla Dqa1

HLA class II genes encode highly polymorphic heterodimeric proteins functioning to present antigens to T cells and stimulate a specific immune response. Many HLA genes are strongly associated with autoimmune diseases as they stimulate self-antigen specific CD4+ T cells driving pathogenic responses against host tissues or organs. High expression of HLA class II risk genes is associated with autoimmune diseases, influencing the strength of the CD4+ T-mediated autoimmune response. The expression of HLA class II genes is regulated at both transcriptional and post-transcriptional levels. Protein components of the RNP complex binding the 3′UTR and affecting mRNA processing have previously been identified. Following on from this, the regulation of HLA-DQ2.5 risk genes, the main susceptibility genetic factor for celiac disease (CD), was investigated. The DQ2.5 molecule, encoded by HLA-DQA1*05 and HLA-DQB1*02 alleles, presents the antigenic gluten peptides to CD4+ T lymphocytes, activating the autoimmune response. The zinc-finger protein Tristetraprolin (TTP) or ZFP36 was identified to be a component of the RNP complex and has been described as a factor modulating mRNA stability. The 3′UTR of CD-associated HLA-DQA1*05 and HLA-DQB1*02 mRNAs do not contain canonical TTP binding consensus sequences, therefore an in silico approach focusing on mRNA secondary structure accessibility and stability was undertaken. Key structural differences specific to the CD-associated mRNAs were uncovered, allowing them to strongly interact with TTP through their 3′UTR, conferring a rapid turnover, in contrast to lower affinity binding to HLA non-CD associated mRNA.

scholarly journals Tristetraprolin/ZFP36 regulates the turnover of autoimmune-associated HLA-DQ mRNAs

2018 ◽  
Author(s):  
Laura Pisapia ◽  
Russell S. Hamilton ◽  
Federica Farina ◽  
Vito D’Agostino ◽  
Pasquale Barba ◽  
...  
Keyword(s):  
Celiac Disease ◽  
Rna Binding ◽  
Zinc Finger Protein ◽  
Rna Binding Proteins ◽  
Autoimmune Response ◽  
Affinity Binding ◽  
Hla Dq ◽  
Rnp Complex ◽  
Protein Components ◽  
Hla Dqa1

AbstractWe have previously demonstrated that the expression of HLA class II genes is regulated by the binding of a ribonucleoprotein complex that affects the mRNA processing. We identified protein components of a complex binding transcripts encoding the HLA-DR molecule. Here we investigate whether the same RNA binding proteins interact with 3’UTR of mRNAs encoding the HLA-DQ isotype. Specifically, we focused on the HLA-DQ2.5 molecule, expressed on the surface of antigen presenting cells, and representing the main susceptibility factor for celiac disease (CD). This molecule, encoded by HLA-DQA1*05 and HLA-DQB1*02 alleles, presents the antigenic gluten peptides to CD4+ T lymphocytes, activating the autoimmune response.Here, we identified an additional component of the RNP complex, Tristetraprolin (TTP) or ZFP36, a zinc-finger protein, widely described as a factor modulating mRNA stability. TTP shows high affinity binding to 3’UTR of CD-associated HLA-DQA1*05 and HLA-DQB1*02 alleles, in contrast to lower affinity binding to HLA-DQA1*01 and HLA-DQB1*05 non-CD associated alleles. Our in silico analysis, confirmed by molecular experiments, demonstrates that TTP specifically modulates the stability of the transcripts associated with celiac disease.

scholarly journals Comprehensive Analysis of CD4+ T Cell Response Cross-Reactive to SARS-CoV-2 Antigens at the Single Allele Level of HLA Class II

2022 ◽  
Vol 12 ◽  
Author(s):  
You-Seok Hyun ◽  
Yong-Hun Lee ◽  
Hyeong-A Jo ◽  
In-Cheol Baek ◽  
Sun-Mi Kim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Class Ii ◽  
Hla Class Ii ◽  
T Cell Response ◽  
Hla Dr ◽  
Hla Dq ◽  
Single Allele ◽  
Human Coronaviruses

Common human coronaviruses have been circulating undiagnosed worldwide. These common human coronaviruses share partial sequence homology with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); therefore, T cells specific to human coronaviruses are also cross-reactive with SARS-CoV-2 antigens. Herein, we defined CD4+ T cell responses that were cross-reactive with SARS-CoV-2 antigens in blood collected in 2016–2018 from healthy donors at the single allele level using artificial antigen-presenting cells (aAPC) expressing a single HLA class II allotype. We assessed the allotype-restricted responses in the 42 individuals using the aAPCs matched 22 HLA-DR alleles, 19 HLA-DQ alleles, and 13 HLA-DP alleles. The response restricted by the HLA-DR locus showed the highest magnitude, and that by HLA-DP locus was higher than that by HLA-DQ locus. Since two alleles of HLA-DR, -DQ, and -DP loci are expressed co-dominantly in an individual, six different HLA class II allotypes can be used to the cross-reactive T cell response. Of the 16 individuals who showed a dominant T cell response, five, one, and ten showed a dominant response by a single allotype of HLA-DR, -DQ, and -DP, respectively. The single allotype-restricted T cells responded to only one antigen in the five individuals and all the spike, membrane, and nucleocapsid proteins in the six individuals. In individuals heterozygous for the HLA-DPA and HLA-DPB loci, four combinations of HLA-DP can be expressed, but only one combination showed a dominant response. These findings demonstrate that cross-reactive T cells to SARS-CoV-2 respond with single-allotype dominance.

Identification of Phosphatidylinositol 4-Kinase Type II β as the First HLA Class II Associated Minor Histocompatibility Antigen Involved in Graft Versus Leukemia Reactivity.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1800-1800
Author(s):  
Marieke Griffioen ◽  
Edith D. van der Meijden ◽  
M. Willy Honders ◽  
Caroline Rutten ◽  
Simone A.P. van Luxemburg-Heijs ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Class Ii ◽  
Hla Class Ii ◽  
Type Ii ◽  
Cell Therapies ◽  
Graft Versus Leukemia ◽  
Hla Dq ◽  
Phosphatidylinositol 4

Abstract Patients with hematological malignancies can be successfully treated with HLA-matched T cell-depleted allogeneic stem cell transplantation (alloSCT) and subsequent donor lymphocyte infusions (DLI). The efficacy of DLI is mediated by donor T cells recognizing minor histocompatibility antigens (mHags) on malignant recipient cells. Since HLA class II molecules are predominantly expressed on hematopoietic cells, mHag specific CD4+ T cells may selectively mediate Graft-versus-Leukemia (GvL) reactivity without Graft-versus-Host Disease (GvHD). Clinical studies have shown that adoptive transfer of CD4+ donor lymphocytes after HLA-matched alloSCT may lead to clinical remissions with a reduced incidence of GvHD, emphasizing the relevance of CD4+ T cells and HLA class II associated mHags for development of effective anti-tumor T cell therapies after alloSCT with a low risk for GvHD. The aim of this study was to identify the HLA class II associated mHag that is recognized by CD4+ T cells induced in a patient with relapsed chronic myeloid leukemia (CML) after HLA-matched alloSCT who developed strong GvL reactivity with mild GvHD of the skin after treatment with DLI. We previously developed recombinant bacteria cDNA expression libraries based on delivery of exogenous antigens for identification of HLA class II antigens and used this method for identification of the first autosomal HLA class II (HLA-DQB1*0603) associated mHag LB-PI4K2B-1S. LB-PI4K2B-1S has a population frequency of 40–50% and is encoded by the broadly-expressed phosphatidylinositol 4-kinase type II β gene. In the patient with CML, a polyclonal CD4+ T cell response against LB-PI4K2B-1S and simultaneous mHag specific CD8+ T cells were demonstrated. LB-PI4K2B-1S specific CD4+ T cells were shown to recognize the CD34+ CML cells of the patient as well as other leukemic cells. Recognition and lysis of normal hematopoietic cells by LB-PI4K2B-1S specific CD4+ T cells critically depended on the number of HLA-DQ molecules expressed at the cell surface and was restricted to high HLA-DQ-expressing B cells, mature dendritic cells (DC) and EBV-transformed B cells. HLA-DQ expression on T cells, PHA-stimulated blasts, monocytes and immature DC was absent or low and not sufficient for T cell recognition. We also demonstrated that HLA-DQ expression on normal cells of non-hematopoietic origin after extensive culturing with IFN-γ was moderately upregulated as compared to HLA-DR and -DP and not sufficient for recognition by LB-PI4K2B-1S specific CD4+ T cells. In conclusion, the data suggest that LB-PI4K2B-1S specific CD4+ T cells mediated tumor rejection by directly eliminating the malignant cells of the patient as effector cells and stimulating the induction and maintenance of CD8+ T cell immunity as helper cells, and HLA-DQ associated mHags may be appropriate targets for T cell therapies with the aim to selectively stimulate GvL after HLA-matched alloSCT with a low risk for GvHD.

scholarly journals Specific killing of cytotoxic T cells and antigen-presenting cells by CD4+ cytotoxic T cell clones. A novel potentially immunoregulatory T-T cell interaction in man.

1990 ◽  
Vol 171 (6) ◽  
pp. 2011-2024 ◽  
Author(s):  
T H Ottenhoff ◽  
T Mutis
Keyword(s):  
T Cells ◽  
T Cell ◽  
Class Ii ◽  
Cytolytic Activity ◽  
Hla Class Ii ◽  
Cytotoxic T Cell ◽  
Target Antigen ◽  
T Cell Clones ◽  
Cell Clones ◽  
Hla Dq

Mycobacterial antigens not only stimulate Th cells that produce macrophage-activating factors, but also CD4+ and CD8+ CTL that lyse human macrophages. The mycobacterial recombinant 65-kD hsp was previously found to be an important target antigen for polyclonal CD4+ CTL. Because of the major role of 65-kD hsp in the immune response to mycobacterial as well as autoantigens, we have studied CTL activity to this protein at the clonal level. HLA-DR or HLA-DQ restricted, CD4+CD8- T cell clones that recognize different peptides of the M. leprae 65-kD hsp strongly lysed EBV-BLCL pulsed with specific but not irrelevant peptide. No bystander lysis of B cells, T cells, or tumor cells was seen. Target cell lysis could not be triggered by PMA + Ca2+ ionophore alone and depended on active metabolism. Interestingly, these CD4+ CTL also strongly lysed themselves and other HLA-class II compatible CD4+ (TCR-alpha/beta or -gamma/delta) or CD8+ CTL clones in the presence of peptide, suggesting that CTL are not actively protected from CTL-mediated lysis. Cold target competition experiments suggested that EBV-BLCL targets were more efficiently recognized than CD4+ CTL targets. These results demonstrate that hsp65 peptide-specific HLA class II-restricted CD4+ T cell clones display strong peptide-dependent cytolytic activity towards both APCs, and, unexpectedly, CD4+ and CD8+ CTL clones, including themselves. Since, in contrast to murine T cells human T cells express class II, CTL-mediated T cell killing may represent a novel immunoregulatory pathway in man.

scholarly journals Common Denominators in the Immunobiology of IgG4 Autoimmune Diseases: What Do Glomerulonephritis, Pemphigus Vulgaris, Myasthenia Gravis, Thrombotic Thrombocytopenic Purpura and Autoimmune Encephalitis Have in Common?

2021 ◽  
Vol 11 ◽  
Author(s):  
Inga Koneczny ◽  
Vuslat Yilmaz ◽  
Konstantinos Lazaridis ◽  
John Tzartos ◽  
Tobias L. Lenz ◽  
...  
Keyword(s):  
T Cells ◽  
Nervous System ◽  
Autoimmune Diseases ◽  
Myasthenia Gravis ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Autoimmune Encephalitis ◽  
Pemphigus Vulgaris ◽  
Class Ii ◽  
Hla Class Ii ◽  
Thrombocytopenic Purpura

IgG4 autoimmune diseases (IgG4-AID) are an emerging group of autoimmune diseases that are caused by pathogenic autoantibodies of the IgG4 subclass. It has only recently been appreciated, that members of this group share relevant immunobiological and therapeutic aspects even though different antigens, tissues and organs are affected: glomerulonephritis (kidney), pemphigus vulgaris (skin), thrombotic thrombocytopenic purpura (hematologic system) muscle-specific kinase (MuSK) in myasthenia gravis (peripheral nervous system) and autoimmune encephalitis (central nervous system) to give some examples. In all these diseases, patients’ IgG4 subclass autoantibodies block protein-protein interactions instead of causing complement mediated tissue injury, patients respond favorably to rituximab and share a genetic predisposition: at least five HLA class II genes have been reported in individual studies to be associated with several different IgG4-AID. This suggests a role for the HLA class II region and specifically the DRβ1 chain for aberrant priming of autoreactive T-cells toward a chronic immune response skewed toward the production of IgG4 subclass autoantibodies. The aim of this review is to provide an update on findings arguing for a common pathogenic mechanism in IgG4-AID in general and to provide hypotheses about the role of distinct HLA haplotypes, T-cells and cytokines in IgG4-AID.

scholarly journals LAG3 and Its Ligands Show Increased Expression in High-Risk Uveal Melanoma

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4445
Author(s):  
Zahra Souri ◽  
Annemijn P. A. Wierenga ◽  
Wilma G. M. Kroes ◽  
Pieter A. van der Velden ◽  
Robert M. Verdijk ◽  
...  
Keyword(s):  
High Risk ◽  
Uveal Melanoma ◽  
Lymphocyte Activation ◽  
Class Ii ◽  
Hla Class Ii ◽  
Uveal Tract ◽  
Hla Dq ◽  
Monosomy 3 ◽  
Galectin 3 ◽  
Hla Dqa1

Uveal melanoma (UM) is a rare ocular malignancy which originates in the uveal tract, and often gives rise to metastases. Potential targets for immune checkpoint inhibition are lymphocyte-activation gene 3 (LAG3) and its ligands. We set out to analyse the distribution of these molecules in UM. The expression of mRNA was determined using an Illumina array in 64 primary UM from Leiden. The T lymphocyte fraction was determined by digital droplet PCR. In a second cohort of 15 cases from Leiden, mRNA expression was studied by Fluidigm qPCR, while a third cohort consisted of 80 UM from TCGA. In the first Leiden cohort, LAG3 expression was associated with the presence of epithelioid cells (p = 0.002), monosomy of chromosome 3 (p = 0.004), and loss of BAP1 staining (p = 0.001). In this Leiden cohort as well as in the TCGA cohort, LAG3 expression correlated positively with the expression of its ligands: LSECtin, Galectin-3, and the HLA class II molecules HLA-DR, HLA-DQ, and HLA-DP (all p < 0.001). Furthermore, ligands Galectin-3 and HLA class II were increased in monosomy 3 tumours and the expression of LAG3 correlated with the presence of an inflammatory phenotype (T cell fraction, macrophages, HLA-A and HLA-B expression: all p < 0.001). High expression levels of LAG3 (p = 0.01), Galectin-3 (p = 0.001), HLA-DRA1 (p = 0.002), HLA-DQA1 (p = 0.04), HLA-DQB2 (p = 0.03), and HLA-DPA1 (p = 0.007) were associated with bad survival. We conclude that expression of the LAG ligands Galectin-3 and HLA class II strongly correlates with LAG3 expression and all are increased in UM with Monosomy 3/BAP1 loss. The distribution suggests a potential benefit of monoclonal antibodies against LAG3 or Galectin-3 as adjuvant treatment in patients with high-risk UM.

T Cells: A Growing Universe of Roles in Neurodegenerative Diseases

2021 ◽  
pp. 107385842110249
Author(s):  
Dallin Dressman ◽  
Wassim Elyaman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Neurodegenerative Diseases ◽  
Human Leukocyte ◽  
Autoimmune Response ◽  
Antigen Specificity ◽  
Risk Genes ◽  
Leukocyte Antigen ◽  
Histocompatibility Complex ◽  
The Central Nervous System

T cells play a central role in homeostasis and host defense against infectious diseases. T cell dysregulation can lead to recognizing self-antigens as foreign antigens, causing a detrimental autoimmune response. T cell involvement in multiple sclerosis (MS), long understood to be an autoimmune-mediated neurodegenerative disease, is well characterized. More recently, a role for T cells has also been identified for the neurodegenerative diseases Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Interestingly, several alleles and variants of human leukocyte antigen (HLA) genes have been classified as AD and PD risk genes. HLA codes for components of major histocompatibility complex (MHC) class I or class II, both of which are expressed by microglia, the innate immune cells of the central nervous system (CNS). Thus, both microglia and T cells may potentially interact in an antigen-dependent or independent fashion to shape the inflammatory cascade occurring in neurodegenerative diseases. Dissecting the antigen specificity of T cells may lead to new options for disease-modifying treatments in neurodegenerative diseases. Here, we review the current understanding of T cells in neurodegenerative diseases. We summarize the subsets of T cells, their phenotype and potential functions in animal models and in human studies of neurodegenerative diseases.

HLA class II restriction repertoire of antigen-specific T cells. II. Evidence for a new restriction determinant associated with DRw52 and LB-Q1

1985 ◽  
Vol 13 (2) ◽  
pp. 117-123 ◽  
Author(s):  
Tom H.M. Ottenhoff ◽  
Dienne G. Elferink ◽  
Annemarie Termijtelen ◽  
Frits Koning ◽  
RenéR.P. de Vries
Keyword(s):  
T Cells ◽  
Class Ii ◽  
Hla Class Ii

scholarly journals Shared HLA Class II in Six Autoimmune Diseases in Latin America: A Meta-Analysis

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Paola Cruz-Tapias ◽  
Oscar M. Pérez-Fernández ◽  
Adriana Rojas-Villarraga ◽  
Alberto Rodríguez-Rodríguez ◽  
María-Teresa Arango ◽  
...  
Keyword(s):  
Risk Factor ◽  
Autoimmune Diseases ◽  
Lupus Erythematosus ◽  
Meta Analysis ◽  
Human Leukocyte ◽  
Class Ii ◽  
Hla Class Ii ◽  
Genetic Characteristics ◽  
Latin Americans ◽  
Leukocyte Antigen

The prevalence and genetic susceptibility of autoimmune diseases (ADs) may vary depending on latitudinal gradient and ethnicity. The aims of this study were to identify common human leukocyte antigen (HLA) class II alleles that contribute to susceptibility to six ADs in Latin Americans through a meta-analysis and to review additional clinical, immunological, and genetic characteristics of those ADs sharing HLA alleles. DRB1∗03:01 (OR: 4.04; 95%CI: 1.41–11.53) was found to be a risk factor for systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), and type 1 diabetes mellitus (T1D). DRB1∗04:05 (OR: 4.64; 95%CI: 2.14–10.05) influences autoimmune hepatitis (AIH), rheumatoid arthritis (RA), and T1D; DRB1∗04:01 (OR: 3.86; 95%CI: 2.32–6.42) is a susceptibility factor for RA and T1D. Opposite associations were found between multiple sclerosis (MS) and T1D. DQB1∗06:02 and DRB1∗15 alleles were risk factors for MS but protective factors for T1D. Likewise, DQB1∗06:03 allele was a risk factor for AIH but a protective one for T1D. Several common autoantibodies and clinical associations as well as additional shared genes have been reported in these ADs, which are reviewed herein. These results indicate that in Latin Americans ADs share major loci and immune characteristics.

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