The risk of tick-borne encephalitis virus (TBEV) infection after a tick bite remains largely unknown. To address this, we investigated the presence of TBEV in ticks detached from humans in an attempt ...to relate viral copy number, TBEV subtype, and tick feeding time with the serological and clinical response of the tick-bitten participants. Ticks, blood samples, and questionnaires were collected from tick-bitten humans at 34 primary health care centers in Sweden and in the Åland Islands (Finland). A total of 2167 ticks was received from 1886 persons in 2008-2009. Using a multiplex quantitative real-time PCR, 5 TBEV-infected ticks were found (overall prevalence 0.23%, copy range <4×10(2)-7.7×10(6)per tick). One unvaccinated person bitten by a tick containing 7.7×10(6) TBEV copies experienced symptoms. Another unvaccinated person bitten by a tick containing 1.8×10(3) TBEV copies developed neither symptoms nor TBEV antibodies. The remaining 3 persons were protected by vaccination. In contrast, despite lack of TBEV in the detached ticks, 2 persons developed antibodies against TBEV, one of whom reported symptoms. Overall, a low risk of TBEV infection was observed, and too few persons got bitten by TBEV-infected ticks to draw certain conclusions regarding the clinical outcome in relation to the duration of the blood meal and virus copy number. However, this study indicates that an antibody response may develop without clinical symptoms, that a bite by an infected tick not always leads to an antibody response or clinical symptoms, and a possible correlation between virus load and tick feeding time.
Persistent symptoms after treatment of neuroborreliosis (NB) are well-documented, although the causative mechanisms are mainly unknown. The effect of repeated antibiotic treatment has not been ...studied in detail. The aim of this study was to determine whether: (1) persistent symptoms improve with doxycycline treatment; (2) doxycycline has an influence on systemic cytokine responses, and; (3) improvement of symptoms could be due to doxycycline-mediated immunomodulation.
15 NB patients with persistent symptoms ≥6 months post-treatment were double-blindly randomized to receive 200 mg of doxycycline or a placebo for three weeks. After a six-week wash-out period, a cross-over with a three-week course of a placebo or doxycycline was conducted. The primary outcome measures were improvement of persistent symptoms assessed by neurological examinations, a symptom severity score and estimation of the quality of life. The secondary outcome measure was changes in systemic cytokine responses.
All 15 patients finished the study. No doxycycline-mediated improvement of post-treatment symptoms or quality of life was observed. Nor could any doxycycline-mediated changes in systemic cytokine responses be detected. The study was completed without any serious adverse events.
No doxycycline-mediated improvement of post-treatment symptoms or quality of life was observed. Nor could any doxycycline-mediated changes in systemic cytokine responses be detected. The study was completed without any serious adverse events. To conclude, in this pilot study, doxycycline-treatment did not lead to any improvement of either the persistent symptoms or quality of life in post-NB patients. Accordingly, doxycycline does not seem to be the optimal treatment of diverse persistent symptoms post-NB. However, the results need to be confirmed in larger studies.
NCT01205464 (clinicaltrials.gov).
Here we investigated the role of complement activation in phagocytosis and the release of cytokines and chemokines in response to two clinical isolates: Borrelia afzelii K78, which is resistant to ...complement-mediated lysis, and Borrelia garinii LU59, which is complement-sensitive.
Borrelia spirochetes were incubated in hirudin plasma, or hirudin-anticoagulated whole blood. Complement activation was measured as the generation of C3a and sC5b-9. Binding of the complement components C3, factor H, C4, and C4BP to the bacterial surfaces was analyzed. The importance of complement activation on phagocytosis, and on the release of cytokines and chemokines, was investigated using inhibitors acting at different levels of the complement cascade.
1) Borrelia garinii LU59 induced significantly higher complement activation than did Borrelia afzelii K78. 2) Borrelia afzelii K78 recruited higher amounts of factor H resulting in significantly lower C3 binding. 3) Both Borrelia strains were efficiently phagocytized by granulocytes and monocytes, with substantial inhibition by complement blockade at the levels of C3 and C5. 4) The release of the pro-inflammatory cytokines and chemokines IL-1β, IL-6, TNF, CCL20, and CXCL8, together with the anti-inflammatory IL-10, were increased the most (by>10-fold after exposure to Borrelia). 5) Both strains induced a similar release of cytokines and chemokines, which in contrast to the phagocytosis, was almost totally unaffected by complement blockade.
Our results show that complement activation plays an important role in the process of phagocytosis but not in the subsequent cytokine release in response to live Borrelia spirochetes.
Exposure to ubiquitous allergens early in life, even before birth, may influence the incidence of allergic diseases later in life. During pregnancy, the fetomaternal interface is surrounded by high ...levels of T‐helper (Th)2‐like cytokines, possibly favouring the development of Th2‐like immune responses in the offspring. The aim of this study was to evaluate the relation between cord blood (CB) IgE antibodies, Th1‐ and Th2‐like cytokines and chemokines, maternal allergy and development of allergic disease during the first 2 yr of life in the offspring. The CB cytokine and chemokine levels from children of 20 allergic and 36 non‐allergic women were determined by a multiplexed Luminex assay and ELISA. Total CB and maternal IgE antibody concentrations were quantified using ImmunoCAP technology. The maternal IgE levels during and after pregnancy correlated with CB IgE and Th2‐associated macrophage‐derived chemokine MDC (CCL22) levels. Development of allergic disease and sensitization was associated with increased CB IgE and MDC (CCL22) levels, as well as high ratios of MDC (CCL22) to Th1‐associated interferon‐γ inducible protein 10 IP‐10 (CXCL10) and interferon‐γ inducible T‐cell α‐chemoattractant I‐TAC (CXCL11) (n = 7 allergic vs. n = 25 non‐allergic). The correlations between maternal IgE and CB IgE and MDC (CCL22) levels possibly indicate that the maternal immunity can affect the Th1/Th2 profile in the neonate. Development of allergic disease is associated with a more marked Th2‐like deviation already at birth, shown as increased levels of CB IgE and MDC (CCL22) and higher ratios of MDC (CCL22) to IP‐10 (CXCL10) and I‐TAC (CXCL11).
A successful pregnancy requires that the maternal immune system adapts properly to avoid rejection of the semi‐allogeneic fetus without compromising the ability to protect the mother and the fetus ...against infections. In this review, we describe the role of decidual macrophages in creating a homeostatic environment at the fetal–maternal interface. We also discuss their role in pregnancy complications as well as future possibilities to modulate macrophage function therapeutically. Decidual macrophages are enriched at the fetal–maternal interface and play a major role in the regulation of inflammatory responses and the maintenance of a tolerant environment. Their function is, however, not restricted to immune tolerance, but extends to include functions such as the recognition and clearance of infections, the clearance of apoptotic debris, and tissue remodeling. Decidual macrophages seem to largely function as tissue‐resident macrophages that are crucial for maintaining homeostasis and reproductive success.
Loading influences tendon healing, and so does inflammation. We hypothesized that the two are connected. 48 rats underwent Achilles tendon transection. Half of the rats received Botox injections into ...calf muscles to reduce mechanical loading. Cells from the regenerating tissue were analyzed by flow cytometry. In the loaded group, the regenerating tissue contained 83% leukocytes (CD45(+)) day 1, and 23% day 10. The M1/M2 macrophage ratio (CCR7/CD206) peaked at day 3, while T helper (CD3(+)CD4(+)) and Treg cells (CD25(+) Foxp3(+)) increased over time. With Botox, markers associated with down-regulation of inflammation were more common day 5 (CD163, CD206, CD25, Foxp3), and M1 or M2 macrophages and Treg cells were virtually absent day 10, while still present with full loading. The primary variable, CCR7/CD206 ratio day 5, was higher with full loading (p = 0.001) and the Treg cell fraction was lower (p < 0.001). Free cage activity loading is known to increase size and strength of the tendon in this model compared to Botox. Loading now appeared to delay the switch to an M2 type of inflammation with more Treg cells. It seems a prolonged M1 phase due to loading might make the tendon regenerate bigger.
Background and purpose
Improved biomarkers are needed to facilitate clinical decision‐making and as surrogate endpoints in clinical trials in multiple sclerosis (MS). We assessed whether ...neurodegenerative and neuroinflammatory markers in cerebrospinal fluid (CSF) at initial sampling could predict disease activity during 2 years of follow‐up in patients with clinically isolated syndrome (CIS) and relapsing–remitting MS.
Methods
Using multiplex bead array and enzyme‐linked immunosorbent assay, CXCL1, CXCL8, CXCL10, CXCL13, CCL20, CCL22, neurofilament light chain (NFL), neurofilament heavy chain, glial fibrillary acidic protein, chitinase‐3‐like‐1, matrix metalloproteinase‐9 and osteopontin were analysed in CSF from 41 patients with CIS or relapsing–remitting MS and 22 healthy controls. Disease activity (relapses, magnetic resonance imaging activity or disability worsening) in patients was recorded during 2 years of follow‐up in this prospective longitudinal cohort study.
Results
In a logistic regression analysis model, NFL in CSF at baseline emerged as the best predictive marker, correctly classifying 93% of patients who showed evidence of disease activity during 2 years of follow‐up and 67% of patients who did not, with an overall proportion of 85% (33 of 39 patients) correctly classified. Combining NFL with either neurofilament heavy chain or osteopontin resulted in 87% overall correctly classified patients, whereas combining NFL with a chemokine did not improve results.
Conclusions
This study demonstrates the potential prognostic value of NFL in baseline CSF in CIS and relapsing–remitting MS and supports its use as a predictive biomarker of disease activity.
Background: Common variable immunodeficiency (CVID) is a disorder characterized by antibody deficiency. A significant fraction of the patients suffer from immune dysregulation, which leads to ...increased morbidity and mortality. The pathogenesis of this condition is poorly understood. Objective: Our aim was to find out whether the plasma protein signature in CVID is associated with clinical characteristics and lymphocyte aberrations. Methods: A highly sensitive proximity extension assay was used for targeted profiling of 145 plasma proteins in 29 patients with CVID. Phenotyping of peripheral lymphocytes was done by flow cytometry. The findings were correlated with the burden of immune dysregulation. Results: Unsupervised clustering of plasma protein profiles identified 2 distinct groups of patients with CVID that differed significantly in terms of the degree of complications due to immune dysregulation and in terms of the frequency of activated B- and T-cell subpopulations. Pathway analysis identified IFN-gamma and IL-1 beta as the top enriched upstream regulators associated with higher grade of immune dysregulation. In addition, CVID was found to be associated with increased plasma levels of the B-cell attracting chemokine CXCL13. Conclusion: Clustering based on plasma protein profiles delineated a subgroup of patients with CVID with activated T cells and clinical complications due to immune dysregulation. Thus, data indicate that CVID-associated immune dysregulation is a T(H)1-mediated inflammatory process driven by the IFN-gamma pathway.
In pregnancy, the decidua is infiltrated by leukocytes promoting fetal development without causing immunological rejection. Murine regulatory T (Treg) cells are known to be important immune ...regulators at this site. The aim of the study was to characterize the phenotype and origin of Treg cells and determine the quantitative relationship between Treg, T-helper type 1 (TH1), TH2, and TH17 cells in first-trimester human decidua. Blood and decidual CD4⁺ T cells from 18 healthy first-trimester pregnant women were analyzed for expression of Treg-cell markers (CD25, FOXP3, CD127, CTLA4, and human leukocyte antigen-DR HLA-DR), chemokine receptors (CCR4, CCR6, and CXCR3), and the proliferation antigen MKI67 by six-color flow cytometry. Treg cells were significantly enriched in decidua and displayed a more homogenous suppressive phenotype with more frequent expression of FOXP3, HLA-DR, and CTLA4 than in blood. More decidual Treg cells expressed MKI67, possibly explaining their enrichment at the fetal-maternal interface. Using chemokine receptor expression profiles of CCR4, CCR6, and CXCR3 as markers for TH1, TH2, and TH17 cells, we showed that TH17 cells were nearly absent in decidua, whereas TH2-cell frequencies were similar in blood and decidua. CCR6⁺ TH1 cells, reported to secrete high levels of interferon gamma (IFNG), were fewer, whereas the moderately IFNG-secreting CCR6⁻ TH1 cells were more frequent in decidua compared with blood. Our results point toward local expansion of Treg cells and low occurrence of TH17 cells. Furthermore, local, moderate TH1 activity seems to be a part of normal early pregnancy, consistent with a mild inflammatory environment controlled by Treg cells.
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