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Autoinflammatory syndrome is characterized by: 1) episodes of seemingly unprovoked inflammation, 2) the absence of a high titer of autoantibodies or auto-reactive T cells, and 3) an inborn error of innate immunity. In this decade, many autoinflammatory syndromes have been reported in Japan, and so many Japanese physicians have become aware of this syndrome. Monogenic autoinflammatory syndromes present with excessive systemic inflammation including fever, rashes, arthritis, and organ-specific inflammation and are caused by defects in single genes encoding proteins that regulate innate inflammatory pathways. The main monogenic autoinflammatory syndromes are familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), cryopyrin-associated periodic syndrome (CAPS), Blau syndrome, and syndrome of pyogenic arthritis with pyoderma gangrenosum and acne (PAPA). We diagnosed these syndromes as clinical manifestations and performed genetic screening. Many serum cytokines are elevated in patients with autoinflammatory syndrome, but this is not disease-specific. The pathogeneses of many autoinflammatory syndromes are known to be related to inflammasomes, which are multiprotein complexes that serve as a platform for caspase 1 activation and interleukin-1β(IL-1β) and IL-18 maturation. Especially, NLRP3 inflammasomes may play a crucial role in the initiation and progression of FMF and CAPS. Recently, it was reported that NETs (neutrophil extracellular traps) derived from neutrophils may also play an important role in the pathogenesis of FMF. In the future, we hope to discover new clinical examinations which can provide evidence of inflammasome activation independent of genetic screening. In this issue, I introduce autoinflammatory syndromes and discuss the pathogenesis and clinical examination of these syndromes.

Chronic obstructive pulmonary disease(COPD) is a chronic airway disorder characterized by obstructive airflow limitation which is not completely reversible with treatment. Inflammatory changes in the peripheral airways, especially those with the diameter less than 2 mm(so-called small airway disease) have been speculated to be initial steps of COPD. However, it remains unclear which types of the cells play an essential role in the pathogenesis of these lesions. Studies with bronchoalveolar lavage demonstrated an increase in neutrophil numbers and the neutrophil chemoattractant interleukin-8. Tobacco smoke-induced IL-8 expression in the airway epithelial cells and macrophages results in neutrophil accumulation and activation. Immunohistochemical analysis recently demonstrated that T lymphocytes, especially CD8(+) cells are increased in the pathologic lesions. However, their role in the pathogenesis of inflammatory changes remains unelucidated. Further studies are necessary for the new development of treatment for this progressive lung disease.

Neutrophil disfunction, caused by a decreased production of effective radical oxygen species by myeloperoxidase (MPO) and NADPH oxidase within the neutrophil, may result in susceptibility to opportunistic fungal infections. In vitro, MPO produces OCl, which kills bacteria and viruses. In the case of MPO deficiency, susceptibility to Candida albicans infection was observed. Furthermore, it was demonstrated that MPO knockout mice were primarily susceptible to C. albicans infection. With regards to NADPH oxidase deficiency, such a patient was found to have severe chronic granulomatous disease (CGD) due to Aspergillus infection. This deficiency may have resulted from a gene mutation and/or abnormality of the NADH oxidase components, particularly cytochrome b558 (gp91phox and p22phox) in membrane and cytosol factors p47phox, p67phox, p40phox and others in neutrophil. Thus,irregular regulation of transcription factors for gene expression of phox molecules and MPO permits susceptibility to Aspergillus and Candida infections.

Cigarette smoking is a most important factor of COPD. IL-8 is elevated by cigarette smoking and increases the number of neutrophils in the lung. Surfactant is a complex mixture of phospholipids (PL) and proteins (SP). Both PL and SPs (SP-A and SP-D) decrease in bronchoalveolar lavage fluid in smokers. Decrease of PL enhances injury by elastase secreted from neutrophils and induces collapse of bronchioles, and decrease of SP-A and SP-D attenuate the defense against microbial agents in peripheral airways. Surfactant is thereby associated with COPD. However, little is known about the interaction, which induces COPD, between cytokines and surfactant. Further investigations are needed to clarify the mechanism on onset of COPD.

Neutrophil activation is considered to play a major role in organ dysfunction after severe trauma. Major surgery like esophagectomy also induces various host responses including neutrophil activation and it may be responsible for postoperative complications. We measured neutrophil elastase releasing capacity in 14 patients undergoing esophagectomy to evaluate perioperative changes of neutrophil activation. Elastase releasing capacity was estimated by the fMLP-induced elastase release from separated neutrophils in vitro and expressed as % increase of released elastase activity induced by 0.2 microM fMLP. Elastase releasing capacity was significantly increased from 28.6 +/- 17.7% after induction of anesthesia to 63.7 +/- 38.8% at 72 hours after induction, and decreased to 57.6 +/- 15.4% at 72 hours after induction. Elastase alpha 1-antitripsin inhibitor complex showed no significant increase during perioperative period. Interleukin-6 showed a peak level 24 hours after induction and interleukin-8 was increased significantly 12 hours after induction and maintained the elevated level until 72 hours postoperatively. We concluded that the neutrophil activity was increased during the perioperative period of esophagectomy and the priming of neutrophil took place during extensive surgical intervention.

We studied the role of neutrophils in lung injury after intestinal ischemia and reperfusion (I/R) in anesthetized dogs with lung lymph fistulae. One group was subjected to 2.5 hours of balloon occlusion of the superior mesenteric artery without laparotomy, followed by 3 hours of reperfusion (I/R group, n = 7). The other group was subjected to the same procedures, except for intestinal I/R (sham operation group, n = 6). In the sham operation group, lung fluid balance, hemodynamics, extravascular water volume (Qw 1: ml/g BFDW), myeloperoxidase activity in the lung (MPO: unit/g DW), H2O2 production by neutrophils in blood (mean DCF/cell), and migration of neutrophils into the lung lymphatic system did not significantly change. In the I/R group, both lung lymph flow (Jv) and protein clearance (Qp) increased more than 2.5 fold as compared with the baseline values, while capillary pressure (Ppc) and the ratio of lymph to plasma protein concentration (CL/Cp) remained almost the same as the baseline values. Qw1 also moderately increased. MPO activity, H2O2 production, and migration of neutrophils into the lung lymphatic system increased after I/R, and were more remarkable than in the sham operation group. These results suggest that activation and migration of primed neutrophils contributes to lung injury after intestinal ischemia and reperfusion.

In order to examine the role of myeloperoxidase (MPO) and neutrophil activation in the pathogenesis of MPO-ANCA related necrotizing crescentic glomerulonephritis (GN), we investigated MPO release and superoxide anion (O-2) production from the neutrophils in MPO ANCA related GN. Plasma effect on MPO release from neutrophils was also studied in MPO-ANCA related GN. Neutrophils and plasma were obtained from 10 patients with MPO-ANCA-related GN (A), 10 patients with MPO-ANCA non related GN (B) and 10 healthy controls (C). MPO release and O-2 production were assayed by using chemotactic factor, N-formyl-methionyl-leucyl-phenyalanine (FMLP) and cytochalasin B (CB). In MPO-ANCA related GN, MPO release and O-2 production were significantly higher than in the other groups. [MPO release (%) A: 43.02 +/- 18.33, B: 33.26 +/- 11.58, C: 19.73 +/- 8.38, sensitivity to FMLP (%) A: 894.56 +/- 381.96, B: 512.86 +/- 314.91, C: 301.12 +/- 139.8, O-2 production (nmoles/min/10(6) cells) A: 13.06 +/- 5.28, B: 3.57 +/- 2.02, C: 2.83 +/- 1.16] Furthermore, MPO release, sensitivity to FMLP and O-2 production were shown to increase in parallel with clinical disease activity. Plasma from MPO-ANCA related GN increased sensitivity to FMLP in neutrophils obtained from healthy controls [plasma concentration 1%, A: 311.5 +/- 110.3, B: 227.2 +/- 101.4, C: 215.5 +/- 93.7], and plasma from MPO-ANCA related GN suppressed %MPO release from neutrophils with MPO-ANCA related GN [plasma concentration 0.1%, A: 11.56 +/- 6.17, C: 15.51 +/- 8.01]. It was concluded that in patients with MPO-ANCA related GN, large amounts of MPO can be easily released from activated neutrophils and this might be influenced by some stimulating and suppressing factors contained in the plasma.

Interstitial pneumonia has been reported to be a side effect of treatment with interferon, and Sho-saiko-to (Xiao-Chai-Hu-Tang) may enhance this side effect. It is well known that activated neutrophils are important mediators of pulmonary fibrosis, so we studied the effects of interferon and Sho-saiko-to on neutrophil activation. Homogenized lung myeloperoxidase (MPO) activity was assayed after intraperitoneal injection of interferon with or without pretreatment with Sho-saiko-to. Although Sho-saiko-to alone did not change the lung MPO content, MPO in the lung was significantly increased by interferon administration. The increase was enhanced further by pretreatment with Sho-saiko-to. When the accumulated neutrophils are activated by some cytokines, such as TNF alpha or IL-1 beta from monocytes/macrophages, they may damage lung tissue. We therefore studied the effects of Sho-saiko-to and interferon on TNF alpha production in freshly isolated human monocytes. Sho-saiko-to increased the production of TNF alpha, but interferon did not. In addition, Sho-saiko-to significantly increased the production of TNF alpha by monocytes stimulated by lipopolysaccharide. Taken together, these data indicate that interferon causes neutrophils to accumulate in the lung. Sho-saiko-to alone may not injure lung tissue, but it increases the effect of interferon. When stimulated by some antigen, Sho-saiko-to may overstimulate the neutrophils. Granulocytes elastase and oxygen radicals released from activated neutrophils may damage lung tissue. The fibroblasts that repair the damaged tissue may increase the risk of pulmonary fibrosis.