Memory CD4+ T Cells in Immunity and Autoimmune Diseases

CD4+ T helper (Th) cells play central roles in immunity in health and disease. While much is known about the effector function of Th cells in combating pathogens and promoting autoimmune diseases, the roles and biology of memory CD4+ Th cells are complex and less well understood. In human autoimmune diseases such as multiple sclerosis (MS), there is a critical need to better understand the function and biology of memory T cells. In this review article we summarize current concepts in the field of CD4+ T cell memory, including natural history, developmental pathways, subsets, and functions. Furthermore, we discuss advancements in the field of the newly-described CD4+ tissue-resident memory T cells and of CD4+ memory T cells in autoimmune diseases, two major areas of important unresolved questions in need of answering to advance new vaccine design and development of novel treatments for CD4+ T cell-mediated autoimmune diseases

Risk of Subsequent Coronary Heart Disease in Patients Hospitalized for Immune-Mediated Diseases: A Nationwide Follow-Up Study from Sweden

Background: Certain immune-mediated diseases (IMDs), such as rheumatoid arthritis and systemic lupus erythematosus, have been linked to cardiovascular disorders. We examined whether there is an association between 32 different IMDs and risk of subsequent hospitalization for coronary heart disease (CHD) related to coronary atherosclerosis in a nationwide follow up study in Sweden. Methods and Findings: All individuals in Sweden hospitalized with a main diagnosis of an IMD (n = 336,479) without previous or coexisting CHD, between January 1, 1964 and December 31 2008, were followed for first hospitalization for CHD. The reference population was the total population of Sweden. Standardized incidence ratios (SIRs) for CHD were calculated. Overall risk of CHD during the first year after hospitalization for an IMD was 2.92 (95 % CI 2.84–2.99). Twentyseven of the 32 IMDs studied were associated with an increased risk of CHD during the first year after hospitalization. The overall risk of CHD decreased over time, from 1.75 after 1–5 years (95 % CI 1.73–1.78), to 1.43 after 5–10 years (95 % CI 1.41– 1.46) and 1.28 after 10+ years (95 % CI 1.26–1.30). Females generally had higher SIRs than males. The IMDs for which the SIRs of CDH were highest during the first year after hospitalization included chorea minor 6.98 (95 % CI 1.32–20.65), systemic lupus erythematosus 4.94 (95 % CI 4.15–5.83), rheumatic fever 4.65 (95 % CI 3.53–6.01), Hashimoto’s thyroiditis 4.30 (95 % CI 3.87–4.75), polymyositis/dermatomyositis 3.81 (95 % CI 2.62–5.35), polyarteritis nodosa 3.81 (95 % CI 2.72–5.19), rheumatoi

A role for calreticulin in the pathogenesis of rheumatoid arthritis

Calreticulin (CRT) plays a role in the clearance of dying cells and has been implicated in autoimmunity. Recent evidence indicates that cell surface CRT (csCRT) acts as a signal transducing receptor for the rheumatoid arthritis (RA) shared epitope (SE). The SE binding site on CRT has been mapped to amino acid residues 217–223 in the P-domain. Upon interaction with dendritic cells (DCs), the SE activates potent immune regulatory events. In CD8α + DCs, which express higher abundance of csCRT, the SE inhibits the tolerogenic enzyme indoleamine 2,3 dioxygenase with resultant inhibition of regulatory T (Treg) cell differentiation. In CD8α − DCs, the SE ligand increases secretion of IL-6 and IL-23 and facilitates generation of Th17 cells, a T cell subset known to play a role in autoimmunity. On the basis of these recent findings, we discuss the possibility that the csCRT may play a pathogenic role in RA by transducing SE-activated Th17-polarizing signals.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79357/1/j.1749-6632.2010.05745.x.pd

The effect of infectious dose on humoral and cellular immune responses in Chlamydophila caviae primary ocular infection

Following infection, the balance between protective immunity and immunopathology often depends on the initial infectious load. Several studies have investigated the effect of infectious dose; however, the mechanism by which infectious dose affects disease outcomes and the development of a protective immune response is not known. The aim of this study was to investigate how the infectious dose modulates the local and systemic humoral and the cellular immune responses during primary ocular chlamydial infection in the guinea pig animal model. Guinea pigs were infected by ocular instillation of a Chlamydophila caviae-containing eye solution in the conjunctival sac in three different doses: 1x10(2), 1x10(4), and 1x10(6) inclusion forming units (IFUs). Ocular pathology, chlamydial clearance, local and systemic C. caviae-specific humoral and cellular immune responses were assessed. All inocula of C. caviae significantly enhanced the local production of C. caviae-specific IgA in tears, but only guinea pigs infected with the higher doses showed significant changes in C. caviae-specific IgA levels in vaginal washes and serum. On complete resolution of infection, the low dose of C. caviae did not alter the ratio of CD4(+) and CD8(+) cells within guinea pigs' submandibular lymph node (SMLN) lymphocytes while the higher doses increased the percentages of CD4(+) and CD8(+) cells within the SMLN lymphocytes. A significant negative correlation between pathology intensity and the percentage of CD4(+) and CD8(+) cells within SMLN lymphocyte pool at selected time points post-infection was recorded for both 1x10(4), and 1x10(6) IFU infected guinea pigs. The relevance of the observed dose-dependent differences on the immune response should be further investigated in repeated ocular chlamydial infections

Subsidised housing and its influence on urban renewal - the example of the Lehen district in Salzburg

Abweichender Titel nach Übersetzung der Verfasserin/des VerfassersDie vorliegende Dissertation untersucht die urbanistischen Planungseingriffe durch den geförderten Wohnbau in dem zunehmend verfallenden Salzburger Stadtteil Lehen. Die stadtplanerischen Interventionen und Steuerungsmethoden in diesem Stadtteil legen komplexe Ursachen und Zusammenhänge, die gesetzlich, politisch wie auch ökonomisch beeinflusst werden, offen. Die Planungseingriffe in diesem Stadtteil erfolgten primär durch den geförderten Wohnbau, weshalb ein wesentliches Ziel der Stadtteiluntersuchung ist, die Positionen der einzelnen Stakeholder des geförderten Wohnbaus herauszuarbeiten, deren Beweggründe zu analysieren und sie transparent in Verbindung zu den realisierten Projekten zu setzen. Es soll der primären Forschungsfrage, ob Stadtteilerneuerungsimpulse durch Nachverdichtung eines Stadtraums insbesondere über den geförderten Wohnbau gesetzt werden können und welche stadtplanerischen Kriterien für die Umsetzung relevant sind, nachgegangen werden. Ebenso werden erforderliche Themenfelder und Prozesse für eine spezifische Stadtteilerneuerung und die Anwendung dieser Kriterien auf das tatsächlich geplante und gebaute Umfeld dargestellt. Die qualitative Forschungsmethodik in der Stadtteiluntersuchung setzt sich zusammen aus einer Stadt- und Stadtteilanalyse, einer wissenschaftlichen Inhaltsanalyse der gebauten Stadtteilinterventionen aus den vergangenen 20 Jahren, einer qualitativen Inhaltsanalyse anhand eines Fragebogens, der von unterschiedlichen Stakeholdern ausgefüllt wurde, sowie Experteninterviews. Die Forschungsarbeit gliedert sich in sechs Teilabschnitte, wobei sich der erste Abschnitt mit der Theorie der europäischen Stadtentwicklung, den suburbanen Stadtagglomerationen, der Stadterneuerung, der inneren Peripherie der Stadt sowie den theoretisch-wissenschaftlichen Teildisziplinen der Raumtheorie, der sozialen Raumforschung, der Stadtsoziologie, der Umweltpsychologie und der auseinandersetzt. Der zweite Abschnitt thematisiert die komplexen lokalen und internationalen Zusammenhänge und Rahmenbedingungen des geförderten Wohnbaus, die Probleme und Aufgabenstellungen dieser Wohnformen, Konzepte für Nachverdichtung sowie Aspekte der Stadtteilerneuerung durch den geförderten Wohnbau. Der dritte Abschnitt behandelt die Stadtentwicklung Salzburgs und die Stadtteilanalyse des Stadtteils Lehen und zeigt die kontextuellen Zusammenhänge, Grundlagen und Ursachen für eine mögliche Stadtteilerneuerung in Lehen auf. Der vierte Abschnitt legt die qualitativen Ergebnisse der Befragung der Stakeholder über die Stadtteilerneuerung sowie deren Analysen und Einflüsse auf die umfassende Themenstellung des geförderten Wohnbaus dar. Der fünfte Abschnitt beinhaltet die konkrete qualitative Inhaltsanalyse von sieben geförderten Wohnbauten, ihre Strukturanalyse, ihre Vernetzung mit Freiräumen und dem Stadtteil. Der abschließende sechste Teil versucht die gewonnenen Erkenntnisse aus den theoretischen Grundlagen wie auch der Stadtanalyse zu bewerten, relevante Entwicklungen im geförderten Wohnbau und in der Stadterneuerung herauszuarbeiten und Verbesserungsvorschläge aufzuzeigen. Stadtteilerneuerung bedarf konkreter Anforderungsprofile an den geförderten Wohnbau wie Nutzungsmischung, soziale Diversität, neue Gebäudetypologien, eine innovative Wohnbauprogrammatik, verbesserte und vernetzte Freiraumqualitäten, Änderungen der gesetzlichen Rahmenbedingungen, neue Wege der Entscheidungsfindung und eine Lösung der Verkehrsproblematik. Die aufgestellten Anforderungsprofile sind die Grundlage für eine zukunftsorientierte Erneuerung der Stadtplanung in Lehen, die als strukturelles Leitbild für andere Stadterneuerungskonzepte gelten soll.This thesis examines urban planning interventions by subsidized housing projects in Lehen, an increasingly deteriorating district in the city of Salzburg. Town planning and regulations in this district reveal comprehensive causes and correlations, which are influenced by law, politics, and economy. As the majority of interventions in this district can be attributed to subsidized housing, the district survey focuses primarily on identifying the stakeholders positions and analyzing their motives as well as interrelating them with the implemented projects. The thesis aims at clarifying the eminent research question whether subsidized housing projects can stimulate urban renewal, in particular by means of redensification of urban space. Furthermore, it wants to identify which urban planning criteria are relevant for a successful implementation. In addition, it portrays relevant topics and processes for a specific district renewal and their application to the planned and implemented environment. The qualitative research method in the district survey comprises a city - as well as a district analysis, a scientific content analysis of implemented district interventions over the past 20 years, a qualitative content analysis based on a questionnaire completed by stakeholders, as well as expert interviews. The thesis is composed of six chapters. Chapter one deals with the European City, suburban agglomerations, urban renewal, the inner periphery, as well as the sub-disciplines of the Spatial Theory, namely Space Sociology, Urban Sociology, Environmental Psychology, and Urban Psychology. Chapter two highlights the comprehensive local and international correlations and basic parameters of subsidized housing, its problems and tasks, concepts for re-densification as well as considerations for district renewal by subsidized housing. The topic of chapter three is the urban development of Salzburg and the district analysis of Lehen, an urban district of the city of Salzburg. Contextual interrelations, basic principles, and motivations for a possible district renewal in Lehen are presented. Chapter four includes the qualitative results of the stakeholder questionnaire as well as their analysis and influences on subsidized housing. Chapter five includes the qualitative analysis findings of seven subsidized housing projects, their structure analysis, their connectedness with urban open spaces as well as with the urban district. In the final chapter six, research findings derived from the theoretical basis and the urban analysis are evaluated. Relevant developments for subsidized housing and the urban renewal are expounded and suggestions for improvements are presented. Urban district renewal calls for a requirements profile addressed to the subsidized housing: mixed used architecture, social diversity, new building typologies, new objectives for residential developments, upgraded, interlinked open urban spaces, amendments and adjustments of laws and regulations, new decision-making models, and a solution of the traffic problems. These parameters provide a basis for a future-oriented renewal of urban planning in Lehen, which in turn should serve as general principle of further urban renewal concepts.88

Immunoregulation via Cell Density and Quorum Sensing-like Mechanisms: An Underexplored Emerging Field with Potential Translational Implications

Quorum sensing (QS) was historically described as a mechanism by which bacteria detect and optimize their population density via gene regulation based on dynamic environmental cues. Recently, it was proposed that QS or similar mechanisms may have broader applications across different species and cell types. Indeed, emerging evidence shows that the mammalian immune system can also elicit coordinated responses on a population level to regulate cell density and function, thus suggesting that QS-like mechanisms may also be a beneficial trait of the immune system. In this review, we explore and discuss potential QS-like mechanisms deployed by the immune system to coordinate cellular-level responses, such as T cell responses mediated via the common gamma chain (γc) receptor cytokines and the aryl hydrocarbon receptors (AhRs). We present evidence regarding a novel role of QS as a multifunctional mechanism coordinating CD4+ and CD8+ T cell behavior during steady state and in response to infection, inflammatory diseases, and cancer. Successful clinical therapies such as adoptive cell transfer for cancer treatment may be re-evaluated to harness the effects of the QS mechanism(s) and enhance treatment responsiveness. Moreover, we discuss how signaling threshold perturbations through QS-like mediators may result in disturbances of the complex crosstalk between immune cell populations, undesired T cell responses, and induction of autoimmune pathology. Finally, we discuss the potential therapeutic role of modulating immune-system-related QS as a promising avenue to treat human diseases