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1.  Effect of aging on microRNAs and regulation of pathogen recognition receptors 
Immunosenescence is the multifactorial age-associated immune deteriorization that leads to increased susceptibility to infections and decreased responses to vaccines. Recent studies have shown a fundamental role for microRNAs (miRNAs) in regulating immune responses, and nearly all the miRNAs involved in immune regulation show modulation during aging. Aging-associated miRNAs are largely negative regulators of the immune innate response and target central nodes of aging-associated networks, in particular, NF-κB, the downstream effector of TLR signals that leads to induction of proinflammatory responses. Multiple miRNAs have been reported to share similar regulatory activity. Here we review miRNA regulation of human innate immune recognition in aging, including both activation and resolution of inflammation, critical issues in detection, and areas of active investigation into our understanding of immunosenescence.
PMCID: PMC4119513  PMID: 24769423
2.  A systems biology approach to the effect of aging, immunosenescence and vaccine response 
Aging can lead to immunosenescence, which dramatically impairs the hosts’ ability to develop protective immune responses to vaccine antigens. Reasons for this are not well understood. This topic’s importance is reflected in the increases in morbidity and mortality due to infectious diseases among elderly persons, a population growing in size globally, and the significantly lower adaptive immune responses generated to vaccines in this population. Here, we endeavor to summarize the existing data on the genetic and immunologic correlates of immunosenescence with respect to vaccine response. We cover how the application of systems biology can advance our understanding of vaccine immunosenescence, with a view toward how such information could lead to strategies to overcome the lower immunogenicity of vaccines in the elderly.
PMCID: PMC4119552  PMID: 24820347
3.  Autophagy and the immune function in aging 
Just when you thought that you had heard it all about autophagy - the conserved cellular process that mediates turnover of cellular constituents in the lysosomes - studies keep coming out highlighting new types of autophagy, new functions for autophagy or even new autophagy-independent roles for the proteins associated with this process. The field of immunology has been riding the autophagic wave since the beginning of its revival; first due to its role in the host defense against pathogens, and more recently through the better understanding of the unique characteristics and functions of different autophagic pathways in immune cells. Here, we describe some of these new functions that are tightening the connection between autophagy and acquired or innate immunity and their malfunctioning with age.
PMCID: PMC4119564  PMID: 24929664
4.  Defining Features of Protective CD4 T cell responses to Mycobacterium tuberculosis 
CD4 T cells are critical for control of Mycobacterium tuberculosis (Mtb) infection and represent the best hope for vaccine-elicited protection. However, little is understood about the properties of Mtb-specific CD4 T cells that mediate control, and the lack of correlates of protection present a significant barrier to the rational development of new vaccination and therapeutic strategies which are sorely needed. Here we discuss the features of protective CD4 T cells including recent evidence for IFN-γ dependent and independent mechanisms of protection, poor protection by terminally differentiated cells and the importance of T cell migratory capacity for the control of Mtb infection.
PMCID: PMC4122329  PMID: 25000593
5.  Aging of the Human Innate Immune System in HIV Infection 
HIV infection is associated with a chronic inflammatory state arising from multiple factors, including innate immune recognition of HIV, increased microbial translocation, and release of endogenous ligands from damaged cells (such as CD4 T cells). In many respects, this heightened pro-inflammatory environment resembles that associated with aging in the absence of HIV infection, and evidence of dysregulated innate immune responses can be found in not only older HIV-negative adults, but also adults with HIV infection. While the study of innate immune aging in HIV infection is still in its early stages, it seems likely that at least additive, or potentially synergistic effects of aging and HIV infection will be found.
PMCID: PMC4145838  PMID: 24997358
6.  Commensal bacteria mediated defenses against pathogens 
Commensal bacterial communities residing within the intestinal lumen of mammals have evolved to flourish in this microenvironment. To preserve this niche, commensal bacteria act with the host to prevent colonization by invasive pathogens that induce inflammation and disrupt the intestinal niche commensal bacteria rely upon. Thus, it is mutually beneficial to the host and commensal bacteria to inhibit a pathogen's ability to establish an infection. Commensal bacteria express factors that support colonization, maximize nutrient uptake, and produce metabolites that confer a survival advantage over pathogens. Further, commensal bacteria stimulate the host's immune defenses and drive tonic expression of anti-microbial factors. In combination, these mechanisms preserve the niche for commensal bacteria and assist the host in preventing infection.
PMCID: PMC4132187  PMID: 24727150
commensal bacteria; intestinal microbiota; bacteria; infection; pathogens; intestinal immune response; colonization resistance
7.  B cell function and influenza vaccine responses in healthy aging and disease 
Current opinion in immunology  2014;29:112-118.
Influenza vaccination is less effective in elderly as compared to young individuals. Several studies have addressed the identification of immune biomarkers able to monitor or predict a protective humoral immune response to the vaccine. In this review, we summarize these data, with emphasis on the effects of aging on influenza vaccine-specific B cell responses in healthy individuals and patients with Type-2 Diabetes, HIV and cardiovascular diseases.
PMCID: PMC4331104  PMID: 24934648
8.  Metabolism in T cell activation and differentiation 
Current opinion in immunology  2010;22(3):314-320.
When naïve or memory T cells encounter foreign antigen along with proper co-stimulation they undergo rapid and extensive clonal expansion. In mammals, this type of proliferation is fair1y unique to cells of the adaptive immune system and requires a considerable expenditure of energy and cellular resources. While research has often focused on the roles of cytokines, antigenic signals, and co-stimulation in guiding T cell responses, data indicate that, at a fundamental level, it is cellular metabolism that regulates T cell function and differentiation and therefore influences the final outcome of the adaptive immune response. This review will focus on some earlier fundamental observations regarding T cell bioenergetics and its role in regulating cellular function, as well as recent work that suggests that manipulating the immune response by targeting lymphocyte metabolism could prove useful in treatments against infection and cancer.
PMCID: PMC4486663  PMID: 20189791
9.  Editorial overview: Autoimmunity 
PMCID: PMC4482451  PMID: 25456769
10.  Sensing of cell death by myeloid C-type lectin receptors 
Current opinion in immunology  2013;25(1):46-52.
Molecules associated with dead or dying cells can be detected by receptors on macrophages and dendritic cells. Signals from these receptors impact myeloid cell function and play a role in determining whether death is silent or proinflammatory, tolerogenic or immunogenic. Prominent among myeloid receptors detecting dead cells are C-type lectin receptors (CLRs). Signals from these receptors variably induce endocytosis of cell corpses, corpse degradation, retrieval of dead cell-associated antigens and/or modulation of immune responses. The sensing of tissue damage by myeloid CLRs complements detection of pathogens in immunity and represents an ancient response aimed at restoring tissue homeostasis.
PMCID: PMC4480265  PMID: 23332826
11.  MicroRNA regulation of the germinal center response 
The generation of germinal centers (GCs) is a hallmark feature of the adaptive immune response, resulting in the production of high-affinity antibodies that neutralize pathogens and confer protection upon reinfection. The GC response requires interactions between different immune cell types, and the coordination of complex and dynamic gene expression networks within these cells. Here we provide deeper insights into how microRNAs, small endogenously expressed RNAs, regulate the cellular processes involved in the differentiation and function of T follicular helper cells and germinal center B cells, the two main players of the T cell-dependent humoral immune response.
PMCID: PMC4037353  PMID: 24530656
12.  Vaccine Approaches for Multidrug Resistant Gram negative infections 
Multidrug resistant (MDR) Gram negative bacterial infections are increasing in frequency and are associated with significant financial costs, morbidity and mortality. Current antibiotic therapies are associated with unacceptably poor clinical outcomes and toxicity. Unfortunately, the development of novel antimicrobials is stagnant leaving a significant clinical need for alternative treatments of MDR Gram negative rod infections. Recent preclinical studies have identified Th17 cells as critical mediators of broadly protective adaptive immunity, including protection against MDR infections. Studies of Th17 eliciting antigens, adjuvants and routes of immunization have identified potential vaccine strategies that may confer long-lived adaptive immunity against MDR Gram negative bacterial infections.
PMCID: PMC4037349  PMID: 24637162
13.  Vaccine Immunity against Fungal Infections 
Only a handful of the many fungal species on our planet cause infections in humans. Despite many medical advances, invasive fungal infections have skyrocketed in recent years and pose a growing health problem in both immune-competent and -deficient hosts. Recent strides in our understanding of fungal immunity have raised the prospect that vaccines against fungi can be developed that are effective, safe and able to elicit lasting immunity even in immune deficient individuals. We discuss progress in vaccine development and understanding mechanisms of protection against fungi including in patients with impaired CD4+ T-cell immunity.
PMCID: PMC4037332  PMID: 24583636
Fungi; yeast; vaccines; immunity
14.  Novel vaccine approaches for protection against intracellular pathogens 
Vaccination against intracellular pathogens requires generation of a pool of memory T cells able to respond upon infection and mediate either killing of the infected cell or induce killing mechanisms in the infected cell. T cell-inducing vaccines must aim to target the antigen to antigen-presenting cells so that it can be presented on MHC molecules on the cell surface. Methods to do this include making use of vectors such as plasmid DNA or viruses, live attenuated pathogens or subunit vaccines targeted and enhanced using adjuvants. The choice of approach should be guided by the phenotype and localization of the desired T cell response. This review will discuss current approaches in the pipeline for the development of T cell-inducing vaccines, including vectored, live attenuated, and subunit vaccines.
PMCID: PMC4037333  PMID: 24608070
Germinal centers (GCs) are the site of antibody affinity maturation, a process that involves complex clonal and cellular dynamics. Selection of B cells bearing higher-affinity immunoglobulins proceeds via a stereotyped pattern where B cells migrate cyclically between the GC’s two anatomical compartments. This process occurs in a timeframe that is well suited to analysis by intravital microscopy, and much has been learned in recent years by use of these techniques. On a longer time scale, the diversity of B cell clones and variants within individual GCs is also thought to change as affinity maturation progresses; however, our understanding of clonal dynamics in individual GCs is limited. We discuss recent progress in the elucidation of clonal and cellular dynamics patterns.
PMCID: PMC4037377  PMID: 24681449
16.  Regulatory Constraints in the Generation and Differentiation of IgE-Expressing B Cells 
B cells expressing antibodies of the immunoglobulin E (IgE) isotype are rare, yet are heavily implicated in the pathogenesis of allergies and asthma. This review discusses recent methodological advances that permit sensitive probing of IgE-expressing (IgE+) B cells in vivo and have accordingly clarified the basic behavior and fate of IgE+ B cells during immune responses in mouse models. IgE antibody secreting plasma cells can arise from extrafollicular foci, germinal centers, and memory B cells. However, compared to B cells expressing other isotypes, IgE+ B cells are susceptible to multiple additional regulatory constraints that restrict the size of the IgE+ B cell pool at each stage, coordinately limiting the overall magnitude, affinity, and duration of the IgE antibody response.
PMCID: PMC4069329  PMID: 24632082
17.  Interleukin 33: A Switch-Hitting Cytokine 
Current opinion in immunology  2014;28:102-106.
For many years IL-33 has been widely studied in the context of T helper type 2 (TH2)-driven inflammatory disorders. Interestingly, IL-33 has now emerged as a cytokine with a plethora of pleiotropic properties. Depending on the immune cells targeted by IL-33, it is reported to not only promote TH2 immunity, but also to induce T helper type 1 (TH1) immunity. Furthermore, recent studies have revealed that IL-33 can activate CD8+ T cells. These new studies provide evidence for its beneficial role in antiviral and antitumor immunity. Here we review the evidence of IL-33 to drive protective T cell immunity plus its potential use as an adjuvant in vaccination and tumor therapy.
PMCID: PMC4118594  PMID: 24762410
18.  Invariant NKT cells provide innate and adaptive help for B cells 
B cells rely on CD4+ T cells helper signals to optimize their responses to T-dependent antigens. Recently another subset of T cells has been identified which provides help for B cells, invariant natural killer T (iNKT) cells. INKT cells are unique because they provide both innate and adaptive forms of help to B cells, with divergent outcomes. iNKT cells are widely distributed throughout the spleen at rest, consolidate in the marginal zone of the spleen early after activation, and are later found in germinal centers. Understanding the activation requirements for iNKT cells has led to the development of glycolipid containing nanoparticles which efficiently activate iNKT cells, enhance their cooperation with B cells, and which hold promise for vaccine development.
PMCID: PMC4346131  PMID: 24514004
19.  Immune Senescence: Known Knowns And Unknown Unknowns 
PMCID: PMC4389771  PMID: 24996928
20.  New insights into cancer immunoediting and its three component phases — elimination, equilibrium and escape 
The principles of cancer immunoediting have set the foundations for understanding the dual host-protective and tumor sculpting actions of immunity on cancer and establishing the basis for novel individualized cancer immunotherapies. During cancer immunoediting, the host immune system shapes tumor fate in three phases through the activation of innate and adaptive immune mechanisms. In the first phase, Elimination, transformed cells are destroyed by a competent immune system. Sporadic tumor cells that manage to survive immune destruction may then enter an Equilibrium phase where editing occurs. The Escape phase represents the third and final phase of the process, where immunologically sculpted tumors begin to grow progressively, become clinically apparent and establish an immunosuppressive tumor microenvironment. This review focuses on important recent developments that have enhanced our understanding of each phase of the cancer immunoediting process, summarizes the discovery of new predictive and prognostic biomarkers and discusses development of novel and objectively effective cancer immunotherapies.
PMCID: PMC4388310  PMID: 24531241
21.  Dual immunoglobulin light chain B cells: Trojan horses of autoimmunity? 
Receptor editing, a major mechanism of B cell tolerance, can also lead to allelic inclusion at the immunoglobulin light chain loci and the development of B cells that co-express two different immunoglobulin light chains and, therefore, two antibody specificities. Most allelically included B cells express two κ chains, although rare dual-λ cells are also observed. Moreover, these cells typically co-express an autoreactive and a nonautoreactive antibody. Thus, allelically included B cells could operate like “Trojan horses”: expression and function of the nonautoreactive antigen receptors might promote their maturation, activation, and terminal differentiation into effector cells that also express and secrete autoantibodies. Indeed, dual-κ B cells are greatly expanded into effector B cell subsets in some autoimmune mice, thus indicating they might play an important role in disease.
PMCID: PMC3972342  PMID: 24549093
22.  Regulation of the adaptive immune system by innate lymphoid cells 
Innate lymphoid cells (ILCs) are a group of lymphocytes that promote rapid cytokine-dependent innate immunity, inflammation and tissue repair. In addition, a growing body of evidence suggests ILCs can influence adaptive immune cell responses. During fetal development a subset of ILCs orchestrate the generation and maturation of secondary lymphoid tissues. Following birth, ILCs continue to modulate adaptive immune cell responses indirectly through interactions with stromal cells in lymphoid tissues and epithelial cells at barrier surfaces. In this review we summarize the current understanding of how ILCs modulate the magnitude and quality of adaptive immune cell responses, and in particular focus on recent evidence suggesting that ILCs can also directly regulate CD4+ T cells. Further, we discuss the implications that these pathways may have on human health and disease.
PMCID: PMC3979357  PMID: 24594491
23.  [No title available] 
PMCID: PMC3932004  PMID: 24556395
24.  [No title available] 
PMCID: PMC3932006  PMID: 24556408
25.  [No title available] 
PMCID: PMC3932007  PMID: 24556406

Results 1-25 (380)