HLA genotyping meets response to immune checkpoint inhibitors prediction: A story just started.

The implementation of the immune checkpoint blockade as a therapeutic option in contemporary oncology is one of the significant immunological achievements in the last century. Constantly accumulating evidence suggests that the response to immune checkpoint inhibitors (ICIs) is not universal. Therefore, it is critical to identify determinants for response, resistance and adverse effects of immune checkpoint therapy that could be developed as prognostic and predictive markers. Recent large scale analyses of cancer genome data revealed the key role of HLA class I and class II molecules in cancer immunoediting, and it appears that HLA diversity can predict response to ICIs. In the present review, we summarize the emerging data on the role of HLA germline variations as a marker for response to ICIs.

Post-copulatory genetic matchmaking: HLA-dependent effects of cervical mucus on human sperm function.

Several studies have demonstrated that women show pre-copulatory mating preferences for human leucocyte antigen (HLA)-dissimilar men. A fascinating, yet unexplored, possibility is that the ultimate mating bias towards HLA-dissimilar partners could occur after copulation, at the gamete level. Here, we explored this possibility by investigating whether the selection towards HLA-dissimilar partners occurs in the cervical mucus. After combining sperm and cervical mucus from multiple males and females (full factorial design), we found that sperm performance (swimming velocity, hyperactivation, and viability) was strongly influenced by the male-female combination. This indicates that sperm fertilization capability may be dependent on the compatibility between cervical mucus (female) and sperm (male). We also found that sperm viability was associated with partners' HLA dissimilarity, indicating that cervical mucus may selectively facilitate later gamete fusion between immunogenetically compatible partners. Together, these results provide novel insights into the female-mediated sperm selection (cryptic female choice) in humans and indicate that processes occurring after copulation may contribute to the mating bias towards HLA-dissimilar partners. Finally, by showing that sperm performance in cervical mucus is influenced by partners' genetic compatibility, the present findings may promote a deeper understanding of infertility.

Distinct HLA associations of LGI1 and CASPR2-antibody diseases.

The recent biochemical distinction between antibodies against leucine-rich, glioma-inactivated-1 (LGI1), contactin-associated protein-2 (CASPR2) and intracellular epitopes of voltage-gated potassium-channels (VGKCs) demands aetiological explanations. Given established associations between human leucocyte antigen (HLA) alleles and adverse drug reactions, and our clinical observation of frequent adverse drugs reactions in patients with LGI1 antibodies, we compared HLA alleles between healthy controls (n = 5553) and 111 Caucasian patients with VGKC-complex autoantibodies. In patients with LGI1 antibodies (n = 68), HLA-DRB1*07:01 was strongly represented [odds ratio = 27.6 (95% confidence interval 12.9-72.2), P = 4.1 × 10-26]. In contrast, patients with CASPR2 antibodies (n = 31) showed over-representation of HLA-DRB1*11:01 [odds ratio = 9.4 (95% confidence interval 4.6-19.3), P = 5.7 × 10-6]. Other allelic associations for patients with LGI1 antibodies reflected linkage, and significant haplotypic associations included HLA-DRB1*07:01-DQA1*02:01-DQB1*02:02, by comparison to DRB1*11:01-DQA1*05:01-DQB1*03:01 in CASPR2-antibody patients. Conditional analysis in LGI1-antibody patients resolved further independent class I and II associations. By comparison, patients with both LGI1 and CASPR2 antibodies (n = 3) carried yet another complement of HLA variants, and patients with intracellular VGKC antibodies (n = 9) lacked significant HLA associations. Within LGI1- or CASPR2-antibody patients, HLA associations did not correlate with clinical features. In silico predictions identified unique CASPR2- and LGI1-derived peptides potentially presented by the respective over-represented HLA molecules. These highly significant HLA associations dichotomize the underlying immunology in patients with LGI1 or CASPR2 antibodies, and inform T cell specificities and cellular interactions at disease initiation.10.1093/brain/awy109_video1awy109media15796480660001.

Comparison of Physical Crossmatch and Virtual Crossmatch to Identify Preexisting Donor-Specific Human Leukocyte Antigen (HLA) Antibodies and Outcome Following Kidney Transplantation.

BACKGROUND Physical crossmatch (PXM) and virtual crossmatch (VXM) are applied to identify preexisting donor-specific human leukocyte antigen (HLA) antibodies in patients awaiting kidney transplantation. Recently, high-resolution epitope analysis has emerged as a novel strategy for VXM. A retrospective clinical study compared PXM with VXM before kidney transplantation and recipient outcome following transplantation. MATERIAL AND METHODS Between August 2017 and March 2018, 239 patients underwent crossmatching and 94 patients received a donor kidney. A complement-dependent cytotoxicity (CDC) PXM assay and VXM using serological and epitope analysis identified donor-specific antibodies (DSA). Crossmatch results and clinical outcome at 3 months were compared. RESULTS VXM identified serological DSA (sDSA), verified epitope DSA, and total epitope DSA in 74 (31.0%), 39 (16.3%), and 49 (20.5%) cases, respectively. Eleven cases (4.6%) had a positive PXM detected by the CDC assay. Of 94 kidney transplant recipients, 21 had preexisting sDSA but were negative in PXM; there was 1 case of delayed graft function (DGF) and no cases of hyperacute rejection or acute rejection. Of the rest of the 73 recipients who were negative for sDSA, 8 had acute rejection (P=0.253) and 19 had DGF (P=0.037). No significant differences were found in graft survival at 3 months. CONCLUSIONS High-resolution epitope analysis identified fewer cases with DSA compared with serological analysis. Because patients with and without sDSA had a similar short-term outcome in the setting of a negative PXM, the presence of preexisting sDSA, determined by VXM, should not be an absolute contraindication for kidney transplantation.

Synergism of tapasin and human leukocyte antigens in resolving hepatitis C virus infection.

UNLABELLED: CD8+ T-cell responses to hepatitis C virus (HCV) are important in generating a successful immune response and spontaneously clearing infection. Human leukocyte antigen (HLA) class I presents viral peptides to CD8+ T cells to permit detection of infected cells, and tapasin is an important component of the peptide loading complex for HLA class I. We sought to determine if tapasin polymorphisms affected the outcome of HCV infection. Patients with resolved or chronic HCV infection were genotyped for the known G/C coding polymorphism in exon 4 of the tapasin gene. In a European, but not a US, Caucasian population, the tapasin G allele was significantly associated with the outcome of HCV infection, being found in 82.5% of resolvers versus 71.3% of persistently infected individuals (P = 0.02, odds ratio [OR] = 1.90 95% confidence interval [CI] = 1.11-3.23). This was more marked at the HLA-B locus at which heterozygosity of both tapasin and HLA-B was protective (P < 0.03). Individuals with an HLA-B allele with an aspartate at residue 114 and the tapasin G allele were more likely to spontaneously resolve HCV infection (P < 0.00003, OR = 3.2 95% CI = 1.6-6.6). Additionally, individuals with chronic HCV and the combination of an HLA-B allele with an aspartate at residue 114 and the tapasin G allele also had stronger CD8+ T-cell responses (P = 0.02, OR = 2.58, 95% CI-1.05-6.5). CONCLUSION: Tapasin alleles contribute to the outcome of HCV infection by synergizing with polymorphisms at HLA-B in a population-specific manner. This polymorphism may be relevant for peptide vaccination strategies against HCV infection.

Desensitization for prevention of chronic antibody-mediated rejection after kidney transplantation.

Chronic antibody-mediated rejection (C-AMR) is the most important and leading cause of graft loss after kidney transplantation. Although it is well known that chronic renal allograft dysfunction or failure is caused by various immunological or non-immunological factors, donor-specific anti-human leukocyte antigen antibodies (DSAs) are considered to be the most detrimental to graft survival and could cause C-AMR. Despite the use of intensive treatment for C-AMR, outcomes have not always been promising. Recently, prevention, rather than treatment, of C-AMR has been attempted, and this approach appears to be a more effective option for reducing the incidence of C-AMR and, ultimately, improving long-term survival. To prevent C-AMR, removal of antibodies, inactivation of antibodies, and prevention of antibody production after kidney transplantation are essential. Preconditioning treatment including plasmapheresis, intravenous immunoglobulin, and rituximab injection seems the most effective of current desensitization protocols. In this minireview, we will focus on the prevention of C-AMR through desensitization and improving long-term graft survival.

The crystal structure of human endoplasmic reticulum aminopeptidase 2 reveals the atomic basis for distinct roles in antigen processing.

Endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 cooperate to trim a vast variety of antigenic peptide precursors to generate mature epitopes for binding to major histocompatibility class I molecules. We report here the first structure of ERAP2 determined at 3.08 Å by X-ray crystallography. On the basis of residual electron density, a lysine residue has been modeled in the active site of the enzyme; thus, the structure corresponds to an enzyme-product complex. The overall domain organization is highly similar to that of the recently determined structure of ERAP1 in its closed conformation. A large internal cavity adjacent to the catalytic site can accommodate large peptide substrates. The ERAP2 structure provides a structural explanation for the different peptide N-terminal specificities between ERAP1 and ERAP2 and suggests that such differences extend throughout the whole peptide sequence. A noncrystallographic dimer observed may constitute a model for a proposed ERAP1-ERAP2 heterodimer. Overall, the structure helps explain how two homologous aminopeptidases cooperate to process a large variety of sequences, a key property of their biological role.

[Association of HLA class I antigens with Behçet disease in South Tunisia]. / Étude d'association des antigènes HLA classe I avec la maladie de Behçet dans le Sud tunisien.

PURPOSE: To study antigen HLA class I association with different clinical forms of Behçet's disease in South Tunisian population. PATIENTS AND METHODS: We retrospectively reviewed 129 clinical case patients. All of the patients fulfilled the criteria of the international study group for Behçet's disease, and were followed at the department of internal medicine of the university hospital of Sfax. HLA class I phenotyping was performed by microlymphocytotoxicity complement dependent for our 129 patients and for 123 healthy controls. We used the program SPSS 11.0 to analyse clinical data and to compare HLA class I antigen distribution between these two populations. RESULTS: The study group concerned a total of 129 patients (81 males and 48 females). The mean age at disease onset was of 32 years. HLA-B51 antigen was the only antigen significantly more frequent among patients (24.81%) than controls (9.76%, p=0.002). HLA-B44 was significantly more frequent among patients having familial history of recurrent buccal aphthosis or Behçet disease. HLA-A11 antigen was associated with early disease onset, and HLA-A1 was negatively associated with severe form of the disease (neurological, vascular or ocular manifestations). CONCLUSION: Our study confirmed the HLA-B51 association with Behçet disease. Nevertheless, B51 frequency in South Tunisian patients was lower than that found in other studies regardless of the clinical manifestation.

[Pathogenesis of narcolepsy: from HLA association to hypocretin deficiency]. / Zur Pathogenese der Narkolepsie: Vom HLA-Typus als Risikoprofil zum Hypocretinmangel als Ursache.

Narcolepsy is a rare and chronic sleep disorder, characterised by excessive daytime sleepiness. Frequently associated signs are cataplexy, sleep paralysis and hypnagogic or hypnopompic hallucinations. Advances in understanding the pathogenesis of the disease have essentially been elucidated during the last fifteen years. The most significant finding has been the discovery of hypocretin-1 and -2 in 1998. Hypocretin-containing cells have widespread projections throughout the entire CNS and play a crucial role in the regulation of the sleep-wake cycle. They also contribute to olefaction and to the regulation of food intake. Animal models and human studies concordantly show that the disturbed hypocretin system is the probable cause of narcolepsy. However, it remains unclear why there is neuronal death of hypocretin-producing cells in the lateral hypothalamus. As the HLA-allele DQB1*0602 is associated with narcolepsy and hypocretin deficiency, an autoimmune reaction against hypocretin-producing neurons has been vigorously discussed. Newly discovered gene polymorphisms as well as previously unknown pathogenetic mechanisms, linking the sleep-wake cycle with the immune system, may also contribute to the pathogenetic cascade. Worthy of mention in this context is, e.g., the "insulin-like growth factor"-binding protein 3 (IGFBP3), whose overexpression causes a down-regulation of the hypocretin production. Substitution of the deficient neuropeptides by hypocretin agonists may become the causal treatment strategy of the future, if an adequate administration route can be found. Presently, animal trials, including genetic therapy, cell transplantations or the administration of hypocretin receptor agonists, are underway.

Human leukocyte antigen-G is closely associated with tumor immune escape in gastric cancer by increasing local regulatory T cells.

Human leukocyte antigen-G (HLA-G) plays an important role in tumor cell escape. We investigated HLA-G expression and regulatory T cells (Tregs) infiltrates in patients with gastric cancer (GC), analyzed their relationship with clinicopathologic features, and characterized their role in tumor immune escape. We also investigated the plasma soluble HLA-G level and its potential in the diagnosis of GC. Effect of HLA-G on Tregs was further assessed by coculture experiments in vitro. Most interestingly, HLA-G positive expression was detected in GC tissues and it was significantly correlated with the presence of tumor-infiltrating Tregs. Patients with HLA-G positive expression or high Tregs had significantly poorer survival at 5 years after operation. Multivariate analysis indicated that HLA-G positive expression was an independent prognostic factor of GC. The coculture experiment showed overexpression of HLA-G in GC cell lines significantly enhanced the frequency of Tregs when GC cells were directly cocultured with human peripheral blood mononuclear cell. However, this effect disappeared when the indirect coculture system was applied. Some cytokines such as interleukin-6, interleukin-10, and tumor necrosis factor-α significantly changed in the coculture system. Moreover, plasma soluble HLA-G level in GC patients was higher than that in normal controls. Taken together, our results indicated that HLA-G expression was closely associated with tumor progression and involved in tumor evasion by increasing the frequency of infiltrating Tregs locally. Thus, HLA-G might be a promising predictor for disease prognosis and a possible novel target for immunotherapy in GC patients.

Pharmacogenetics of drug-induced liver injury.

Recent progress in research on drug-induced liver injury (DILI) has been determined by key developments in two areas. First, new technologies allow the identification of genetic risk factors with improved sensitivity, specificity, and efficiency. Second, new mechanistic concepts of DILI emphasize the importance of unspecific "downstream" events following drug-specific initial "upstream" hepatocyte injury and of complex interactions between environmental and genetic risk factors. The integration of genetic and mechanistic concepts is essential for current research approaches, and genetic studies of DILI now focus on targets that affect the function and transcriptional regulation of genes relating not only to drug metabolism but also to human leukocyte antigens (HLAs), cytokines, oxidative stress, and hepatobiliary transporters. Risk factors affecting unspecific downstream mechanisms may be identified using pooled DILI cases caused by various drugs. The power to detect variants that confer a low risk can be increased by recruitment of strictly selected cases through large networks, whereas controls may also be obtained from genotyped reference populations. The first genomewide studies of DILI identified HLA variants as risk factors for hepatotoxicity associated with flucloxacillin and ximelagatran, and their design has defined a new standard for pharmacogenetic studies. From a clinical and regulatory point of view, there is a need for genetic tests that identify patients at increased hepatotoxic risk. However, DILI is a rare complex disease, and pharmacogenetic studies have so far not been able to identify interactions of several risk factors defining a high population-attributable risk and clinically relevant absolute risk for DILI.

Minor histocompatibility antigen-specific cytotoxic T cell lines, capable of lysing human hematopoietic progenitor cells, can be generated in vitro by stimulation with HLA-identical bone marrow cells.

Recipient-antidonor alloreactivity before HLA genotypically identical bone marrow transplantation (BMT) between donor-recipient pairs that are negative in the mixed lymphocyte reaction (MLR), the cell-mediated lympholysis (CML) assay, and the lymphocyte crossmatch was not detectable in the majority of cases, using recipient peripheral blood lymphocytes (PBL) collected before BMT as responder cells and donor PBL as stimulator cells. However, when donor bone marrow mononuclear cells (BMMNC) instead of PBL were used as stimulator cells, we could detect donor-specific alloreactivity in 7 of 10 HLA genotypically identical donor-recipient pairs. To demonstrate that this alloreactivity was minor histocompatibility (mH) antigen specific and not directed against HLA class I splits or variants, two cytotoxic T lymphocyte (CTL) lines were tested in further detail against phytohemagglutinin (PHA) blasts from pairs of HLA genotypically identical siblings positive for the HLA class I restriction molecule. Both CTL lines recognized mH antigens, as illustrated by the differential recognition of PHA blasts of one of the two siblings from several pairs. The potential role of these mH antigen-specific CTLs in bone marrow graft rejection was demonstrated by the mH antigen-specific growth inhibition of hematopoietic progenitor cells from the original bone marrow donor and from HLA class I restriction molecule-positive individuals who expressed the mH antigens on their PBL and BMMNC. Our assay can be used in HLA genotypically identical BMT to detect a recipient-antidonor response, directed against cellularly defined mH antigens expressed on donor HPC, BMMNC, and PBL, before transplantation.

Cell-cell adhesion mediated by CD8 and human histocompatibility leukocyte antigen G, a nonclassical major histocompatibility complex class 1 molecule on cytotrophoblasts.

The lymphocyte differentiation marker CD8 acts as a coreceptor with the T cell receptor (TCR) during recognition of peptide presented by major histocompatibility complex (MHC) class I molecules. The functions of CD8 in the TCR complex are thought to be signaling through the association of CD8 with the protein tyrosine kinase p56lck and adhesion to MHC class I through the alpha 3 domain. While the ability of the CD8 alpha/alpha homodimer to bind to classical MHC class I molecules has been shown, it is unclear whether CD8 can also bind nonclassical molecules. Of particular interest is human histocompatibility leukocyte antigen (HLA)-G which is expressed on placental cytotrophoblast cells. These cells do not express HLA-A, -B and -C molecules. In this report, we demonstrate that CD8 can bind to HLA-G. It is possible, therefore, that a cell bearing CD8 may interact with HLA-G-expressing cells.

Human histocompatibility leukocyte antigen (HLA)-G molecules inhibit NKAT3 expressing natural killer cells.

The crucial immunological function of the classical human major histocompatibility complex (MHC) class I molecules, human histocompatibility leukocyte antigen (HLA)-A, -B, and -C, is the presentation of peptides to T cells. A secondary function is the inhibition of natural killer (NK) cells, mediated by binding of class I molecules to NK receptors. In contrast, the function of the nonclassical human MHC class I molecules, HLA-E, -F, and -G, is still a mystery. The specific expression of HLA-G in placental trophoblast suggests an important role for this molecule in the immunological interaction between mother and child. The fetus, semiallograft by its genotype, escapes maternal allorecognition by downregulation of HLA-A and HLA-B molecules at this interface. It has been suggested that the maternal NK recognition of this downregulation is balanced by the expression of HLA-G, thus preventing damage to the placenta. Here, we describe the partial inhibition of NK lysis of the MHC class I negative cell line LCL721.221 upon HLA-G transfection. We present three NK lines that are inhibited via the interaction of their NKAT3 receptor with HLA-G and with HLA-Bw4 molecules. Inhibition can be blocked by the anti-NKAT3 antibody 5.133. In conclusion, NK inhibition by HLA-G via NKAT3 may contribute to the survival of the fetal semiallograft in the mother during pregnancy.

HLA-E-dependent presentation of Mtb-derived antigen to human CD8+ T cells.

Previous studies in mice and humans have suggested an important role for CD8+ T cells in host defense to Mtb. Recently, we have described human, Mtb-specific CD8+ cells that are neither HLA-A, B, or C nor group 1 CD1 restricted, and have found that these cells comprise the dominant CD8+ T cell response in latently infected individuals. In this report, three independent methods are used to demonstrate the ability of these cells to recognize Mtb-derived antigen in the context of the monomorphic HLA-E molecule. This is the first demonstration of the ability of HLA-E to present pathogen-derived antigen. Further definition of the HLA-E specific response may aid development of an effective vaccine against tuberculosis.

Major histocompatibility complex class I molecules modulate activation threshold and early signaling of T cell antigen receptor-gamma/delta stimulated by nonpeptidic ligands.

Killer cell inhibitory receptors and CD94-NKG2-A/B heterodimers are major histocompatibility complex class I-specific inhibitory receptors expressed by natural killer cells, T cell antigen receptor (TCR)-gamma/delta cells, and a subset of TCR-alpha/beta cells. We studied the functional interaction between TCR-gamma/delta and CD94, this inhibitory receptor being expressed on the majority of gamma/delta T cells. When engaged by human histocompatibility leukocyte antigen class I molecules, CD94 downmodulates activation of human TCR-gamma/delta by phosphorylated ligands. CD94-mediated inhibition is more effective at low than at high doses of TCR ligand, which may focus T cell responses towards antigen-presenting cells presenting high amounts of antigen. CD94 engagement has major effects on TCR signaling cascade. It facilitates recruitment of SHP-1 phosphatase to TCR-CD3 complex and affects phosphorylation of Lck and ZAP-70 kinase, but not of CD3 zeta chain upon TCR triggering. These events may cause abortion of proximal TCR-mediated signaling and set a higher TCR activation threshold.

Cell bio-imaging reveals co-expression of HLA-G and HLA-E in human preimplantation embryos.

The non-classical major histocompatibility complex (MHC) class Ib antigens, termed HLA-G and HLA-E, have been associated with fetal maternal tolerance. The role of HLA-G in the preimplantation embryo remains unclear although immunoprotection, adhesion and cell signalling mechanisms have been suggested. Unlike HLA-G, HLA-E protein expression has not been previously studied in preimplantation embryos. Embryos and model trophoblast cell lines JEG-3 and BeWo were labelled with the HLA-G- and HLA-E-specific monoclonal antibodies MEMG9 and MEME07. Flow cytometry, confocal microscopy and single particle fluorescence imaging techniques were employed to investigate the spatial and temporal expression of these receptors. Lipid raft analysis and adhesion assays were performed to investigate the role of these receptors in cell membrane domains and in promoting adhesion by cell-to-cell contact. HLA-E and HLA-G were co-localized in the trophectoderm of day 6 blastocysts. Analysis on trophoblast cell lines revealed that 37% of HLA-G and 41% of HLA-E receptors were co-localized as tetramers or higher order homodimer clusters. HLA-G receptors did not appear to play a role in either cell adhesion or immunoreceptor signalling via lipid raft platforms on the cell membrane. A possible role of HLA-G and HLA-E in implantation via immunoregulation or modulation of uterine maternal leukocytes is discussed.

HLA class I molecules regulate IFN-gamma production induced in NK cells by target cells, viral products, or immature dendritic cells through the inhibitory receptor ILT2/CD85j.

Recent advances support an important role for NK cells in determining immune responses beyond their cytolytic functions, which is supported by their capacity to secrete several cytokines and chemokines. In particular, NK-derived IFN-gamma has proven to be fundamental in shaping adaptive immune responses. Although the role of inhibitory NK receptors (iNKR) in the regulation of cytotoxicity has been widely explored, their involvement in the control of cytokine production has been scarcely analyzed. Specifically, no data are available referring to the role of the iNKR ILT2/CD85j in the regulation of IFN-gamma secretion by NK cells. Published data support a differential regulation of cytotoxicity and cytokine expression. Thus, formal proof of the involvement of HLA class I in regulating the production of cytokines through binding to ILT2/CD85j has been missing. We have determined the response of human NK-92 and primary human ILT2/CD85j(+) NK cells from healthy donors to target cells expressing or not HLA class I. We found specificities of HLA class I-mediated inhibition of IFN-gamma mRNA expression, protein production, and secretion consistent with the specific recognition by ILT2/CD85j. We also found inhibition of IFN-gamma production by ILT2/CD85j(+) T cells in response to superantigen stimulation. Furthermore, ligation of ILT2/CD85j inhibited the production of IFN-gamma in response to poly(I:C), and blocking of ILT2/CD85j-HLA class I interactions increased the secretion of IFN-gamma in NK/immature dendritic cell cocultures. The data support a role for self HLA class I in the regulation of IFN-gamma secretion at the mRNA and protein levels by interacting with the iNKR ILT2/CD85j.

LncRNA HCG18 is critical for vascular smooth muscle cell proliferation and phenotypic switching.

Previous studies have shown that some specific long non-coding RNAs are dysregulated in vascular walls and abnormally expressed in vascular disease. LncRNA HLA complex group 18 (HCG18) is a member of the HLA complex group, which has been rarely investigated in human diseases. In this study, we aimed to investigate the role of HCG in vascular smooth muscle cells. HCG18 was over-expressed by adenovirus transfection and knocked down in vascular smooth muscle cells by shRNA. Cell proliferation was detected by CCK-8 assays. Flow cytometry was employed to test the impacts of HCG18 on vascular smooth muscle apoptotic cells. The expression of associated genes in protein and mRNA levels was detected by western blotting, immunofluorescence and qRT-PCR. The interactions between HCG18 and fused in sarcoma (FUS) were confirmed by RNA EMSA and RIP assays. The expression of serum HCG18 was decreased in hypertensive patients and PDGF-BB-treated vascular smooth muscle cells. HCG18 inhibited proliferation and induced apoptotic cells in vascular smooth muscle cells. In addition, we also found that HCG18 can inhibit vascular smooth muscle cell phenotypic switching from a contractile to a secretory phenotype. Finally, our results showed that HCG18 enhanced apoptotic cells by directly binding with FUS. Our findings reveal that HCG18 is involved in the regulation of proliferation, apoptosis and the expression levels of markers of the contractile and synthetic phenotype.

HLA in Alzheimer's Disease: Genetic Association and Possible Pathogenic Roles.

Alzheimer's disease (AD) is commonly considered as the most prominent dementing disorder globally and is characterized by the deposition of misfolded amyloid-ß (Aß) peptide and the aggregation of neurofibrillary tangles. Immunological disturbances and neuroinflammation, which result from abnormal immunological reactivations, are believed to be the primary stimulating factors triggering AD-like neuropathy. It has been suggested by multiple previous studies that a bunch of AD key influencing factors might be attributed to genes encoding human leukocyte antigen (HLA), whose variety is an essential part of human adaptive immunity. A wide range of activities involved in immune responses may be determined by HLA genes, including inflammation mediated by the immune response, T-cell transendothelial migration, infection, brain development and plasticity in AD pathogenesis, and so on. The goal of this article is to review the recent epidemiological findings of HLA (mainly HLA class I and II) associated with AD and investigate to what extent the genetic variations of HLA were clinically significant as pathogenic factors for AD. Depending on the degree of contribution of HLA in AD pathogenesis, targeted research towards HLA may propel AD therapeutic strategies into a new era of development.