Autoimmune or Autoinflammatory? Bad to the Bone
Autoimmune or Autoinflammatory? Bad to the Bone
Despite the variation in the clinical features within rheumatic diseases bone erosion is a prominent common feature in RA, JIA, PsA and AS, and this is specifically important as bone resorption is only carried out by specialized bone resorbing cell the osteoclast. Osteoclasts are derived from hematopoietic precursors through the regulation of receptor activator for nuclear factor κ B ligand (RANKL) and macrophage colony stimulating factor (MCSF). RANKL is a trans-membrane protein expressed by activated osteoblasts, and activated T cells and synoviocytes and its actions are inhibited by its soluble receptor osteoprotegerin (OPG), which is also produced by a variety of cells. It is generally appreciated that during inflammation the RANKL/RANK/OPG axis that tightly regulates osteoclast formation and bone resorption is shifted towards bone resorption. However, the presence of excess RANKL has not been observed in animal models with prominent bone loss phenotype that emulate inflammatory arthritis, suggesting that other events may be equally important in bone destruction but more importantly provide new links between the innate immune system and the pathogenesis of inflammatory arthritides.
Although the presence of autoantibodies is not required for sJIA it is evident that aberrant cytokine expression and activation of the innate immune system suffices to induce pathology. In agreement with the observations made in sJIA, where aberrant cytokine expression and innate immunity has a protagonist role, overexpression of pro-inflammatory cytokines such as TNF, IL-1, IL-6 and IL-17 in TNFtg IL-1tg and various gene transfer models recapitulate the arthritic phenotype in vivo. The role of cytokines in the pathogenesis of autoimmune arthritis is linked with generalized inflammation as it can affect diverse cellular subtypes including T and B cells, neutrophils and dendritic cells. However, recent evidence suggests that in vivo gene transfer of IL-17 and/or IL-23 is sufficient to induce the activation and differentiation of osteoclasts from their myeloid precursors and therefore implicates pro-inflammatory cytokines in more elaborate roles in inflammatory arthritis. The activation of myeloid cells in rheumatic diseases has been challenging to study due to the enormous heterogeneity of macrophages and their ability to respond to a variety of complex stimulus.
Macrophages get activated during infection and tissue injury to perform their routine innate immune functions through Toll-like receptors (TLRs), NOD-like receptors, RIG-I like receptors, C-type lectin receptors, leukotriene receptors and immunoreceptor tyrosine-based activation motif associated receptors. In inflammatory arthritis, cross-talk among these pathways result in osteoclast differentiation with catastrophic consequences for bone and joint function. New and old evidence also point to the fact that these alternative pathways may also utilize a different subset of osteoclast precursors. Taken together, the specific erosive phenotype of the various inflammatory arthritides may simply be a reflection of the differences in the availability of osteoclast precursors within the inflammatory infiltrate and the nature of the activation signal.
In keeping with these observations, in other inflammatory arthritides such as RA the association of several autoantibodies such as anti-tissue transglutaminases and anti-thyroid peroxidase (anti-TPO) autoantibodies has been challenged. As less and less autoantibodies seem to contribute to pathogenicity in arthritis the role of the innate immune system becomes more prevalent. Recent analysis revealed that monoclonal IgG antibodies generated from joint derived B cells of RA patients exhibited a strong bias toward citrullinated autoantigen recognition. Antibodies targeting citrullinated proteins (anticitrullinated protein antibodies) have recently been linked with cells of the mononuclear phagocyte system and their activation and differentiation to osteoclasts. It is therefore possible that B cells and autoantibodies present in the inflammatory infiltrate of rheumatic diseases provide RANKL-costimulatory or RANKL-independent signals to facilitate and/or induce osteoclast differentiation.
Osteoclasts at the Intersection of Innate & Adaptive Immunity
Despite the variation in the clinical features within rheumatic diseases bone erosion is a prominent common feature in RA, JIA, PsA and AS, and this is specifically important as bone resorption is only carried out by specialized bone resorbing cell the osteoclast. Osteoclasts are derived from hematopoietic precursors through the regulation of receptor activator for nuclear factor κ B ligand (RANKL) and macrophage colony stimulating factor (MCSF). RANKL is a trans-membrane protein expressed by activated osteoblasts, and activated T cells and synoviocytes and its actions are inhibited by its soluble receptor osteoprotegerin (OPG), which is also produced by a variety of cells. It is generally appreciated that during inflammation the RANKL/RANK/OPG axis that tightly regulates osteoclast formation and bone resorption is shifted towards bone resorption. However, the presence of excess RANKL has not been observed in animal models with prominent bone loss phenotype that emulate inflammatory arthritis, suggesting that other events may be equally important in bone destruction but more importantly provide new links between the innate immune system and the pathogenesis of inflammatory arthritides.
Although the presence of autoantibodies is not required for sJIA it is evident that aberrant cytokine expression and activation of the innate immune system suffices to induce pathology. In agreement with the observations made in sJIA, where aberrant cytokine expression and innate immunity has a protagonist role, overexpression of pro-inflammatory cytokines such as TNF, IL-1, IL-6 and IL-17 in TNFtg IL-1tg and various gene transfer models recapitulate the arthritic phenotype in vivo. The role of cytokines in the pathogenesis of autoimmune arthritis is linked with generalized inflammation as it can affect diverse cellular subtypes including T and B cells, neutrophils and dendritic cells. However, recent evidence suggests that in vivo gene transfer of IL-17 and/or IL-23 is sufficient to induce the activation and differentiation of osteoclasts from their myeloid precursors and therefore implicates pro-inflammatory cytokines in more elaborate roles in inflammatory arthritis. The activation of myeloid cells in rheumatic diseases has been challenging to study due to the enormous heterogeneity of macrophages and their ability to respond to a variety of complex stimulus.
Macrophages get activated during infection and tissue injury to perform their routine innate immune functions through Toll-like receptors (TLRs), NOD-like receptors, RIG-I like receptors, C-type lectin receptors, leukotriene receptors and immunoreceptor tyrosine-based activation motif associated receptors. In inflammatory arthritis, cross-talk among these pathways result in osteoclast differentiation with catastrophic consequences for bone and joint function. New and old evidence also point to the fact that these alternative pathways may also utilize a different subset of osteoclast precursors. Taken together, the specific erosive phenotype of the various inflammatory arthritides may simply be a reflection of the differences in the availability of osteoclast precursors within the inflammatory infiltrate and the nature of the activation signal.
In keeping with these observations, in other inflammatory arthritides such as RA the association of several autoantibodies such as anti-tissue transglutaminases and anti-thyroid peroxidase (anti-TPO) autoantibodies has been challenged. As less and less autoantibodies seem to contribute to pathogenicity in arthritis the role of the innate immune system becomes more prevalent. Recent analysis revealed that monoclonal IgG antibodies generated from joint derived B cells of RA patients exhibited a strong bias toward citrullinated autoantigen recognition. Antibodies targeting citrullinated proteins (anticitrullinated protein antibodies) have recently been linked with cells of the mononuclear phagocyte system and their activation and differentiation to osteoclasts. It is therefore possible that B cells and autoantibodies present in the inflammatory infiltrate of rheumatic diseases provide RANKL-costimulatory or RANKL-independent signals to facilitate and/or induce osteoclast differentiation.
Source...