BACKGROUND: Peripheral blood monocytes are key effectors of innate immunity. Dysfunction, changes in their counts or altered expression of cytokines and pattern-recognition receptors on monocytes may contribute to the development of the autoimmune type of diabetes mellitus (AD). AIMS: We aimed to analyze the counts and proportions of the two main subtypes of monocyte cells, CD14(++) and CD14(+), and to look for potential changes in the expression of toll-like receptors 2 (TLR2) and 4 (TLR4) as well as cytokine prolactin (PRL) in adult-onset AD, including diabetes mellitus type 1 (T1DM) and latent autoimmune diabetes in adults (LADA). METHODS: We examined 21 T1DM patients, 9 patients with LADA, 16 control patients with type 2 diabetes mellitus (T2DM) and 24 healthy individuals. All diabetic patients were diagnosed after the age of 18 years. Expression at the mRNA level was determined by quantitative PCR. Flow cytometry was used to ascertain membrane expression and cell counts. RESULTS: T1DM patients had fewer CD14(++) (P < 0.01) and CD14(+) (P < 0.0001) monocytes whereas T2DM subjects showed decreased counts of CD14(+) monocytes compared to healthy controls (P < 0.001). TLR2 protein expression was significantly increased in T1DM CD14(+) monocytes compared to healthy controls (P < 0.05), while TLR4 expression in T1DM CD14(++) cells was significantly lower (P < 0.0001). There was no significant difference between the groups in terms of PRL mRNA expression in monocytes. CONCLUSIONS: The observed changes in the proportions of both immune cell types and in the expression of functional pattern-recognition receptors on monocytes in the subjects examined may arise as a consequence of chronic inflammation that accompanies long-term diabetes.
- MeSH
- diabetes mellitus 1. typu imunologie MeSH
- diabetes mellitus 2. typu imunologie MeSH
- dospělí MeSH
- down regulace fyziologie MeSH
- kvantitativní polymerázová řetězová reakce MeSH
- leukocyty mononukleární metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- lipopolysacharidové receptory metabolismus MeSH
- messenger RNA metabolismus MeSH
- přirozená imunita fyziologie MeSH
- průtoková cytometrie MeSH
- studie případů a kontrol MeSH
- toll-like receptor 2 metabolismus MeSH
- toll-like receptor 4 metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Our study explored the role of extrapituitary prolactin (PRL) and toll-like receptors (TLR)2 and TLR4 in defense reaction of immune system to bacterial infection. Forty-two patients diagnosed with sepsis were recruited and blood samples were withdrawn after patients' admission to hospital, after the end of acute phase of sepsis and after the sepsis has been resolved, respectively. Seventeen patients died of sepsis; thus, only one sample collected just before death could be processed. PRL and TLR2/4 mRNA levels were measured in CD14+ blood monocytes by QPCR and PRL -1149 G/T SNP genotyped. The TLRs mRNA expression was markedly elevated in all patients groups in comparison to healthy controls mRNA levels; the highest upregulation of monocytic TLR2 in sepsis (16.4 times, P<0.0001) was detected in patients who did not survive septic complications. PRL mRNA expression in monocytes from non-survivors tended to be lower (4.5 fold decrease, P=NS) compared to control levels and it was 6.2 times reduced compared to PRL mRNA expression in second blood sample from survivors (P<0.05). The PRL -1149 G/T SNP had no effect on PRL mRNA response during sepsis. Our data suggest that increased prolactin mRNA expression in monocytes is associated with better outcome and improved survival rate in sepsis with no apparent effect of PRL -1149 G/T SNP on monocytic prolactin response.
- MeSH
- bakteriální infekce krev MeSH
- hematologické nádory krev MeSH
- hypofýza imunologie MeSH
- leukocyty mononukleární imunologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- prolaktin krev MeSH
- sepse krev MeSH
- toll-like receptor 2 krev MeSH
- toll-like receptor 4 krev MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Pituitary hormone and cytokine prolactin (PRL) is one of the mediators of the bidirectional communication between neuroendocrine and immune systems. It participates in many immunomodulatory activities, affects differentiation and maturation of both, B and T lymphocytes and enhances inflammatory responses and production of immunoglobulins. Hyperprolactinemia has been described in many autoimmune diseases, both systemic (SLE, RA, PsA) and organ-specific (T1D, CD and others) and the activity of PRL has been intensively studied. Nevertheless, no data on PRL contribution to pathogenesis of diabetes mellitus is available, although the effect of PRL on beta cells of the pancreas and insulin secretion has been observed.
- MeSH
- B-lymfocyty imunologie metabolismus patologie MeSH
- beta-buňky imunologie metabolismus patologie MeSH
- buněčná diferenciace MeSH
- diabetes mellitus imunologie metabolismus MeSH
- hyperprolaktinemie metabolismus MeSH
- inzulin sekrece MeSH
- lidé MeSH
- mediátory zánětu imunologie metabolismus MeSH
- neuroimunomodulace MeSH
- prolaktin imunologie metabolismus MeSH
- protilátky imunologie metabolismus MeSH
- T-lymfocyty imunologie metabolismus patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Both the human leucocyte antigen (HLA) DRB1 and the HLA DQB1 gene loci play a role in the development and progression of autoimmune diabetes mellitus (T1DM). Similarly, the insulin promoter variable number tandem repeats (INS-VNTR) polymorphism is also involved in the pathogenesis of diabetes mellitus (DM). We studied the association between each of these polymorphisms and DM diagnosed in patients older than age 35 years. Furthermore, we analysed possible interactions between HLA DRB1/DQB1 and INS-VNTR polymorphisms. Based on C-peptide and GADA levels we were able to distinguish three types of diabetes: T1DM, latent autoimmune diabetes in adults (LADA) and T2DM. INS-VNTR was genotyped indirectly by typing INS-23HphI A/T polymorphism. The genotype and allele frequencies of INS-23HphI did not differ between each of the diabetic groups and group of healthy subjects. We did, however, observe an association between the INS-23HphI alleles, genotypes and C-peptide secretion in all diabetic patients: A allele frequency was 86.2% in the C-peptide-negative group vs. 65.4% in the C-peptide-positive group (P(corr.) < 0.005); AA genotype was found to be 72.4% in the C-peptide-negative group vs. 42.6% in the C-peptide-positive groups (P(corr.) < 0.01). The HLA genotyping revealed a significantly higher frequency of HLA DRB1*03 allele in both T1DM and LADA groups when compared to healthy subjects: T1DM (25.7%) vs. control group (10.15%), odds ratio (OR) = 3.06, P < 0.05; LADA (27.6%) vs. control (10.15%), OR = 3.37, P < 0.01. The simultaneous presence of both HLA DRB1*04 and INS-23HphI AA genotype was detected in 37.5% of the T1DM group compared to only 9.2% of the healthy individuals group (OR = 5.9, P(corr.) < 0.007). We summarize that in the Central Bohemian population of the Czech Republic, the INS-23HphI A allele appears to be associated with a decrease in pancreatic beta cell secretory activity. HLA genotyping points to at least a partial difference in mechanism, which leads to T1DM and LADA development as well as a more diverse genetic predisposition in juvenile- and adult-onset diabetes. The simultaneous effect of HLA and INS-VNTR alleles/genotypes predispose individuals to an increased risk of diabetes development.
- MeSH
- alely MeSH
- diabetes mellitus 1. typu genetika imunologie MeSH
- dospělí MeSH
- frekvence genu genetika imunologie MeSH
- genetická predispozice k nemoci MeSH
- HLA-DQ antigeny genetika imunologie MeSH
- HLA-DR antigeny genetika imunologie MeSH
- inzulin genetika imunologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- minisatelitní repetice genetika MeSH
- věk při počátku nemoci MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- multicentrická studie MeSH
- Geografické názvy
- Česká republika MeSH
In this work, we studied the association of the E23K polymorphism of the Kir6.2 ATP-sensitive potassium channels in 212 Czech patients with diabetes mellitus who were diagnosed after the age of 35. Patients were classified into T1DM, LADA and T2DM groups based on C-peptide and GADA levels. Carriers of the predisposing Kir6.2 E23K K allele showed no increased risk of either type of diabetes mellitus development. On the other hand, we found a correlation between E23K SNP of the KCNJ11 gene and C-peptide levels, which may be considered a measure of pancreatic ß-cell activity, although this correlation was not statistically significant. In conclusion, we failed to confirm the Kir6.2 E23K as a genetic marker for T1DM, LADA and T2DM in the Central Bohemian population of the Czech Republic.
