The coexistence of immune-mediated inflammatory diseases with depression has long been recognised. Data that illustrate the intimate associations between peripheral and brain immune responses raise ...the possibility of shared pathophysiological mechanisms. These associations include the negative effects of proinflammatory cytokines on monoaminergic neurotransmission, neurotrophic factors, and measures of synaptic plasticity. The evidence supporting this association is accumulating and includes findings from clinical trials of immunomodulatory therapy, indicating that these interventions can provide benefits to mental health independent of improvements in physical disease scores. In this Review, we assess this evidence in relation to rheumatoid arthritis and depression, with a focus on innate immune and molecular responses to inflammation, and discuss the challenges of assessing causation in this population, acknowledging the difficulty of assessing the confounding and contributory effects of pain and fatigue. We also discuss how future clinical and preclinical research might improve diagnosis of depression in people with rheumatoid arthritis and shed light on mechanisms that could be substrates for therapeutic interventions.
Topical application of Aldara cream, containing the Toll-like receptor 7/8 agonist Imiquimod, is a widely used mouse model for investigating the pathogenesis of psoriasis. We have previously used ...this model to study the effects of peripheral inflammation on the brain, and reported a brain-specific response characterised by increased transcription, infiltration of immune cells and anhedonic-like behavior. Here, we perform a more robust characterisation of the systemic response to Aldara application and find a potent but transient response in the periphery, followed by a prolonged response in the brain. Mass spectrometry analysis of plasma and brain samples identified significant levels of Imiquimod in both compartments at molar concentrations likely to evoke a biological response. Indeed, the association of Imiquimod with the brain correlated with increased Iba1 and GFAP staining, indicative of microglia and astrocyte reactivity. These results highlight the potency of this model and raise the question of how useful it is for interpreting the systemic response in psoriasis-like skin inflammation. In addition, the potential impact on the brain should be considered with regards to human use and may explain why fatigue, headaches and nervousness have been reported as side effects following prolonged Aldara use.
Emotional concerns (defined as any expression of low mood, anxiety, or psychosocial stress) are an important part of the biopsychosocial care model used in modern medical practice. Previous work has ...demonstrated variable engagement with emotional concerns and that improved communication has been associated with reductions in emotional distress.
To examine how emotional concerns are engaged with during routine GP consultations.
Secondary study using the Harnessing Resources from the Internet (HaRI) database. The available dataset contains 231 recordings from 10 GPs across eight urban and suburban practices recorded in 2017 and 2018.
The dataset was reviewed to identify any consultations containing emotional concerns (as defined as any expression of low mood, anxiety, or psychosocial stress) before being imported into NVivo (version 12) to facilitate thematic analysis and coding. Reflexive inductive thematic analysis resulted in two major themes.
The two main themes were as follows: engagement with emotional concerns as dynamic throughout consultations; and GPs engage with emotional concerns both diagnostically and therapeutically. In theme 1, this dynamism relates to competing areas of focus, immediate versus delayed engagement and reiteration of concerns throughout consultations. Emotional concerns can be engaged with in a similar way to physical concerns (theme 2) using a diagnostic and treatment-based approach; however, in addition to this, therapeutic listening and conversation is utilised.
Awareness of the dynamic nature of emotional concerns within consultations and encouraging engagement with concerns in a flexible and patient-oriented manner may help improve doctor-patient communication. In addition, investigating how GPs and patients build shared understanding around emotional concerns may identify methods to reduce patients' emotional distress.
Limbal stem cell deficiency (LSCD) is a disease resulting from the loss or dysfunction of epithelial stem cells, which seriously impairs sight. Autologous limbal stem cell transplantation is ...effective in unilateral or partial bilateral disease but not applicable in total bilateral disease. An allogeneic source of transplantable cells for use in total bilateral disease can be obtained from culture of donated cadaveric corneal tissue. We performed a controlled multicenter study to examine the feasibility, safety, and efficacy of allogeneic corneal epithelial stem cells in the treatment of bilateral LSCD. Patients were randomized to receive corneal epithelial stem cells cultured on amniotic membrane (AM): investigational medicinal product (IMP) or control AM only. Patients received systemic immunosuppression. Primary endpoints were safety and visual acuity, secondary endpoint was change in composite ocular surface score (OSS). Sixteen patients were treated and 13 patients completed all assessments. Safety was demonstrated and 9/13 patients had improved visual acuity scores at the end of the trial, with no significant differences between IMP and control groups. Patients in the IMP arm demonstrated significant, sustained improvement in OSS, whereas those in the control arm did not. Serum cytokine levels were measured during and after the period of immune suppression and we identified strongly elevated levels of CXCL8 in the serum of patients with aniridia, which persisted throughout the trial. This first randomized control trial of allogeneic corneal epithelial stem cells in severe bilateral LSCD demonstrates the feasibility and safety of this approach. Stem Cells Translational Medicine 2019;8:323–331
Patients with severe ocular surface disorder received transplants of amniotic membrane with (black bars) or without (gray bars) cadaveric‐donor‐derived cultured limbal stem cells. All patients received immune suppression. Only patients who received transplants containing limbal stem cells showed sustained significant improvements (reductions) in combined ocular surface scores (5 factors scored 0–3 where 0 is a normal eye score).
The relationship between the brain and the immune system has become increasingly topical as, although it is immune-specialised, the CNS is not free from the influences of the immune system. Recent ...data indicate that peripheral immune stimulation can significantly affect the CNS. But the mechanisms underpinning this relationship remain unclear. The standard approach to understanding this relationship has relied on systemic immune activation using bacterial components, finding that immune mediators, such as cytokines, can have a significant effect on brain function and behaviour. More rarely have studies used disease models that are representative of human disorders.
Here we use a well-characterised animal model of psoriasis-like skin inflammation-imiquimod-to investigate the effects of tissue-specific peripheral inflammation on the brain. We used full genome array, flow cytometry analysis of immune cell infiltration, doublecortin staining for neural precursor cells and a behavioural read-out exploiting natural burrowing behaviour.
We found that a number of genes are upregulated in the brain following treatment, amongst which is a subset of inflammatory chemokines (CCL3, CCL5, CCL9, CXCL10, CXCL13, CXCL16 and CCR5). Strikingly, this model induced the infiltration of a number of immune cell subsets into the brain parenchyma, including T cells, NK cells and myeloid cells, along with a reduction in neurogenesis and a suppression of burrowing activity.
These findings demonstrate that cutaneous, peripheral immune stimulation is associated with significant leukocyte infiltration into the brain and suggest that chemokines may be amongst the key mediators driving this response.
Neuroimmune Biomarkers in Mental Illness Herron, James W; Nerurkar, Louis; Cavanagh, Jonathan
Current topics in behavioral neurosciences,
01/2018, Letnik:
40
Journal Article
Recenzirano
Exploration of neuroimmune mechanisms is vital to the understanding of the pathogenesis and pathophysiology of mental disorders. Inflammatory and immune mechanisms are increasingly understood to ...underpin a number of neuropsychiatric disorders, with an ever-expanding evidence base drawn from basic science to large-scale epidemiological data. Unravelling of these mechanisms should lead to biomarker discovery and potential new avenues for therapeutics that modulate immunological mechanisms. Identification of neuroimmune biomarkers is vital to improving diagnosis, stratification and treatment of mental disorders. There is an urgent clinical need for new therapeutic approaches with poor treatment response and treatment resistance a major problem for many psychiatric disorders including depression and schizophrenia. Neurodegenerative psychiatric disorders such as Alzheimer's also have clear neuroimmune underpinnings and manifest an urgent clinical need for improvements in diagnosis and research towards transformative disease-modifying treatments. This chapter provides some background on the role of the neuroimmune system in mental illness, exploring the role for biomarkers, in addition to reviewing the current state of knowledge in this exciting field. We also reflect on the inherent challenges and methodological pitfalls faced by research in this field, including the complexity of conceptualising multidimensional mental disorders and the dynamic shifting sands of the immune system.
Depression is a major disease burden worldwide and, despite its prevalence and socioeconomic costs, around 30% of patients do not respond to currently available treatments. Inflammation is ...increasingly associated with, not only depressive illness but also resistance to existing therapies. This highlights the need for investigation of the mechanisms of neuro-inflammation, particularly in the context of peripheral inflammatory stimuli. Specifically, the chemokine molecular family is increasingly associated with human depressive illness, and neuro-inflammation and behavioural change in rodent models, making this an attractive molecular family for study. This thesis describes research aimed at investigating the association of these molecules with human depression and analysis of their role in an animal model of peripherally stimulated neuro-inflammation, the Aldara model of psoriasis-like inflammation. Systematic review and meta-analysis of the human biomarker literature using a random effects, inverse variance model revealed that a number of chemokines (CCL2, CCL3, CCL4, CCL11, CXCL4, CXCL7, CXCL8) are significantly associated with depressive illness in a human population. However this work revealed that there are a number of limitations of the human literature primarily associated with the methodological challenges of studies in human populations and confounding factors. Alongside this work, the Aldara model, which utilises the toll-like receptor 7 (TLR7) ligand imiquimod (IMQ), was investigated as a tool for studying neuroinflammation. Initial time-course investigation revealed that significant chemokine and cytokine transcriptional alterations occur within four hours at the local site of cutaneous treatment, the peripheral tissues and the brain. In addition, protein quantification in the brain confirmed that many of these transcriptional responses are translated to protein. Interestingly, it was shown that the brain response was temporally distinct from that of the peripheral tissues, and that in general brain responses were induced slightly more slowly and persisted for a longer period of time than those in the periphery. Investigation of Iba1+ (microglia/monocytes), GFAP+ (astrocytes) and CD3+ (T-cells) cells within the brain revealed significant changes in the microglial and T-cell populations, which were consistent with microgliosis and T-cell recruitment to the brain parenchyma. Changes in astrocyte populations were more equivocal although there was evidence of astrogliosis. Mechanistic investigations into responses to the Aldara model in inflammatory chemokine receptor (iCCR) KO mice did not reveal significant alterations in chemokine and cytokine transcription or in microglial responses to cutaneous Aldara treatment in the absence of the iCCRs (CCR1, CCR2, CCR3 and CCR5), but there did appear to be evidence of reduced CD3+ T-cell recruitment. In contrast, investigations in type I interferon receptor (IFNAR) KO mice identified a clear role for type I IFN signalling through IFNAR in the induction of chemokine and cytokine gene expression in the brain, and associated changes in Iba1+ microglial and CD3+ T-cell populations in response to cutaneous Aldara treatment. Mass spectrometric analysis of IMQ, the main active ingredient of Aldara, revealed that within four hours it enters both the circulation and the brain. The finding of IMQ within the brain parenchyma suggests that, while it is not an appropriate tool for studying peripheral-central immune crosstalk, it is a useful non-invasive model of TLR7 mediated neuroinflammation. These data provide compelling evidence of a role for chemokines in human depression and in neuro-inflammation, although the precise actions of this family of molecules remain unclear. In addition, building on previous work, the Aldara model appears to be a suitable tool for the study of neuro-inflammation, particularly interferon-driven immune responses, but is less appropriate for studying peripherally driven CNS immune reactions. Further work into the specific role of chemokines and associated cellular populations will hopefully provide additional insight into how CNS immune reactions are co-ordinated.
Depression is a major disease burden worldwide and, despite its prevalence and socioeconomic costs, around 30% of patients do not respond to currently available treatments. Inflammation is ...increasingly associated with, not only depressive illness but also resistance to existing therapies. This highlights the need for investigation of the mechanisms of neuro-inflammation, particularly in the context of peripheral inflammatory stimuli. Specifically, the chemokine molecular family is increasingly associated with human depressive illness, and neuro-inflammation and behavioural change in rodent models, making this an attractive molecular family for study. This thesis describes research aimed at investigating the association of these molecules with human depression and analysis of their role in an animal model of peripherally stimulated neuro-inflammation, the Aldara model of psoriasis-like inflammation. Systematic review and meta-analysis of the human biomarker literature using a random effects, inverse variance model revealed that a number of chemokines (CCL2, CCL3, CCL4, CCL11, CXCL4, CXCL7, CXCL8) are significantly associated with depressive illness in a human population. However this work revealed that there are a number of limitations of the human literature primarily associated with the methodological challenges of studies in human populations and confounding factors. Alongside this work, the Aldara model, which utilises the toll-like receptor 7 (TLR7) ligand imiquimod (IMQ), was investigated as a tool for studying neuroinflammation. Initial time-course investigation revealed that significant chemokine and cytokine transcriptional alterations occur within four hours at the local site of cutaneous treatment, the peripheral tissues and the brain. In addition, protein quantification in the brain confirmed that many of these transcriptional responses are translated to protein. Interestingly, it was shown that the brain response was temporally distinct from that of the peripheral tissues, and that in general brain responses were induced slightly more slowly and persisted for a longer period of time than those in the periphery. Investigation of Iba1+ (microglia/monocytes), GFAP+ (astrocytes) and CD3+ (T-cells) cells within the brain revealed significant changes in the microglial and T-cell populations, which were consistent with microgliosis and T-cell recruitment to the brain parenchyma. Changes in astrocyte populations were more equivocal although there was evidence of astrogliosis. Mechanistic investigations into responses to the Aldara model in inflammatory chemokine receptor (iCCR) KO mice did not reveal significant alterations in chemokine and cytokine transcription or in microglial responses to cutaneous Aldara treatment in the absence of the iCCRs (CCR1, CCR2, CCR3 and CCR5), but there did appear to be evidence of reduced CD3+ T-cell recruitment. In contrast, investigations in type I interferon receptor (IFNAR) KO mice identified a clear role for type I IFN signalling through IFNAR in the induction of chemokine and cytokine gene expression in the brain, and associated changes in Iba1+ microglial and CD3+ T-cell populations in response to cutaneous Aldara treatment. Mass spectrometric analysis of IMQ, the main active ingredient of Aldara, revealed that within four hours it enters both the circulation and the brain. The finding of IMQ within the brain parenchyma suggests that, while it is not an appropriate tool for studying peripheral-central immune crosstalk, it is a useful non-invasive model of TLR7 mediated neuroinflammation. These data provide compelling evidence of a role for chemokines in human depression and in neuro-inflammation, although the precise actions of this family of molecules remain unclear. In addition, building on previous work, the Aldara model appears to be a suitable tool for the study of neuro-inflammation, particularly interferon-driven immune responses, but is less appropriate for studying peripherally driven CNS immune reactions. Further work into the specific role of chemokines and associated cellular populations will hopefully provide additional insight into how CNS immune reactions are co-ordinated.
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