Tanja Lange

University of Lübeck · Abteilung Klinische Rheumatologie

Background and Aims Chronic inflammation and autoimmunity contribute to cardiovascular (CV) disease. Recently, autoantibodies (aAbs) against the CXC-motif-chemokine receptor 3 (CXCR3), a G protein-coupled receptor with a key role in atherosclerosis, have been identified. The role of anti-CXCR3 aAbs for CV risk and disease is unclear. Methods Anti-...

Over the past four decades, research on 24-h rhythms has yielded numerous remarkable findings, revealing their genetic, molecular, and physiological significance for immunity and various diseases. Thus, circadian rhythms are of fundamental importance to mammals, as their disruption and misalignment have been associated with many diseases and the ab...

Background Autoantibodies (ab) against G protein-coupled receptors (GPCR), such as ab against angiotensin II receptor type 1 (AT1R), endothelin receptor type A (ETAR) or CXC chemokine receptor 3 and 4 (CXCR3/4) may contribute to the pathogenesis of systemic sclerosis (SSc) [1]. AT1R- and ETAR-ab are associated with SSc-related mortality and CXCR3/4...

Background Systemic sclerosis is a rare connective tissue disorder characterized by a triad of inflammation, vasculopathy, and fibrosis. Vasculopathic disease manifestations occur early in disease development and include Raynaud’s phenomenon, acral ulcers, necrosis, and pulmonary arterial hypertension. Currently, acral vasculopathy is assessed in c...

Vaccination is a major strategy to control a viral pandemic. Simple behavioral interventions that might boost vaccine responses have yet to be identified. We conducted meta-analyses to summarize the evidence linking the amount of sleep obtained in the days surrounding vaccination to antibody response in healthy adults. Authors of the included studi...

Shift work is associated with systemic chronic inflammation, impaired host and tumor defense and dysregulated immune responses to harmless antigens such as allergens or auto-antigens. Thus, shift workers are at higher risk to develop a systemic autoimmune disease and circadian disruption with sleep impairment seem to be the key underlying mechanism...

Approximately 5% of the world-wide population is affected by autoimmune diseases. Overall, autoimmune diseases are still difficult to treat, impose a high burden on patients, and have a significant economic impact. Like other complex diseases, e.g., cancer, autoimmune diseases develop over several years. Decisive steps in the development of autoimm...

Most patients with Post COVID Syndrome (PCS) present with a plethora of symptoms without clear evidence of organ dysfunction. A subset of them fulfills diagnostic criteria of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Symptom severity of ME/CFS correlates with natural regulatory autoantibody (AAB) levels targeting several G-protei...

Background Fibromyalgia syndrome (FMS) is often present in autoimmune diseases but can also occur in its primary form. Biomarkers for FMS are currently missing. Systemic chronic inflammation, dysautonomia and metabolic dysfunction have been suggested to contribute to the disease. Recent studies indicate that FMS involves autoantibodies (abs), which...

Background Fatigue has an adaptive function and serves as a temporary signal to rest and save energy often in response to immune activation. It may, however, also persist in a pathological condition incurring significant burden. While subjective symptoms and scientific consensus indicate that both physical and mental determinants of motivated behav...

With newly rising coronavirus disease 2019 (COVID-19) cases, important data gaps remain on (i) long-term dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rates in fixed cohorts (ii) identification of risk factors, and (iii) establishment of effective surveillance strategies. By polymerase chain reaction and antibod...

The circadian clock is an evolutionarily highly conserved endogenous timing program that structures physiology and behavior according to the time of day. Disruption of circadian rhythms is associated with many common pathologies. The emerging field of circadian medicine aims to exploit the mechanisms of circadian physiology and clock–disease intera...

Twenty-four-hour rhythms in immune parameters and functions are robustly observed phenomena in biomedicine. Here, we summarize the important role of sleep and associated parameters on the neuroendocrine regulation of rhythmic immune cell traffic to different compartments, with a focus on human leukocyte subsets. Blood counts of “stress leukocytes”...

Several studies suggest a link between acute changes in inflammatory parameters due to an endotoxin or (psychological) stressor and the brain’s stress response. The extent to which basal circulating levels of inflammatory markers are associated with the brain’s stress response has been hardly investigated so far. In the present study, baseline plas...

The coronavirus disease 2019 (COVID-19) can evolve to clinical manifestations resembling systemic autoimmune diseases, with the presence of autoantibodies that are still poorly characterized. To address this issue, we performed a cross-sectional study of 246 individuals to determine whether autoantibodies targeting G protein-coupled receptors (GPCR...

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an acquired complex disease with patients suffering from the cardinal symptoms of fatigue, post-exertional malaise (PEM), cognitive impairment, pain and autonomous dysfunction. ME/CFS is triggered by an infection in the majority of patients. Initial evidence for a potential...

Background More than one year into the COVID-19 pandemic, important data gaps remain on longitudinal prevalence of SARS-CoV-2 infection at the population level and in defined risk groups, efficacy of specific lockdown measures, and on (cost-)effective surveillance. Methods The ELISA (Luebeck Longitudinal Investigation of SARS-CoV-2 Infection) study...

Background: While clustering of bullous pemphigoid (BP) with neuropsychiatric diseases is well-established, the clinical and immunological profile of BP patients with this comorbidity remains to be decisively determined. Objectives: To evaluate the burden of neurological and psychiatric comorbidities among patients with BP and to elucidate the c...

Several studies suggest a link between acute changes in inflammatory parameters due to an endotoxin or (psychological) stressor and the brain’s stress response. The extent to which basal circulating levels of inflammatory markers are associated with the brain’s stress response has been hardly investigated so far. In the present study, plasma levels...

We have previously shown that conformational change in the β2-integrin is a very early activation marker that can be detected with fluorescent multimers of its ligand intercellular adhesion molecule (ICAM)-1 for rapid assessment of antigen-specific CD8⁺ T cells. In this study, we describe a modified protocol of this assay for sensitive detection of...

We have previously shown that beta 2 -integrin conformational change is a very early activation marker that can be detected with fluorescent multimers of its ligand ICAM-1 for a rapid assessment of antigen-specific CD8 ⁺ T cells. Here, we describe a modified protocol of this assay for sensitive detection of functional antigen-specific CD4 ⁺ T cells...

Sleep strongly impacts both humoral and cellular immunity; however, its acute effects on the innate immune defense against pathogens are unclear. Here, we elucidated in mice whether sleep affects the numbers and functions of innate immune cells and their defense against systemic bacterial infection. Sleep significantly increased numbers of classica...

Objective: Vasculopathy in systemic sclerosis (SSc) is characterized by the obliteration of arterioles and a reduced capillary density in various tissues. In SSc, atrophic alterations of the choroid have been suggested based on morphological data acquired by optical coherence tomography (OCT). In this study, we aimed to assess the choroid in eyes o...

Sleep and immunity are bidirectionally linked. Immune system activation alters sleep, and sleep in turn affects the innate and adaptive arm of our body's defense system. Stimulation of the immune system by microbial challenges triggers an inflammatory response, which, depending on its magnitude and time course, can induce an increase in sleep durat...

Sleep and the immune system are bi-directionally linked. An immune activation induces fatigue, sleepiness and changes in sleep architecture. These range from a deepening of sleep to severe sleep disturbances with shallow and fragmented sleep. Patients with rheumatic and musculoskeletal diseases (RMDs) often complain about feelings of debilitating f...

The mechanisms of CD4+ T-cell memory formation in the immune system are debated. With the well-established concept of memory formation in the central nervous system (CNS), we propose that formation of CD4+ T-cell memory depends on the interaction of two different cell systems handling two types of stored information. First, information about antige...

Efficient T cell responses require the firm adhesion of T cells to their targets, e.g., virus-infected cells, which depends on T cell receptor (TCR)–mediated activation of β 2 -integrins. Gα s -coupled receptor agonists are known to have immunosuppressive effects, but their impact on TCR-mediated integrin activation is unknown. Using multimers of p...

Autoantibodies have been associated with autoimmune diseases. However, studies have identified autoantibodies in healthy donors (HD) who do not develop autoimmune disorders. Here we provide evidence of a network of immunoglobulin G (IgG) autoantibodies targeting G protein-coupled receptors (GPCR) in HD compared to patients with systemic sclerosis,...

Sleep and circadian disruptions are frequently observed in patients across hospital wards. This is alarming, since impaired nocturnal sleep and disruption of a normal circadian rhythm can compromise health and disturb processes involved in recovery from illness (eg, immune functions). With this in mind, the present narrative review discusses how pa...

Graphical summary to the article "Activated integrins identify functional antigen-specific CD8 + T cells within minutes after antigen stimulation": Following T-cell receptor-mediated stimulation, integrin activation occurs within seconds through a process known as "inside-out" signaling that leads to an affinity increase and clustering of membran...

Supplementary information to the article "Activated integrins identify functional antigen-specific CD8 + T cells within minutes after antigen stimulation"

Significance Assessing antigen-specific T cells is crucial for our understanding of immune reactions against pathogens and tumors, and for evaluating immunotherapies in patients. Existing techniques to evaluate the functionality of T lymphocytes all rely on de novo expression of proteins, typically intracellular cytokines, and therefore require ela...

Anti-neutrophil cytoplasmic autoantibodies (ANCA) targeting proteinase 3 (PR3) and myeloperoxidase expressed by innate immune cells (neutrophils and monocytes) are salient diagnostic and pathogenic features of small vessel vasculitis, comprising granulomatosis with polyangiitis (GPA), microscopic polyangiitis, and eosinophilic GPA. Genetic studies...

Background There is growing evidence that nervous and immune system communicate with each other through soluble mediators.¹ Immune cells such as neutrophils express muscarinic acetylcholine receptors (mAChR), which are neuroimmune receptors and highly prevalent in the nervous system.² Aberrant neutrophil functioning plays an important role in vario...

In humans, the numbers of cytotoxic T lymphocytes (CTLs) in blood display a strong circadian rhythm with a steep decrease from night to daytime. However, CTLs are composed of various subsets and exert antigen-specific responses which are highly adapted to the specific pathogen. We therefore investigated whether CTL subpopulations of distinct antige...

An efficient immune response requires a selective and strong interaction of T cells with endothelium or target cells. These interactions are strengthened by the rapid induction of beta2-integrin-mediated adhesion upon chemokine receptor or T-cell receptor (TCR) stimulation, respectively. We and others have shown that an increase in G-alpha-s-protei...

In humans numbers of circulating T cells show a circadian rhythm with peak counts during the night and a steep decline in the morning. Sleep per se appears to counter this rhythm by acutely reducing the number of total T cells. The T-cell population, however, is rather heterogeneous comprising various subpopulations with different features and func...

Pro-inflammatory cytokines can promote sleep and neuronal processes underlying memory formation. However, this has mainly been revealed in animal studies. In this double-blind, placebo-controlled within-subject designed study, we examined how changes in the balance between pro- and anti-inflammatory signalling affect sleep and sleep-associated memo...

Sleep and immunity are linked by bidirectional interactions. On the one hand, immune activation induces fatigue, sleepiness and non-rapid eye movement (NREM) sleep, whereas REM sleep is suppressed. On the other hand, sleep, in particular NREM sleep, regulates immune functions in an overall immunosupportive manner. Thus, NREM sleep drives the releas...

Beta2-integrin activation in response to inside-out signaling by chemokines plays a major role in T-cell adhesion to the endothelium and the following extravasation into the inflamed tissue. We and others have previously shown that daytime increase in G-alpha-s-coupled receptor (GαsPCR) signaling, such as via beta2-adrenergic receptors counteracts...

Antigen stimulation of T-cell receptors on T cells induces an immediate increase in ligand-binding affinity and clustering in the plasma membrane of beta2-integrins, resulting in a strong binding to intercellular adhesion molecules (ICAMs) on target cells. This firm adhesion, e.g. of cytotoxic T cells to virus-infected or tumor cells with formation...

Sleep benefits the consolidation of psychological memory, and there are hints that sleep likewise supports immunological memory formation. Comparing psychological and immunological domains, we make the case for active system consolidation that is similarly established in both domains and partly conveyed by the same sleep-associated processes. In th...

Circulating T cells show circadian rhythms, the direction and extent of which depend on the specific subset. Naïve and memory T cells peak during nocturnal sleep, whereas cytotoxic effector T cells show an opposite rhythm with highest numbers during daytime. In the current study, we were interested in how sleep affects these different circadian rhy...

Sleep serves memory functions. We posit the concept that, both in the brain and in the immune system, memory processes can be divided into (i) uptake of new information into an initial store (encoding), (ii) transfer of the information into a long-term store (consolidation), and (iii) retrieval of the information (recall), and that in both systems...

Cortisol’s effects on memory follow an inverted U-shaped function such that memory retrieval is impaired with very low concentrations, presumably due to insufficient activation of high-affine mineralocorticoid receptors (MR), or with very high concentrations, due to predominant low-affine glucocorticoid receptor (GR) activation. Through correspondi...

Pro-inflammatory cytokines like interleukin-1 beta (IL-1) are major players in the interaction between the immune system and the central nervous system. Various animal studies report a sleep-promoting effect of IL-1 leading to enhanced slow wave sleep (SWS). Moreover, this cytokine was shown to affect hippocampus-dependent memory. However, the role...

Tumor necrosis factor (TNF) is considered a key molecule in the regulation of sleep in health and disease. Conversely, sleep compared to sleep deprivation can modulate TNF release, but overall results are conflicting. In this study we focused on the influence of sleep on spontaneous, i.e., unstimulated TNF production, which might be involved in sle...

The role of mineralocorticoid receptors (MRs) in human T-cell migration is not yet understood. We have recently shown that the MR antagonist spironolactone selectively increases the numbers of circulating naïve and central memory T cells during early sleep, which is the time period in the 24-hour cycle hallmarked by predominant MR activation. To in...

Glucocorticoids are well-known to affect T-cell migration, leading to a redistribution of the cells from blood to the bone marrow, accompanied by a concurrent suppression of lymph node homing. Despite numerous studies in this context with most of them employing synthetic glucocorticoids in rather non-physiological doses, the mechanisms of this redi...

CD4(+) T (helper) cells migrate in huge numbers through lymphoid organs. However, little is known about traffic routes and kinetics of CD4(+) T-cell subsets within different organ compartments. Such information is important because there are indications that CD4(+) T cells may influence the function of microenvironments depending on their developme...

In humans, numbers of circulating naive T cells strongly decline in the morning, which was suggested to be mediated by cortisol, inducing a CXCR4 up-regulation with a subsequent extravasation of the cells. As a systematic evaluation of this assumption is lacking, we investigated in two human placebo-controlled studies the effects of the glucocortic...

One of the most pronounced circadian rhythms in human immune parameters is the decline in naive T cell numbers from early night to morning. It is believed to be a consequence of CXCR4 up-regulation on T cells in the morning by cortisol with a subsequent extravasation of the cells. However, a systematic evaluation of this assumption is lacking. We t...

Human blood T cell numbers show a high amplitude rhythm that peaks during sleep. This rhythm mainly reflects temporal changes in numbers of T cell subsets that are at early stages of differentiation like naive and central memory CD4 and CD8 T cells. In a set of experiments in healthy men we show that the early morning rise in endogenous cortisol en...

Sleep plays a pivotal role for the consolidation of declarative memory. The coordinated neuronal replay of information encoded prior to sleep has been identified as a key process. It is assumed that the repeated reactivation of firing patterns in glutamatergic neuron assemblies translates into plastic synaptic changes underlying the formation of lo...

Various features, components, and functions of the immune system present daily variations. Immunocompetent cell counts and cytokine levels present variations according to the time of day and the sleep-wake cycle. Moreover, different immune cell types, such as macrophages, natural killer cells, and lymphocytes, contain a circadian molecular clockwor...

In humans, blood T cell numbers are highest at 2 AM and lowest at 11 PM. This rhythm mainly reflects changes in numbers of CD4 and CD8 naïve (TN) and central memory T cells (TCM) that are reduced due to rising cortisol levels in the morning. Preliminary data indicate that cortisol induces an upregulation of CXCR4 on TN and TCM and, thereby, redirec...

Sleep supports adaptive immune functions. However, the underlying mechanisms are still obscure. Animal studies point to a supporting effect of sleep on the migration of T cells to lymph nodes, where adaptive immunity is generated. In line with this assumption, we were able to show in humans that sleep, compared to nocturnal wakefulness, acutely red...

Memory retrieval is impaired at very low as well as very high cortisol levels, but not at intermediate levels. This inverted-U shaped relationship between cortisol levels and memory retrieval may originate from different roles of the mineralocorticoid (MR) and glucocorticoid receptor (GR) that bind cortisol with distinctly different affinity. Here...

Background : Memory functions involve three stages: encoding, consolidation, and retrieval. Modulating effects of glucocorticoids (GCs) have been consistently observed for encoding and retrieval. However, little is known on how GCs affect consolidation. Methods : In Study I, after encoding emotional and neutral texts, cortisol or placebo was intrav...