Immune dysfunction in chronic kidney disease

Chronic kidney disease is characterized by immune dysfunction that increases predisposition to infections, virus-associated cancers and impaired response to vaccination. The altered immune response is caused by impairment of both innate and adaptive immune systems, as well as other factors that are hallmarks of renal disease, such as uremia, malnutrition, chronic inflammation, mineral bone disease and anemia. The aim of this article is to review the causes and mechanisms that lead to immune dysfunction in patients with chronic kidney disease.

Innate Immune Mechanisms and Immunotherapy of Myeloid Malignancies

Similar to other cancers, myeloid malignancies are thought to subvert the immune system during their development. This subversion occurs via both malignant cell-autonomous and non-autonomous mechanisms and involves manipulation of the innate and adaptive immune systems. Multiple strategies are being studied to rejuvenate, redirect, or re-enforce the immune system in order to fight off myeloid malignancies. So far, the most successful strategies include interferon treatment and antibody-based therapies, though chimeric antigen receptor (CAR) cells and immune checkpoint inhibitors are also promising therapies. In this review, we discuss the inherent immune mechanisms of defense against myeloid malignancies, currently-approved agents, and agents under investigation. Overall, we evaluate the efficacy and potential of immuno-oncology in the treatment of myeloid malignancies.

Mesenchymal Stem Cell-Based Therapy for Rheumatoid Arthritis

Mesenchymal stem cells (MSCs) have great potential to differentiate into various types of cells, including but not limited to, adipocytes, chondrocytes and osteoblasts. In addition to their progenitor characteristics, MSCs hold unique immunomodulatory properties that provide new opportunities in the treatment of autoimmune diseases, and can serve as a promising tool in stem cell-based therapy. Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder that deteriorates quality and function of the synovium membrane, resulting in chronic inflammation, pain and progressive cartilage and bone destruction. The mechanism of RA pathogenesis is associated with dysregulation of innate and adaptive immunity. Current conventional treatments by steroid drugs, antirheumatic drugs and biological agents are being applied in clinical practice. However, long-term use of these drugs causes side effects, and some RA patients may acquire resistance to these drugs. In this regard, recently investigated MSC-based therapy is considered as a promising approach in RA treatment. In this study, we review conventional and modern treatment approaches, such as MSC-based therapy through the understanding of the link between MSCs and the innate and adaptive immune systems. Moreover, we discuss recent achievements in preclinical and clinical studies as well as various strategies for the enhancement of MSC immunoregulatory properties.

Immune lag is a major cost of prokaryotic adaptive immunity during viral outbreaks

Clustered regularly interspaced short palindromic repeat (CRISPR)-Cas adaptive immune systems enable bacteria and archaea to efficiently respond to viral pathogens by creating a genomic record of previous encounters. These systems are broadly distributed across prokaryotic taxa, yet are surprisingly absent in a majority of organisms, suggesting that the benefits of adaptive immunity frequently do not outweigh the costs. Here, combining experiments and models, we show that a delayed immune response which allows viruses to transiently redirect cellular resources to reproduction, which we call ‘immune lag’, is extremely costly during viral outbreaks, even to completely immune hosts. Critically, the costs of lag are only revealed by examining the early, transient dynamics of a host–virus system occurring immediately after viral challenge. Lag is a basic parameter of microbial defence, relevant to all intracellular, post-infection antiviral defence systems, that has to-date been largely ignored by theoretical and experimental treatments of host-phage systems.

Optimization of Methods for the Accurate Characterization of Whole Blood Neutrophils

Neutrophils are the most abundant circulating leukocyte population with critical roles in immune defense, regulation of innate and adaptive immune systems, and disease pathogenesis. Our progress in understanding precise mechanisms of neutrophil activation, recruitment, and function has been hampered by the lack of optimized and standardized methods for the characterization and phenotyping of this readily activated population. By comparing eight methods of neutrophil characterization, we demonstrate that the level of neutrophil activation and degranulation is associated with specific experimental conditions and the number and type of manipulation steps employed. Staining whole blood at 4ºC and removal of remaining unbound antibodies prior to one-step fixation and red blood cell lysis minimizes neutrophil activation, decreases phenotypic alterations during processing, and prevents nonspecific antibody binding. The effects of anticoagulants used for collection, processing delays, and time and temperature during sample analysis on neutrophil phenotype are addressed. The presented data provide a foundation for higher quality standards of neutrophil characterization improving consistency and reproducibility among studies.

Immune Function in Critically Ill Septic Children

The inflammatory response in pediatric sepsis is highly dynamic and includes both pro- and anti-inflammatory elements that involve the innate and adaptive immune systems. While the pro-inflammatory response is responsible for the initial clinical signs and symptoms of sepsis, a concurrent compensatory anti-inflammatory response often results in an occult, but highly clinically relevant, form of acquired immunodeficiency. When severe, this is termed “immunoparalysis” and is associated with increased risks for nosocomial infection, prolonged organ dysfunction, and death. This review focuses on the pathophysiology and clinical implications of both over- and under-active immune function in septic children. Host-, disease-, and treatment-specific risk factors for immunoparalysis are reviewed along with immune phenotype-specific approaches for immunomodulation in pediatric sepsis which are currently the subject of clinical trials.

Diversity and dynamics of the CRISPR-Cas systems associated with Bacteroides fragilis in human population

The CRISPR-Cas systems are important prokaryotic adaptive immune systems and effectively record the arms-race between bacteria and invading mobile elements in their CRISPR arrays. Using data from culture-based population genomics and metagenomics, we investigated the CRISPR-Cas systems associated with Bacteriodes fragilis, an important gut bacterium, and studied their diversity and dynamics. We analyzed genomes of 601 B. fragilis isolates derived from 12 healthy individuals, among which include time-series isolates from 6 individuals. In addition, we analyzed 222 reference B. fragilis genomes. Three different types of CRISPR-Cas systems (Type I-B, II-C and III-B) were found in analyzed B. fragilis genomes, with Type III-B being the most prevalent whereas the Type II-C being the most dynamic with varying arrays among isolates. Our graph-based summary and visualization of CRISPR arrays provided a holistic view of the organization and the composition of the CRISPR spacers. We observed insertions of different new spacers at the leader ends of the CRISPR arrays of Type II-C CRISPR-Cas systems in different B. fragilis sub-populations in one individual, an example of B. fragilis’ adaptation and parallel evolution within individual microbiomes. A network of B. fragilis and its predicted invaders also revealed microdynamics of B. fragilis CRISPR array, with hairball-like structures representing spacers with multi-target capabilities and network modules revealing the collective targeting of selected mobile elements by many spacers. This work demonstrates the power of using culture-based population genomics to reveal the activities and evolution of the CRISPR-Cas systems of the important gut bacterium B. fragilis in human population.

Insights into the Pathogenesis of HS and Therapeutical Approaches

Hidradenitis suppurativa (HS) is a debilitating, chronic, (auto)inflammatory disease primarily affecting apocrine gland-rich areas of the body. Although pathogenic mechanisms responsible for HS have not yet been fully elucidated, it is a multifactorial process whose main target is the terminal follicle. The role of the inflammatory process (and consequently of cytokine milieu) and of several other factors (genetics, lifestyle, hormonal status, microbiome, innate and adaptive immune systems) involved in HS pathogenesis has been investigated (and often defined) over the years with a view to transferring research results from bench to bedside and describing a unique and universally accepted pathogenetic model. This review will update readers on recent advances in our understanding of HS pathogenesis and novel (potential) medical therapies for patients with moderate-to-severe HS.

Insulin/IGF-1 signaling promotes immunosuppression via the STAT3 pathway: impact on the aging process and age-related diseases

Background The insulin/IGF-1 signaling pathway has a major role in the regulation of longevity both in Caenorhabditis elegans and mammalian species, i.e., reduced activity of this pathway extends lifespan, whereas increased activity accelerates the aging process. The insulin/IGF-1 pathway controls protein and energy metabolism as well as the proliferation and differentiation of insulin/IGF-1-responsive cells. Insulin/IGF-1 signaling also regulates the functions of the innate and adaptive immune systems. The purpose of this review was to elucidate whether insulin/IGF-1 signaling is linked to immunosuppressive STAT3 signaling which is known to promote the aging process. Methods Original and review articles encompassing the connections between insulin/IGF-1 and STAT3 signaling were examined from major databases including Pubmed, Scopus, and Google Scholar. Results The activation of insulin/IGF-1 receptors stimulates STAT3 signaling through the JAK and AKT-driven signaling pathways. STAT3 signaling is a major activator of immunosuppressive cells which are able to counteract the chronic low-grade inflammation associated with the aging process. However, the activation of STAT3 signaling stimulates a negative feedback response through the induction of SOCS factors which not only inhibit the activity of insulin/IGF-1 receptors but also that of many cytokine receptors. The inhibition of insulin/IGF-1 signaling evokes insulin resistance, a condition known to be increased with aging. STAT3 signaling also triggers the senescence of both non-immune and immune cells, especially through the activation of p53 signaling. Conclusions Given that cellular senescence, inflammaging, and counteracting immune suppression increase with aging, this might explain why excessive insulin/IGF-1 signaling promotes the aging process.