CNS Infiltration of Peripheral Immune Cells: D-Day for Neurodegenerative Disease?

While the central nervous system (CNS) was once thought to be excluded from surveillance by immune cells, a concept known as “immune privilege,” it is now clear that immune responses do occur in the CNS—giving rise to the field of neuroimmunology. These CNS immune responses can be driven by endogenous (glial) and/or exogenous (peripheral leukocyte) sources and can serve either productive or pathological roles. Recent evidence from mouse models supports the notion that infiltration of peripheral monocytes/macrophages limits progression of Alzheimer's disease pathology and militates against West Nile virus encephalitis. In addition, infiltrating T lymphocytes may help spare neuronal loss in models of amyotrophic lateral sclerosis. On the other hand, CNS leukocyte penetration drives experimental autoimmune encephalomyelitis (a mouse model for the human demyelinating disease multiple sclerosis) and may also be pathological in both Parkinson's disease and human immunodeficiency virus encephalitis. A critical understanding of the cellular and molecular mechanisms responsible for trafficking of immune cells from the periphery into the diseased CNS will be key to target these cells for therapeutic intervention in neurodegenerative diseases, thereby allowing neuroregenerative processes to ensue

Multilocus ISSR Markers Reveal Two Major Genetic Groups in Spanish and South African Populations of the Grapevine Fungal Pathogen Cadophora luteo-olivacea

Cadophora luteo-olivacea is a lesser-known fungal trunk pathogen of grapevine which has been recently isolated from vines showing decline symptoms in grape growing regions worldwide. In this study, 80 C. luteo-olivacea isolates (65 from Spain and 15 from South Africa) were studied. Inter-simple-sequence repeat-polymerase chain reaction (ISSR-PCR) generated 55 polymorphic loci from four ISSR primers selected from an initial screen of 13 ISSR primers. The ISSR markers revealed 40 multilocus genotypes (MLGs) in the global population. Minimum spanning network analysis showed that the MLGs from South Africa clustered around the most frequent genotype, while the genotypes from Spain were distributed all across the network. Principal component analysis and dendrograms based on genetic distance and bootstrapping identified two highly differentiated genetic clusters in the Spanish and South African C. luteo-olivacea populations, with no intermediate genotypes between these clusters. Movement within the Spanish provinces may have occurred repeatedly given the frequent retrieval of the same genotype in distant locations. The results obtained in this study provide new insights into the population genetic structure of C. luteo-olivacea in Spain and highlights the need to produce healthy and quality planting material in grapevine nurseries to avoid the spread of this fungus throughout different grape growing regions

Primary vulvar squamous cell carcinomas with high T cell infiltration and active immune signaling are potential candidates for neoadjuvant PD-1/PD-L1 immunotherapy

Background A profound insight into the immune landscape of vulvar squamous cell carcinoma (VSCC) is lacking. Here, an in-depth interrogation of T cell infiltration, local immune contexture, signaling pathways and checkpoint molecule expression was performed in early-stage and late-stage VSCC. Methods The type, location, and infiltration pattern of T cells were studied in 109 patients with primary VSCC FIGO stage I-III. RNA expression of genes involved in immune oncology and oncogenic signaling pathways was analyzed in 40 VSCC, matched for prognostic clinicopathological variables, analyzed for HPV and p53 status, and selected based on T cell infiltration. Results High intraepithelial infiltration with CD4 or CD8 T cells was associated with longer overall and recurrence-free survival and formed an independent prognostic factor, outperforming molecular subtype and stage of the disease. Strong T cell infiltrated VSCC displayed a coordinated immune response reflected by a positive association between T cells and different lymphocyte and myeloid cell subsets. The expression of genes involved in the migration of T cells and myeloid cells, T cell activation and costimulation, interferon (IFN)-γsignaling, cytotoxicity and apoptosis was higher than in low infiltrated tumors. An active immune signaling profile was observed in all inflamed, part of the altered-excluded and not in altered-immunosuppressed or deserted VSCC. While several checkpoint molecules were overexpressed, only PD-L1 expression displayed discriminatory ability and clinical usefulness. High PD-L1 expression was detected in all inflamed and ∼60% of the altered-excluded VSCC. Conclusion An active immune signaling profile is present in 35% of primary FIGO I-III VSCCs, suggesting potential responsiveness to neoadjuvant PD-1/PD-L1 immunotherapy

Similar aneurysm progression in AAA patients using an ACE inhibitor (dashed line, n = 82) and those not using an ACE-inhibitor (solid line, n = 204) (data from the PHAST study¹⁷).

<p>The mean 18 month difference between AAA patients on an ACE inhibitor and those not was −0.24 mm (95% CI: −0.90–0.45 mm).</p

Baseline patient characteristics of the PHAST population.

<p>Median [inter quartile range].</p><p>*) significant difference between the two groups (P<0.05). Abbreviations: BMI, body mass index; ApoA, apolipoprotein A; ApoB, apolipoprotein B.</p><p>Baseline patient characteristics of the PHAST population.</p

Effect of ramipril on aneurysm wall leucocyte content.

<p>Semi-quantitative analysis of aortic wall monocyte/macrophage (CD68), neutrophil (myeloperoxidase (MPO)), B-cell (CD20), plasma cell (CD138), T-cell (CD3), T-helper cell (CD4), and cytotoxic T-cells (CD8). Cell counts are based on reflect the number of double positive cells per 6 medium power fields. Cell content is expressed as the number of cells per mm². Non-treated controls (white bars); ramipril-treated patients (grey bars). *P<0.009.</p

Relative mRNA expression of selected inflammatory mediators, proteases, cytokines, and cell activation markers (log transcript level relative to GAPDH (GAPDH = 0)).

<p>*⁾Significance reached after Benjamini-Hochberg correction.</p><p>Abbreviations: IL, interleukin; TNF-α, tumor necrosis factor-α; MCP-1, monocyte chemotactic protein-1; IFN-γ, interferon-γ; MMP, matrix metalloproteinase; TGF-β, transforming growth factor β; PAI-1, plasminogen activator inhibitor-1.</p><p>*⁾Snap frozen material was available from 10 patients.</p><p>Relative mRNA expression of selected inflammatory mediators, proteases, cytokines, and cell activation markers (log transcript level relative to GAPDH (GAPDH = 0)).</p

Aneurysm wall protein interleukin-6, interleukin-8, and monocyte chemoattractant protein 1 content.

<p>(*) levels significantly lower in Ramipril-treated individuals (P<0.014 and P<0.008 for IL-8 and MCP-1 respectively). Non-treated controls (white bars); Ramipril-treated patients (grey bars).</p

Ramipril reduces (P<0.004) macrophage activation as assessed by CD68/HLA-Dr double staining and increases aortic wall M2 content (CD68/CD163 double positive cells, P<0.006) content, thus resulting in a shift in the M1/M2 balance (P<0.002).

<p>Cell counts are based on the number of double positive cells per 6 medium power fields. Cell content is expressed as the number of cells per mm². Non-treated controls (white bars); ramipril-treated patients (grey bars).</p

Baseline patient characteristics of the Ramipril intervention study.

<p>Median [inter quartile range].</p><p>Baseline patient characteristics of the Ramipril intervention study.</p