Current Immunology Reviews (Discontinued) - Volume 11, Issue 1, 2015

The vasculitides are a highly heterogeneous group of disorders characterized by the presence of inflammatory leukocytes in the vessel walls and reactive inflammation. Giant cell arteritis (GCA) and Takayasu’s arteritis (TA) are the two primary large-vessel vasculitides. Two distinct cellular pathways have been identified in GCA: Th17 polarization and IL-17 secretion and generation of Th1 cells which secrete IFN-γ. These two pathways may play different roles in the pathogenesis of vasculitides. The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are small vessel vasculitis associated with antibodies directly to myeloperoxidase (MPO-ANCA) such as eosinophilic granulomatosis with polyangiitis (EGPA) and microscopic polyangiitis (MPA) or with antibodies directly to proteinase 3 (PR3-ANCA) such as granulomatosis with polyangiitis (GPA). Both in vitro and in vivo experimental data have shown that MPO-ANCA can induce necrotizing smallvessel vasculitis; however the presence of granulomatous lesions suggests the involvement of cell-mediated immune responses. Behçet syndrome (BS) is a chronic relapsing vasculitis of arteries and veins with unclear etiology. Exogenous and endogenous antigens, innate immune cells such as dendritic, NK, neutrophils and adaptive-immune cells are involved.

Numerous researches have detected immune cellular elements in coronary lesions of atherosclerotic origin in human and animal models, and these cells are suspected of contributing to plaque instability. Patients affected by acute coronary syndrome present high levels of pro-inflammatory molecules, as shown in numerous studies. This finding implies similarity between CAD and well-known immune-mediated inflammatory diseases. Due to incongruent findings, this “infection hypothesis” cannot be rejected, thus further research is needed to better understand the relationship between pathogen-induced chronic inflammatory response, with its pathogenic mechanisms, and the atherosclerotic process. Several clinical studies have consistently reported the involvement of polymorphonuclear neutrophils in atherosclerotic coronary disease; autoptic studies have showed their presence in unstable lesions. The evidence of their features of activation suggests that polymorphonucleates take part in atherosclerotic pathogenesis and in its worst evolution. The evidence of a systemic activation of T lymphocytes in individuals affected by ischemic heart disease, as shown in recent work, underlines the significant role of adaptive immunity in this pathological condition. Three subpopulations of T-cells with unusual features have been described: CD4+CD28- T lymphocytes, which lack of CD28 expression (CD28 is a co-stimulatory molecule engaged in the antigen recognition by T lymphocytes), naturally occurring regulatory T-lymphocytes and interleukin-17-producing T-cells. To date the main therapeutic target is coronary thrombosis, which represents the final event causing life threatening complications related to atherosclerosis, so targeting immune cells could represent a future therapeutic aim.

Inflammation seems to play a major role in the pathogenesis of ischemic stroke as well as in other forms of brain damage. Ischemic brain injury induces a strong inflammatory response that begins in the microcirculation and involves several cell types and molecules, leading to neuronal death. The immune system is actively involved in the pathogenesis of acute brain damage through a set of events that include leukocyte and monocyte infiltration into the brain, activation of resident cells, including microglia, astrocytes and endothelial cells, and the elevated production of several inflammatory molecules, such as cytokines, that together play a complex role in the pathophysiology of ischemic brain damage, as illustrated in animal models and stroke patients. These immune cells are activated and recruited in damaged tissues at different times. Immunity and inflammation are thus key elements in the pathogenic processes of acute cerebral ischemia, and therefore the use of anti-inflammatory therapeutic strategies to antagonize inflammatory mechanisms triggered by cerebral ischemia may improve the outcome of stroke. Several drugs have been produced to counteract inflammation. However, while they have proven effective in animal models of stroke they have not been successful in clinical trials because of unacceptable side-effects. Although several aspects of the inflammatory cerebral response to ischemia are still unclear and many questions have not been answered yet, it is clear that inflammation plays an important role and represents an integral part of the complex pathogenic mechanisms that characterize stroke, and therefore the study of inflammatory responses to post-ischemia and the development of agents able to counteract it represent the future of treating ischemic stroke. In this primer we will reexamine some aspects of involvment of inflammatory cells in cerebrovascular disease.

Cutaneous adverse drug-induced reactions are difficult to manage in daily clinical practice, mainly owing to their heterogeneous clinical manifestations and the lack of selective biological markers. Patients with cutaneous adverse drug-induced reactions are often exposed simultaneously to a few potentially culprit drugs. Diagnosis of cutaneous adverse drug-induced hypersensitivity relies on clinical history, skin tests, in vitro tests and provocation tests. In vitro methods are necessary to establish a diagnosis, especially given the low sensitivity of skin tests and the inherent risk of drug provocation testing. In this review we focus on best investigated in vitro techniques for the diagnosis of T cellmediated delayed-type drug hypersensitivity reactions (DTHs) during the resolution phase. As drug hypersensitivity involves different pathomechanisms and a single diagnostic test usually does not cover all possible reactions, the combination of different tests is required to increase overall sensitivity. Standard proliferation-based assays have been supplemented by a panel of novel in vitro tests allowing analysis of the cytotoxic or secretory potential of effectors cells, and up-regulation of cell surface activation markers. We discuss the latest findings and readout systems to identify causative drugs by detecting functional and phenotypic markers of drug-reacting cells, and their ability to enable a more conclusive diagnosis of drug allergy.

Cells of the immune system utilize multiple mechanisms to respond to environmental signals and recent studies have demonstrated roles for two closely related proteins, the aryl hydrocarbon receptor (AHR) and hypoxia inducible factor-1α (HIF1α), in these processes. The AHR is a transcription factor that is activated by diverse ligands found in the diet and environmental pollution as well as by microbial and host-derived products. In contrast, HIF1α is a transcription factor that is active under low oxygen conditions and mediates cellular responses to hypoxia. These evolutionarily conserved proteins have roles in the interrelated processes of metabolism, tumorigenesis, and vascular development. Additionally, the AHR and HIF1α have multiple effects on innate and adaptive immunity. This article provides an overview of the biology of these transcription factors and reviews the effects of AHR and HIF1α signaling on immunity to infection. There are many parallels between these two pathways and their functions highlight the importance of AHR and HIF1α activity particularly at barrier surfaces in coordinating responses to pathogens.

The Latin term immunitas has come a long way from its first registered use in the context of health and disease two thousand years ago. At first, it was employed mainly by non-physicians and understood as a passive exemption from diseases provoked by gods or demons. After the introduction of variolation and Jenner’s inoculation of cowpox in Europe in the eighteenth century, the term began to be used widely by physicians. Soon after came the demonstration of the germ theory of disease and of the first immune mechanisms of defense, which boosted the use of “immunity”, then understood as a protective battle against the germs. In the twentieth century it became clear that immunity could also provoke side effects in the host, and this was followed by the first criticisms of the outdated term, with little success. In next the following decades, the complexity of immunity increased and the military model was substituted by the self/non-self simile and by the neurological one, both complicated by the attribution of new functions to the immune system, which made the term even more obsolete. At present, immunity is mainly regarded as a complex mechanism of integration of microbes into the cell community of the host. From a conceptual point of view, the “immune” system is now considered a “commune” system, but the terminology has not been challenged: does the old term immunitas hamper the understanding of the new idea of immunity? Would it be appropriate to update it? Our main objective will be to answer these questions on the basis of the historical evolution of the term.

Hansen’s disease commonly called leprosy is an infectious disease caused by M. leprae. Lepromatous leprosy is a generalized infection accompanied by T cell anergy towards M. leprae bugs with chronicity of lesions throughout the body [1]. The reason for unresponsiveness and T cells anergy against M. leprae antigens still remains a mystery. Recent studies have focused on regulatory T cells (Treg) as one of the foremen of all aspects of the immune response [2]. In this review, we have discussed the mechanism of Treg cells mediated immune suppression of M. leprae specific T cells and subsequently explained the epigenetic modification of FoxP3, which is the master regulator of Treg cells, during the course of progression from tuberculoid to lepromatous leprosy. This review aims at compiling and adding on to the knowledge about suppressor T cells mechanisms in leprosy, it also outlines an insight into manipulation of suppressor T cell function for overcoming disease manifestation.