Organ transplantation is a lifesaving option for patients with advanced diseases. Rejection is regarded as one of the most severe risk factors post-transplantation. A molecule that contributes to immune tolerance and resisting rejection is human leukocyte antigen (HLA)-G, which belongs to the non-classical major histocompatibility complex class (MHC) I family. HLA-G was originally found to play a role during pregnancy to maintain immune tolerance between mother and child. It is expressed in the placenta and detected in several body fluids as soluble factor as well as different membrane isoforms on cells. Recent findings on HLA-G show that it can also play multifaceted roles during transplantation. This review will explain the general characteristics and biological function of HLA-G and summarize the views supporting the tolerogenic and other roles of HLA-G to better understand its role in solid organ transplantation (SOT) and its complications. Finally, we will discuss potential future research on the role of HLA-G in prevention, diagnosis, and treatment in SOT.

• Female
• HLA-G Antigens/immunology
• Humans
• Immune Tolerance
• Organ Transplantation
• Placenta/immunology
• Pregnancy/immunology
• Protein Isoforms

• Chinese Government Scholarship

• autoimmune diseases
• human G-leukocyte antigen (HLA-G)
• major histocompatibility complex (MHC)

As a non-classic major histocompatibility complex (MHC) class I molecule, human leukocyte antigen G (HLA-G) is expressed in fetal-maternal interface and immunoprivileged site only in healthy condition, and in pathological conditions such as cancer, it can be de novo expressed. It is now widely accepted that HLA-G is a key molecule in the process of immune escape of cancer cells, which is ubiquitously expressed in the tumor environment. This raises the possibility that it may play an adverse role in tumor immunity. The expression level of HLA-G has been demonstrated to be highly correlated with clinical parameters in many tumors, and its potential significance in the diagnosis and prognosis of cancer has been postulated. However, because HLA-G itself has up to seven different subtypes, and for some subtypes, detected antibodies are few or absent, it is hard to evaluate the actual expression of HLA-G in tumors. In the present work, we described (a) the structure and three main forms of HLA-G, (b) summarized the mechanism of HLA-G in the immune escape of tumor cells, (c) discussed the potential role of HLA-G as a tumor marker, and reviewed (d) the methods for detecting and quantifying HLA-G.

• HLA-G
• biomarker
• extracellular vesicles
• immune escape
• tumor

Neurofilament Light (NfL) chain levels in both cerebrospinal fluid (CSF) and serum have been correlated with the reduction of axonal damage in multiple sclerosis (MS) patients treated with Natalizumab (NTZ). However, little is known about the function of plasmacytoid cells in NTZ-treated MS patients.

To evaluate CSF NfL, serum levels of soluble-HLA-G (sHLA-G), and eventual tolerogenic behavior of plasmacytoid dendritic cells (pDCs) in MS patients during NTZ treatment.

CSF NfL and serum sHLA-G levels were measured using an ELISA assay, while pDCs (BDCA-2⁺) were accessed through flow cytometry analyses.

CSF levels of NfL were significantly reduced during NTZ treatment, while the serum levels of sHLA-G were increased. Moreover, NTZ treatment enhanced tolerogenic (HLA-G⁺, CD274⁺, and HLA-DR⁺) molecules and migratory (CCR7⁺) functions of pDCs in the peripheral blood.

These findings suggest that NTZ stimulates the production of molecules with immunoregulatory function such as HLA-G and CD274 programmed death-ligand 1 (PD-L1) which may contribute to the reduction of axonal damage represented by the decrease of NfL levels in patients with MS.

• HLA-DR
• HLA-G
• PD-L1
• cerebrospinal fluid
• neurofilament light chain
• neuroinflammation

• Biomarker
• immune tolerance
• immunosenescence
• inflammageing
• multiple sclerosis
• premature immune ageing

• HLA-G
• hematopoietic tumors
• immune checkpoint
• immunotherapy
• solid tumors

• Animals
• Antibodies, Monoclonal/therapeutic use
• Antigens, Neoplasm/immunology
• Antigens, Neoplasm/metabolism
• Antineoplastic Agents, Immunological/therapeutic use
• HLA-G Antigens/immunology
• HLA-G Antigens/metabolism
• Humans
• Immunotherapy, Adoptive
• Neoplasms/immunology
• Neoplasms/metabolism
• Neoplasms/pathology
• Neoplasms/therapy
• Tumor Escape
• Tumor Microenvironment

Natural killer (NK) cell therapies are a tool to antagonize a dysfunctional immune system. NK cells recognize malignant cells, traffic to a tumor location, and infiltrate the solid tumor. The immune checkpoint molecule human leukocyte antigen (HLA)-G is upregulated on malignant cells but not on healthy surrounding cells, the requirement of understanding the basis of receptor mediated events at the HLA-G/NK cell interface becomes obvious. The NK cell receptors ILT2 and KIR2DL4 have been described to bind to HLA-G; however, their differential function and expression levels on NK cell subsets suggest the existence of an unreported receptor. Here, we performed a ligand-based receptor capture on living cells utilizing sHLA-G*01:01 molecules coupled to TriCEPS and bound to NK cells followed by mass spectrometric analyses. We could define NKG2A/CD94 as a cognate receptor of HLA-G. To verify the results, we used the reciprocal method by expressing recombinant soluble heterodimeric NKG2A/CD94 molecules and used them to target HLA-G*01:01 expressing cells. NKG2A/CD94 could be confirmed as an immune receptor of HLA-G*01:01. Despite HLA-G is marginal polymorphic, we could previously demonstrate that the most common allelic subtypes HLA-G*01:01/01:03 and 01:04 differ in peptide repertoire, their engagement to NK cells, their catalyzation of dNK cell proliferation and their impact on NK cell development. Continuing these studies with regard to NKG2A/CD94 engagement we engineered recombinant single antigen presenting K562 cells and targeted the surface expressed HLA-G*01:01, 01:03 or 01:04 molecules with NKG2A/CD94. Specificity and sensitivity of HLA-G*01:04/NKG2A/CD94 engagement could be significantly verified. The binding affinity decreases when using K562-G*01:03 or K562-G*01:01 cells as targets. These results demonstrate that the ligand-receptor assignment between HLA-G and NKG2A/CD94 is dependent of the amino acid composition in the HLA-G heavy chain. Understanding the biophysical basis of receptor-mediated events that lead to NK cell inhibition would help to remove non-tumor reactive cells and support personalized mild autologous NK cell therapies.

• HLA-G
• NK cells
• NKG2A

Inflammation is a common process involved in aging, multiple sclerosis (MS), and age-related neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), but there is limited evidence for the effects of aging on inflammation in the central nervous system. We collected cerebrospinal fluid (CSF) from 105 healthy control subjects representing a wide age range (23–86), and analyzed levels of cytokines associated innate immunity (TNF-α) and different T-helper subtypes: interferon–gamma induced protein 10 (IP-10) for Th1, interleukin-10 (IL-10) for Th2, and interleukin 8 (IL-8/CXCL8) for Th17. We show that CSF levels of TNF-α, IP-10, and IL-8 all increased linearly with age, but levels of IL-10 demonstrated a U-shaped relationship with age. We further found greater age-related increases in TNF-α, IL-10, and IL-8 relative to increases in IP-10 levels, consistent with a shift from Th1 to other inflammatory phenotypes. Finally, when we analyzed the same four cytokines in people with neurological disorders, we found that MS and AD, but not PD or dementia with Lewy bodies, further accentuated the age-related shift from Th1- to non-Th1-related cytokines. We propose that CSF cytokine levels represent powerful surrogates of brain inflammation and aging, and some, but not all, neurological disorders accelerate the shift away from Th1 phenotypes.

• Alzheimer's disease
• IL10
• IL8
• IP10
• Parkinsons disease (PD)
• dementia with Lewy bodies (DLB)
• inflammaging
• neuroinflammation and neurodegeneration

Human leukocyte antigen-G (HLA-G) is a nonclassical HLA class I antigen that is expressed during pregnancy contributing to maternal-fetal tolerance. HLA-G can be expressed as membrane-bound and soluble forms. HLA-G expression increases strongly during viral infections such as congenital human cytomegalovirus (HCMV) infections, with functional consequences in immunoregulation. In this work we investigated the expression of soluble (s)HLA-G and beta-2 microglobulin (component of HLA) molecules in correlation with the risk of transmission and severity of congenital HCMV infection. We analyzed 182 blood samples from 130 pregnant women and 52 nonpregnant women and 56 amniotic fluid samples from women experiencing primary HCMV infection. The median levels of sHLA-G in maternal serum of women with primary HCMV infection were higher in comparison with nonprimary and uninfected pregnant women (p < 0.001). AF from HCMV symptomatic fetuses presented higher sHLA-G levels in comparison with infected asymptomatic fetuses (p < 0.001), presence of HLA-G free-heavy chain, and a concentration gradient from amniotic fluid to maternal blood. No significant statistical difference of beta-2 microglobulin median levels was observed between all different groups. Our results suggest the determination of sHLA-G molecules in both maternal blood and amniotic fluid as a promising biomarker of diagnosis of maternal HCMV primary infection and fetal HCMV disease.

• Adult
• Blotting, Western
• Brain/pathology
• Case-Control Studies
• Dimerization
• Female
• HLA-G Antigens/cerebrospinal fluid
• Humans
• Inflammation/cerebrospinal fluid
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Multiple Sclerosis, Relapsing-Remitting/cerebrospinal fluid
• Multiple Sclerosis, Relapsing-Remitting/pathology
• Nervous System Diseases/cerebrospinal fluid
• Spinal Cord/pathology

• Behçet’s disease
• Genetic polymorphism
• HLA-G antigens
• Tunisia

• 3' Untranslated Regions/genetics
• Adolescent
• Adult
• Behcet Syndrome/genetics
• Behcet Syndrome/immunology
• Child
• DNA Mutational Analysis
• Disease Progression
• Female
• Gene Frequency
• Genetic Association Studies
• Genetic Predisposition to Disease
• Genotype
• HLA-G Antigens/blood
• HLA-G Antigens/genetics
• Humans
• Male
• Middle Aged
• Mutagenesis, Insertional/genetics
• Polymorphism, Genetic
• Tunisia
• Young Adult

HLA-G is a regulatory molecule involved in immunologic tolerance. Growing evidence indicates that HLA-G plays a role in the regulation of inflammatory processes and autoimmune diseases. This study aimed at a systematic evaluation of soluble HLA-G (sHLA-G) in plasma of rheumatoid arthritis (RA) patients with long-lasting chronic inflammation. RA patients (n=68) and healthy controls (n=26) had their plasmatic sHLA-G measured by ELISA whereas the binding capability of sHLA-G to its cognate LILRB1 receptor was measured by a Luminex-based assay. All subjects were PCR-genotyped for HLA-G 14bp polymorphism (rs66554220). Significantly higher sHLA-G levels were observed in patients (p<0.001), however no significant differences were observed in LILRB1 binding capacity between RA patients and controls. Remarkably, the proportion of patients presenting specific binding of sHLA-G to LILRB1 was significantly decreased as compared to controls (56% vs. 81%, p=0.027). Patients without rheumatoid factor (RF-) were significantly overrepresented in the group of patients positive for LILRB1 binding as compared to patients without LILRB1 binding (31% vs 10%, p=0.033). Furthermore, methotrexate treated patients (n=58) revealed significantly lower LILRB1 binding to sHLA-G molecules than non-treated patients (medians: 12.2 vs. 67.7 units/ml, p=0.031). Unlike in controls, no significant differences in sHLA-G levels were observed among patients grouped by 14pb genotype. Thus, in a substantial number of late RA patients, the circulating sHLA-G molecules are impaired regarding LILRB1 recognition, meaning that although increased levels are observed; these molecules are not qualified to exert their protective functions against inflammation. Our findings offer new insights into the immunopathology of RA patients with long-lasting anti-RA-treatment and highlight the importance to also measure the binding capability of sHLA-G to LILRB1.

• Adult
• Aged
• Antigens, CD/blood
• Antigens, CD/immunology
• Arthritis, Rheumatoid/blood
• Arthritis, Rheumatoid/immunology
• Arthritis, Rheumatoid/pathology
• Female
• Genotype
• HLA-G Antigens/blood
• HLA-G Antigens/immunology
• Humans
• Inflammation/blood
• Inflammation/immunology
• Inflammation/pathology
• Leukocyte Immunoglobulin-like Receptor B1
• Male
• Middle Aged
• Protein Binding
• Receptors, Immunologic/blood
• Receptors, Immunologic/immunology

• Adolescent
• Adult
• Calcium/blood
• Disability Evaluation
• Dose-Response Relationship, Drug
• Double-Blind Method
• Female
• Humans
• Interleukin-10/blood
• Male
• Middle Aged
• Multiple Sclerosis/blood
• Multiple Sclerosis/diet therapy
• Treatment Outcome
• Vitamin D/therapeutic use
• Vitamins/therapeutic use
• Young Adult

• HLA-G
• autoimmunity
• infection
• inflammation
• regulation

• HLA-G
• T regulatory type 1 cells
• fetal-maternal tolerance
• immune escape
• interleukin-10
• tolerogenic dendritic cells

Human leukocyte antigen-G (HLA-G) is a non-classical HLA class I molecule that differs from classical HLA class I molecules by low polymorphism and tissue distribution. HLA-G is a tolerogenic molecule with an immune-modulatory and anti-inflammatory function on both innate and adaptative immunity. This peculiar characteristic of HLA-G has led to investigations of its role in pathological conditions in order to define possible uses in diagnosis, prevention and treatment. In recent years, HLA-G has been shown to have an important implication in different inflammatory and autoimmune diseases, pregnancy complications, tumor development and aggressiveness, and susceptibility to viral infections. In fact, HLA-G molecules have been reported to alternate at both genetic and protein level in different disease situations, supporting its crucial role in pathological conditions. Specific pathologies show altered levels of soluble (s)HLA-G and different HLA-G gene polymorphisms seem to correlate with disease. This review aims to update scientific knowledge on the contribution of HLA-G in managing pathological conditions.

• Human leukocyte antigen-G
• Pathology
• Prognosis
• Diagnosis
• Treatment
• Marker

Human Leukocyte Antigen-G (HLA-G) contributes to cancer cell immune escape from host antitumor responses. The clinical relevance of HLA-G in several malignancies has been reported. However, the role of HLA-G expression and functions in Acute Myeloid Leukemia (AML) is still controversial. Our group identified a subset of tolerogenic dendritic cells, DC-10 that express HLA-G and secrete IL-10. DC-10 are present in the peripheral blood and are essential in promoting and maintaining tolerance via the induction of adaptive T regulatory (Treg) cells. We investigated HLA-G expression on blasts and the presence of HLA-G-expressing DC-10 and CD4⁺ T cells in the peripheral blood of AML patients at diagnosis. Moreover, we explored the possible influence of the 3′ untranslated region (3′UTR) of HLA-G, which has been associated with HLA-G expression, on AML susceptibility. Results showed that HLA-G-expressing DC-10 and CD4⁺ T cells are highly represented in AML patients with HLA-G positive blasts. None of the HLA-G variation sites evaluated was associated with AML susceptibility. This is the first report describing HLA-G-expressing DC-10 and CD4⁺ T cells in AML patients, suggesting that they may represent a strategy by which leukemic cells escape the host's immune system. Further studies on larger populations are required to verify our findings.

• Adult
• Biomarkers/blood
• Biomarkers/cerebrospinal fluid
• Female
• HLA-G Antigens/blood
• HLA-G Antigens/cerebrospinal fluid
• Histocompatibility Antigens Class I/blood
• Histocompatibility Antigens Class I/cerebrospinal fluid
• Humans
• Inflammation/cerebrospinal fluid
• Inflammation/diagnosis
• Inflammation/pathology
• Killer Cells, Natural/metabolism
• Killer Cells, Natural/pathology
• Male
• Middle Aged
• Multiple Sclerosis/blood
• Multiple Sclerosis/cerebrospinal fluid
• Multiple Sclerosis/diagnosis
• Spinal Puncture
• HLA-E Antigens

• Amino Acid Sequence
• Antibodies, Blocking/pharmacology
• Cell Line, Tumor
• Cell Membrane/drug effects
• Cell Membrane/metabolism
• Cycloheximide/pharmacology
• Edetic Acid/pharmacology
• HLA-G Antigens/chemistry
• HLA-G Antigens/metabolism
• Humans
• Leukocytes, Mononuclear/drug effects
• Leukocytes, Mononuclear/metabolism
• Matrix Metalloproteinase 2/chemistry
• Matrix Metalloproteinase 2/metabolism
• Matrix Metalloproteinase 9/chemistry
• Matrix Metalloproteinase 9/metabolism
• Molecular Sequence Data
• Proteolysis/drug effects

• multiple sclerosis
• central nervous system
• human lymphocyte antigen-g
• immune surveillance
• blood–brain barrier
• immune tolerance

• Animals
• Central Nervous System/immunology
• Central Nervous System/pathology
• HLA Antigens/immunology
• HLA-G Antigens
• Histocompatibility Antigens Class I/immunology
• Humans
• Immune Tolerance

• atopic dermatitis
• celiac disease
• spontaneous intracerebral hemorrhage
• immune cell trafficking
• cytolytic function

• Animals
• HLA Antigens/analysis
• HLA Antigens/genetics
• HLA Antigens/immunology
• HLA-G Antigens
• Histocompatibility Antigens Class I/analysis
• Histocompatibility Antigens Class I/genetics
• Histocompatibility Antigens Class I/immunology
• Humans
• Immunity

• hla-g
• inflammation
• cytokine/chemokine network
• viral infection
• stem cells

• Animals
• Cytokines/immunology
• HLA Antigens/immunology
• HLA-G Antigens
• Histocompatibility Antigens Class I/immunology
• Humans
• Immunologic Surveillance
• Immunomodulation
• Inflammation/immunology
• Stem Cell Transplantation
• Virus Diseases/immunology
• Viruses/immunology

In Northern European descended populations, genetic susceptibility for multiple sclerosis (MS) is associated with alleles of the human leukocyte antigen (HLA) Class II gene DRB1. Whether other major histocompatibility complex (MHC) genes contribute to MS susceptibility is controversial.

A case control analysis was performed using 958 single nucleotide polymorphisms (SNPs) spanning the MHC assayed in two independent datasets. The discovery dataset consisted of 1,018 cases and 1,795 controls and the replication dataset was composed of 1,343 cases and 1,379 controls. The most significantly MS-associated SNP in the discovery dataset was rs3135391, a Class II SNP known to tag the HLA-DRB1*15:01 allele, the primary MS susceptibility allele in the MHC (O.R. = 3.04, p<1×10⁻⁷⁸). To control for the effects of the HLA-DRB1*15:01 haplotype, case control analysis was performed adjusting for this HLA-DRB1*15:01 tagging SNP. After correction for multiple comparisons (false discovery rate = .05) 52 SNPs in the Class I, II and III regions were significantly associated with MS susceptibility in both datasets using the Cochran Armitage trend test. The discovery and replication datasets were merged and subjects carrying the HLA-DRB1*15:01 tagging SNP were excluded. Association tests showed that 48 of the 52 replicated SNPs retained significant associations with MS susceptibility independently of the HLA-DRB1*15:01 as defined by the tagging SNP. 20 Class I SNPs were associated with MS susceptibility with p-values ≤1×10⁻⁸. The most significantly associated SNP was rs4959039, a SNP in the downstream un-translated region of the non-classical HLA-G gene (Odds ratio 1.59, 95% CI 1.40, 1.81, p = 8.45×10⁻¹³) and is in linkage disequilibrium with several nearby SNPs. Logistic regression modeling showed that this SNP's contribution to MS susceptibility was independent of the Class II and Class III SNPs identified in this screen.

A MHC Class I locus contributes to MS susceptibility independently of the HLA-DRB1*15:01 haplotype.

• Aged
• Aged, 80 and over
• Analysis of Variance
• Brain Edema/etiology
• Cerebral Hemorrhage/blood
• Cerebral Hemorrhage/complications
• Cerebral Hemorrhage/diagnostic imaging
• Enzyme-Linked Immunosorbent Assay/methods
• Female
• HLA Antigens/blood
• HLA-G Antigens
• Histocompatibility Antigens Class I/blood
• Humans
• Male
• Middle Aged
• Time Factors
• Tomography, X-Ray Computed/methods

• Adult
• Cell Line, Tumor
• Female
• HLA Antigens/blood
• HLA Antigens/metabolism
• HLA-G Antigens
• Histocompatibility Antigens Class I/blood
• Histocompatibility Antigens Class I/metabolism
• Humans
• Interleukin-10/blood
• Lupus Erythematosus, Systemic/diagnosis
• Lupus Erythematosus, Systemic/immunology
• Lymphocytes/immunology
• Middle Aged
• Skin/immunology

• Adult
• Aged
• Aged, 80 and over
• Biomarkers
• Blood Chemical Analysis
• Colitis, Ulcerative/diagnosis
• Colitis, Ulcerative/immunology
• Crohn Disease/diagnosis
• Crohn Disease/immunology
• Enzyme-Linked Immunosorbent Assay/methods
• Female
• HLA Antigens/biosynthesis
• HLA-G Antigens
• Histocompatibility Antigens Class I/biosynthesis
• Humans
• Interleukin-10/metabolism
• Leukocytes, Mononuclear/immunology
• Male
• Middle Aged

• B-Lymphocytes/immunology
• Cell Division/immunology
• Granulocyte-Macrophage Colony-Stimulating Factor/immunology
• HLA Antigens/blood
• HLA-G Antigens
• Histocompatibility Antigens Class I/blood
• Humans
• Interferon-gamma/immunology
• Interleukins/immunology
• Leukemia, Lymphocytic, Chronic, B-Cell/immunology
• Lymphoma, B-Cell/immunology
• Lymphoma, T-Cell/immunology
• Lymphoproliferative Disorders/immunology
• Monocytes/immunology
• Prospective Studies
• T-Lymphocytes/immunology
• Transforming Growth Factor beta/immunology
• Tumor Cells, Cultured

• Adult
• Aged
• Asian People
• Autoimmune Diseases/genetics
• Base Sequence
• Cardiomyopathy, Dilated/genetics
• China
• Female
• Genetic Predisposition to Disease
• HLA Antigens/genetics
• HLA-G Antigens
• Histocompatibility Antigens Class I/genetics
• Humans
• INDEL Mutation
• Male
• Middle Aged
• Mutagenesis, Insertional
• Polymorphism, Genetic
• Risk Factors
• Sequence Deletion

• Autoimmune Diseases/blood
• Autoimmune Diseases/immunology
• Cytokines/immunology
• Cytokines/metabolism
• HLA Antigens/blood
• HLA Antigens/immunology
• HLA-G Antigens
• Histocompatibility Antigens Class I/blood
• Histocompatibility Antigens Class I/immunology
• Humans
• Immune Tolerance
• Monocytes/immunology
• Monocytes/metabolism
• Neoplasms/blood
• Neoplasms/immunology
• Neuroblastoma/blood
• Neuroblastoma/immunology
• Transplantation Immunology

• R01 CA067108-08 NCI NIH HHS
• R01CA67108 NCI NIH HHS
• R01 CA067108 NCI NIH HHS
• R01CA110249 NCI NIH HHS
• R01 CA110249 NCI NIH HHS
• P01 CA109688-020003 NCI NIH HHS
• P01CA109688 NCI NIH HHS
• P01 CA109688 NCI NIH HHS
• R01 CA110249-02 NCI NIH HHS

• Adult
• Analysis of Variance
• Down-Regulation/physiology
• Enzyme-Linked Immunosorbent Assay/methods
• Female
• Flow Cytometry/methods
• Gene Expression Profiling
• HLA Antigens/metabolism
• HLA-G Antigens
• Histocompatibility Antigens Class I/metabolism
• Humans
• Immune Tolerance
• Multiple Sclerosis/blood
• Multiple Sclerosis/etiology
• Multiple Sclerosis/immunology
• Oligonucleotide Array Sequence Analysis/methods
• Postpartum Period
• Pregnancy
• Severity of Illness Index

• CD4-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/immunology
• DNA Primers
• Dendritic Cells/immunology
• HLA Antigens/genetics
• HLA-G Antigens
• Histocompatibility Antigens Class I/genetics
• Humans
• Immunosuppression Therapy
• Inflammation/immunology
• Lymphocyte Activation
• Muscle, Skeletal/immunology
• Muscle, Skeletal/physiopathology
• Phenotype
• Polymerase Chain Reaction
• RNA/genetics
• RNA/isolation & purification
• T-Lymphocyte Subsets/immunology
• T-Lymphocytes/immunology
• T-Lymphocytes, Regulatory/immunology

Celiac disease (CD) is a common autoimmune disorder characterized by an immune response to ingested gluten and has a strong HLA association with HLA-DQ2 and HLA-DQ8 molecules, but human HLA-DQ risk factors do not explain the entire genetic susceptibility to gluten intolerance. CD is caused by the lack of immune tolerance (oral tolerance) to wheat gluten. In this sense, the expression of soluble HLA-G in CD is of special interest because the molecule plays an important role in the induction of immune tolerance. The enhanced expression of soluble HLA-G found in CD may be part of a mechanism to restore the gluten intolerance. In this editorial, we review recent progress in understanding CD in relation to its prevalence, diagnosis and possible mechanisms of pathogenesis.

• Celiac disease
• Oral tolerance
• IL-10
• TGF-beta
• Gluten intolerance

• Celiac Disease/diagnosis
• Celiac Disease/epidemiology
• Celiac Disease/immunology
• Cytokines/immunology
• Europe/epidemiology
• HLA Antigens/immunology
• HLA-G Antigens
• Histocompatibility Antigens Class I/immunology
• Humans
• Immune Tolerance
• Prevalence
• United States/epidemiology

• Biomarkers/cerebrospinal fluid
• Cerebrospinal Fluid Proteins/metabolism
• Humans
• Immunoglobulins/cerebrospinal fluid
• Multiple Sclerosis/cerebrospinal fluid