ABSTRACT
The pathophysiology of chronic nonbacterial osteomyelitis (CNO) remains incompletely understood. Increased NLRP3 inflammasome activation and IL-1ß release in monocytes from CNO patients was suggested to contribute to bone inflammation. Here, we dissect immune cell infiltrates and demonstrate the involvement of monocytes across disease stages. Differences in cell density and immune cell composition may help to discriminate between BOM and CNO. However, differences are subtle and infiltrates vary in CNO. In contrast to other cells involved, monocytes are a stable element during all stages of CNO, which makes them a promising candidate in the search for "drivers" of inflammation. Furthermore, we link increased expression of inflammasome components NLRP3 and ASC in monocytes with site-specific DNA hypomethylation around the corresponding genes NLRP3 and PYCARD. Our observations deliver further evidence for the involvement of pro-inflammatory monocytes in the pathophysiology of CNO. Cellular and molecular alterations may serve as disease biomarkers and/or therapeutic targets.
Subject(s)
Bone and Bones/immunology , CARD Signaling Adaptor Proteins/genetics , Inflammasomes/genetics , Interleukin-1beta/genetics , Monocytes/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Osteomyelitis/immunology , Bacterial Infections/genetics , Bacterial Infections/immunology , Bacterial Infections/metabolism , Bacterial Infections/pathology , Blotting, Western , Bone and Bones/metabolism , Bone and Bones/pathology , CARD Signaling Adaptor Proteins/immunology , CARD Signaling Adaptor Proteins/metabolism , Case-Control Studies , Chronic Disease , DNA Methylation , Gene Expression Regulation , Humans , Inflammasomes/immunology , Inflammasomes/metabolism , Inflammation , Interleukin-1beta/immunology , Interleukin-1beta/metabolism , Lipopolysaccharide Receptors/metabolism , Monocytes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Osteomyelitis/genetics , Osteomyelitis/metabolism , Osteomyelitis/pathology , Real-Time Polymerase Chain ReactionABSTRACT
Celiac disease (CD) is an autoimmune/inflammatory condition triggered by dietary gluten intake in genetically predisposed individuals. Though associations with MHC class II HLA-DQ2 or -DQ8 are the primary and necessary genetic predisposition for CD, >97% of genetically predisposed individuals never develop CD. Cytokines were measured in the serum of CD patients and controls. Possible associations with IL10 promoter variants were investigated. Cytokine expression from PBMCs was monitored in response to gluten exposure, or CD3/TCR complex stimulation in the absence or presence of recombinant IL-10. Serum cytokines varied between patients with CD at the time of diagnosis, after dietary elimination of gluten, and healthy controls. Serum IL-17A reflected disease activity. Reduced IL-10 serum levels and altered IL-10 expression by PBMCs coincided with IL10 promoter haplotypes that encode for "low" IL-10 expression (ATA). Increased prevalence of ATA IL10 promoter haplotypes and subsequently reduced IL-10 expression may be an immunological cofactor in individuals genetically predisposed for the development of CD. Resulting cytokine imbalances may be utilized as disease biomarkers in CD.
Subject(s)
Celiac Disease/immunology , Cytokines/immunology , Haplotypes/immunology , Inflammation/immunology , Interleukin-10/immunology , Promoter Regions, Genetic/immunology , Adolescent , Celiac Disease/blood , Celiac Disease/genetics , Child , Child, Preschool , Cytokines/blood , Cytokines/genetics , Genetic Predisposition to Disease/genetics , Genotype , Glutens/immunology , Haplotypes/genetics , Humans , Inflammation/blood , Inflammation/genetics , Interleukin-10/blood , Interleukin-10/genetics , Interleukin-17/blood , Interleukin-17/genetics , Interleukin-17/immunology , Polymorphism, Single Nucleotide , Promoter Regions, Genetic/geneticsABSTRACT
The autoimmune/inflammatory disorder psoriasis is characterized by keratinocyte proliferation and immune cell infiltration of the skin. TCR+CD3+CD4-CD8- "double negative" (DN) T cells can derive from CD8+ T cells through the down-regulation of CD8. The inhibitory molecule programmed death (PD-)1 is expressed on activated T cells and plays a role in the maintenance of peripheral tolerance. A subset of DN T cells, characterized by the expression of PD-1, has recently been demonstrated to be self-reactive. We demonstrate that a majority of DN T cells exhibits effector memory phenotypes, express IFN-γ, and fail to proliferate. DN T cells from psoriasis patients are characterized by reduced DNA methylation of the IFNG gene and increased PD-1 expression. Furthermore, PD-1 positive DN T cells infiltrate the epidermis in psoriatic skin lesions. Our observations offer additional insight into the molecular pathophysiology of plaque psoriasis and show promise as potential disease biomarkers and/or therapeutic targets for future interventions.