Overexpression of immunomodulatory mediators in oral precancerous lesions

Human leukocyte antigen (HLA) G and E, programmed cell death 1 ligand 1 (PD-L1), IL-10 and TGF-β are proteins involved in failure of the antitumor immune response. We investigated the expression of these immunomodulatory mediators in oral precancerous lesions (oral leukoplakia-OL; n = 80) and whether these molecules were related to the risk of malignant transformation. Samples of normal mucosa (n = 20) and oral squamous cells carcinoma (OSCC, n = 20) were included as controls. Tissue and saliva samples were analyzed by immunohistochemistry and ELISA respectively. Fifteen OL samples showed severe dysplasia (18.7%) and 40 samples (50%) presented combined high Ki-67/p53. Irrespective of the degree of epithelial dysplasia and the proliferation/apoptosis index of OL, the expression of HLA-G, -E, PD-L1, IL-10, TGF-β2 and -β3 was higher to control (P < 0.05) and similar to OSCC (P > 0.05). The number of granzyme B⁺ cells in OL was similar to control (P = 0.28) and lower compared to OSCC (P < 0.01). Salivary concentrations of sHLA-G, IL-10 and TGF-β did not allow for a distinction between OL and healthy individuals. Overexpression of immunosuppressive mediators in the OL reflects the immune evasion potential of this lesion, which is apparently independent of at cytological and proliferation/apoptosis status.     

Parietal cortex integrates contextual and saliency signals during the encoding of natural scenes in working memory

The Brief presentation of a complex scene entails that only a few objects can be selected, processed indepth, and stored in memory. Both low‐level sensory salience and high‐level context‐related factors (e.g., the conceptual match/mismatch between objects and scene context) contribute to this selection process, but how the interplay between these factors affects memory encoding is largely unexplored. Here, during fMRI we presented participants with pictures of everyday scenes. After a short retention interval, participants judged the position of a target object extracted from the initial scene. The target object could be either congruent or incongruent with the context of the scene, and could be located in a region of the image with maximal or minimal salience. Behaviourally, we found a reduced impact of saliency on visuospatial working memory performance when the target was out‐of‐context. Encoding‐related fMRI results showed that context–congruent targets activated dorsoparietal regions, while context–incongruent targets de‐activated the ventroparietal cortex. Saliency modulated activity both in dorsal and ventral regions, with larger context‐related effects for salient targets. These findings demonstrate the joint contribution of knowledge‐based and saliency‐driven attention for memory encoding, highlighting a dissociation between dorsal and ventral parietal regions. Hum Brain Mapp 36:5003–5017, 2015. © 2015 Wiley Periodicals, Inc .     

Differential dependence on nuclear factor‐κB‐inducing kinase among natural killer T‐cell subsets in their development

Natural killer T cells (NKT cells) are comprised of several subsets. However, the possible differences in their developmental mechanisms have not been fully investigated. To evaluate the dependence of some NKT subpopulations on nuclear factor-κB-inducing kinase (NIK) for their generation, we analysed the differentiation of NKT cells, dividing them into subsets in various tissues of alymphoplasia (aly/aly), a mutant mouse strain that lacks functional NIK. The results indicated that the efficient differentiation of both invariant NKT (iNKT) and non-iNKT cells relied on NIK expression in non-haematopoietic cells; however, the dependence of non-iNKT cells was lower than that of iNKT cells. Especially, the differentiation of CD8⁺ non-iNKT cells was markedly resistant to the aly mutation. The proportion of two other NKT cell subsets, NK1.1⁺ γδ T cells and NK1.1⁻ iNKT cells, was also significantly reduced in aly/aly mice, and this defect in their development was reversed in wild-type host mice given aly/aly bone marrow cells. In exerting effector functions, NIK in NKT-αβ cells appeared dispensable, as NIK-deficient NKT-αβ cells could secrete interleukin-4 or interferon-γ and exhibit cytolytic activity at a level comparable to that of aly/+ NKT-αβ cells. Collectively, these results imply that the NIK in thymic stroma may be critically involved in the differentiation of most NKT cell subsets (although the level of NIK dependence may vary among the subsets), and also that NIK in NKT-αβ cells may be dispensable for their effector function.     

Therapeutic envelope vaccination in combination with antiretroviral therapy temporarily rescues SIV‐specific CD4+ T‐cell‐dependent natural killer cell effector responses in chronically infected rhesus macaques

Natural killer (NK) cells are essential components of the immune system, and due to their rapid response potential, can have a great impact during early anti‐viral immune responses. We have previously shown that interleukin‐2‐dependent NK and CD4⁺ T‐cell co‐operative immune responses exist in long‐term simian immunodeficiency virus (SIV) ‐infected controlling macaques and can be rescued in SIV‐infected non‐controlling macaques by a short course of antiretroviral therapy (ART). Given that co‐operative responses may play an important role in disease prevention and therapeutic treatment, in the present study we sought to determine if these responses can be enhanced in chronically SIV‐infected macaques by vaccination with a single‐dose of envelope protein given during ART. To this end, we treated 14 chronically SIV‐infected macaques with ART for 11 weeks and gave 10 of these macaques a single intramuscular dose of SIV gp120 at week 9 of treatment. ART significantly decreased plasma and mucosal viral loads, increased the numbers of circulating CD4⁺ T cells in all macaques, and increased T‐cell‐dependent envelope‐ and gag‐specific interferon‐γ and tumour necrosis factor‐α production by circulatory CD56⁺ NK cells. The therapeutic envelope immunization resulted in higher envelope‐specific responses compared with those in macaques that received ART only. Functional T‐cell responses restored by ART and therapeutic Env immunization were correlated with transiently reduced plasma viraemia levels following ART release. Collectively our results indicate that SIV‐specific T‐cell‐dependent NK cell responses can be efficiently rescued by ART in chronically SIV‐infected macaques and that therapeutic immunization may be beneficial in previously vaccinated individuals.     

Interleukin‐15‐activated natural killer cells kill autologous osteoclasts via LFA‐1, DNAM‐1 and TRAIL,and inhibit osteoclast‐mediated bone erosion in vitro

Osteoclasts reside on bone and are the main bone resorbing cells playing an important role in bone homeostasis, while natural killer (NK) cells are bone‐marrow‐derived cells known to play a crucial role in immune defence against viral infections. Although mature NK cells traffic through bone marrow as well as to inflammatory sites associated with enhanced bone erosion, including the joints of patients with rheumatoid arthritis, little is known about the impact NK cells may have on mature osteoclasts and bone erosion. We studied the interaction between human NK cells and autologous monocyte‐derived osteoclasts from healthy donors in vitro. We show that osteoclasts express numerous ligands for receptors present on activated NK cells. Co‐culture experiments revealed that interleukin‐15‐activated, but not resting, NK cells trigger osteoclast apoptosis in a dose‐dependent manner, resulting in drastically decreased bone erosion. Suppression of bone erosion requires contact between NK cells and osteoclasts, but soluble factors also play a minor role. Antibodies masking leucocyte function‐associated antigen‐1, DNAX accessory molecule‐1 or tumour necrosis factor‐related apoptosis‐inducing ligand enhance osteoclast survival when co‐cultured with activated NK cells and restore the capacity of osteoclasts to erode bone. These results suggest that interleukin‐15‐activated NK cells may directly affect bone erosion under physiological and pathological conditions.     

Surveillance of cell and tissue perturbation by receptors in the LRC

The human leukocyte receptor complex (LRC) encompasses several sets of genes with a common evolutionary origin and which form a branch of the immunoglobulin superfamily (IgSF). Comparisons of LRC genes both within and between species calls for a high degree of plasticity. The drive for this unprecedented level of variation is not known, but it relates in part to interaction of several LRC products with polymorphic human leukocyte antigen (HLA) class I molecules. However, the range of other proposed ligands for LRC products indicates a dynamic set of receptors that have adapted to detect target molecules relating to numerous cellular pathways. Several receptors in the complex bind a molecular signature in collagenous ligands. Others detect a variety of motifs relating to pathogens in addition to cellular stress, attesting to the opportunistic versatility of LRC receptors.     

NK cells: tuned by peptide?

Natural killer cells express multiple receptors for major histocompatibility complex (MHC) class I, including the killer cell immunoglobulin-like receptors (KIRs) and the C-type lectin-like CD94:NKG2 receptors. The KIR locus is extremely polymorphic, paralleling the diversity of its classical MHC class I ligands. Similarly, the conservation of the NKG2 family of receptors parallels the conservation of MHC-E, the ligand for CD94:NKG2A/C/E. Binding of both CD94:NKG2 heterodimers and KIR to their respective MHC class I ligand is peptide dependent, and despite the evolution of these receptors, they have retained the property of peptide selectivity. Such peptide selectivity affects these two systems in different ways. HLA-E binding non-inhibitory peptides augment inhibition at CD94:NKG2A, while HLA-C binding non-inhibitory peptides antagonize inhibition at KIR2DL2/3, implying that KIRs are specialized to respond positively to changes in peptide repertoire. Thus, while specific KIRs, such as KIR2DL3, are associated with beneficial outcomes from viral infections, viral peptides augment inhibition at CD94:NKGA. Conversely, NKG2A-positive NK cells sense MHC class I downregulation more efficiently than KIRs. Thus, these two receptor:ligand systems appear to have complementary functions in recognizing changes in MHC class I.     

Future expectations in digestive endoscopy: competition with other novel imaging techniques

Digestive endoscopy has been evolving from primary diagnostic to extensive therapeutic modalities in the management of gastrointestinal diseases. The present endoscopic imaging includes (A) standard endoscopy alone and /or with adjunct technologies such as point enhancement, e.g. confocal endomicroscopy and field enhancement technologies such as chromoendoscopy, NBI and FICE and (B) endoscopic ultrasound. Other novel imaging technologies including virtual colonoscopy or CT/MR colonography, CT or MRI enterography and capsule endoscopy have also been developed. This article reviews the diagnostic and therapeutic role of digestive endoscopy and future directions of digestive endoscopy are discussed. Digestive endoscopy is also compared with emerging novel imaging techniques in gastrointestinal diseases such as capsule endoscopy and CT colonography. The fact that digestive endoscopy has become a multidisciplinary specialty combining advances in all fields (radiology, bioengineering, surgery and gastroenterology) is highlighted.     

A study of lymphoma of large granular lymphocytes with modern modalities: report of two cases and review of the literature.

Two cases of lymphoma of large granular lymphocytes are reported. The first case expressed natural killer (NK) cell, some T-cell (CD 2, CD 5, CD 8), and HLA-DR antigens, but was negative for other T-cell (CD 3, CD 4, CD 7), T-cell receptor (TCR), B-cell, and myeloid antigens. Germline configuration was demonstrated for TCR, and immunoglobulin heavy and light chain genes. The second case expressed NK cell, some T-cell (CD 3, CD 7, CD 8), and TCR antigens, but was negative for other T-cell (CD 4, CD 5), B-cell, myeloid, and HLA-DR antigens. Rearrangement of TCR alpha and beta chains were detected. Thus, the findings of case 1 were consistent with true NK cell lineage and case 2 with NK-like T-cell lineage. Our report underscores the heterogeneity of this newly recognized lymphoma, which nevertheless carries a consistently poor prognosis and is probably more prevalent in the Asian population. This study also provides information concerning immunophenotypes of cellular infiltrates in internal organs and cytogenetic abnormalities in this lymphoma; neither has been reported frequently in the literature. The importance of detecting cytoplasmic granules in tissue imprints or electron micrographs for differentiating other T-cell lymphomas is emphasized, and the classification of large granular lymphoproliferative disorders is discussed.