Immediate systemic neuroimmune responses following spinal mobilisation and manipulation in people with non-specific neck pain: a randomised placebo-controlled trial.

Spinal mobilisation/manipulation is a common intervention for spinal pain, yet the working mechanisms are largely unknown. A randomised placebo-controlled trial was conducted to (1) compare the immediate neuroimmune responses following spinal mobilisation/manipulation and placebo spinal mobilisation/manipulation; (2) compare the immediate neuroimmune responses of those with a good outcome with those of a poor outcome following spinal mobilisation/manipulation; and (3) explore the association between neuroimmune responses and pain reduction. One hundred patients were randomly allocated to spinal mobilisation/manipulation or a placebo mobilisation/manipulation. Primary outcomes were whole blood in-vitro evoked released concentrations of IL-1ß and TNF-α measured 10 min and 2 h after the intervention. Immediate effects were studied because successful mobilisation/manipulation is often associated with immediate pain reduction, and immediate neuroimmune responses are less affected by potential confounders than long-term responses. Secondary outcomes included multiple systemic inflammatory marker concentrations, phenotypic analysis of white blood cells and clinical outcomes. Outcomes were compared between the experimental and placebo group, and between people with a good and poor outcome in the experimental group. Estimates of intervention effects were based on intention-to-treat analyses, by using linear mixed-effect models. Although there was a substantial difference in pain reduction between groups (mean (SD) difference visual analogue scale: 30 (21) mm at 10 min and 32 (21) mm at 2 h (p < 0.001) in favour of mobilisation/manipulation, there were no differences in primary outcomes between groups or between people with a good and poor outcome (p ≥ 0.10). In conclusion, possible neuroimmune responses following spinal mobilisations/manipulation cannot be identified at a systemic level. Future research may focus on longer treatment duration and more localised neuroimmune responses.

Enrichment of CCR6+ CD8+ T cells and CCL20 in the lungs of mechanically ventilated patients with COVID-19.

Despite high levels of CXCR3 ligands in mechanically ventilated COVID-19 patients, BALF CD8 T cells were not enriched in CXCR3+ cells but rather CCR6+ , likely due to high CCL20 levels in BALF, and had very high PD-1 expression. In mechanically ventilated, but not ward, patients Th-1 immunity is impaired. ​.

Preliminary Notes on Equine Tissue Transglutaminase Serology and A Case of Equine Gluten-Sensitive Enteropathy and Dermatitis in an 11-Year-Old Dutch Warmblood Horse.

It has been suggested that gluten may play a role in equine inflammatory small bowel disease (ISBD). Previous work showed an association between equine gluten-sensitive enteropathy and IgA antibodies to tissue transglutaminase (TGA) in serum. The purpose of this study is to investigate the prevalence of IgA antibodies to TGA in a group of healthy non-gluten-free sport ponies and to present a case of tentative gluten-sensitive enteropathy and dermatitis in a horse. Blood samples were obtained from 40 healthy jumping ponies. The ponies comprised 12 mares, 8 stallions, and 20 geldings with an average age of 9.0 ± 3.8 years (±SD; range 3-19 years). Sera were tested for IgA antibodies against human recombinant TGA. Significance (P < .05) of the correlation between TGA titer and age in these ponies was assessed using Pearson test (two tailed). In addition, to further illustrate tentative equine gluten-sensitive enteropathy and dermatitis, the clinical course in an 11-year-old Dutch Warmblood sport horse gelding has been described. The average TGA titer was 21.4 ± 13.6 AU/mL (range 2-65 AU/mL). There was a significant (P = .013) correlation (r = 0.389) between age and TGA titer in ponies. One of the 40 ponies (2.5%) showed an elevated TGA titer. An elevated TGA titer decreased after a gluten-free ration for 3 months in an 11-year-old Warmblood gelding with a tentative diagnosis of ISBD associated with full remission of the generalized skin reaction. To our best knowledge, this is the first study assessing TGA antibodies in sera from healthy non-gluten-free ponies and showing a correlation with age. The presented case could be the first one of a horse with a tentative diagnosis of gluten-sensitive enteropathy combined with dermatitis. Given the reported findings, this study warrants further investigations into gluten-sensitive enteropathy and dermatitis in individual horses affected with ISBD.

Gamma-Delta T Lymphocytes in the Diagnostic Approach of Coeliac Disease.

GOALS: To validate cut-off values of CD3 T-cell receptor gamma-delta chain (TCRγδ) intraepithelial lymphocyte (IEL) in the (differential) diagnosis of celiac disease (CD). BACKGROUND: CD is characterized by an increase in gamma-delta IEL (CD3TCRγδ IEL). STUDY: Percentages were determined by flow cytometric analysis of IELs from small bowel biopsies in 213 CD and 13 potential CD (PCD) patients and in total 112 controls. A cut-off value for percentages of CD3TCRγδ IEL to differentiate active CD and controls was obtained from a receiver operating characteristic curve and implemented in controls and PCD patients. RESULTS: Percentage of CD3TCRγδ IEL was significantly increased in the majority of CD patients, irrespective of the presence of villous atrophy. A cut-off value of 14% for CD3TCRγδ IEL resulted in 66.3% sensitivity and 96.6% specificity for CD diagnosis (area under the curve, 88.6%). CONCLUSIONS: A percentage of ≥14% CD3TCRγδ IEL has a high specificity for CD diagnosis and can be of diagnostic help in cases where diagnosis is not straightforward.

The effects of systemic treatment with aminobisphosphonates and statins on circulating Vγ9Vδ2-T cells in patients with advanced cancer.

Aminobisphosphonates (NBP) are used for treatment of metastatic bone disease. Frequently, patients undergoing NBP-treatment experience side-effects, known as acute phase response (APR), resulting from cytokine production by Vγ9Vδ2-T cells. As opposed to NBP, statins reduce intracellular phosphoantigen levels and prevent NBP-induced Vγ9Vδ2-T cell activation in vitro. We conducted a pilot study in patients with (bone-)metastasized malignancies receiving NBP-treatment and evaluated the phenotype and function of circulating Vγ9Vδ2-T cells in vivo and the effects of statins on Vγ9Vδ2-T cell responses and the associated APR. We observed reduced expression of perforin, granzyme B and HLA-DR on Vγ9Vδ2-T cells in patients treated with NBP and statins. However, statins could not prevent NBP-induced changes in circulating Vγ9Vδ2-T cell numbers or production of IFNγ and TNFα. Consistent with this, simvastatin could not prevent the occurrence of APR upon NBP-infusion. These observations call for the exploration of alternative strategies to prevent collateral APR upon NBP treatment.

Changes in peripheral blood lymphocyte subsets during arthritis development in arthralgia patients.

BACKGROUND: Multiple lymphocyte subsets like T and B cells have been connected to joint infiltration and inflammation in rheumatoid arthritis (RA). Identification of leucocyte subsets that are dysregulated in arthritis development could provide insight into the aetiology of RA. This study aimed to investigate the composition of the peripheral blood components, i.e. CD14(+) monocytes, CD4(+) and CD8(+) T lymphocytes (CD3(+)), CD80(+), C-X-C chemokine receptor 3 (CXCR3)(+) and CD27(+) B lymphocytes (CD19(+)), CD16(+)CD56(+)CD3(-) natural killer (NK) cells and activated CD56(+)CD3(+) T cells, for association with arthritis development in patients with arthralgia. METHODS: Peripheral blood was collected from 89 patients with early RA (disease duration <6 months), 37 healthy controls (HC) and 113 patients with arthralgia (22 developed arthritis within ≤1 year, 18 developed arthritis after >1 year and 73 did not develop arthritis). Absolute numbers of monocytes and lymphocyte subsets in whole heparinized blood were determined with flow cytometry using quantification beads in combination with fluorescent labelled antibodies for T cells, B cells, monocytes, NK cells and activated T cells. RESULTS: In patients with early RA, significant decreases in numbers of (activated) T cells, CD80(+) and memory B cells and a trend towards smaller numbers of CD8(+) T cells was observed compared to HC. Similar differences were seen in patients with arthralgia who developed or did not develop arthritis (non-converters), with significantly decreased CD8(+) T cells and memory B cells. Patients with arthralgia who developed arthritis were split into groups that developed arthritis within 1 year (early converters) or after 1 year (late converters). Late converters had a significantly decreased number of CD8(+) T cells compared to non-converters; early converters had a decreased number of memory B cells. Longitudinal analysis of converters showed a significant relative increase in CD80(+) B cells towards the conversion time point compared to 24 months prior to conversion. CONCLUSIONS: This study revealed that patients with arthralgia who develop arthritis demonstrate a change in cellular immune parameters apparent in the periphery, starting with a decrease in cytotoxic T cells 24 months prior to arthritis development, followed by a decrease in the number of memory B cells 12 months prior to disease onset.

T cell profiling reveals high CD4+CTLA-4 + T cell frequency as dominant predictor for survival after prostate GVAX/ipilimumab treatment.

Immune checkpoint blockade enhances antitumor responses, but can also lead to severe immune-related adverse events (IRAE). To avoid unnecessary exposure to these potentially hazardous agents, it is important to identify biomarkers that correlate with clinical activity and can be used to select patients that will benefit from immune checkpoint blockade. To understand the consequences of CTLA-4 blockade and identify biomarkers for clinical efficacy and/or survival, an exploratory T cell monitoring study was performed in a phase I/II dose escalation/expansion trial (n = 28) of combined Prostate GVAX/ipilimumab immunotherapy. Phenotypic T cell monitoring in peripheral blood before and after Prostate GVAX/ipilimumab treatment revealed striking differences between patients who benefited from therapy and patients that did not. Treatment-induced rises in absolute lymphocyte counts, CD4(+) T cell differentiation, and CD4(+) and CD8(+) T cell activation were all associated with clinical benefit. Moreover, significantly prolonged overall survival (OS) was observed for patients with high pre-treatment frequencies of CD4(+)CTLA-4(+), CD4(+)PD-1(+), or differentiated (i.e., non-naive) CD8(+) T cells or low pre-treatment frequencies of differentiated CD4(+) or regulatory T cells. Unsupervised clustering of these immune biomarkers revealed cancer-related expression of CTLA-4(+) in CD4(+) T cells to be a dominant predictor for survival after Prostate GVAX/ipilimumab therapy and to thus provide a putative and much-needed biomarker for patient selection prior to therapeutic CTLA4 blockade.

Cutting edge: Rapid recovery of NKT cells upon institution of highly active antiretroviral therapy for HIV-1 infection.

CD1d-restricted NKT cells play important regulatory roles in various immune responses and are rapidly and selectively depleted upon infection with HIV-1. The cause of this selective depletion is incompletely understood, although it is in part due to the high susceptibility of CD4+ NKT cells to direct infection and subsequent cell death by HIV-1. Here, we demonstrate that highly active antiretroviral therapy (HAART) results in the rapid recovery of predominantly CD4(-) NKT cells with kinetics that are strikingly similar to those of mainstream T cells. As it is well known that the early recovery of mainstream T cells in response to HAART is due to their redistribution from tissues to the circulation, our data suggest that the selective depletion of circulating NKT cells is likely due to a combination of cell death and tissue sequestration and indicates that HAART can improve immune functions by reconstituting both conventional T cells and immunoregulatory NKT cells.