Myeloid precursors, osteoclastogenesis, and Spondyloarthropathies

Spondyloarthropathies (or Spondyloarthritides; SpAs) are a group of heterogeneous but genetically related inflammatory disorders in which ankylosing spondylitis (AS) is considered the prototypic form. Among the genes associated with AS, HLA-B27 allele has the strongest association although the cause is still not clear. Rats transgenic for the human HLA-B27 gene (B27 rats) develop a systemic inflammation mirroring the human SpA symptoms and thus provide a useful model to study the contribution of this MHC class I molecule in the disease development. Of particular interest was the observation of absence of arthritis in B27 rats grown in germ-free conditions and a recent theory suggests that microbial dysbiosis and gut inflammation might play a key role in initiating the HLA-B27-associated diseases. Studies in our laboratory have previously demonstrated that HLA-B27 expression alters the development of the myeloid compartment within the bone marrow (BM) in B27 rat and causes loss of a specific dendritic cell (DC) population involved in self-tolerance mechanisms within the gut. The aim of this thesis was to further analyse the myeloid compartment in B27 rats with a particular focus on the osteoclast progenitors and the bone phenotype and to link this to the gut inflammation. In addition, translational studies analysed peripheral monocyte/pre-osteoclasts in AS patients and teased apart the role of cytokines in in vitro human osteoclast differentiation. To understand the dynamics of the myeloid/monocyte compartment within the B27-associated inflammation, monocytes within the bloodstream and BM of B27 rats were characterised via flow cytometry and their ability to differentiate into osteoclast was assessed in vitro. Moreover, an antibiotic regime was used to reduce the B27 ileitis and to evaluate whether this could affect the migration, the phenotype, and the osteoclastogenic potential of B27 monocytes. B27 animals display a systemic and central increase of “inflammatory” CD43low MOs, which are the main contributors to osteoclastogenesis in vitro. Antibiotic treatment reduced ileitis and also reverted the B27 monocyte phenotype. This was also associated with the reduction of the previous described TNFα-enhancement of osteoclast differentiation from B27 BM precursors. These evidences support the idea that in genetically susceptible individuals inflammation in the gut might influence the myeloid compartment within the BM; in other terms, pre-emptively educate precursor cells to acquire specific phenotype end functions after being recruited into the tissue. This might explain the enhanced differentiation of osteoclast from B27 BM progenitors and thus the HLA-B27-associated bone loss. The data shown in this thesis suggest a link between the immunity within the gut and BM haematopoiesis. This provides an attractive and novel research prospective that could help not only to increase the understanding of the HLA-B27-associated aetiopathogenesis but also to unravel the cellular crosstalk that allows the mucosal immunity to program central cell differentiation. Human translational studies on monocyte subsets, cytokines and cytokine network in AS osteoclastogenesis evidenced altered osteoclast differentiation in the presence of IL-22 although no differences in the phenotype and functions of circulating CD14+ monocytes were observed. In addition, studies on the role of TNFα and TNFRs showed a dual role of this inflammatory cytokine in the human OC differentiation. In particular, the activation of TNFR1 in monocytes in early osteoclastogenesis inhibits OC differentiation while TNFα-biasing for TNFR2 on osteoclast precursors mediates the osteoclastogenic effect. Whether similar mechanisms are involved in the TNFα-mediated joint destruction in human rheumatic diseases needs further investigations. This could contribute to the development of novel and more specific anti-TNFα agents for the treatment of bone erosion. In conclusion, taken together my studies support the idea of a crosstalk between the periphery and the central system during the inflammatory response and provide new insights to the mechanisms behind the enhancement of osteoclastogenesis in B27-associated disorders.

Investigating assistive technology to support memory for people with cognitive impairments

Technologies such as automobiles or mobile phones allow us to perform beyond our physical capabilities and travel faster or communicate over long distances. Technologies such as computers and calculators can also help us perform beyond our mental capabilities by storing and manipulating information that we would be unable to process or remember. In recent years there has been a growing interest in assistive technology for cognition (ATC) which can help people compensate for cognitive impairments. The aim of this thesis was to investigate ATC for memory to help people with memory difficulties which impacts independent functioning during everyday life. Chapter one argues that using both neuropsychological and human computing interaction theory and approaches is crucial when developing and researching ATC. Chapter two describes a systematic review and meta-analysis of studies which tested technology to aid memory for groups with ABI, stroke or degenerative disease. Good evidence was found supporting the efficacy of prompting devices which remind the user about a future intention at a set time. Chapter three looks at the prevalence of technologies and memory aids in current use by people with ABI and dementia and the factors that predicted this use. Pre-morbid use of technology, current use of non-tech aids and strategies and age (ABI group only) were the best predictors of this use. Based on the results, chapter four focuses on mobile phone based reminders for people with ABI. Focus groups were held with people with memory impairments after ABI and ABI caregivers (N=12) which discussed the barriers to uptake of mobile phone based reminding. Thematic analysis revealed six key themes that impact uptake of reminder apps; Perceived Need, Social Acceptability, Experience/Expectation, Desired Content and Functions, Cognitive Accessibility and Sensory/Motor Accessibility. The Perceived need theme described the difficulties with insight, motivation and memory which can prevent people from initially setting reminders on a smartphone. Chapter five investigates the efficacy and acceptability of unsolicited prompts (UPs) from a smartphone app (ForgetMeNot) to encourage people with ABI to set reminders. A single-case experimental design study evaluated use of the app over four weeks by three people with severe ABI living in a post-acute rehabilitation hospital. When six UPs were presented through the day from ForgetMeNot, daily reminder-setting and daily memory task completion increased compared to when using the app without the UPs. Chapter six investigates another barrier from chapter 4 – cognitive and sensory accessibility. A study is reported which shows that an app with ‘decision tree’ interface design (ApplTree) leads to more accurate reminder setting performance with no compromise of speed or independence (amount of guidance required) for people with ABI (n=14) compared to a calendar based interface. Chapter seven investigates the efficacy of a wearable reminding device (smartwatch) as a tool for delivering reminders set on a smartphone. Four community dwelling participants with memory difficulties following ABI were included in an ABA single case experimental design study. Three of the participants successfully used the smartwatch throughout the intervention weeks and these participants gave positive usability ratings. Two participants showed improved memory performance when using the smartwatch and all participants had marked decline in memory performance when the technology was removed. Chapter eight is a discussion which highlights the implications of these results for clinicians, researchers and designers.