ABSTRACT
Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease characterized by leukocyte infiltration into the central nervous system (CNS). Migration of lymphocyte subpopulations towards CXCL12 was analyzed coupled to six-color flow cytometry in untreated patients in the remitting phase, during relapse, in patients with clinically isolated syndrome (CIS), and in healthy volunteers. Significantly higher migration rates of natural killer cells (CD45+CD3-CD16/56+) were observed in patients in remission and CIS patients than in patients during relapse and in controls. Moreover, the frequency of CD3-CD16/56+CXCR4+ cells is higher in patients in remission and in CIS patients, but not during relapse.
Subject(s)
Central Nervous System/pathology , Chemokine CXCL12/pharmacology , Chemotaxis, Leukocyte/drug effects , Killer Cells, Natural/drug effects , Multiple Sclerosis/pathology , Receptors, CXCR4/metabolism , Adult , Analysis of Variance , Chemotaxis, Leukocyte/physiology , Cytokines/metabolism , Female , Flow Cytometry , Humans , Killer Cells, Natural/metabolism , Lymphocyte Subsets/pathology , Male , Middle Aged , Young AdultABSTRACT
BACKGROUND: Human embryonic stem cells (hESCs) are an attractive resource for new therapeutic approaches that involve tissue regeneration. hESCs have exhibited low immunogenicity due to low levels of Mayor Histocompatibility Complex (MHC) class-I and absence of MHC class-II expression. Nevertheless, the mechanisms regulating MHC expression in hESCs had not been explored. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the expression levels of classical and non-classical MHC class-I, MHC class-II molecules, antigen-processing machinery (APM) components and NKG2D ligands (NKG2D-L) in hESCs, induced pluripotent stem cells (iPSCs) and NTera2 (NT2) teratocarcinoma cell line. Epigenetic mechanisms involved in the regulation of these genes were investigated by bisulfite sequencing and chromatin immunoprecipitation (ChIP) assays. We showed that low levels of MHC class-I molecules were associated with absent or reduced expression of the transporter associated with antigen processing 1 (TAP-1) and tapasin (TPN) components in hESCs and iPSCs, which are involved in the transport and load of peptides. Furthermore, lack of beta2-microglobulin (beta2m) light chain in these cells limited the expression of MHC class I trimeric molecule on the cell surface. NKG2D ligands (MICA, MICB) were observed in all pluripotent stem cells lines. Epigenetic analysis showed that H3K9me3 repressed the TPN gene in undifferentiated cells whilst HLA-B and beta2m acquired the H3K4me3 modification during the differentiation to embryoid bodies (EBs). Absence of HLA-DR and HLA-G expression was regulated by DNA methylation. CONCLUSIONS/SIGNIFICANCE: Our data provide fundamental evidence for the epigenetic control of MHC in hESCs and iPSCs. Reduced MHC class I and class II expression in hESCs and iPSCs can limit their recognition by the immune response against these cells. The knowledge of these mechanisms will further allow the development of strategies to induce tolerance and improve stem cell allograft acceptance.
Subject(s)
Antigen Presentation , Embryonic Stem Cells/immunology , Epigenesis, Genetic , Histocompatibility Antigens , Induced Pluripotent Stem Cells/immunology , Histocompatibility Antigens Class I , Histocompatibility Antigens Class II , Humans , ImmunityABSTRACT
OBJECTIVE: To investigate the contribution of HLA class I alleles in the susceptibility to primary ankylosing spondylitis (AS) in West African patients living in Togo. METHODS: A large epidemiologic analysis of 9,065 West African rheumatology patients living in Togo was performed in order to identify those who had AS. Eight Togolese patients with AS were identified. HLA was typed by polymerase chain reaction using sequence-specific oligonucleotide probes. DNA typing was also performed on a control population of 85 healthy subjects matched for ethnic background. RESULTS: A significant association between AS and B*14 was identified. This allele was found in 62.5% of the AS patients (odds ratio 69), but was carried by only 2% of the healthy controls. Analysis for B14 subtypes showed that B*1403 was the predominant allele in AS patients (odds ratio 171), and that this allele was absent in healthy controls. B27 was virtually absent, being observed in only 1 AS patient (B*2705). CONCLUSION: HLA-B*1403 shows the B27 "supertype" motif and may exert an effect on AS susceptibility according to the arthritogenic peptide model. The association of B*1403 with AS has not previously been reported in either population.
