Identification of myeloid cells in the human enthesis as the main source of local IL-23 production

ObjectiveWe investigated whether the normal human spinal enthesis contained resident myeloid cell populations, capable of producing pivotal proinflammatory cytokines including tumour necrosis factor (TNF) and interleukin (IL)-23 and determined whether these could be modified by PDE4 inhibition.MethodsNormal human enthesis soft tissue (ST) and adjacent perientheseal bone (PEB) (n=15) were evaluated using immunohistochemistry (IHC), digested for myeloid cell phenotyping, sorted and stimulated with different adjuvants (lipopolysaccharide and mannan). Stimulated enthesis fractions were analysed for inducible production of spondyloarthropathy disease-relevant mediators (IL-23 full protein, TNF, IL-1β and CCL20). Myeloid populations were also compared with matched blood populations for further mRNA analysis and the effect of PDE4 inhibition was assessed.ResultsA myeloid cell population (CD45+ HLADR+ CD14+ CD11c+) phenotype was isolated from both the ST and adjacent PEB and termed ‘CD14+ myeloid cells’ with tissue localisation confirmed by CD14+ IHC. The CD14− fraction contained a CD123+ HLADR+ CD11c− cell population (plasmacytoid dendritic cells). The CD14+ population was the dominant entheseal producer of IL-23, IL-1β, TNF and CCL20. IL-23 and TNF from the CD14+ population could be downregulated by a PDE4I and other agents (histamine and 8-Bromo-cAMP) which elevate cAMP. Entheseal CD14+ cells had a broadly similar gene expression profile to the corresponding CD14+ population from matched blood but showed significantly lower CCR2 gene expression.ConclusionsThe human enthesis contains a CD14+ myeloid population that produces most of the inducible IL-23, IL-1β, TNF and CCL20. This population has similar gene expression profile to the matched blood CD14+ population.

POLYMORPHISM THE CCR2 GENE IN THE ST. PETERSBURG POPULATION

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Combinations of Polymorphic Markers of Chemokine Genes, Their Receptors and Acute Phase Protein Genes As Potential Predictors of Coronary Heart Diseases

Atherosclerosis, the main factor in the development of coronary heart diseases (CHD), is an inflammatory response to endothelial layer damage in the arterial bed. We have analyzed the association between CHD and the polymorphic markers of genes that control the synthesis of proteins involved in the processes of adhesion and chemotaxis of immunocompetent cells: rs1024611 (-2518AG, CCL2 gene), rs1799864 (V64I, CCR2 gene), rs3732378 (T280M, CX3CR1 gene), rs1136743 (A70V, SAA1 gene), and rs1205 (2042CT, CRP gene) in 217 patients with CHD and 250 controls. Using the Monte Carlo method and Markov chains (APSampler), we revealed a combination of alleles/genotypes associated with both a reduced and increased risk of CHD. The most significant alleles/genotypes areSAA1*T/T+CRP*C+CX3CR1*G/A (Pperm = 0.0056, OR = 0.07 95%CI 0.009-0.55),SAA1*T+CRP*T+CCR2*G/A+CX3CR1*G (Pperm = 0.0063, OR = 14.58 95%CI 1.88-113.04), SAA1*T+CCR2*A+CCL2* G/G (Pperm = 0.0351, OR = 10.77 95%CI 1.35-85.74).

Chemokine Coreceptor-2 Gene Polymorphisms among HIV-1 Infected Individuals in Kenya

Chemokine Coreceptor-2 (CCR2) is an entry coreceptor for HIV-1. A mutation in the coding gene for this coreceptor, CCR2-64I, has been shown to be an important factor for delaying disease progression. In Kenya no studies have been done to determine the status of CCR2 gene polymorphisms among HIV-1 infected individuals. To determine the existence and distribution of CCR2 gene mutations and identify polymorphic groups of the coreceptor gene in the population, a cross-sectional study was conducted to analyze the differences in allelic frequencies of CCR2-64I among HIV-1 seropositive individuals. Blood samples were collected from HIV/AIDS screening centers and analyzed for the presence of CCR2-64I using restriction fragment length polymorphism (RFLP). One hundred and eighteen samples collected from different regions of the country were genotyped for the CCR2-64I mutation. Of these, 4 (3.4%) were homozygous mutants (I/I) and 21 (17.8%) were heterozygous (V/I). Ninety-three subjects (78.8%) were wild type (V/V). With the search for a preventive/therapeutic HIV vaccine elusive, the presence of CCR-2 gene polymorphisms that delay disease progression and prolong the lives of the infected in the Kenyan population may contribute to the growing evidence that host genetic factors are important in predicting susceptibility to HIV-1 infection.