Educational paper: Defects in number and function of neutrophilic granulocytes causing primary immunodeficiency

The neutrophilic granulocyte (neutrophil) is the most important cellular component of the innate immune system. A total absence of neutrophils or a significant decrease in their number leads to severe immunodeficiency. A mature neutrophil, released from the bone marrow, should be able to migrate from the blood towards the tissues, following a chemotactic gradient to a pathogen. In order to be neutralized, this pathogen has to be recognized, phagocytosed, and destroyed by lytic enzymes contained in the neutrophil's granules and reactive oxygen species formed by the enzyme complex NADPH oxidase. Rare genetic defects leading to the loss of each one of these biological properties of the neutrophil have been described and are associated with immunodeficiency. This review provides a summary of the normal development and biological functions of neutrophils and describes the diseases caused by defects in neutrophil number and function

The alarmin IL-1α is a master cytokine in acute lung inflammation induced by silica micro- and nanoparticles

BackgroundInflammasome-activated IL-1ß plays a major role in lung neutrophilic inflammation induced by inhaled silica. However, the exact mechanisms that contribute to the initial production of precursor IL-1ß (pro-IL-1ß) are still unclear. Here, we assessed the implication of alarmins (IL-1¿, IL-33 and HMGB1) in the lung response to silica particles and found that IL-1¿ is a master cytokine that regulates IL-1ß expression.MethodsPro- and mature IL-1ß as well as alarmins were assessed by ELISA, Western Blot or qRT-PCR in macrophage cultures and in mouse lung following nano- and micrometric silica exposure. Implication of these immune mediators in the establishment of lung inflammatory responses to silica was investigated in knock-out mice or after antibody blockade by evaluating pulmonary neutrophil counts, CXCR2 expression and degree of histological injury.ResultsWe found that the early release of IL-1¿ and IL-33, but not HMGB1 in alveolar space preceded the lung expression of pro-IL-1ß and neutrophilic inflammation in silica-treated mice. In vitro, the production of pro-IL-1ß by alveolar macrophages was significantly induced by recombinant IL-1¿ but not by IL-33. Neutralization or deletion of IL-1¿ reduced IL-1ß production and neutrophil accumulation after silica in mice. Finally, IL-1¿ released by J774 macrophages after in vitro exposure to a range of micro- and nanoparticles of silica was correlated with the degree of lung inflammation induced in vivo by these particles.ConclusionsWe demonstrated that in response to silica exposure, IL-1¿ is rapidly released from pre-existing stocks in alveolar macrophages and promotes subsequent lung inflammation through the stimulation of IL-1ß production. Moreover, we demonstrated that in vitro IL-1¿ release from macrophages can be used to predict the acute inflammogenic activity of silica micro- and nanoparticles

Regional specialization within the intestinal immune system.

The intestine represents the largest compartment of the immune system. It is continually exposed to antigens and immunomodulatory agents from the diet and the commensal microbiota, and it is the port of entry for many clinically important pathogens. Intestinal immune processes are also increasingly implicated in controlling disease development elsewhere in the body. In this Review, we detail the anatomical and physiological distinctions that are observed in the small and large intestines, and we suggest how these may account for the diversity in the immune apparatus that is seen throughout the intestine. We describe how the distribution of innate, adaptive and innate-like immune cells varies in different segments of the intestine and discuss the environmental factors that may influence this. Finally, we consider the implications of regional immune specialization for inflammatory disease in the intestine