Critical Role In Disease Pathogenesis Research Articles

Pathogenesis of multiple sclerosis: genetic, environmental and random mechanisms

BackgroundThe pathogenesis of multiple sclerosis (MS) requires both genetic factors and environmental events. The question remains, however, whether these factors and events completely describe the MS disease process. This question...

Commentary on the role of berberine in addition to methimazole compare to methimazole alone in the treatment of Graves’ Diseas

Graves’ Disease (GD) is the most common form of hyperthyroidism. It affects 3% of female patients and 0.5% of male patients usually between the age of 30-60. It is the cause of 80% of hyperthyroid cases in the USA. The pathogenesis of the disease is complex and autoimmunity plays a key role. The antibodies stimulating the thyrotropin receptor (TRAb) lead to uncontrolled Thyroid-stimulating Hormone (TSH) overproduction of thyroid hormones from the overactive thyroid gland. The disease is frequently associated with Graves's ophthalmopathy, dermatopathy, and clubbing. It affects the whole body with deleterious effects on the Cardiovascular system, vision, bones, etc. The treatment of the disease is with anti-thyroid medications, Radioactive iodine, or thyroid surgery each one of which has its pluses and minuses. Other factors like Genetic, inflammatory, immune, environmental factors, etc. play critical roles in disease pathogenesis as well. In this article, we are discussing the newfound role of the gut-thyroid axis in the pathogenesis of GD. We are describing the role of the probiotic Berberine added to the anti-thyroid medication Methimazole in changing the gut microbiota by increasing the benefits and decreasing the deleterious bacteria in the gut. This can lead to the induction of anti-inflammatory cytokines and reduction of inflammatory ones which can regulate the immune system faster and better than with treatment with Methimazole alone. This treatment combination can eventually lead through the effect on the gut-thyroid axis to faster disappearance of the TRAb and remission and cure of GD.

Longitudinal Characterization of a Neutralizing and Total Antibody Response in Patients with Severe COVID-19 and Fatal Outcomes.

The host immune response to SARS-CoV-2 appears to play a critical role in disease pathogenesis and clinical manifestations in severe COVID-19 cases. Until now, the importance of developing a neutralizing antibody response in the acute phase and its relationship with progression to severe disease or fatal outcome among hospitalized patients remains unclear. In this study, we aim to characterize and compare longitudinally the primary humoral immune host response in the early stages of the disease, looking for an association between neutralization, antibody titers, infective viral lineage, and the clinical outcome in hospitalized and non-hospitalized patients. A total of 111 patients admitted at INER from November 2021 to June 2022 were included. We found that patients with negative or low neutralization showed a significant reduction in survival probability compared to patients with medium or high neutralization. We observed a significant decrease in the median of neutralization in patients infected with viral variants with changes in RBD of the spike protein. Our results suggest that developing an early and robust neutralizing response against SARS-CoV-2 may increase survival probability in critical patients.

Total oxidant capacity, total antioxidant capacity, ischemic modified albumin, microRNA levels, and their relationship with psoriasis area and severity index.

Aims To examine the differences in the levels of microRNA, ischemic modified albumin (IMA), total oxidant capacity (TOC), and total antioxidant capacity (TAC) of persons with and without psoriasis and, in the case group, the relationship between these parameters and psoriasis area and severity index (PASI). Methods Blood samples were collected from patients and healthy participants to examine levels of these parameters. Results The mean serum TOC level was higher in the case group. The mean serum TAC and IMA levels were significantly lower in the case group (P <0.001). It was observed that the mean serum miR-203 and miR-146a levels were increased in psoriasis patients. It was determined that there was only a significant positive weak correlation between miR-203 and PASI (r = 0.232, P = 0.027). Limitations The small sample size, not controlling serum albumin and not evaluating the effects of the treatment agents used by the patients on oxidative and inflammatory processes. Conclusion In the case group changes in the mean serum TOC and TAC levels provide evidence that oxidative stress may play a critical role in disease pathogenesis. The increase in the mean serum miR-203 and miR-146a levels suggest the possibility of therapies targeting these microRNAs as a new option.

A multifaceted evaluation of microgliosis and differential cellular dysregulation of mammalian target of rapamycin signaling in neuronopathic Gaucher disease.

Neuronopathic Gaucher disease (nGD) is an inherited neurodegenerative disease caused by mutations in GBA1 gene and is associated with premature death. Neuroinflammation plays a critical role in disease pathogenesis which is characterized by microgliosis, reactive astrocytosis, and neuron loss, although molecular mechanisms leading to neuroinflammation are not well-understood. In this report, we developed a convenient tool to quantify microglia proliferation and activation independently and uncovered abnormal proliferation of microglia (∼2-fold) in an adult genetic nGD model. The nGD-associated pattern of inflammatory mediators pertinent to microglia phenotypes was determined, showing a unique signature favoring pro-inflammatory chemokines and cytokines. Moreover, highly polarized (up or down) dysregulations of mTORC1 signaling with varying lysosome dysfunctions (numbers and volume) were observed among three major cell types of nGD brain. Specifically, hyperactive mTORC1 signaling was detected in all disease-associated microglia (Iba1high) with concurrent increase in lysosome function. Conversely, the reduction of neurons presenting high mTORC1 activity was implicated (including Purkinje-like cells) which was accompanied by inconsistent changes of lysosome function in nGD mice. Undetectable levels of mTORC1 activity and low Lamp1 puncta were noticed in astrocytes of both diseased and normal mice, suggesting a minor involvement of mTORC1 pathway and lysosome function in disease-associated astrocytes. These findings highlight the differences and complexity of molecular mechanisms that are involved within various cell types of the brain. The quantifiable parameters established and nGD-associated pattern of neuroinflammatory mediators identified would facilitate the efficacy evaluation on microgliosis and further discovery of novel therapeutic target(s) in treating neuronopathic Gaucher disease.

S1P analogues SEW2871, BAF312 and FTY720 affect human Th17 and Treg generation ex vivo

Multiple Sclerosis is an immune-mediated neurodegenerative disease. IL-23-mediated signaling and Th17 cells play critical roles in disease pathogenesis in murine models of disease and humans. Sphingosine 1 phosphate (S1P) regulates migration of several types of immune cells including Th17 cells. S1P analogues (fingolimod (FTY720) and Siponimod (BAF312)) have been approved and currently used for MS treatment. Immunomodulatory roles for FTY720 have been defined, however, how different S1P analogues impact human Th17 and Treg cell generation and cytokine production, and IL-23-mediated signaling have not yet been explored in detail. In the current study, we investigated the effects of S1P receptor 1 (S1P1) specific S1P analogue SEW2871, S1P1 and S1P5 specific BAF312, and non-selective FTY720 on human Th17 and Treg differentiation and IL-23-mediated signaling. All three S1P analogues directly inhibited Th17 cell differentiation ex vivo while increasing Treg differentiation from naive CD4 + T cells. All three S1P analogues suppressed IL-23-mediated STAT4, NF-kB and AKT activation. Lastly, all three S1P analogues also inhibited Dectin-1 expression by both mature and immature monocyte-derived dendritic cells (moDCs) and in turn curdlan-mediated production of IL-23p19, p40, IL-6 and IL-1β cytokines. Our results provide novel insight into the immunomodulatory roles of different S1P analogues on human Th17 and Treg cell biology.

Evaluation and correlation of laboratory, radiological markers, and cytokine inflammation in patients with severe acute respiratory syndrome coronavirus disease 2019

Aim and objectiveFever and lymphocyte count to start the interventions and not wait for the upregulation of IL-6 and down regulation of SpO2 levels amongst the patients.BackgroundIn SARS-CoV-2 host immune response play a critical role in disease pathogenesis. The coronavirus not only activates antiviral immune responses, but it can also cause uncontrolled inflammatory responses categorized by marked proinflammatory cytokine release in patients with severe COVID-19, leading to lymphopenia. In this present article we have studied the basic parameters of COVID-19 that includes fever and lymphocyte count and their deep association with markers of disease prognosis and cytokine storm such as IL-6, HRCT score and SpO2 levels. With this basic routine clinical and laboratory parameters we can consider recurrent/prolonged fever and low count of lymphocytes are the earliest biomarkers of the upcoming cytokine storm.MethodWe conducted a hospital-based case-control study of patients who visited to the tertiary healthcare centre in Amravati (Maharashtra), India with a positive SARS-CoV-2 polymerase chain reaction (PCR) assay, from August 01, 2020 to July 03, 2021. Upon hospital visit, all patients underwent a HRCT chest score, complete blood count (CBCs), renal and liver panel, IL-6. Patients with fever and other symptoms which were not responsive to the treatment were admitted to the hospital. Patients who tested positive and admitted to the hospital were not discharged until they had 2 negative RTPCR tests 24 hours apart. Patient details including demographics, history of comorbidities associated with every patient, the records of the vital signs, symptoms and all the reports of radiological and blood assays were obtained from computerized medical records of the hospital.ResultsWe screened total 1324 patients admitted to Tertiary health care center Amravati (Maharashtra), India, from 01 August 2020 to 03 July 2021. From these study, total 156 patients are excluded because of the number of patients, i.e. 106/156 patients founded with no prolonged fever but having same common symptoms. And remaining 50 patients excluded because of they were found with no short duration of fever and asymptomatic. Data was collected from the remaining 1168 (88.21%) as a cohort control group. The cases with recurrent/prolonged fever and short duration had median age [52 (21-83) v/s 52 (17-92) p=0.42] it shows that age is not statistically significant. On the other hand, the cases with recurrent/prolonged fever were more likely to have hypoxia were SpO2 level [90 (50-98)] v/s in short duration of fever were observed.[95 (45-98) p=0.02] shows statistically associated. Similarly, the HRCT chest score in recurrent/prolonged fever were found to be around [8 (0-24)] v/s [6 (0-22) p=0.027] it represents the significant difference.ConclusionFever and lymphocyte count and their deep association with markers of disease prognosis and cytokine storm such as IL-6, HRCT score and SpO2 level. With this basic routine clinical and labortory parameters we can consider recurrent/prolonged fever and low count of lymphocytes are the earliest biomarkers of the upcoming cytokine storm. Therefore, study recommends the use of fever and lymphocyte count to start the interventions and not wait for the upregulation of IL-6 and down regulation of SpO2 which occurs in late stage.

The Challenges and Opportunities in the Development of MicroRNA Therapeutics: A Multidisciplinary Viewpoint.

microRNAs (miRs) are emerging as attractive therapeutic targets because of their small size, specific targetability, and critical role in disease pathogenesis. However, <20 miR targeting molecules have entered clinical trials, and none progressed to phase III. The difficulties in miR target identification, the moderate efficacy of miR inhibitors, cell type-specific delivery, and adverse outcomes have impeded the development of miR therapeutics. These hurdles are rooted in the functional complexity of miR’s role in disease and sequence complementarity-dependent/-independent effects in nontarget tissues. The advances in understanding miR’s role in disease, the development of efficient miR inhibitors, and innovative delivery approaches have helped resolve some of these hurdles. In this review, we provide a multidisciplinary viewpoint on the challenges and opportunities in the development of miR therapeutics.

MicroRNAs in Genetic Etiology of Human Diseases.

Since their first discovery more than 20years ago, miRNAs have been subject to deliberate research and analysis for revealing their physiological or pathological involvement. Regulatory roles of miRNAs in signal transduction, gene expression, and cellular processes in development, differentiation, proliferation, apoptosis, and homeostasis also imply their critical role in disease pathogenesis. Their roles in cancer, neurodegenerative diseases, and other systemic diseases have been studied broadly. In these regulatory pathways, their mutations and target sequence variations play critical roles to determine their functional repertoire. In this chapter, we summarize studies that investigated the role of mutations, polymorphisms, and other variations of miRNAs in respect to pathological processes.

A systematic review of immune pathogenesis of SARS-COV-2 infection

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared a pandemic by the world health organization on March 11, 2020. The host immune response to SARS-CoV-2 appears to play a critical role in disease pathogenesis and clinical manifestations. SARS-CoV-2 causes direct activation of anti-viral immune responses and leads to the release of uncontrolled inflammatory mediators. These SARS-CoV-2-induced immune responses may lead to various other abnormalities like lymphopenia, thrombocytopenia and granulocyte and monocyte dysfunction, making the patient more prone to secondary infections by microorganisms, which may result in further further serious complications like septic shock, severe multiple organ dysfunction and eventually death. Therefore, mechanisms underlying immune abnormalities in patients with COVID-19 disease must be elucidated to guide clinical management of the disease. Rational management in combating the disease includes enhancing anti-viral immunity and inhibiting systemic inflammation, which is key to successful treatment.

Immune characterization and profiles of SARS-CoV-2 infected patients reveals potential host therapeutic targets and SARS-CoV-2 oncogenesis mechanism

The spread of SARS-CoV-2 and the increasing mortality rates of COVID-19 create an urgent need for treatments, which are currently lacking. Although vaccines have been approved by the FDA for emergency use in the U.S., patients will continue to require pharmacologic intervention to reduce morbidity and mortality as vaccine availability remains limited. The rise of new variants makes the development of therapeutic strategies even more crucial to combat the current pandemic and future outbreaks. Evidence from several studies suggests the host immune response to SARS-CoV-2 infection plays a critical role in disease pathogenesis. Consequently, host immune factors are becoming more recognized as potential biomarkers and therapeutic targets for COVID-19. To develop therapeutic strategies to combat current and future coronavirus outbreaks, understanding how the coronavirus hijacks the host immune system during and after the infection is crucial. In this study, we investigated immunological patterns or characteristics of the host immune response to SARS-CoV-2 infection that may contribute to the disease severity of COVID-19 patients. We analyzed large bulk RNASeq and single cell RNAseq data from COVID-19 patient samples to immunoprofile differentially expressed gene sets and analyzed pathways to identify human host protein targets. We observed an immunological profile of severe COVID-19 patients characterized by upregulated cytokines, interferon-induced proteins, and pronounced T cell lymphopenia, supporting findings by previous studies. We identified a number of host immune targets including PERK, PKR, TNF, NF-kB, and other key genes that modulate the significant pathways and genes identified in COVID-19 patients. Finally, we identified genes modulated by COVID-19 infection that are implicated in oncogenesis, including E2F transcription factors and RB1, suggesting a mechanism by which SARS-CoV-2 infection may contribute to oncogenesis. Further clinical investigation of these targets may lead to bonafide therapeutic strategies to treat the current COVID-19 pandemic and protect against future outbreaks and viral escape variants.

Systems biology drug screening identifies statins as enhancers of current therapies in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a B lymphoid malignancy highly dependent on the microenvironment. Despite new targeted therapies such as ibrutinib and venetoclax, disease progression and relapse remain an issue. CLL cell interactions with the supportive tissue microenvironment play a critical role in disease pathogenesis. We used a platform for drug discovery based on systems biology and artificial intelligence, to identify drugs targeting key proteins described to have a role in the microenvironment. The selected compounds were screened in CLL cell lines in the presence of stromal cells to mimic the microenvironment and validated the best candidates in primary CLL cells. Our results showed that the commercial drug simvastatin was the most effective and selective out of the tested compounds. Simvastatin decreased CLL cell survival and proliferation as well as cell adhesion. Importantly, this drug enhanced the antitumor effect of venetoclax and ibrutinib. We proposed that systems biology approaches combined with pharmacological screening could help to find new drugs for CLL treatment and to predict new combinations with current therapies. Our results highlight the possibility of repurposing widely used drugs such as statins to target the microenvironment and to improve the efficacy of ibrutinib or venetoclax in CLL cells.

Tumor-stroma interaction increases CD147 expression in neoplastic B lymphocytes in chronic lymphocytic leukemia

BackgroundChronic lymphocytic leukemia (CLL) microenvironment plays a critical role in disease pathogenesis. Matrix metalloproteinases (MMPs) are involved in CLL-B cell migration and survival. CD147 is associated with MMPs production by tumor and stromal cells. AimTo analyze CD147, MMP2 and MMP9 expression in CLL-B cells and its modulation by fibroblasts (Fb)-CLL-B cell interaction. MethodsCLL-B cells were co-cultured with Fb, as a simulation of CLL microenvironment. CD147 was evaluated in healthy donor (HD)-B cells and CLL-B cells by flow cytometry. MMP2 and MMP9 activity in CLL-plasma samples and conditioned media (CMs) was studied by zymography. ResultsMMP9/MMP2 plasma levels were significantly higher in CLL patients than in HD. CD147 expression (median fluorescence intensity) in CLL patients characterized 3 groups: low- (19.1 ± 3.2; n=3), middle- (42.7 ± 12.8; n=18) and high- (76.5 ± 9.6; n=5) related to CD147 expression in HD-B cells. CD147 expression significantly increased in CLL-B cells after Fb-CLL-B cell co-culture. A significant increase in proMMP2 activity was observed in CMs obtained from Fb-CLL-B cell co-cultures in comparison with isolated CLL-B cells. ConclusionsCD147 expression in CLL-B cells and MMPs secretion was induced by Fb-CLL-B cell contact, suggesting CD147 participation in the CLL pathophysiology.

The Impact and Modulation of Microenvironment-Induced Immune Resistance Against CAR T Cell and Antibody Treatments in Multiple Myeloma

The tumor microenvironment of multiple myeloma (MM) is known to play a critical role in disease pathogenesis, MM cell survival, and drug resistance. In addition, we have previously demonstrated the impact of the microenvironment also on immunotherapies. We discovered that bone marrow mesenchymal stromal cells (BMMSCs) protected MM cells from HLA restricted CD4 and CD8 cytotoxic T cells and NK cell-mediated daratumumab dependent cytotoxicity through a cell-adhesion mediated immune resistance (CAM-IR). This CAM-IR corresponded with the upregulation of anti-apoptotic proteins Survivin and Mcl-1 in MM cells and could be modulated by small inhibitors of these molecules. We now extended our studies to investigate the impact of the microenvironment on novel immunotherapeutic approaches such as chimeric antigen receptor-transduced T cells (CAR T cells) and death receptor mediated antibody treatments, which can induce direct apoptosis in MM cells. We also investigated the possibility to modulate CAM-IR with small molecule inhibitors of Survivin, XIAP, and Mcl-1. To this end, we tested a panel of MM reactive CAR T cells directed against CD38, BCMA, and CD138, with different target affinities, for their potential to kill MM cells in the absence or presence of BMMSCs. We observed no effect of BMMSCs on the cytotoxic capacity of BCMA- and CD38-targeting CAR T cells with high affinity for the target and that were capable of inducing high levels of MM cell lysis at very low effector to target ratios. In contrast, BMMSCs effectively protected MM cells against killing by BCMA- and CD38-targeting CAR T cells with relative low affinity, or CD138-targeting CAR T cells that were less powerful in their lytic activity. Taken together, we discovered a significant inverse correlation between the lytic capacity of the CAR T cells and the extent of BMMSC-mediated protection. Additionally, we found that BMMSCs protected MM cells from apoptosis induction by death receptor 5 (DR5; or TRAIL receptor 2) antibodies. In all cases of BMMSC-mediated protection against CAR T cells as well as DR5 antibodies or daratumumab, the protection could be abrogated by an inhibitor of Survivin, XIAP, and Mcl-1. This indicates that BMMSC-mediated protection against CAR T cell or antibody-mediated lysis is indeed associated with an upregulation of anti-apoptotic proteins, similarly to the well-described cell adhesion mediated drug resistance. In conclusion, our results confirm the potential negative impact of the tumor microenvironment in the development of an adaptive resistance of MM cells against immunotherapies. Our data further suggest that this microenvironmental shielding of MM cells can be overcome either by increasing the avidity of immune killer cells or through combination of immunotherapy with inhibitors of anti-apoptotic mediators. Figure 1 Disclosures Li: Canget Bio Tekpharma LLC: Membership on an entity's Board of Directors or advisory committees. Zweegman:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Themeli:Covagen: Consultancy. Van De Donk:Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Mutis:Aduro: Research Funding; Celgene: Research Funding; BMS: Research Funding; Amgen: Research Funding; Onkimmune: Research Funding; Janssen Pharmaceuticals: Research Funding; Novartis: Research Funding.

An RNA-seq primer for pulmonologists.

With the evolution of high throughput sequencing technologies, the past decade has seen an exponential rise in the use of RNA sequencing (RNA-seq). RNA-seq has deepened our understanding of biological systems to unprecedented levels of resolution, identifying not only gene expression signatures but also regulatory RNA molecules that may play critical roles in disease pathogenesis. Pulmonary research has quickly incorporated this technology, from characterizing the IL-17 signature of steroid-unresponsive COPD patients [1] to discovering pathogen-host interactions of M. tuberculosis [2]. This mini-review provides an overview of core features and applications of RNA-seq to familiarize non-experts with the methodology and how it has impacted our understanding of lung pathophysiology.

The impact of spliceosome mutations in MDS.

The impact of spliceosome mutations in MDS.

Entamoeba histolytica Cyclooxygenase-Like Protein Regulates Cysteine Protease Expression and Virulence.

The intestinal protozoan parasite Entamoeba histolytica (Eh) causes amebiasis associated with severe diarrhea and/or liver abscess. Eh pathogenesis is multifactorial requiring both parasite virulent molecules and host-induced innate immune responses. Eh-induced host pro-inflammatory responses plays a critical role in disease pathogenesis by causing damage to tissues allowing parasites access to systemic sites. Eh cyclooxygenase (EhCox) derived prostaglandin E2 stimulates the chemokine IL-8 from mucosal epithelial cells that recruits neutrophils to the site of infection to exacerbate disease. At present, it is not known how EhCox is regulated or whether it affects the expression of other proteins in Eh. In this study, we found that gene silencing of EhCox (EhCoxgs) markedly increased endogenous cysteine protease (CP) protein expression and virulence without altering CP gene transcripts. Live virulent Eh pretreated with arachidonic acid substrate to enhance PGE2 production or aspirin to inhibit EhCox enzyme activity or addition of exogenous PGE2 to Eh had no effect on EhCP activity. Increased CP enzyme activity in EhCoxgs was stable and significantly enhanced erythrophagocytosis, cytopathic effects on colonic epithelial cells and elicited pro-inflammatory cytokines in mice colonic loops. Acute infection with EhCoxgs in colonic loops increased inflammation associated with high levels of myeloperoxidase activity. This study has identified EhCox protein as one of the important endogenous regulators of cysteine protease activity. Alterations of CP activity in response to Cox gene silencing may be a negative feedback mechanism in Eh to limit proteolytic activity during colonization that can inadvertently trigger inflammation in the gut.

Toll-Like Receptor Stimulation by MicroRNAs in Acute Graft-vs.-Host Disease

Acute graft-vs.-host disease (aGVHD) is a frequent complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), accounting for substantial morbidity and mortality associated with this treatment modality. The pathogenesis of aGVHD involves a complex cascade of humoral and cellular interactions in which donor T cells target HLA mismatched host tissues, causing tissue injury through secretion of pro-inflammatory cytokines and induction of direct cytotoxicity. Toll-like receptors (TLRs) are key components of the innate immune system that recognize endogenous danger-associated molecular patterns (DAMPs) and exogenous pathogen-associated molecular patterns (PAMPs). Patients receiving conditioning chemotherapy and/or whole-body irradiation prior to all-HSCT are prone to gastrointestinal damage and translocation of microbiota across compromised intestinal epithelium, resulting in release of PAMPs and DAMPs. These “danger signals” play critical roles in disease pathogenesis by both initiating and propagating aGVHD through dendritic cell maturation and alloreactive T cell responses. There are 10–15 TLRs identified in mammalian species, a subset of which recognize single-stranded RNA (ssRNA) and serve as a key component of viral immunity. Recently, ssRNAs other than those of viral origin have been investigated as potential ligands of TLRs. MicroRNAs (miRs) are short (19–24 nt) non-coding RNAs that play critical roles in a variety of diseases. While traditionally miRs post-translationally modulate gene expression, non-canonical functions such as regulating TLR stimulation by acting as TLR ligands have been described. Here, we review the role of TLRs in aGVHD pathogenesis, the function of miRs in TLR stimulation, and the recent literature describing miRs as TLR ligands in aGVHD.

The current state of the art for biological therapies and new small molecules in inflammatory bowel disease.

The emergence of biologic therapies is arguably the greatest therapeutic advance in the care of inflammatory bowel disease (IBD) to date, allowing directed treatments targeted at highly specific molecules shown to play critical roles in disease pathogenesis, with advantages in potency and selectivity. Furthermore, a large number of new biologic and small-molecule therapies in IBD targeting a variety of pathways are at various stages of development that should soon lead to a dramatic expansion in our therapeutic armamentarium. Additionally, since the initial introduction of biologics, there have been substantial advances in our understanding as to how biologics work, the practical realities of their administration, and how to enhance their efficacy and safety in the clinical setting. In this review, we will summarize the current state of the art for biological therapies in IBD, both in terms of agents available and their optimal use, as well as preview future advances in biologics and highly targeted small molecules in the IBD field.

Tissue-specific Role of CX3CR1 Expressing Immune Cells and Their Relationships with Human Disease.

Chemokine (C-X3-C motif) ligand 1 (CX3CL1, also known as fractalkine) and its receptor chemokine (C-X3-C motif) receptor 1 (CX3CR1) are widely expressed in immune cells and non-immune cells throughout organisms. However, their expression is mostly cell type-specific in each tissue. CX3CR1 expression can be found in monocytes, macrophages, dendritic cells, T cells, and natural killer (NK) cells. Interaction between CX3CL1 and CX3CR1 can mediate chemotaxis of immune cells according to concentration gradient of ligands. CX3CR1 expressing immune cells have a main role in either pro-inflammatory or anti-inflammatory response depending on environmental condition. In a given tissue such as bone marrow, brain, lung, liver, gut, and cancer, CX3CR1 expressing cells can maintain tissue homeostasis. Under pathologic conditions, however, CX3CR1 expressing cells can play a critical role in disease pathogenesis. Here, we discuss recent progresses of CX3CL1/CX3CR1 in major tissues and their relationships with human diseases.