Multiple sclerosis (MS) is a chronic autoimmune neuroinflammatory and neurodegenerative disorder of the central nervous system. Pregnancy represents a natural modulation of the disease course, where ...the relapse rate decreases, especially in the 3
rd
trimester, followed by a transient exacerbation after delivery. Although the exact mechanisms behind the pregnancy-induced modulation are yet to be deciphered, it is likely that the immune tolerance established during pregnancy is involved. In this study, we used the highly sensitive and specific proximity extension assay technology to perform protein profiling analysis of 92 inflammation-related proteins in MS patients (n=15) and healthy controls (n=10), longitudinally sampled before, during, and after pregnancy. Differential expression analysis was performed using linear models and p-values were adjusted for false discovery rate due to multiple comparisons. Our findings reveal gradual dynamic changes in plasma proteins that are most prominent during the 3
rd
trimester while reverting post-partum. Thus, this pattern reflects the disease activity of MS during pregnancy. Among the differentially expressed proteins in pregnancy, several proteins with known immunoregulatory properties were upregulated, such as PD-L1, LIF-R, TGF-β1, and CCL28. On the other hand, inflammatory chemokines such as CCL8, CCL13, and CXCL5, as well as members of the tumor necrosis factor family, TRANCE and TWEAK, were downregulated. Further in-depth studies will reveal if these proteins can serve as biomarkers in MS and whether they are mechanistically involved in the disease amelioration and worsening. A deeper understanding of the mechanisms involved may identify new treatment strategies mimicking the pregnancy milieu.
Epigenetics may play a central, yet unexplored, role in the profound changes that the maternal immune system undergoes during pregnancy and could be involved in the pregnancy-induced modulation of ...several autoimmune diseases. We investigated changes in the methylome in isolated circulating CD4
+
T-cells in non-pregnant and pregnant women, during the 1
st
and 2
nd
trimester, using the Illumina Infinium Human Methylation 450K array, and explored how these changes were related to autoimmune diseases that are known to be affected during pregnancy. Pregnancy was associated with several hundreds of methylation differences, particularly during the 2
nd
trimester. A network-based modular approach identified several genes, e.g., CD28, FYN, VAV1 and pathways related to T-cell signalling and activation, highlighting T-cell regulation as a central component of the observed methylation alterations. The identified pregnancy module was significantly enriched for disease-associated methylation changes related to multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus. A negative correlation between pregnancy-associated methylation changes and disease-associated changes was found for multiple sclerosis and rheumatoid arthritis, diseases that are known to improve during pregnancy whereas a positive correlation was found for systemic lupus erythematosus, a disease that instead worsens during pregnancy. Thus, the directionality of the observed changes is in line with the previously observed effect of pregnancy on disease activity. Our systems medicine approach supports the importance of the methylome in immune regulation of T-cells during pregnancy. Our findings highlight the relevance of using pregnancy as a model for understanding and identifying disease-related mechanisms involved in the modulation of autoimmune diseases.
Abbreviations: BMIQ: beta-mixture quantile dilation; DMGs: differentially methylated genes; DMPs: differentially methylated probes; FE: fold enrichment; FDR: false discovery rate; GO: gene ontology; GWAS: genome-wide association studies; MDS: multidimensional scaling; MS: multiple sclerosis; PBMC: peripheral blood mononuclear cells; PBS: phosphate buffered saline; PPI; protein-protein interaction; RA: rheumatoid arthritis; SD: standard deviation; SLE: systemic lupus erythematosus; SNP: single nucleotide polymorphism; T
H
: CD4
+
T helper cell; VIStA: diVIsive Shuffling Approach.
Changes in the blood lymphocyte composition probably both mediate and reflect the effects of natalizumab treatment in multiple sclerosis, with implications for treatment benefits and risks.
A broad ...panel of markers for lymphocyte populations, including states of activation and co-stimulation, as well as functional T cell responses to recall antigens and mitogens, were assessed by flow cytometry in 40 patients with relapsing multiple sclerosis before and after one-year natalizumab treatment.
Absolute numbers of all major lymphocyte populations increased after treatment, most markedly for NK and B cells. The fraction of both memory and presumed regulatory B cell subsets increased, as did CD3(-)CD56(dim) cytotoxic NK cells, whereas CD3(-)CD56(bright) regulatory NK cells decreased. The increase in cell numbers was further associated with a restored T cell responsiveness to recall antigens and mitogens in functional assays.
Our data confirms that natalizumab treatment increases the number of lymphocytes in blood, likely mirroring the expression of VLA-4 being highest on NK and B cells. This finding supports reduction of lymphocyte extravasation as a main mode of action, although the differential effects on subpopulation composition suggests that cell-signalling may also be affected. The systemic increase in T cell responsiveness reflects the increase in numbers, and while augmenting anti-infectious responses systemically, localized responses may become correspondingly decreased.
Members of the genus Borrelia are among the most common infectious agents causing tick-borne disease in humans worldwide. Here, we developed a Light Upon eXtension (LUX) real-time PCR assay that can ...detect and quantify Borrelia species in ticks that have fed on humans, and we applied the assay to 399 such ticks. Borrelia PCR-positive ticks were identified to species level by sequencing the products of conventional PCR performed using Borrelia group-specific primers. There was a 19% prevalence of Borrelia spp. in the detached ticks, and the number of spirochetes per Borrelia PCR-positive tick ranged from 2.0 x 10² to 4.9 x 10⁵, with a median of 7.8 x 10³ spirochetes. Adult ticks had a significantly larger number of spirochetes, with a median of 8.4 x 10⁴ compared to the median of nymphs of 4.4 x 10⁴. Adult ticks also exhibited a higher prevalence of Borrelia (33%) than nymphs (14%). Among the identified species, Borrelia afzelii was found to predominate (61%) and was followed by B. garinii (23%), B. valaisiana (13%), B. burgdorferi sensu stricto (1%), B. lusitaniae (1%), and B. miyamotoi-like (1%). Also, 3% of the ticks were coinfected with multiple strains of B. afzelii. Notably, this is the first report of B. lusitaniae being detected in ticks in Sweden. Our LUX real-time PCR assay proved to be more sensitive than a corresponding TaqMan assay. In conclusion, the novel LUX real-time PCR method is a rapid and sensitive tool for detection and quantification of Borrelia spp. in ticks.
...we identified a population of lineage negative (Lin-) cells lacking the expression of cell surface markers associated with T cells (CD3, CD4, T-cell receptor TCRalphaβ, and TCRγδ), B cells ...(CD19), dendritic cells (CD11c, CD123, CD303, CD1a), macrophages/monocytes (CD14), mast cells and basophils (Fcstraight epsilonR1alpha), and hematopoietic progenitor cells (CD34). ...we demonstrated that ILC2 are present in cord blood and display a higher GATA-3 expression than in adult ILC2.\n Cells were then placed in a freezing container at -70°C for 24 hours and thereafter stored in liquid nitrogen, pending analysis.
Abstract
Background
Fatty degeneration of thymus (or thymus involution) has long been considered a normal ageing process. However, there is emerging evidence that thymic involution is linked to T ...cell aging, chronic inflammation and increased morbidity. Other factors, aside from chronological age, have been proposed to affect the involution rate. In the present study, we investigated the imaging characteristics of thymus on computed tomography (CT) in a Swedish middle-aged population. The major aims were to establish the prevalence of fatty degeneration of thymus and to determine its associations with demographic, lifestyle and clinical factors, as well as inflammation, T cell differentiation and thymic output.
Results
In total, 1 048 randomly invited individuals (aged 50–64 years, 49% females) were included and thoroughly characterized. CT evaluation of thymus included measurements of attenuation, size and a 4-point scoring system, with scale 0–3 based on the ratio of fat and soft tissue. A majority, 615 (59%) showed complete fatty degeneration, 259 (25%) predominantly fatty attenuation, 105 (10%) half fatty and half soft-tissue attenuation, while 69 (6.6%) presented with a solid thymic gland with predominantly soft-tissue attenuation. Age, male sex, high BMI, abdominal obesity and low dietary intake of fiber were independently associated with complete fatty degeneration of thymus. Also, fatty degeneration of thymus as well as low CT attenuation values were independently related to lower proportion of naïve CD8
+
T cells, which in turn was related to lower thymic output, assessed by T-cell receptor excision circle (TREC) levels.
Conclusion
Among Swedish middle-aged subjects, nearly two-thirds showed complete fatty degeneration of thymus on CT. This was linked to depletion of naïve CD8
+
T cells indicating that CT scans of thymus might be used to estimate immunological aging. Furthermore, our findings support the intriguing concept that obesity as well as low fiber intake contribute to immunological aging, thereby raising the possibility of preventive strategies.
Background:
The aim of this study was to determine the influence of selected physiological, psychological and situational factors on experience of fatigue, and functional limitations due to fatigue ...in patients with stable chronic obstructive pulmonary disease (COPD).
Methods:
In total 101 patients with COPD and 34 control patients were assessed for experience of fatigue, functional limitation due to fatigue (Fatigue Impact Scale), physiological lung function, 6-minute walk distance (6MWD), body mass index (BMI), dyspnoea, interleukin (IL)-6, IL-8, high sensitivity C-reactive protein (hs-CRP), surfactant protein D, psychological (anxiety, depression, insomnia), situational variables (age, sex, smoking, living alone, education), and quality of life.
Results:
Fatigue was more common in patients with COPD than in control patients (72% versus 56%, p < 0.001). Patients with COPD and fatigue had lower lung function, shorter 6MWD, more dyspnoea, anxiety and depressive symptoms, and worse health status compared with patients without fatigue (all p < 0.01). No differences were found for markers of systemic inflammation. In logistic regression, experience of fatigue was associated with depression odds ratio (OR) 1.69, 95% confidence interval (CI) 1.28–2.25) and insomnia (OR 1.75, 95% CI 1.19–2.54). In linear regression models, depression, surfactant protein D and dyspnoea explained 35% (R2) of the variation in physical impact of fatigue. Current smoking and depression explained 33% (R2) of the cognitive impact of fatigue. Depression and surfactant protein D explained 48% (R2) of the psychosocial impact of fatigue.
Conclusions:
Experiences of fatigue and functional limitation due to fatigue seem to be related mainly to psychological but also to physiological influencing factors, with depressive symptoms, insomnia problems and dyspnoea as the most prominent factors. Systemic inflammation was not associated with perception of fatigue but surfactant protein D was connected to some dimensions of the impact of fatigue
Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS and has a varying disease course as well as variable response to treatment. Biomarkers may therefore aid personalized treatment. ...We tested whether in vitro activation of MS patient-derived CD4+ T cells could reveal potential biomarkers. The dynamic gene expression response to activation was dysregulated in patient-derived CD4+ T cells. By integrating our findings with genome-wide association studies, we constructed a highly connected MS gene module, disclosing cell activation and chemotaxis as central components. Changes in several module genes were associated with differences in protein levels, which were measurable in cerebrospinal fluid and were used to classify patients from control individuals. In addition, these measurements could predict disease activity after 2 years and distinguish low and high responders to treatment in two additional, independent cohorts. While further validation is needed in larger cohorts prior to clinical implementation, we have uncovered a set of potentially promising biomarkers.
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•Dynamic CD4+ T cell responses in vitro revealed a dysregulated network module in MS•This module was highly enriched for GWAS genes and translated into protein expression•A combined protein score readily predicted disease activity and treatment response•Integrating GWASs with dynamic expression profiling disclosed personalized biomarkers
Hellberg et al. have constructed a highly connected gene module of dysregulated genes in multiple sclerosis patients in which the gene products can collectively be used to classify patients and predict disease activity and response to treatment. This set of key proteins holds promise as clinically useful biomarkers in personalized MS treatment.
Atherosclerosis is characterized by a chronic inflammatory response involving activated T cells and impairment of natural killer (NK) cells. An increased T cell activity has been associated with ...plaque instability and risk of acute cardiac events. Lymphocyte analyses in blood are widely used to evaluate the immune status. However, peripheral blood contains only a minor proportion of lymphocytes. In this study, we hypothesized that thoracic lymph nodes from patients with stable angina (SA) and acute coronary syndrome (ACS) might add information to peripheral blood analyses.
Peripheral blood and lymph nodes were collected during coronary by-pass surgery in 13 patients with SA and 13 patients with ACS. Lymphocyte subpopulations were assessed by flow cytometry using antibodies against CD3, CD4, CD8, CD19, CD16/56, CD25, Foxp3, CD69, HLA-DR, IL-18 receptor (R) and CCR4.
Lymph nodes revealed a lymphocyte subpopulation profile substantially differing from that in blood including a higher proportion of B cells, lower proportions of CD8(+) T cells and NK cells and a 2-fold higher CD4/CD8 ratio. CD4(+)CD69(+) cells as well as Foxp3(+) regulatory T cells were markedly enriched in lymph nodes (p<0.001) while T helper 1-like (CD4(+)IL-18R+) cells were more frequent in blood (p<0.001). The only significant differences between ACS and SA patients involved NK cells that were reduced in the ACS group. However, despite being reduced, the NK cell fraction in ACS patients contained a significantly higher proportion of IL-18R(+) cells compared with SA patients (p<0.05).
There were several differences in lymphocyte subpopulations between blood and lymph nodes. However, the lymphocyte perturbations in peripheral blood of ACS patients compared with SA patients were not mirrored in lymph nodes. The findings indicate that lymph node analyses in multivessel coronary artery disease may not reveal any major changes in the immune response that are not detectable in blood.
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