ABSTRACT
OBJECTIVE: To determine the association between endoplasmic reticulum aminopeptidase (ERAP)1 and ERAP2 single-nucleotide polymorphisms (SNPs) and human leukocyte antigens (HLA)-B27+ or HLA-B15+ patients with spondyloarthritis (SpA). METHODS: 104 patients with SpA according to Assessment of Spondyloarthritis International Society criteria were included in the study. HLA typing was performed by PCR. The polymorphisms were determined by real-time PCR on genomic DNA using customised probes for SNPs rs27044, rs17482078, rs10050860 and rs30187 in ERAP1, and rs2910686, rs2248374 and rs2549782 in ERAP2. RESULTS: 70 of the104 patients with SpA were HLA-B27+ and 34 were HLA-B15+. The distribution of ERAP1 and ERAP2 SNPs between the HLA-B15+ and HLA-B27+ patients with SpA did not reveal differences. Likewise, no differences in the frequencies of ERAP1 SNP haplotypes and alleles HLA-B15 or HLA-B27 were found. Interestingly, however, the frequencies of three particular haplotypes formed by ERAP2 SNPs rs2549782/rs2248374/rs2910686 varied between HLA-B15+ and HLA-B27+ patients: the ERAP2 SNPs haplotype TGT was more common in HLA-B15+ patients with SpA (OR 2.943, 95% CI 1.264 to 6.585; P=0.009), whereas the ERAP2 SNP haplotypes TGC and CAT were more associated with HLA-B27+ patients with SpA: (OR 4.483, 95% CI 1.524 to 13.187; p=0.003) and (OR 9.014, 95% CI 1.181 to 68.807; p=0.009), respectively. CONCLUSION: An association was found between HLA-B15+ patients with SpA and haplotype TGT of ERAP2 SNPs. On the other hand, HLA-B27+ patients with SpA were associated with ERAP2 haplotypes TGC and CAT. These associations could be related to the clinical presentation of the disease, specifically with a peripheral or axial predominance, respectively.
Subject(s)
Aminopeptidases/genetics , Genetic Predisposition to Disease , HLA-B15 Antigen/genetics , HLA-B27 Antigen/genetics , Polymorphism, Single Nucleotide , Spondylarthritis/diagnosis , Spondylarthritis/etiology , Adult , Alleles , Autoimmunity , Biomarkers/blood , Biomarkers/metabolism , Colombia , Cytokines/blood , Cytokines/metabolism , Female , Genetic Association Studies , Genotype , HLA-B15 Antigen/immunology , HLA-B27 Antigen/immunology , Histocompatibility Testing , Humans , Inflammation Mediators , Magnetic Resonance Imaging , Male , Middle Aged , Phenotype , Radiography , Spondylarthritis/metabolismABSTRACT
Mesenchymal stem/stromal cells (MSCs) exhibit multidifferentiation potential, paralleled with immunomodulatory and trophic properties that make them viable alternative tools for the treatment of degenerative disorders, allograft rejection, autoimmune diseases, and tissue regeneration. MSC functional attributes can be modulated by exposing them to inflammatory-stimulating microenvironments (i.e., priming) before their therapeutic use. Granulocyte-colony stimulating factor (G-CSF) is a cytokine that plays key roles in immune response and hematopoiesis modulation through direct effects on hematopoietic progenitors' proliferation, survival, and mobilization. Despite the established roles of MSCs supporting hematopoiesis, the effects of G-CSF on MSCs biology have not been thoroughly explored. This study reveals that G-CSF has also direct effects on adipose-derived MSCs (ADSCs), modulating their functions. Herein, microarray-based transcriptomic analysis shows that G-CSF stimulation in vitro results in modulation of various signaling pathways including ones related with the metabolism of hyaluronan (HA), conferring a profile of cell mobilization to ADSCs, mediated in a cell-intrinsic fashion in part by reducing CD44 expression and HA synthesis-related genes. Collectively, these data suggest a direct modulatory effect of G-CSF on ADSC function, potentially altering their therapeutic capacity and thus the design of future clinical protocols.
