Killer immunoglobulin-like receptor locus polymorphisms in multiple sclerosis

Objective: The objective of this study was to analyze whether inhibitory and activating killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I alleles defined by their KIR binding motifs are associated with multiple sclerosis (MS) susceptibility or severity. Method: We performed a population-based case–control study in 321 patients with clinically isolated syndrome (CIS) and clinically definite MS (CDMS) and 156 healthy blood donors (HD). Inhibitory and activating KIRs and HLA class I alleles were genotyped using polymerase chain reaction (PCR) sequence-specific primers. Allelic frequencies were correlated with prevalence, age of onset, disability and disease duration of CIS and CDMS. Results: The frequency of the inhibitory KIR2DL3 gene was significantly reduced in patients with CIS and CDMS ( p = 3.1 × 10−5). KIR2DL3-dependent risk reduction remained significant after elimination of patients carrying MS-associated DRB1*15, DRB1*03, DRB1*01 alleles. In addition, individuals carrying two copies for KIR2DL2/KIR2DS2 but lacking KIR2DL3 were overrepresented in the CIS/CDMS cohort. However, both genes did not affect disease risk in presence of KIR2DL3. We did not detect any association between the presence or absence of KIR genes with clinical disease parameters. Conclusion: Absence of the inhibitory KIR2DL3 gene is associated with the development of CIS/CDMS. These findings, if confirmed in larger cohorts, suggest that KIR-mediated recognition of HLA class I molecules should be further explored as potential disease mechanism in MS.

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The Interaction of LILRB2 with HLA-B is Associated with Psoriasis Susceptibility

10.1101/741983 ◽

2019 ◽

Author(s):

Rebecca L. Yanovsky ◽

Haoyan Chen ◽

Stephen Leslie ◽

Mary Carrington ◽

Wilson Liao

Keyword(s):

Genome Wide Association Study ◽

Killer Cell ◽

Human Leukocyte ◽

Antigen Presenting Cells ◽

Hla Class I ◽

Class I ◽

Hla Class I Molecules ◽

Genome Wide ◽

Related Group ◽

Antigen Presenting

ABSTRACTGenetic variation within the major histocompatibility complex (MHC) class I is a well-known risk factor for psoriasis. While the mechanisms behind this variation are still being fully elucidated, human leukocyte antigen (HLA) presentation of auto-antigens as well as the interaction of HLA-B with killer cell immunoglobulin-like receptors (KIRs) have been shown to contribute to psoriasis susceptibility. Here we demonstrate that the interaction of HLA class I molecules with leukocyte immunoglobulin-like receptors (LILR), a related group of immunomodulatory receptors primarily found on antigen presenting cells, also contributes to psoriasis susceptibility. We used previously characterized binding capacities of HLA-A, HLA-B, and HLA-C allotypes to two inhibitory LILRs, LILRB1 and LILRB2, to investigate the effect of LILRB1/2 binding in two large genome wide association study cohorts of psoriasis patients and controls (N = 10,069). We found that the strength of binding of LILRB2 to HLA-B was inversely associated with psoriasis risk (p = 2.34E-09, OR [95% CI], 0.41 [0.30−0.55]) independent of individual class I or II allelic effects. We thus propose that weak binding of inhibitory LILRB2 to HLA-B may play a role in patient susceptibility to psoriasis via increased activity of antigen presenting cells.

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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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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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Human natural killer cell receptors for HLA-class I molecules. Evidence that the Kp43 (CD94) molecule functions as receptor for HLA-B alleles.

Journal of Experimental Medicine ◽

10.1084/jem.180.2.545 ◽

1994 ◽

Vol 180 (2) ◽

pp. 545-555 ◽

Cited By ~ 146

Author(s):

A Moretta ◽

M Vitale ◽

S Sivori ◽

C Bottino ◽

L Morelli ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Killer Cell ◽

Hla Class I ◽

Cytolytic Activity ◽

Class I ◽

Target Cells ◽

Human Natural Killer Cell ◽

Ligand Interaction ◽

Hla Class I Molecules

GL183 or EB6 (p58) molecules have been shown to function as receptors for different HLA-C alleles and to deliver an inhibitory signal to natural killer (NK) cells, thus preventing lysis of target cells. In this study, we analyzed a subset of NK cells characterized by a p58-negative surface phenotype. We show that p58-negative clones, although specific for class I molecules do not recognize HLA-C alleles. In addition, by the use of appropriate target cells transfected with different HLA-class I alleles we identified HLA-B7 as the protective element recognized by a fraction of p58-negative clones. In an attempt to identify the receptor molecules expressed by HLA-B7-specific clones, monoclonal antibodies (mAbs) were selected after mice immunization with such clones. Two of these mAbs, termed XA-88 and XA-185, and their F(ab')2 fragments, were found to reconstitute lysis of B7+ target cells by B7-specific NK clones. Both mAbs were shown to be directed against the recently clustered Kp43 molecule (CD94). Thus, mAb-mediated masking of Kp43 molecules interferes with recognition of HLA-B7 and results in target cell lysis. Moreover, in a redirected killing assay, the cross-linking of Kp43 molecules mediated by the XA185 mAb strongly inhibited the cytolytic activity of HLA-B7-specific NK clones, thus mimicking the functional effect of B7 molecules. Taken together, these data strongly suggest that Kp43 molecules function as receptors for HLA-B7 and that this receptor/ligand interaction results in inhibition of the NK-mediated cytolytic activity. Indirect immunofluorescence and FACS analysis of a large number of random NK clones showed that Kp43 molecules (a) were brightly expressed on a subset of p58-negative clones, corresponding to those specific for HLA-B7; (b) displayed a medium/low fluorescence in the p58-negative clones that are not B7-specific as well as in most p58+ NK clones; and (c) were brightly expressed as in the p58+ clone ET34 (GL183-/EB6+, Cw4-specific). Functional analysis revealed that Kp43 functioned as an inhibitory receptor only in NK clones displaying bright fluorescence. These studies also indicate that some NK clones (e.g., the ET34) can coexpress two distinct receptors (p58 and Kp43) for different class I alleles (Cw4 and B7). Finally, we show that Kp43 molecules function as receptors only for some HLA-B alleles and that still undefined receptor(s) must exist for other HLA-B alleles including B27.

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The CD94 and NKG2-A C-type lectins covalently assemble to form a natural killer cell inhibitory receptor for HLA class I molecules

European Journal of Immunology ◽

10.1002/eji.1830270230 ◽

1997 ◽

Vol 27 (2) ◽

pp. 563-567 ◽

Cited By ~ 185

Author(s):

Marta Carretero ◽

Claudia Cantoni ◽

Teresa Bellón ◽

Cristina Bottino ◽

Roberto Biassoni ◽

...

Keyword(s):

Natural Killer Cell ◽

Natural Killer ◽

Killer Cell ◽

Hla Class I ◽

Class I ◽

Inhibitory Receptor ◽

Hla Class I Molecules ◽

Killer Cell Inhibitory Receptor

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A Viral, Transporter Associated with Antigen Processing (TAP)-independent, High Affinity Ligand with Alternative Interactions Endogenously Presented by the Nonclassical Human Leukocyte Antigen E Class I Molecule

Journal of Biological Chemistry ◽

10.1074/jbc.m112.362293 ◽

2012 ◽

Vol 287 (42) ◽

pp. 34895-34903 ◽

Cited By ~ 12

Author(s):

Elena Lorente ◽

Susana Infantes ◽

David Abia ◽

Eilon Barnea ◽

Ilan Beer ◽

...

Keyword(s):

Human Leukocyte Antigen ◽

Antigen Processing ◽

Human Leukocyte ◽

Hla Class I ◽

Class I ◽

Structural Motif ◽

Leukocyte Antigen ◽

High Affinity ◽

Hla Class I Molecules ◽

Infected Cells

The transporter associated with antigen processing (TAP) enables the flow of viral peptides generated in the cytosol by the proteasome and other proteases to the endoplasmic reticulum, where they complex with nascent human leukocyte antigen (HLA) class I. Later, these peptide-HLA class I complexes can be recognized by CD8+ lymphocytes. Cancerous cells and infected cells in which TAP is blocked, as well as individuals with unusable TAP complexes, are able to present peptides on HLA class I by generating them through TAP-independent processing pathways. Here, we identify a physiologically processed HLA-E ligand derived from the D8L protein in TAP-deficient vaccinia virus-infected cells. This natural high affinity HLA-E class I ligand uses alternative interactions to the anchor motifs previously described to be presented on nonclassical HLA class I molecules. This octameric peptide was also presented on HLA-Cw1 with similar binding affinity on both classical and nonclassical class I molecules. In addition, this viral peptide inhibits HLA-E-mediated cytolysis by natural killer cells. Comparison between the amino acid sequences of the presenting HLA-E and HLA-Cw1 alleles revealed a shared structural motif in both HLA class molecules, which could be related to their observed similar cross-reactivity affinities. This motif consists of several residues located on the floor of the peptide-binding site. These data expand the role of HLA-E as an antigen-presenting molecule.

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Killer cell inhibitory receptor interactions with HLA class I molecules

Human Immunology ◽

10.1016/s0198-8859(96)00258-3 ◽

1997 ◽

Vol 52 (1) ◽

pp. 1-11 ◽

Cited By ~ 13

Author(s):

Neil T. Young ◽

Mike Bunce ◽

Peter J. Morris ◽

Ken I. Welsh

Keyword(s):

Killer Cell ◽

Hla Class I ◽

Class I ◽

Inhibitory Receptor ◽

Hla Class I Molecules ◽

Receptor Interactions ◽

Killer Cell Inhibitory Receptor

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Co-evolution of Human Leukocyte Antigen (HLA) Class I Ligands with Killer-Cell Immunoglobulin-Like Receptors (KIR) in a Genetically Diverse Population of Sub-Saharan Africans

PLoS Genetics ◽

10.1371/journal.pgen.1003938 ◽

2013 ◽

Vol 9 (10) ◽

pp. e1003938 ◽

Cited By ~ 80

Author(s):

Paul J. Norman ◽

Jill A. Hollenbach ◽

Neda Nemat-Gorgani ◽

Lisbeth A. Guethlein ◽

Hugo G. Hilton ◽

...

Keyword(s):

Human Leukocyte Antigen ◽

Killer Cell ◽

Human Leukocyte ◽

Hla Class I ◽

Class I ◽

Diverse Population ◽

Leukocyte Antigen ◽

Sub Saharan

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In silico investigation of binding affinities between human leukocyte antigen class I molecules and SARS-CoV-2 virus spike and ORF1ab proteins

10.37349/ei.2021.00003 ◽

2021 ◽

Author(s):

Spyros A. Charonis ◽

Effie-Photini Tsilibary ◽

Apostolos P. Georgopoulos

Keyword(s):

Human Leukocyte Antigen ◽

In Silico ◽

Human Leukocyte ◽

Hla Class I ◽

Hla Class Ii ◽

Class I ◽

Binding Affinities ◽

S Protein ◽

Leukocyte Antigen ◽

Hla Class I Molecules

Aim: The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019, a global pandemic. There is hence an urgent need for effective approaches to understand the mechanism of viral interaction with immune cells that lead to viral elimination and subsequent long-term immunity. The first, immediate response to the viral infection involves mobilization of native immunity and human leukocyte antigen (HLA) class I mechanisms to kill infected cells and eliminate the virus. The second line of defense involves the activation of HLA class II system for the production of antibodies against the virus which will add to the elimination of the virus and prevent future infections. In a previous study, investigated the relations between SARS-CoV-2 spike glycoprotein (S protein) and HLA class II alleles were investigaed; here report on the relations of the S protein and the open reading frame 1ab (ORF1ab) of SARS-CoV-2 to HLA class I alleles. Methods: An in silico sliding window approach was used to determine exhaustively the binding affinities of linear epitopes of 10 amino acid length (10-mers) to each of 61 common (global frequency ≥ 0.01) HLA class I molecules (17, 24 and 20 from gene loci A, B and C, respectively). A total of 8,354 epitopes were analyzed; 1,263 from the S protein and 7,091 from ORF1ab. Results: HLA-A genes were the most effective at binding SARS-CoV-2 epitopes for both spike and ORF1ab proteins. Good binding affinities were found for all three genes and were distributed throughout the length of the S protein and ORF1ab polyprotein sequence. Conclusions: Common HLA class I molecules, as a population, are very well suited to binding with high affinity to SARS-CoV-2 spike and ORF1ab proteins and hence should be effective in aiding the early elimination of the virus.

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Immunogenetic Epidemiology of Multiple Sclerosis in 14 Continental Western European Countries

Journal of Immunological Sciences ◽

10.29245/2578-3009/2021/2.1216 ◽

2021 ◽

Vol 5 (2) ◽

pp. 40-46

Author(s):

Lisa M. James ◽

Apostolos P. Georgopoulos

Keyword(s):

Multiple Sclerosis ◽

Human Leukocyte ◽

Hla Class I ◽

European Countries ◽

Class I ◽

Hla Alleles ◽

Susceptibility Effect ◽

Pathogen Elimination ◽

Western European

Human leukocyte antigen (HLA), a system involved in immune response to foreign antigens and in autoimmunity, has been strongly implicated in multiple sclerosis (MS). Prior research has shown that HLA DRB1*15:01 exerts the strongest susceptibility effect, although other HLA alleles have been implicated in both susceptibility to, and protection against, MS. Here we utilized an immunogenetic epidemiological approach to evaluate correlations between the population frequencies of 127 HLA Class I and II alleles and the population prevalence of MS in 14 Continental Western European countries to identify an HLA profile for MS. The results of these analyses, which largely corroborated prior findings and revealed several novel and highly robust HLA associations with MS, revealed a larger number of protective HLA alleles than susceptibility alleles, particularly for HLA Class I. Given the role of HLA in pathogen elimination and autoimmunity, these findings point to a contributory role of exposure to pathogens in the absence of protective HLA in underlying the inflammation and autoimmunity associated with MS.

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