Role of Human Leukocyte Antigens at the Feto-Maternal Interface in Normal and Pathological Pregnancy: An Update

The successful maternal tolerance of the semi-allogeneic fetus provides an apparent immunologic paradox. Indeed, deep invasion of placental trophoblast cells into maternal uterine tissue and the following growth of the fetus have to be tolerated by a pregnant woman’s immune system. Among the various possible protective mechanisms that may be involved in human pregnancy, the expression of a non-classical pattern of human leukocyte antigen (HLA) class I molecules and the complete lack of expression of HLA class II molecules in placental tissues seem to be the most relevant mechanisms of fetal escape from maternal immune recognition. The importance of HLA molecules in fetal toleration by the maternal immune system is highlighted by pregnancy complications occurring in cases of abnormal HLA molecule expression at the maternal–fetal interface. In this review, we summarize evidences about the role of placental HLA molecules in normal and pathological pregnancies.

Download Full-text

HLA Expression at the Maternal-Fetal Interface

Developmental Immunology ◽

10.1155/1998/65065 ◽

1998 ◽

Vol 6 (3-4) ◽

pp. 197-204 ◽

Cited By ~ 21

Author(s):

Heinz Hutter ◽

Astrid Hammer ◽

Gottfried Dohr ◽

Joan S. Hunt

Keyword(s):

Immune System ◽

Hla Class I ◽

Short Review ◽

Maternal Blood ◽

Protective Mechanisms ◽

Hla Class I Molecules ◽

Recent Developments ◽

The Subject ◽

Class Ii Antigens ◽

Maternal Fetal Interface

Pregancy in the human presents an “immunological paradox,” because of the unexpected willingness of mothers to accept genetically disparate tissues. The fact that the fetus can develop unharmed for nine months shows that protective mechanisms must exist to permit its survival. The conditions that permit the genetically dissimilar human fetus to evade rejection by its mother's immune system have been the subject of intense interest for several decades. As the placental cells, which are in contact with maternal blood or tissue, are devoid of HLA class II antigens, interest has focused on the expression of HLA class molecules. Recent developments in the constitutive, transcriptional, and translational expression of HLA class I molecules on anatomically and morphologically different subpopulations of trophoblast cells will form the basis of this short review.

Download Full-text

The role of HLA genes: from autoimmune diseases to COVID-19

Problems of Endocrinology ◽

10.14341/probl12470 ◽

2020 ◽

Vol 66 (4) ◽

pp. 9-15

Author(s):

Ekaterina A. Troshina ◽

Marina Yu. Yukina ◽

Nurana F. Nuralieva ◽

Natalia G. Mokrysheva

Keyword(s):

Immune System ◽

Autoimmune Diseases ◽

Genetic Predisposition ◽

Human Leukocyte ◽

Normal Functioning ◽

Leukocyte Antigen ◽

Hla Genes ◽

Histocompatibility Complex ◽

Hla Molecules

Genes of HLA system (Human Leukocyte Antigen) play an essential role in the normal functioning of the immune system. There are three classes of genes: I, II, and III. The function of HLA molecules class I is to present antigens of peptides from the cytoplasm to T-lymphocytes on the cell surface, and class II — to present antigens of peptides from the extracellular space. In the classical view, the pathological activation of the immune system in patients with a genetic predisposition can result in the development of autoimmune diseases. However, the influence of this system on the development of non-autoimmune diseases, their severity and prognosis, has been recently considered. Besides, HLA molecules provide a presentation of various infectious agents. In this connection, the loci of the main histocompatibility complex can be considered candidates for determining the genetic predisposition to infectious diseases themselves and their course. This review hypothesizes that specific variants of HLA genes may cause the formation of a «cytokine storm» in patients with COVID-19. Identification of a group of patients with particular genetic variations that cause violation of immune tolerance and hyperresponse in the setting of viral infection will help to optimize the algorithm for disease prevention and treatment of such patients and, as a result, to reduce the severity of the epidemiological situation.

Download Full-text

Spliced HLA bound peptides; a Black-Swan event in Immunology

10.22541/au.160976778.87618567/v1 ◽

2021 ◽

Author(s):

Pouya Faridi ◽

Mohammadreza .Dorvash ◽

Anthony Purcell

Keyword(s):

Global Analysis ◽

Critical Role ◽

Human Leukocyte ◽

Hla Class I ◽

Peptide Ligands ◽

Considerable Proportion ◽

Immune Recognition ◽

Leukocyte Antigens ◽

Long Time ◽

Hla Molecules

Peptides that bind to and are presented on the cell surface by Human Leukocyte Antigens (HLA) molecules play a critical role in adaptive immunity. For a long time, it was believed all of the HLA bound peptides were generated through simple proteolysis of linear sequences of cellular proteins, and therefore, are templated in the genome and proteome. However, evidence for untemplated peptide ligands of HLA molecules has accumulated over the last two decades, with a recent global analysis of HLA-bound peptides suggesting that a considerable proportion of HLA bound peptides are potentially generated through splicing/fusion of discontinuous peptide segments from one or two distinct proteins. In this review, we will review recent discoveries and debates on the contribution of spliced peptides to the HLA class I immunopeptidome, consider biochemical rules for splicing, and the potential role of these spliced peptides in immune recognition.

Download Full-text

Immune system regulation and role of the human leukocyte antigen in posttraumatic stress disorder

Neurobiology of Stress ◽

10.1016/j.ynstr.2021.100366 ◽

2021 ◽

pp. 100366

Author(s):

Seyma Katrinli ◽

Alicia K. Smith

Keyword(s):

Posttraumatic Stress Disorder ◽

Immune System ◽

Human Leukocyte Antigen ◽

Posttraumatic Stress ◽

Stress Disorder ◽

Human Leukocyte ◽

Leukocyte Antigen ◽

Immune System Regulation

Download Full-text

General role of HLA class I molecules in the protection of target cells from lysis by natural killer cells: evidence that the free heavy chains of class I molecules are not sufficient to mediate the protective effect

International Immunology ◽

10.1093/intimm/7.3.393 ◽

1995 ◽

Vol 7 (3) ◽

pp. 393-400 ◽

Cited By ~ 25

Author(s):

Ermanno Ciccone ◽

Daniela Pende ◽

Luca Nannl ◽

Carolina Di Donato ◽

Oriane Viale ◽

...

Keyword(s):

Natural Killer Cells ◽

Protective Effect ◽

Natural Killer ◽

Hla Class I ◽

Class I ◽

Target Cells ◽

General Role ◽

Heavy Chains ◽

Hla Class I Molecules

Download Full-text

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.

Download Full-text

Class-I human leukocyte alleles in leprosy patients from Southern Brazil

Revista da Sociedade Brasileira de Medicina Tropical ◽

10.1590/s0037-86822011000500018 ◽

2011 ◽

Vol 44 (5) ◽

pp. 616-620 ◽

Cited By ~ 8

Author(s):

Danilo Santana Alessio Franceschi ◽

Luiza Tamie Tsuneto ◽

Priscila Saamara Mazini ◽

William Sergio do Sacramento ◽

Pâmela Guimarães Reis ◽

...

Keyword(s):

Human Leukocyte ◽

Hla Class I ◽

Innate Immune ◽

Class I ◽

Control Group ◽

Southern Brazil ◽

Hla Genotyping ◽

Leprosy Patients ◽

Direct Counting

INTRODUCTION: The present study was designed to investigate a possible role of HLA (histocompatibility leucocyte antigen) class-I alleles (HLA-A, -B, and -C) in leprosy patients from Southern Brazil. METHODS: Two hundred and twenty-five patients with leprosy and 450 individuals for the control group were involved in this research. HLA genotyping was performed through PCR-SSO protocols (One Lambda, USA); the frequency of these alleles was calculated in each group by direct counting, and the frequencies were then compared. RESULTS: There was an association between HLA-A*11 (6.9% vs 4.1%, p=0.0345, OR=1.72, 95% CI=1.05-2.81), HLA-B*38 (2.7% vs. 1.1%, p=0.0402, OR=2.44, 95% CI=1.05-5.69), HLA-C*12 (9.4% vs. 5.4%, p=0.01, OR=1.82, 95% CI=1.17-2.82), and HLA-C*16 (3.1% vs. 6.5%, p=0.0124, OR=0.47, 95% CI=0.26-0.85) and leprosy per se. In addition, HLA-B*35, HLA-C*04, and HLA-C*07 frequencies were different between lepromatous (LL) and tuberculoid (TT) patients. However, after adjusting for the number of alleles compared, Pc values became nonsignificant. CONCLUSIONS: Although our results do not support the previous findings that HLA class-I alleles play a role in leprosy pathogenesis, we suggest new studies because of the importance of the association between the HLA and KIR in the innate immune response to leprosy.

Download Full-text

Thrombocyte HLA molecules retain nonrenewable endogenous peptides of megakaryocyte lineage and do not stimulate direct allocytotoxicity in vitro

Blood ◽

10.1182/blood.v95.10.3168.010k11_3168_3175 ◽

2000 ◽

Vol 95 (10) ◽

pp. 3168-3175

Author(s):

Cécile Gouttefangeas ◽

Marianne Diehl ◽

Wieland Keilholz ◽

Rainer Frank Hörnlein ◽

Stefan Stevanović ◽

...

Keyword(s):

Mononuclear Cells ◽

Hla Class I ◽

T Cell Response ◽

Third Party ◽

Class I ◽

Cytotoxic T Cell ◽

Endogenous Peptides ◽

Hla Class I Molecules ◽

Hla Molecules

The origin and the function of HLA class I molecules present on the surface of human platelets are still unclear. In particular, it is controversial which fraction of these class I molecules represents integral membrane components derived from the megakaryocyte-platelet lineage versus soluble plasma HLA molecules acquired by adsorption. Results of the present study show that HLA-A2 ligands isolated from platelets possess the same peptide motif as described for HLA-A2-associated peptides obtained from nucleated cells. Sequencing of these platelet-derived peptides reveals that they originate mainly from ubiquitously expressed proteins also present in the megakaryocyte-platelet lineage. Moreover, one of these peptides derives from the GPIX protein, which is specifically expressed by platelets and their precursors. Platelet HLA molecules are unstable in vitro at 37°C, but can be partially stabilized by addition of exogenous β2-microglobulin and HLA class I binding peptide, suggesting that platelets cannot load HLA molecules with endogenous peptides. In in vitro experiments platelets were used to stimulate peripheral blood mononuclear cells. No allospecific cytotoxicity was observed after primary stimulation, or secondary restimulation, with allogenic resting or activated platelets, even in the presence of additional third-party helper activity. These data indicate that HLA class I molecules from platelets cannot directly induce allogenic CD8+ cytotoxic T-cell response in vitro.

Download Full-text

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.

Download Full-text