Lymphoid Tissue Inducer Cells: Pivotal Cells in the Evolution of CD4 Immunity and Tolerance?

Phylogeny suggests that the evolution of placentation in mammals was accompanied by substantial changes in the mammalian immune system: in particular lymph nodes and CD4 high affinity memory antibody responses co-evolved during the same period. Lymphoid tissue inducer cells (LTi) are members of an emerging family of innate lymphoid cells (ILCs) that are crucial for lymph node development, but our studies have indicated that they also play a pivotal role in the long-term maintenance of memory CD4 T cells in adult mammals through their expression of the tumor necrosis family members, OX40- and CD30-ligands. Additionally, our studies have shown that these two molecules are also key operators in CD4 effector function, as their absence obviates the need for the FoxP3 dependent regulatory T (Tregs) cells that prevent CD4 driven autoimmune responses. In this perspective article, we summarize findings from our group over the last 10 years, and focus specifically on the role of LTi in thymus. We suggest that like memory CD4 T cells, LTi also play a role in the selection and maintenance of the Tregs that under normal circumstances are absolutely required to regulate CD4 effector cells

Restoration of SMN in Schwann cells reverses myelination defects and improves neuromuscular function in spinal muscular atrophy

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by low levels of SMN protein, primarily affecting lower motor neurons. Recent evidence from SMA and related conditions suggests that glial cells can influence disease severity. Here, we investigated the role of glial cells in the peripheral nervous system by creating SMA mice selectively overexpressing SMN in myelinating Schwann cells (Smn(−/−);SMN2(tg/0);SMN1(SC)). Restoration of SMN protein levels restricted solely to Schwann cells reversed myelination defects, significantly improved neuromuscular function and ameliorated neuromuscular junction pathology in SMA mice. However, restoration of SMN in Schwann cells had no impact on motor neuron soma loss from the spinal cord or ongoing systemic and peripheral pathology. This study provides evidence for a defined, intrinsic contribution of glial cells to SMA disease pathogenesis and suggests that therapies designed to include Schwann cells in their target tissues are likely to be required in order to rescue myelination defects and associated disease symptoms

RANK signals from CD4+3− inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla

Aire-expressing medullary thymic epithelial cells (mTECs) play a key role in preventing autoimmunity by expressing tissue-restricted antigens to help purge the emerging T cell receptor repertoire of self-reactive specificities. Here we demonstrate a novel role for a CD4+3− inducer cell population, previously linked to development of organized secondary lymphoid structures and maintenance of T cell memory in the functional regulation of Aire-mediated promiscuous gene expression in the thymus. CD4+3− cells are closely associated with mTECs in adult thymus, and in fetal thymus their appearance is temporally linked with the appearance of Aire+ mTECs. We show that RANKL signals from this cell promote the maturation of RANK-expressing CD80−Aire− mTEC progenitors into CD80+Aire+ mTECs, and that transplantation of RANK-deficient thymic stroma into immunodeficient hosts induces autoimmunity. Collectively, our data reveal cellular and molecular mechanisms leading to the generation of Aire+ mTECs and highlight a previously unrecognized role for CD4+3−RANKL+ inducer cells in intrathymic self-tolerance

Protecting eyewitness evidence: Examining the efficacy of a self-administered interview tool

Given the crucial role of eyewitness evidence, statements should be obtained as soon as possible after an incident. This is not always achieved due to demands on police resources. Two studies trace the development of a new tool, the Self-Administered Interview (SAI), designed to elicit a comprehensive initial statement. In Study 1, SAI participants reported more correct details than participants who provided a free recall account, and performed at the same level as participants given a Cognitive Interview. In Study 2, participants viewed a simulated crime and half recorded their statement using the SAI. After a delay of 1 week, all participants completed a free recall test. SAI participants recalled more correct details in the delayed recall task than control participants

Literacy outcomes for Deaf and Hard of Hearing primary school children: A cohort comparison study

Purpose: This study compared the language and literacy of two cohorts of children with severe-profound hearing loss, recruited 10 years apart, to determine whether outcomes had improved in line with the introduction of newborn hearing screening and access to improved hearing aid technology. Method: Forty-two deaf children, aged 5 -7 years with a mean unaided loss of 102 DB, were assessed on language, reading and phonological skills. Their performance was compared to that of a similar group of 32 deaf children assessed 10 years earlier, and also a group of 40 hearing children of similar single word reading ability. Results: English vocabulary was significantly higher in the new cohort, although it was still below chronological age. Phonological awareness and reading ability had not significantly changed over time. In both cohorts English vocabulary predicted reading but phonological awareness was only a significant predictor for the new cohort. Conclusions: The current results show that vocabulary knowledge of children with severe-profound hearing loss has improved over time but there has not been a commensurate improvement in phonological skills or reading. They suggest that children with severe-profound hearing loss will require continued support to develop robust phonological coding skills to underpin reading

Abrogation of CD30 and OX40 signals prevents autoimmune disease in FoxP3-deficient mice

FoxP3-deficient mice are rescued from tissue and organ destruction and subsequent lethal autoimmune disease by the combined absence of OX40 and CD30 signals

Physiotherapy and occupational therapy vs no therapy in mild to moderate Parkinson disease: a randomized clinical trial

IMPORTANCE It is unclear whether physiotherapy and occupational therapy are clinically effective and cost-effective in Parkinson disease (PD). OBJECTIVE To perform a large pragmatic randomized clinical trial to evaluate the clinical effectiveness of individualized physiotherapy and occupational therapy in PD. DESIGN, SETTING, AND PARTICIPANTS The PD REHAB Trial was a multicenter, open-label, parallel group, controlled efficacy trial. A total of 762 patients with mild to moderate PD were recruited from 38 sites across the United Kingdom. Recruitment took place between October 2009 and June 2012, with 15 months of follow-up. INTERVENTIONS Participants with limitations in activities of daily living (ADL) were randomized to physiotherapy and occupational therapy or no therapy. MAIN OUTCOMES AND MEASURES The primary outcome was the Nottingham Extended Activities of Daily Living (NEADL) Scale score at 3 months after randomization. Secondary outcomes were health-related quality of life (assessed by Parkinson Disease Questionnaire–39 and EuroQol-5D); adverse events; and caregiver quality of life. Outcomes were assessed before trial entry and then 3, 9, and 15 months after randomization. RESULTS Of the 762 patients included in the study (mean [SD] age, 70 [9.1] years), 381 received physiotherapy and occupational therapy and 381 received no therapy. At 3 months, there was no difference between groups in NEADL total score (difference, 0.5 points; 95%CI, −0.7 to 1.7; P = .41) or Parkinson Disease Questionnaire–39 summary index (0.007 points; 95%CI, −1.5 to 1.5; P = .99). The EuroQol-5D quotient was of borderline significance in favor of therapy (−0.03; 95%CI, −0.07 to −0.002; P = .04). The median therapist contact time was 4 visits of 58 minutes over 8 weeks. Repeated-measures analysis showed no difference in NEADL total score, but Parkinson Disease Questionnaire–39 summary index (diverging 1.6 points per annum; 95%CI, 0.47 to 2.62; P = .005) and EuroQol-5D score (0.02; 95%CI, 0.00007 to 0.03; P = .04) showed small differences in favor of therapy. There was no difference in adverse events. CONCLUSIONS AND RELEVANCE Physiotherapy and occupational therapy were not associated with immediate or medium-term clinically meaningful improvements in ADL or quality of life in mild to moderate PD. This evidence does not support the use of low-dose, patient-centered, goal-directed physiotherapy and occupational therapy in patients in the early stages of PD. Future research should explore the development and testing of more structured and intensive physical and occupational therapy programs in patients with all stages of PD

Preventing disease through opportunistic, rapid engagement by primary care teams using behaviour change counselling (PRE-EMPT): protocol for a general practice-based cluster randomised trial

BACKGROUND: Smoking, excessive alcohol consumption, lack of exercise and an unhealthy diet are the key modifiable factors contributing to premature morbidity and mortality in the developed world. Brief interventions in health care consultations can be effective in changing single health behaviours. General Practice holds considerable potential for primary prevention through modifying patients' multiple risk behaviours, but feasible, acceptable and effective interventions are poorly developed, and uptake by practitioners is low. Through a process of theoretical development, modeling and exploratory trials, we have developed an intervention called Behaviour Change Counselling (BCC) derived from Motivational Interviewing (MI). This paper describes the protocol for an evaluation of a training intervention (the Talking Lifestyles Programme) which will enable practitioners to routinely use BCC during consultations for the above four risk behaviours. METHODS/DESIGN: This cluster randomised controlled efficacy trial (RCT) will evaluate the outcomes and costs of this training intervention for General Practitioners (GPs) and nurses. Training methods will include: a practice-based seminar, online self-directed learning, and reflecting on video recorded and simulated consultations. The intervention will be evaluated in 29 practices in Wales, UK; two clinicians will take part (one GP and one nurse) from each practice. In intervention practices both clinicians will receive training. The aim is to recruit 2000 patients into the study with an expected 30% drop out. The primary outcome will be the proportion of patients making changes in one or more of the four behaviours at three months. Results will be compared for patients seeing clinicians trained in BCC with patients seeing non-BCC trained clinicians. Economic and process evaluations will also be conducted. DISCUSSION: Opportunistic engagement by health professionals potentially represents a cost effective medical intervention. This study integrates an existing, innovative intervention method with an innovative training model to enable clinicians to routinely use BCC, providing them with new tools to encourage and support people to make healthier choices. This trial will evaluate effectiveness in primary care and determine costs of the intervention

Outcomes following SARS-CoV-2 infection in patients with primary and secondary immunodeficiency in the UK

In March 2020, the United Kingdom Primary Immunodeficiency Network (UKPIN) established a registry of cases to collate the outcomes of individuals with PID and SID following SARS-CoV-2 infection and treatment. A total of 310 cases of SARS-CoV-2 infection in individuals with PID or SID have now been reported in the UK. The overall mortality within the cohort was 17.7% (n = 55/310). Individuals with CVID demonstrated an infection fatality rate (IFR) of 18.3% (n = 17/93), individuals with PID receiving IgRT had an IFR of 16.3% (n = 26/159) and individuals with SID, an IFR of 27.2% (n = 25/92). Individuals with PID and SID had higher inpatient mortality and died at a younger age than the general population. Increasing age, low pre-SARS-CoV-2 infection lymphocyte count and the presence of common co-morbidities increased the risk of mortality in PID. Access to specific COVID-19 treatments in this cohort was limited: only 22.9% (n = 33/144) of patients admitted to the hospital received dexamethasone, remdesivir, an anti-SARS-CoV-2 antibody-based therapeutic (e.g. REGN-COV2 or convalescent plasma) or tocilizumab as a monotherapy or in combination. Dexamethasone, remdesivir, and anti-SARS-CoV-2 antibody-based therapeutics appeared efficacious in PID and SID. Compared to the general population, individuals with PID or SID are at high risk of mortality following SARS-CoV-2 infection. Increasing age, low baseline lymphocyte count, and the presence of co-morbidities are additional risk factors for poor outcome in this cohort