Immunology in clinic review series; focus on autoinflammatory diseases: inflammasomes: mechanisms of activation.

UNLABELLED: OTHER THEMES PUBLISHED IN THIS IMMUNOLOGY IN THE CLINIC REVIEW SERIES Allergy, Host Responses, Cancer, Type 1 diabetes and viruses, Metabolic diseases. SUMMARY: Initiation of a successful immune response requires a working set of sensors that detect any noxious agent within the cellular microenvironment and molecular platforms that process this signal to trigger an appropriate effector response. Pattern recognition receptors can engage different signalling cascades that lead to proinflammatory gene expression. At the same time, transcription-independent events such as activation of proteases and/or phagocytosis are also initiated. The inflammasome pathway constitutes a signalling platform that leads to the activation of so-called inflammatory caspases, most notably caspase-1, which plays a pivotal role in the cleavage and thus maturation of proinflammatory cytokines, but also in the induction of pyroptosis, a special type of cell death. In this review we elaborate on the currently known inflammasome complexes with a special focus on the mechanism behind their activation. Understanding these mechanisms could provide important information regarding the potential signalling nodes that might be targeted for therapeutic intervention.

Highly sensitivity adhesion molecules detection in hereditary haemochromatosis patients reveals altered expression.

Several abnormalities in the immune status of patients with hereditary haemochromatosis (HH) have been reported, suggesting an imbalance in their immune function. This may include persistent production of, or exposure to, altered immune signalling contributing to the pathogenesis of this disorder. Adhesion molecules L-, E- and P-Selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) are some of the major regulators of the immune processes and altered levels of these proteins have been found in pathological states including cardiovascular diseases, arthritis and liver cancer. The aim of this study was to assess L-, E- and P-Selectin, ICAM-1 and VCAM-1 expression in patients with HH and correlate these results with HFE mutation status and iron indexes. A total of 139 subjects were diagnosed with HH (C282Y homozygotes = 87, C282Y/H63D = 26 heterozygotes, H63D homozygotes = 26), 27 healthy control subjects with no HFE mutation (N/N), 18 normal subjects heterozygous for the H63D mutation served as age-sex-matched controls. We observed a significant decrease in L-selectin (P = 0.0002) and increased E-selectin and ICAM-1 (P = 0.0006 and P = 0.0059) expression in HH patients compared with healthy controls. This study observes for the first time that an altered adhesion molecules profile occurs in patients with HH that is associated with specific HFE genetic component for iron overload, suggesting that differential expression of adhesion molecules may play a role in the pathogenesis of HH.

Characterization of tumour necrosis factor-alpha genetic variants and mRNA expression in patients with severe sepsis.

Tumour necrosis factor-alpha (TNFalpha) has been implicated in the pathogenicity of severe sepsis by both genetic association studies and animal models. Conflicting functional data have emerged in relation to genetic variants and TNFalpha protein production. Therefore, we assessed the functionality of TNFalpha genetic variants in terms of mRNA production and their potential influence on outcome in the setting of severe sepsis. Sixty-two Irish Caucasian patients presenting with severe sepsis were recruited and TNFalpha mRNA and protein levels were quantified. Patient DNA was analysed for the presence of common promoter polymorphisms and haplotypes were inferred. An A allele at position -863 was associated with more TNFalpha mRNA on day 1 compared to C homozygotes (P = 0.037). There was a trend for G homozygotes at position -308 to produce more TNFalpha mRNA on day 1 than those carrying an A allele (P = 0.059). The presence of an A allele at -863 was associated with greater levels of TNFalpha mRNA in comparison with patients carrying the A allele at -308 on day 1 (P = 0.02). Patients homozygous for the A allele at position -308 had a higher mortality than those carrying the G allele (P = 0.01). Our data are consistent with recent reports suggesting that a deficient proinflammatory response may be harmful in human sepsis. This deficient inflammatory response may be mediated in part by polymorphisms in the TNFalpha promoter.

Elevated MCP-1 serum levels are associated with the H63D mutation and not the C282Y mutation in hereditary hemochromatosis.

Monocyte chemoattractant protein-1 (MCP-1) is a major lymphocyte and inflammatory chemokine associated with persistent inflammatory states. Several abnormalities in the immune status of patients with hereditary hemochromatosis (HH) have been reported, suggesting an imbalance in their immune function. This may include persistent production of, or exposure to, inflammatory cytokines contributing to the pathogenesis of this disorder. The aim of this study was to assess MCP-1 levels in patients with HH and correlate these results with HFE status and iron indexes. One hundred and thirty-nine subjects diagnosed with HH (C282Y homozygotes = 87, C282Y/H63D = 26 heterozygotes, H63D homozygotes = 26), 27 healthy control subjects with no HFE mutation (N/N), and 18 normal subjects heterozygous for the H63D mutation served as age- and sex-matched controls. Ferritin and transferrin saturation and the presence of HFE mutation status were correlated with MCP-1 levels. Full white blood cell count analysis was also performed. We found a strongly significant decrease in MCP-1 protein levels in the C282Y homozygotes compared with the H63D homozygotes (P = 0.0009) and C282Y/H63D heterozygotes (P = 0.002). Similarly, MCP-1 protein levels in the C282Y homozygotes were decreased compared with the healthy controls (P = 0.00076). Furthermore, MCP-1 serum levels were elevated in H63D patients compared with the healthy controls (P = 0.0008). This study suggests for the first time that a differential expression of MCP-1 protein in patients with HH is associated with the specific HFE genetic component for iron overload. Therefore, these findings offer a possible explanation in the variable clinical spectrum of pathogenesis in patients with HH through abnormalities of an imbalance in the immune states of patients with HH.