Psoriasis is a common autoimmune and hyper proliferative skin disease, characterized by thick, silvery scale patches. Numerous family studies have provided compelling evidence of a genetic predisposition to psoriasis, although the inheritance pattern is unclear. However, few of these studies have achieved consistent results, except for the MHC locus, a problem frequently encountered in the investigation of complex disease. Using high-throughput techniques to genotype hundreds of thousands of single nucleotide polymorphisms explore their relationship with phenotypes, genome-wide association studies (GWAS) are now proven to be a powerful approach for screening the susceptibility genes (loci) of complex disease. Recently, three GWAS on psoriasis published in Nature Genetics have provided us with many novel clues concerning disease pathogenesis, in both immune and non-immune pathways. The MHC locus (HLA-Cw6 and other MHC variance), the major locus involved in the immune reactions of human immune disease, has consistently been shown to be associated with psoriasis, both in previous linkage and present GWAS. IL-12B and IL23R, which are the two non-MHC genes with highly associated evidence with psoriasis in multiple studies performed so far and potent cytokines with complex biological activities, should be of great importance in the pathogenesis of psoriasis. Recent clinical trials, in which anti-IL-12p40 antibodies were used for the treatment of psoriasis, have provided further evidence of the role of IL-12/23 in the pathophysiology of psoriasis,and highlighted a new road of treatment for psoriasis. In 2008,we performed the first large GWAS in the Chinese population and identified a novel susceptibility locus within the late cornified envelope (LCE) gene cluster: LCE3A and LCE3D on chromosome 1q21, with conclusive evidence (rs4085613, p(combined)=6.69*10(-30); odds ratio=0.76). Meanwhile, another group also identified a deletion comprising and LCE gene cluster of LCE3B and LCE3C, which is significantly associated with a risk of psoriasis in Spain, Netherland, Italy and USA. Both of these independent studies provided substantial association evidence for the LCE genes involved in the pathogenesis of psoriasis. The LCE genes encode the stratum-corneum proteins of the cornified envelope, which plays an important role in epidermal terminal differentiation. As we know, psoriasis is a disease of interfollicular epidermis and rapid keratinocyte proliferation may cause the production of parakeratotic keratinocytes in psoriatic skin and, thus, the formation of poorly adherent stratum corneum, which in turn results in the characteristic scale or flakes of psoriasis lesions. Although some of the highlighted genes are already targeted by effective psoriasis therapies, others could become future targets for treatments,especially for the LCE genes, which will be very useful for unlocking new drug targets and tailored treatments for this painful, disfiguring skin disease. Meanwhile larger samples and improved strategy for identification of other susceptibility variants to psoriasis and downstream functional study to elucidate the underlying mechanisms of diseases are also needed. Taken together, unremitting efforts of the basic research on psoriasis will lead us to achieve a better treatment and diagnosis for psoriasis in the near future.
Autoimmunity ; genetics ; Cornified Envelope Proline-Rich Proteins ; genetics ; Genetic Predisposition to Disease ; Genome, Human ; genetics ; Genome-Wide Association Study ; Humans ; Interleukin-12 Subunit p40 ; genetics ; Major Histocompatibility Complex ; genetics ; Psoriasis ; genetics ; immunology ; Receptors, Interleukin ; genetics

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by selective destruction of pancreatic beta-cells resulting in insulin deficiency. The genetic determinants of T1D susceptibility have been linked to several loci, in particular to the human leukocyte antigen (HLA) region, which accounts for 50% of the genetic risk of developing T1D. Multiple genes in the HLA region, which are in strong linkage disequilibrium, are thought to be involved. Another important locus, with a smaller effect on genetic predisposition to T1D, is the insulin gene. The advent of numerous single nucleotide polymorphism markers and genome screening has enabled the identification of dozens of new T1D susceptibility loci. Some of them appear to predispose to T1D independently of the HLA and may be important in families with T1D who lack strong HLA susceptibility. Other loci may interact with each other to cause susceptibility. The autoimmune response against beta-cells can also be triggered by environmental factors in the presence of a predisposing genetic background. Deciphering the environmental and genetic factors involved should help to understand the origin of T1D and aid in the design of individualized prevention programs.
Autoimmune Diseases ; Autoimmunity ; Diabetes Mellitus, Type 1 ; Genetic Predisposition to Disease* ; Genetics ; Genome ; HLA Antigens ; Humans ; Insulin ; Leukocytes ; Linkage Disequilibrium ; Mass Screening ; Polymorphism, Single Nucleotide

Objectives, recent epidemiologic studies in humans suggest an increased prevalence of thyroiditis associated with the excessive administration of iodine. More than three times of recommended daily intake of iodine was observed among people in North America. These people generally presented higher level of anti-thyroglobulin antibody, anti-thyroperoxidase antibody, serum thyroid-stimulating hormone and exacerbation of lymphocytic infiltration in thyroid, which indicated the overconsumption of iodine could induce hypothyroidism and enhance the autoimmune response. However, the precise mechanism of excessive iodine intake induced autoimmune thyroid disease remains largely unknown. Over half a century has elapsed since the 1956 identification of thyroglobulin antibodies and the devising of the first experimental model of autoimmune thyroiditis. Since then an incredible amount of experimental work has led to an ever deeper understanding of the nature of thyroid auto-antigens, the main immune mechanisms responsible for Hashimoto's thyroiditis and graves' disease, their genetics, and therir environmental risk factor. Yet, in the majority of genetically predisposed people the individual trigger of thyroid autoimmunity remains obscure. Similarly, effective prevention strategies still remain to be established and, hopefully, will be the target of future studies.
Antibodies ; Autoimmunity ; Genetics ; Graves Disease ; Humans ; Hypothyroidism ; Iodine ; Models, Theoretical ; North America ; Prevalence ; Recommended Dietary Allowances ; Risk Factors ; Thyroglobulin ; Thyroid Diseases ; Thyroid Gland* ; Thyroiditis ; Thyroiditis, Autoimmune ; Thyrotropin

Human genetic variation is represented by the genetic differences both within and among populations, and most genetic variants do not cause overt diseases but contribute to disease susceptibility and influence drug response. During the last century, various genetic variants, such as copy number variations (CNVs), have been associated with diverse human disorders. Here, we review studies on the associations between CNVs and autoimmune diseases to gain some insight. First, some CNV loci are commonly implicated in various autoimmune diseases, such as Fcgamma receptors in patients with systemic lupus erythemoatosus or idiopathic thrombocytopenic purpura and beta-defensin genes in patients with psoriasis or Crohn's disease. This means that when a CNV locus is associated with a particular autoimmune disease, we should examine its potential associations with other diseases. Second, interpopulation or interethnic differences in the effects of CNVs on phenotypes exist, including disease susceptibility, and evidence suggests that CNVs are important to understand susceptibility to and pathogenesis of autoimmune diseases. However, many findings need to be replicated in independent populations and different ethnic groups. The validity and reliability of detecting CNVs will improve quickly as genotyping technology advances, which will support the required replication.
Animals ; Autoimmune Diseases/ethnology/*genetics/immunology ; Autoimmunity/*genetics ; *DNA Copy Number Variations ; *Gene Dosage ; Genetic Association Studies ; Genetic Markers ; Genetic Predisposition to Disease ; Humans ; Phenotype ; Population Groups/genetics ; Risk Factors

BACKGROUNDKeshan disease (KD) is an endemic cardiomyopathy in China. The etiology of KD is still under debate and there is no effective approach to preventing and curing this disease. Young women of child-bearing age are the most frequent victims in rural areas. The aim of this study was to determine the differences between molecular pathogenic mechanisms in male and female KD sufferers.

METHODSWe extracted RNA from the peripheral blood mononuclear cells of KD patients (12 women and 4 men) and controls (12 women and 4 men). Then the isolated RNA was amplified, labeled and hybridized to Agilent human 4×44k whole genome microarrays. Gene expression was examined using oligonucleotide microarray analysis. A quantitative polymerase chain reaction assay was also performed to validate our microarray results.

RESULTSAmong the genes differentially expressed in female KD patients we identified: HLA-DOA, HLA-DRA, and HLA-DQA1 associated with spontaneous autoimmunity; BMP5 and BMP7, involved in cardiomyocyte differentiation defect; and ADAMTS 8, CCL23, and TNFSF15, implicated in anti-angiogenic activities. These genes are involved in the canonical pathways and networks recognized for the female KD sufferers and might be related to the pathogenic mechanism of KD.

CONCLUSIONOur results might help to explain the higher susceptibility of women to this disease.

ADAM Proteins ; genetics ; ADAMTS Proteins ; Adult ; Autoimmunity ; genetics ; physiology ; Bone Morphogenetic Protein 5 ; genetics ; Bone Morphogenetic Protein 7 ; genetics ; Cardiomyopathies ; genetics ; pathology ; Cell Differentiation ; genetics ; physiology ; Chemokines, CC ; genetics ; Enterovirus Infections ; genetics ; pathology ; Female ; Gene Expression Profiling ; HLA-D Antigens ; genetics ; HLA-DQ alpha-Chains ; genetics ; HLA-DR alpha-Chains ; genetics ; Humans ; Male ; Middle Aged ; Myocytes, Cardiac ; cytology ; metabolism ; Oligonucleotide Array Sequence Analysis ; Sex Factors ; Tumor Necrosis Factor Ligand Superfamily Member 15 ; genetics

Thyroid diseases, including autoimmune thyroid diseases and thyroid cancer, are known to have high heritability. Family and twin studies have indicated that genetics plays a major role in the development of thyroid diseases. Thyroid function, represented by thyroid stimulating hormone (TSH) and free thyroxine (T4), is also known to be partly genetically determined. Before the era of genome-wide association studies (GWAS), the ability to identify genes responsible for susceptibility to thyroid disease was limited. Over the past decade, GWAS have been used to identify genes involved in many complex diseases, including various phenotypes of the thyroid gland. In GWAS of autoimmune thyroid diseases, many susceptibility loci associated with autoimmunity (human leukocyte antigen [HLA], protein tyrosine phosphatase, non-receptor type 22 [PTPN22], cytotoxic T-lymphocyte associated protein 4 [CTLA4], and interleukin 2 receptor subunit alpha [IL2RA]) or thyroid-specific genes (thyroid stimulating hormone receptor [TSHR] and forkhead box E1 [FOXE1]) have been identified. Regarding thyroid function, many susceptibility loci for levels of TSH and free T4 have been identified through genome-wide analyses. In GWAS of differentiated thyroid cancer, associations at FOXE1, MAP3K12 binding inhibitory protein 1 (MBIP)-NK2 homeobox 1 (NKX2-1), disrupted in renal carcinoma 3 (DIRC3), neuregulin 1 (NRG1), and pecanex-like 2 (PCNXL2) have been commonly identified in people of European and Korean ancestry, and many other susceptibility loci have been found in specific populations. Through GWAS of various thyroid-related phenotypes, many susceptibility loci have been found, providing insights into the pathogenesis of thyroid diseases and disease co-clustering within families and individuals.
Autoimmunity ; Genes, Homeobox ; Genetics ; Genome-Wide Association Study* ; Graves Disease ; Hashimoto Disease ; Humans ; Leukocytes ; Neuregulin-1 ; Phenotype ; Protein Tyrosine Phosphatase, Non-Receptor Type 22 ; Receptors, Interleukin-2 ; T-Lymphocytes, Cytotoxic ; Thyroid Diseases* ; Thyroid Gland* ; Thyroid Neoplasms* ; Thyrotropin ; Thyroxine

Using directed mutagenesis and phage display on a soluble fragment of the human immunoglobulin super-family receptor ILT2 (synonyms: LIR1, MIR7, CD85j), we have selected a range of mutants with binding affinities enhanced by up to 168,000-fold towards the conserved region of major histocompatibility complex (MHC) class I molecules. Produced in a dimeric form, either by chemical cross-linking with bivalent polyethylene glycol (PEG) derivatives or as a genetic fusion with human IgG Fc-fragment, the mutants exhibited a further increase in ligand-binding strength due to the avidity effect, with resident half-times (t(1/2)) on the surface of MHC I-positive cells of many hours. The novel compounds antagonized the interaction of CD8 co-receptor with MHC I in vitro without affecting the peptide-specific binding of T-cell receptors (TCRs). In both cytokine-release assays and cell-killing experiments the engineered receptors inhibited the activation of CD8(+) cytotoxic T lymphocytes (CTLs) in the presence of their target cells, with subnanomolar potency and in a dose-dependent manner. As a selective inhibitor of CD8(+) CTL responses, the engineered high affinity ILT2 receptor presents a new tool for studying the activation mechanism of different subsets of CTLs and could have potential for the development of novel autoimmunity therapies.
Amino Acid Sequence ; Antigens, CD ; chemistry ; genetics ; pharmacology ; Autoimmunity ; Biological Assay ; Cell Line ; Cytotoxicity, Immunologic ; genetics ; immunology ; Dose-Response Relationship, Immunologic ; Humans ; Immunoglobulins ; immunology ; metabolism ; Immunologic Factors ; chemistry ; genetics ; pharmacology ; Kinetics ; Leukocyte Immunoglobulin-like Receptor B1 ; Lymphocyte Activation ; genetics ; immunology ; Major Histocompatibility Complex ; genetics ; immunology ; Molecular Sequence Data ; Molecular Targeted Therapy ; Mutagenesis, Site-Directed ; Peptide Library ; Polyethylene Glycols ; Protein Binding ; genetics ; immunology ; Receptors, Immunologic ; chemistry ; genetics ; Recombinant Fusion Proteins ; genetics ; metabolism ; T-Lymphocytes, Cytotoxic ; immunology ; metabolism

OBJECTIVETo investigate the effect of arsenic trioxide (ATO) on the autoimmunity and survival time in BXSB lupus mice.

METHODSThe model BXSB lupus mice were randomly divided into two groups equally, the ATO treated group and the control group, 17 in each group. Mice in the ATO group were given intraperitoneal injection of ATO at the daily dose of 0.4 mg/kg, once every other day for 105 days or 90 days, respectively, and the observation lasted for 210 days. The survival time between the two groups was compared; the serum levels of anti-dsDNA and IgG were detected by enzyme-linked immunosorbent assay (ELISA), and the interferon-gamma (IFN-gamma) mRNA expression in renal and spleen tissue were measured by reverse transcriptase polymerase chain reaction (RT-PCR) technique.

RESULTSTill the 210th day, the total number of death was 8 in the ATO treated group and 13 in the control group, comparison between the two groups showed significantly different (chi2 = 4.20, P < 0.05). The mean OD value of serum anti-dsDNA antibody was lower in the ATO group (0.392 +/- 0.087) than that in the control group (0.566 +/- 0.080, P < 0.001). The serum level of IgG on day 105 in the ATO group was significantly lower than that in the control group and before treatment (P < 0.05). The expression of IFN-gamma mRNA in spleen tissue and renal tissue in the ATO group and the control group was 0.540 +/- 0.300 and 0.338 +/- 0.163, 2.320 +/- 0.522 and 0.588 +/- 0.104 (P < 0.05 and P < 0.01 respectively).

CONCLUSIONATO can prolong the survival time of BXSB lupus mice, decrease the peripheral level of anti-dsDNA antibody and IgG expression, inhibit the over-expression of IFN-gamma mRNA in spleen and kidney tissues.

Animals ; Antibodies, Antinuclear ; blood ; Arsenicals ; administration & dosage ; therapeutic use ; Autoimmunity ; drug effects ; Enzyme-Linked Immunosorbent Assay ; Immunoglobulin G ; blood ; Injections, Intraperitoneal ; Interferon-gamma ; genetics ; Kidney ; drug effects ; metabolism ; Lupus Erythematosus, Systemic ; drug therapy ; genetics ; immunology ; Mice ; Oxides ; administration & dosage ; therapeutic use ; RNA, Messenger ; genetics ; metabolism ; Random Allocation ; Reverse Transcriptase Polymerase Chain Reaction ; Spleen ; drug effects ; metabolism ; Survival Analysis

OBJECTIVETo identify autoepitopes of E2 subunit of pyruvate dehydrogenase complex (PDC-E2) specific CD8+ CTL in primary biliary cirrhosis (PBC) patients.

METHODSAn online database SYFPEITHI was applied to predict HLA-A*0201 restricted epitopes which located in PDC-E2 30-50 aa and 150-190 aa where B-cell epitopes clustered with CD4+ T-cell epitopes. T2 cell line reconstitution and stabilization assay, induction of specific CTL lines from peripheral blood mononuclear cells (PBMCs) of patients with PBC and cytotoxicity of peptides-induced CTL were performed to screen the epitopes from those candidates.

RESULTSFive potential epitopes were predicted by database. Of the 5 candidates, two peptides 159-167 aa and 165-174 aa, with highly binding activity to HLA-A*0201 molecules, could stimulate PBMCs from most HLA-A*0201 positive PBC patients to proliferate and peptide-induced CTL lines showed specific cytotoxicity.

CONCLUSIONPeptides of KLSEGDLLA (159-167 aa) and LLAEIETDKA (165-174 aa) in the inner lipoyl domain of PDC-E2 are HLA-A*0201 restricted CD8+ CTL immunodominant epitopes in PBC.

Antibody-Producing Cells ; cytology ; Autoantigens ; immunology ; Autoimmunity ; CD8-Positive T-Lymphocytes ; cytology ; immunology ; metabolism ; Cell Line ; Dihydrolipoyllysine-Residue Acetyltransferase ; Epitope Mapping ; Epitopes, T-Lymphocyte ; immunology ; HLA-A Antigens ; immunology ; HLA-A2 Antigen ; Humans ; Liver Cirrhosis, Biliary ; enzymology ; genetics ; immunology ; Phenotype ; Protein Binding ; Pyruvate Dehydrogenase Complex ; genetics ; immunology ; metabolism ; T-Lymphocytes, Cytotoxic ; immunology

BACKGROUND: Serum antinuclear antibodies (ANAs) are positive in some patients with chronic lymphocytic leukemia (CLL), but the prognostic value of ANAs remains unknown. The aim of this study was to evaluate the role of ANAs as a prognostic factor in CLL. METHODS: This study retrospectively analyzed clinical data from 216 newly diagnosed CLL subjects with ANAs test from 2007 to 2017. Multivariate Cox regression analyses were used to screen the independent prognostic factors related to time to first treatment (TTFT), progression free survival (PFS) and overall survival (OS). Receiver operator characteristic curves and area under the curve (AUC) were utilized to assess the predictive accuracy of ANAs together with other independent factors for OS. RESULTS: The incidence of ANAs abnormality at diagnosis was 13.9%. ANAs positivity and TP53 disruption were independent prognostic indicators for OS. The AUC of positive ANAs together with TP53 disruption was 0.766 (95% confidence interval [CI]: 0.697-0.826), which was significantly larger than that of either TP53 disruption (AUC: 0.706, 95% CI: 0.634-0.772, P = 0.034) or positive ANAs (AUC: 0.595, 95% CI: 0.520-0.668, P < 0.001) in OS prediction. Besides, serum positive ANAs as one additional parameter to CLL-international prognostic index (IPI) obtained superior AUCs in predicting CLL OS than CLL-IPI alone. CONCLUSION This study identified ANAs as an independent prognostic factor for CLL, and further investigations are needed to validate this finding.
ADP-ribosyl Cyclase 1 ; blood ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antibodies, Antinuclear ; blood ; Autoimmunity ; physiology ; Female ; Humans ; Kaplan-Meier Estimate ; Leukemia, Lymphocytic, Chronic, B-Cell ; blood ; mortality ; Male ; Middle Aged ; Multivariate Analysis ; Mutation ; genetics ; Proportional Hazards Models ; Retrospective Studies ; Survival Analysis ; Tumor Suppressor Protein p53 ; blood ; Young Adult ; ZAP-70 Protein-Tyrosine Kinase ; blood