Immunity (medical) | EPFL Graph Search

In biology, immunity is the state of being insusceptible or resistant to a noxious agent or process, especially a pathogen or infectious disease. Immunity may occur naturally or be produced by prior exposure or immunization. Innate and adaptive The immune system has innate and adaptive components. Innate immunity is present in all metazoans, immune responses: inflammatory responses and phagocytosis. The adaptive component, on the other hand, involves more advanced lymphatic cells that can distinguish between specific "non-self" substances in the presence of "self". The reaction to foreign substances is etymologically described as inflammation while the non-reaction to self substances is described as immunity. The two components of the immune system create a dynamic biological environment where "health" can be seen as a physical state where the self is immunologically spared, and what is foreign is inflammatorily and immunologically eliminated. "Disease" can arise when wh

Immune Engineering Via Differential Antigen Carriers and Co-Stimulatory Molecules

Jackson Eby

There is an increasing clinical need for vaccines capable of enhancing antigen-specific immune responses and treatments that can induce immunological tolerance toward a single antigen. Here we explore two platforms to enhance either immunization or tolerization depending upon the secondary signals involved. First, a poly(ethylene glycol)-bl-poly(propylene sulfide) (PEG-bl-PPS)-based micelle platform capable of conjugating antigen to its surface was developed. Biodistribution studies showed that these micelles (MC) traffic to lymph nodes where they preferentially interact with antigen presenting cells (APC) for over 24 hr. When ovalbumin (Ova)-conjugated micelles (MC-Ova) were delivered intradermally with the adjuvant CpG, they enhanced cytotoxic T cell responses against Ova as well as anti-Ova IgG1 production compared to free Ova with CpG. To change the signals from the MCs to encourage tolerization, hydrophobic corticosteroids capable of preventing APC maturation were incorporated into the PPS core and were shown to be released over the course of 2 days. These vehicles were able to prevent dendritic cell (DC) activation in response to adjuvant both in vitro and in vivo. Ova-conjugated drug-loaded MCs were able to prevent antigen-specific T cell activation in vitro and in vivo as well, but caused an anti-Ova humoral response that was enhanced upon subsequent Ova challenge. Thus, PEG-bl-PPS micelles are valuable tools for enhancing immunization but not tolerization toward exogenous antigens. Second, erythrocytes were labeled in situ for use as apoptotic cell carriers. To enhance immunogenicity, the necrotic signal calreticulin (CRT) was decorated with the erythrocyte- binding peptide ERY (ERY-CRT) and delivered intravenously with ERY-Ova. When combined with chloroquine, this signaling caused production of anti-Ova IgG1 to a level similar to that seen with intradermal MC-Ova + CpG, but showed no cytotoxic T cell response. Because apoptotic cells can be tolerogenic, the Ter119 erythrocyte-binding single- chain antibody fragment (scFv) was used in a fusion with Ova peptides to determine if this technique could delete Ova-recognizing T cells within an immunized repertoire. After immunization with Ova + lipopolysaccharide (LPS), these constructs deleted CD4+ and CD8+ T cell clones specific for Ova without causing adverse reactions from anti-Ova antibodies in circulation. Erythrocytes are therefore encouraging protein-delivery vehicles for induction of both tolerance and humoral immunity.

EPFL2012

Mycobacterium tuberculosis Requires Phosphate-Responsive Gene Regulation To Resist Host Immunity

John McKinney, Anna De Graff Tischler

Mycobacterium tuberculosis persists in the tissues of mammalian hosts despite inducing a robust immune response dominated by the macrophage-activating cytokine gamma interferon (IFN-gamma). We identified the M. tuberculosis phosphate-specific transport (Pst) system component PstA1 as a factor required to resist IFN-gamma-dependent immunity. A Delta pstA1 mutant was fully virulent in IFN-gamma(-/-) mice but attenuated in wild-type (WT) mice and mice lacking specific IFN-gamma-inducible immune mechanisms: nitric oxide synthase (NOS2), phagosome-associated p47 GTPase (Irgm1), or phagocyte oxidase (phox). These phenotypes suggest that Delta pstA1 bacteria are sensitized to an IFN-gamma-dependent immune mechanism(s) other than NOS2, Irgm1, or phox. In other species, the Pst system has a secondary role as a negative regulator of phosphate starvation-responsive gene expression through an interaction with a two-component signal transduction system. In M. tuberculosis, we found that Delta pstA1 bacteria exhibited dysregulated gene expression during growth in phosphate-rich medium that was mediated by the two-component sensor kinase/response regulator system SenX3-RegX3. Remarkably, deletion of the regX3 gene suppressed the replication and virulence defects of Delta pstA1 bacteria in NOS2(-/-) mice, suggesting that M. tuberculosis requires the Pst system to negatively regulate activity of RegX3 in response to available phosphate in vivo. We therefore speculate that inorganic phosphate is readily available during replication in the lung and is an important signal controlling M. tuberculosis gene expression via the Pst-SenX3-RegX3 signal transduction system. Inability to sense this environmental signal, due to Pst deficiency, results in dysregulation of gene expression and sensitization of the bacteria to the host immune response.

American Society for Microbiology2013

An Exploratory Study On The Functional Significance Of Eosinophil Residency In The Small Intestine Under Homeostatic Conditions

Kathleen Shah

The small intestine is a highly dynamic and complex cellular ecosystem, which serves as the primary interface between the host and its environment. A critical component of this ecosystem is the microbiota, which plays a pivotal role in shaping both immune and physiological homeostasis of the host from the moment of birth. However, interaction with the microbiota is a double-edged sword â and the inappropriate establishment of host-microbiota crosstalk could lead to detrimental consequences. Eosinophils are multi-functional granulocytes, recruited into the intestine in early life â but the relevance of this phenomenon has remained enigmatic, given the dogmatic view of these cells as drivers of pathophysiology in type-II immune mediated disorders. Understanding the functional significance of their residency in this tissue under homeostatic conditions warrants further investigation and may provide invaluable insight into their dysregulation in disease. In this thesis, I report our investigation of the contributions of eosinophils to small intestinal homeostasis through a broad characterization of changes in various intestinal functions consequent of eosinophil-deficiency. We approached this expansive question through a combination of histological, cellular and transcriptional analyses, which have afforded us unprecedented insight to eosinophil function in this tissue. Using Îdbl.GATA1 mice, a model of constitutive eosinophil deficiency, we provide evidence for a central role for eosinophils in tissue integrity maintenance in response to the microbiota. We report herein that eosinophil-mediated tissue protection is largely driven by epithelial-derived alarmins, released in response to barrier stress â which equips eosinophils with the capacity to maintain small intestinal integrity and homeostasis through the regulation of extracellular matrix remodelling. In summary, our work provides a functional rationale for the early life recruitment of eosinophils in the small intestine, implicating these cells as key facilitators in the establishment of appropriate host-microbiota crosstalk.

EPFL2018