Quantitative chest computed tomography is associated with two prediction models of mortality in interstitial lung disease related to systemic sclerosis.

Objective: In this multicentre study, we aimed to evaluate the capacity of a computer-assisted automated QCT method to identify patients with SSc-associated interstitial lung disease (SSc-ILD) with high mortality risk according to validated composite clinical indexes (ILD-Gender, Age, Physiology index and du Bois index). Methods: Chest CT, anamnestic data and pulmonary function tests of 146 patients with SSc were retrospectively collected, and the ILD-Gender, Age, Physiology score and DuBois index were calculated. Each chest CT underwent an operator-independent quantitative assessment performed with a free medical image viewer (Horos). The correlation between clinical prediction models and QCT parameters was tested. A value of P < 0.05 was considered statistically significant. Results: Most QCT parameters had a statistically different distribution in patients with diverging mortality risk according to both clinical prediction models (P < 0.01). The cut-offs of QCT parameters were calculated by receiver operating characteristic curve analysis, and most of them could discriminate patients with different mortality risk according to clinical prediction models. Conclusion: QCT assessment of SSc-ILD can discriminate between well-defined different mortality risk categories, supporting its prognostic value. These findings, together with the operator independence, strengthen the validity and clinical usefulness of QCT for assessment of SSc-ILD.

Diagnosis and treatment of rheumatoid arthritis in the Emilia Romagna region: a prospective population-based study.

OBJECTIVES: To perform a population-based study in rheumatoid arthritis (RA) patients, in order to evaluate the efficacy and safety of pharmacologic treatments. METHODS: 1087 patients with RA were enrolled; inclusion criteria were: newly diagnosed RA, already diagnosed RA with high disease activity (HDA) (DAS28≥4.2) starting biologic DMARDs (bDMARDs), already diagnosed RA with HDA continuing with conventional DMARDs (cDMARDs). The following data were collected: demographics, clinical and laboratory features, imaging and prescribed drugs. All parameters except immunology and imaging (performed yearly) were repeated at each follow-up evaluations (after 3, 6 and 12 months, and thereafter every 12 months). In order to evaluate clinical response, the EULAR response criteria were used as the gold standard. RESULTS: 414 (38.1%) newly diagnosed patients with RA, 477 (43.9%) RA patients who started bDMARDs and 196 (18.0%) RA patients who continued with cDMARDs were enrolled from April 2012 to March 2015 at 12 Rheumatology Centres in the Emilia Romagna Region. Statistical analyses showed a relative risk ratio (RRR) for moderate response of 1.65 in RA patients who started bDMARDs (p=0.16) and 2.49 for newly diagnosed RA (p=0.01). Sex, age and Health Assessment Questionnaire were not statistically significant. A RRR of 2.00 has been confirmed for RA patients who started bDMARDs (p<0.0005) for a good response as well as 2.20 for newly diagnosed RA (p<0.0005). An increase in adverse events among bDMARDs was found, but when looking at infections or neoplasia, no differences were highlighted between RA which started bDMARDs and RA who continued with cDMARDs. CONCLUSIONS: Our results are in line with already published papers from British and Swedish Registries: a greater likelihood to have a good response is demonstrated for not longstanding RA starting cDMARDs or RA with HDA when a bDMARD is started. Also a good safety profile is demonstrated.

Quantitative CT indexes are significantly associated with exercise oxygen desaturation in interstitial lung disease related to systemic sclerosis.

INTRODUCTION: Interstitial Lung Disease (ILD) is the first cause of death related to Systemic Sclerosis (SSc). The ILD severity can be assessed with clinical, functional and radiological outcome. Nevertheless none of them is completely validated in clinical practice. Recently a new radiological evaluation based on Quantitative Computed Tomography Indexes (QCTI) was proposed on the basis of voxel-wise quantitative analysis of chest CT. OBJECTIVES: The main aim of this study is to verify if QCTI can identify SSc patients with significant oxygen desaturation during the 6 min walking test. The discrimination performance of QCTI and the other clinical, functional and radiological outcomes was also investigated. METHODS: Sixty three SSc patients were enrolled and underwent clinical, functional and radiological assessment. Inspiratory chest CT of each patient was evaluated with both a visual score and a dedicated software for segmentation of the lung in order to obtained QCTI. RESULTS: Patients with or without severe oxygen desaturation showed different QCTI, CT visual score and functional outcomes (P < 0.05). In particular, QCTI and functional outcomes showed almost the same discriminating ability. CONCLUSION: QCTI detect SSc patients with a severe oxygen desaturation after exercise as well as functional and other radiological outcomes. It is remarkable that QCTI are the only outcome without intra- or inter-reader variability because they are obtained with an algorithm. These findings bring out the QCTI as a concrete tool in SSc-ILD assessment.

Quality of life and functional disability in patients with interstitial lung disease related to Systemic Sclerosis.

BACKGROUND: Systemic Sclerosis (SSc) is a connective disease impairing respiratory function. SSc worsens patients' Health Assessment Questionnaire (HAQ-DI), Short Form 36 Physical and Mental Component Summary (SF36-PCS and SF36-MCS). The aim of this work is to verify whether there is correlation between quality of life and lung interstitiopathy in SSc patients. METHODS: SF36 and HAQ-DI were given to each patient (48 in all). Lung involvement was evaluated with Baseline Dyspnea Index (BDI), spirometry and pulmonary fibrosis radiological assessment (PFRA). Correlations between SF36, HAQ-DI and lung involvement severity were investigated with Spearman's rank test. A p-value<0.05 was considered statistically significant. RESULTS: SF36-PCS and SF36-MCS correlate with BDI (respectively rho=0.553 p=0.0001; rho=0.357 p=0.0150). The best correlating SF36 subsets are Physical Role (rho =0.566 p<0.0001) and Bodily Pain (rho=0.444 p=0.0020). BDI correlates with HAQ-DI (rho=-0.655 p<0.0001). No statistically significant correlation was found between SF36, HAQ-DI and spirometrical values nor PFRA. CONCLUSIONS: The SSc patients enrolled have an impaired quality of life as widely demonstrated in literature. Quality of life reduction and functional ability decrease are only related to respiratory subjective impairment (assessed by BDI). Actually no correlation with objective lung damage (assessed by spirometry and PFRA) was detected.

Operator-independent quantitative chest computed tomography versus standard assessment of interstitial lung disease related to systemic sclerosis: A multi-centric study.

PURPOSE: Interstitial lung disease (ILD) related to systemic sclerosis (SSc) is assessed with pulmonary functional tests (PFTs) and semi-quantitative scores based on extent of ILD detectable on chest computed tomography (CT). CT quantitative indexes (QCTIs) are promising tools to assess extent of ILD. This study's aim is to evaluate the validity of QCTI compared with that of chest CT standard evaluation and PFTs. Moreover, QCTI differences between patients' subgroups according to prognostic stratifications were investigated. METHODS: ILD-SSc of patients from six rheumatological clinics was routinely assessed with chest CT and PFTs. Patients were clustered according to prognosis based on functional and/or radiological examinations. Finally, chest CTs were processed with OsiriX in order to obtain QCTI. RESULTS: Two hundred fifty-seven SSc patients were enrolled. QCTI correlation between extent of ILD and PFTs range from - 0.60 to 0.58 and from - 0.54 to 0.52, respectively. The majority of QCTI have a different distribution in patients' subgroups based on prognosis. Most of QCTI discriminate patients with an ILD severity leading to a poor prognosis. CONCLUSIONS: QCTI assessment of ILD-SSc is comparable to the evaluation based on chest CT and/or PFTs. QCTI values corresponding to severe ILD were identified. QCTIs are excellent candidates for a new and more reliable SSc-ILD assessment.

Interleukins (ILs), a fascinating family of cytokines. Part II: ILs from IL-20 to IL-38.

Every nucleated cell can produce and respond to cytokines, extracellular proteic/glycoproteic mediators that constitute a complex, interconnected, and flexible signaling network, addressed to modulate cell behavior and homeostasis through the interaction with high-affinity surface receptors. These messenger molecules, whose main characteristics are potency, pleiotropism, and redundancy, primarily act in autocrine, paracrine, and juxtacrine way, but can also display systemic activity in endocrine-like modality. They are generally classified according to their cellular sources, three-dimensional structure, or biological functions. Among cytokines, interleukins (ILs) represent a fascinating and multifunctional group of immunomodulators that primarily mediate the leukocyte cross-talk (hence the name), and mainly regulate the immune cell proliferation, differentiation, growth, survival, activation, and functions. Up to 38 ILs have been so far identified, numbered according to the order of discovery, and grouped in different subsets, based on distinguishing structural/functional features. Due to their crucial role in regulating inflammation and immune response, ILs are known to be involved in the pathogenesis of human inflammatory/autoimmune diseases. Therefore, they have increasingly attracted great interest as effective or promising therapeutic targets. The biology and functions of the hitherto identified human ILs are reviewed and discussed: herein, ILs from IL-20 to IL-38 are presented.

Epigenetics in autoimmune connective tissue diseases.

UNLABELLED: Background. Autoimmune connective tissue diseases (ACTDs) encompass a heterogeneous group of chronic immune-mediated inflammatory disorders, primarily affecting connective tissues and clinically characterized by variable multisystem manifestations, frequently overlapping. Environmental factors are thought to promote ACTD development in genetic predisposing/endocrine permissive background through the induction of epigenetic modifications, consisting of stable, heritable, but potentially reversible changes in gene expression, occurring without alterations of the DNA sequence. Actually, epigenetic mechanisms (such as histone modifications, DNA methylation, nucleosome positioning, and RNA interference) link genotype upstream and phenotype downstream, and, if persistently aberrant, may cause a variety of human diseases, including ACTDs. We aimed to review the recent advances in the knowledge of the ACTD epigenetic alterations. METHODS: A detailed search of the available literature was performed in the PubMed (U.S. National Library of Medicine) database. RESULTS: Growing evidence underlines the relevant role of epigenetic defects in the ACTD pathogenesis, and specific epigenetic patterns can represent disease biomarkers. In patients with rheumatoid arthritis (RA), epigenetic variations interact determining the typical "aggressive" phenotype displayed by RA synovial fibroblasts. Epigenetic modifications are involved in the profibrotic process that characterizes systemic sclerosis. In systemic lupus erythematosus and Sjögren's syndrome, complex epigenetic changes altering gene expression have been demonstrated. CONCLUSIONS: Comprehensive studies will contribute to further define the aberrant epigenetic mechanisms involved in the ACTDs etiopathogenesis. Moreover, being epigenetic changes potentially reversible, the identification of ACTDs epigenetic biomarkers will allow the development of therapeutic strategies addressed to target dysregulated genes and correct aberrant epigenomic alterations.

Interleukins (ILs), a fascinating family of cytokines. Part I: ILs from IL-1 to IL-19.

Every nucleated cell can produce and respond to cytokines, extracellular proteic/glycoproteic mediators that constitute a complex, interconnected, and flexible signaling network, addressed to modulate cell behavior and homeostasis through the interaction with high-affinity surface receptors. These messenger molecules, whose main characteristics are potency, pleiotropism, and redundancy, primarily act in autocrine, paracrine, and juxtacrine way, but can also display systemic activity in endocrine-like modality. They are generally classified according to their cellular sources, three-dimensional structure, or biological functions. Among cytokines, interleukins (ILs) represent a fascinating and multifunctional group of immunomodulators that primarily mediate the leukocyte cross-talk (hence the name), and mainly regulate the immune cell proliferation, differentiation, growth, survival, activation, and functions. Up to 38 ILs have been so far identified, numbered according to the order of discovery, and grouped in different subsets, based on distinguishing structural/functional features. Due to their crucial role in regulating inflammation and immune response, ILs are known to be involved in the pathogenesis of human inflammatory/autoimmune diseases. Therefore, they have increasingly attracted great interest as effective or promising therapeutic targets. The biology and functions of the hitherto identified human ILs are reviewed and discussed: in this first section of the article, ILs from IL-1 to IL-19 are presented.

Drug survival of the first course of anti-TNF agents in patients with rheumatoid arthritis and seronegative spondyloarthritis: analysis from the MonitorNet database.

OBJECTIVES: To compare drug survival of different anti-TNF drugs (infliximab, INF, etanercept, ETA, and adalimumab, ADA) in rheumatoid arthritis (RA) and spondyloarthritis (SpA) by analysing data collected from an Italian multicenter observational cohort study. METHODS: All patients with RA or SpA registered in the MonitorNet database who started their first course of anti-TNF therapy were included. Overall drug survival was measured, along with specific reasons of discontinuation (inefficacy or adverse events). A first set of analyses using RA as reference category assessed the relationship between diagnosis and drug survival. A second set of analyses stratified by diagnosis (RA and SpA) used INF as reference drug. Adjustment for confounders was performed. The results are presented as adjusted hazard ratios (adjHR) and 95% confidence intervals (95%CI). RESULTS: 2640 RA patients and 1220 SpA patients with a median follow-up of 17 months (IQR 7.2-33.4) were included in the analyses. Patients with a diagnosis of SpA showed a lower risk of drug discontinuation with an adjHR (95%CI) of 0.81 (0.73, 0.90). In SpA, the subset of patients with ankylosing spondylitis (AS) showed the best survival on treatment. In RA, both ETA and ADA showed a significantly lower probability of withdrawal when compared to INF [adjHR (95%CI) 0.46 (0.38, 0.56) and 0.68 (0.57, 0.81), respectively]. Similar results were found in SpA. CONCLUSIONS: Drug survival for SpA is longer than that in RA mainly due to the AS subgroup. In both RA and SpA, ETA and ADA showed a better retention on treatment when compared to INF.

Does early arthritis clinic organisation improve outcomes? What evidence is there? A systematic review.

OBJECTIVES: To perform a systematic review aimed to identify studies addressing the effect of the establishment of a structured organisation programme, named early arthritis clinic (EAC), finalized to manage patients with early arthritis (EA) or suspected early rheumatoid arthritis (ERA). METHODS: A literature search was performed until May 2012 using electronic databases. Additional information was obtained through a hand and grey literature search. Primary and secondary outcomes and eligibility criteria have been defined. RESULTS: The search provided a total of 3367 citations and, after the selection process, 11 non randomised controlled trials were selected, including a total of 8240 participants. The efficacy of EAC did clearly emerge with regard to reduction of the referral lag time and of the time to treatment (secondary outcomes). Only two studies met the primary outcomes: one study demonstrated that the EAC contributed to reducing disease activity and radiographic progression but not functional disability, while another reported a reduction of pain after a 6-12-month period of follow-up. CONCLUSIONS: Whether the establishment of EAC would improve the prognosis of EA in terms of primary outcomes such as clinical, functional and radiologic progression compared to patients managed outside from EAC does appear a still poorly addressed issue in the literature, which should be recognised as an urgent unmet need by the rheumatology community to gain more evidence-based information on this topic.

Focus on adipokines.

Once considered a passive reservoir for lipid storage and an inert provider of thermal/mechanical insulation, white adipose tissue (WAT) is presently seen as a highly dynamic endocrine organ that actively modulates a variety of physiologic processes, including energy balance, food intake, inflammation, immunity, metabolism, as well as cardio-vascular (CV) and neuroendocrine homeostasis. Actually, other than fatty acids and lipid moieties, WAT secretes a wide range of bioactive factors, considerably different in therms of structure and functions, including cytokines, chemokines, growth factors, complement system molecules, acute phase reactants, and hormones, among which the products predominantly or exclusively synthesized by and released from adipocytes are categorized as "adipokines". The adipokine expression is intimately linked to various parameters of adiposity (such as total body fat, percentage of body fat, and fat distribution), resulting generally (with very few exceptions, such as adiponectin, omentin, and Zinc-alpha2-glycoprotein) in positive correlation with WAT mass. The adipokine profiles undergo opposite changes in WAT excess or deficiency/dystrophy. In obese subjects, the altered adipokine network strikingly contributes to the development of systemic low-grade inflammation, as well as of obesity-related metabolic/CV comorbidities, that collectively define the so called metabolic syndrome. Adipokine dysregulation has been also observed in patients with chronic inflammatory/autoimmune disorders, such as connective tissue diseases, and adipokine pathway targeting has been thought to represent a potential innovative therapeutic perspective. Comprehensive advances in understanding the WAT biology and signaling may provide crucial insights into the physiopathology of the whole body homeostasis.

Psychiatric and neuropsychological manifestations of systemic lupus erythematosus.

BACKGROUND AND AIM: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease which may involve any organ and system, including peripheral, autonomic, and central nervous system (CNS). According to the American College of Rheumatology nomenclature, the term "neuropsychiatric SLE" identifies neurological and psychiatric syndromes occurring in patients at any time, not attributable to other causes, and categorized in three main groups, namely neurological syndromes of CNS, neurological syndromes of peripheral nervous system, and diffuse psychiatric/neuropsychological syndromes. The SLE neurological and psychiatric manifestations are usually reported together, and specific data on SLE psychopathology are limited. We aimed to electively focus on prevalence, pathogenesis, diagnostic aspects, and current therapeutic options of diffuse psychiatric/neuropsychological SLE syndromes in adult and pediatric patients. METHODS: A detailed search of concerning literature was performed in PubMed (U.S. National Library of Medicine) database. RESULTS: In both adulthood and childhood, psychiatric/neuropsychological syndromes are frequent and challenging SLE manifestations, whose prevalence is likely underestimated, owing to systematic assessment is not routinely performed in patients. Ischemia (due to disease-related vascular injury or cerebral vasospasm) and inflammatory/immunopathologic mechanisms appear to be the main pathogenic factors. Standardized treatment guidelines are not presently available, however, therapeutic recommendations have been proposed. CONCLUSIONS: Due to the high prevalence and significant suicidality risk of SLE psychiatric syndromes, systematic assessment to provide prompt diagnosis and adequate care should be critical part of SLE patients' evaluation protocol, and universally accepted and validated evaluating tools should be performed and introduced in the clinical practice, as well as widely experienced therapeutic strategies. (www.actabiomedica.it)

Proteasomes and immunoproteasomes.

In eukaryotic cells, the protein degradation is a highly regulated and selective process. Membrane-associated or extracellular proteins are degraded in lysosomes, whereas intracellular protein dismantling is primarily non-lysosomal, being realized by complex, not-membrane enclosed and energy-dependent effectors, the proteasomes, localized in both cytoplasm and nucleus. In mammals, the proteasomes constitute a structurally and functionally heterogeneous system, with shared general architecture, different molecular compositions and functions, and tissue-specific distribution. The proteasomes regulate a wide range of cellular processes, including protein quality control, gene transcription, cell cycle and death, while a proteasomal subpopulation, the immunoproteasomes, is responsible for the generation of peptides acting as immunogenic epitopes in antigen presentation to the immune cells. Due to the multitude of the targeted substrates and the involved processes, it is not surprising that alterations in the proteasome functions may play a pivotal role in the pathogenesis of several human diseases, such as solid or hematologic malignancies, neurodegenerative, immune and inflammatory disorders. Enormous benefits are emerging from the identification and clinical use of proteasome inhibitors, exhibiting a broad array of biologic properties and providing new and even unpredictable therapeutic opportunities.

Central nervous system effects of natural and synthetic glucocorticoids.

Natural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress, involving almost all organs and tissues, including brain. Since their therapeutic availability, synthetic GC (SGC) have been successfully prescribed for a variety of diseases. Mounting evidence, however, demonstrated pleiotropic adverse effects (AE), including central nervous system (CNS) disturbances, which are often misdiagnosed or underestimated. The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC. A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database. Cortisolemia plays a crucial role in control of behavior, cognition, mood, and early life programming of stress reactivity. Hypercortisolemia or SGC treatments may induce behavioral, psychic and cognitive disturbances, due to functional and, over time, structural alterations in specific brain target areas. These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses <20 mg/day) and usually reversible. Pediatric patients are particularly susceptible. Behavioral changes, including feeding and sleeping modifications, are common. Psychic AE are unpredictable and heterogeneous, usually mild/moderate, severe in 5-10% of cases. Manic symptoms have been mostly associated with short SGC courses, and depressive disorder with long-term treatments. Suicidality has been reported. Cognitive AE peculiarly affect declarative memory performance. Physiologic levels of NGC are essential for efficient brain functions. Otherwise, hypercortisolemia and SGC treatments may cause dose-/time-dependent neuropsychic AE and, over time, structural alterations in brain target areas. Clinicians should carefully monitor patients, especially children and/or when administering high doses SGC.

The effector T helper cell triade.

T lymphocytes play crucial role in immune responses. Effector T helper (Th) cells derive from progenitor naïve CD4+ T cells, after maturational process induced by antigenic stimulation. Their commitment depends on complex interactions with antigen-presenting cells in a permissive milieu, including antigenic type and load, costimulatory molecules and cytokine signaling. Committed CD4+ T cells may differentiate into Th1, Th2, TH17 phenotypes (the effector Th cell triade), with distinct cytokine products and biological functions, or evolve into the inducible regulatory T (Treg) lineage, with immunomodulatory functions. Th1 subset, primarily addressed to face intracellular pathogens, produces interleukin (IL)-2, IL-3, interferon-gamma and tumour necrosis factor-beta, peculiarly supporting cellular immunity. Th2 cells, essential in eliminating extracellular pathogens, including helminthes, express IL-4, IL-5, IL-6, IL-10, IL-13, and IL-25, supporting humoral immunity. Th17 subset, determinant in fighting Gram-negative bacteria, fungi, and some protozoa, secretes IL-17, IL-21, and IL-22, with strong proinflammatory effects. Th responses are tightly controlled to avoid self antigen reactivity or excessive reactions to non-self antigens. In fact, dysregulated Th1 response drives cell-mediated autoimmune disorders, and enhanced Th2 activity is involved in atopy, whereas Th17 cells are probably responsible for chronic tissue inflammation. Skewing of response away from Treg cells may lead to the onset and/or progression of autoimmune diseases or acute transplant rejection in humans. A better understanding of Th triade functions, and a clearer definition of Th response regulatory mechanisms may provide novel therapeutic opportunities in treating immunopathologies.

Focus on human natural killer cells.

Human natural killer (NK) lymphocytes were originally identified by their large granular morphology and their ability to "naturally" kill virus-infected and malignant cells without any priming. Lacking the surface markers of either B or T cells, they constitute the third major lymphocytic population, representing 5-15% of circulating lymphocytes. Their functions are tightly regulated by a delicate balance of signals transmitted by at least four different families of germ-line encoded, non-rearranged activating/inhibitory receptors. Once activated, NK cells produce immunoregulatory cytokines, interact with other immune cells, and finally destroy aberrant/pathogen-infected cells inducing their lysis or their apoptosis. The identification of phenotypically and functionally distinct NK cell subsets has provided advances in understanding the crucial role of these highly specialized and efficient lymphocytes. Traditionally considered as innate cells, NK lymphocytes appear to represent a bridge between the two broad arms of the human immune system. They are not only potent cytotoxic effectors, but also multicompetent cells that can shape and regulate both the innate and adaptive immune responses. A better knowledge of their biology may allow the development of new NK-based therapies addressed to the treatment of infections, malignancies and autoimmune diseases.

Atherogenesis in rheumatoid arthritis: the "rheumatoid vasculopathy"?

BACKGROUND AND AIM: Rheumatoid Arthritis (RA) is associated with accelerated atherogenesis. RA patients have a reduced life expectancy compared to the general population, and cardiovascular (CV) disease (CVD) is recognized as a strong contributor to the excess of morbidity and mortality. Our aim was to review and discuss the recent advances in the knowledge of the RA-associated atherogenesis. METHODS: A detailed search of the available literature was performed in the PubMed (U.S. National Library of Medicine) database. RESULTS: Atherosclerosis is an early and common finding in RA patients, positively correlating to the disease duration and severity. Both traditional CV risk factors and disease-related mechanisms may contribute to the RA atherogenesis, however, clinical and epidemiological studies suggest that the systemic inflammation is the major determinant of the RA vascular comorbidity. Patients with RA show an increased risk for CV events compared with the general population, and CVD accounts for nearly 50% of death causes. CV morbidity and mortality strongly correlate with disease activity, whereas the successful pharmacological control of the chronic inflammation decreases the risk of CV complications. CONCLUSIONS: Atherogenesis is a precocious feature in RA, as extraarticular manifestation of the syndrome, and might be defined the "rheumatoid vasculopathy". The better understanding of molecular mechanisms leading to the RA accelerated atherogenesis, the development of effective screening methods, and the identification of successful strategies to control both systemic inflammation and concomitant CV risk factors will allow to minimize the rheumatoid vasculopathy impact on the patients' morbidity and mortality.

The inflammasomes: the key regulators of inflammation.

Following any threat to tissutal integrity, innate immune system promptly recognizes foreign/damage-associated molecules and orchestrates the global immune response, inducing inflammation, chemotaxis, phagocytosis and production of antimicrobial effector molecules, as well as providing instruction to the adaptive immune system. Innate immune cells detect both exogenous and endogenous danger signals through invariant germline-encoded pattern recognition receptors, including Toll-like receptors, retinoic acid-inducible gene I-like receptors, and nucleotide binding domain and leucine reach repeat containing receptors (NLRs). The recruitment of NLRs, namely IPAF, NAIPs and NALPs, by various potentially harmful stimuli leads to the assembly of inflammasomes, multimeric caspase-activating complexes entailing the sensor NLR, intracellular adaptor proteins, and procaspase-1 and -5. The caspase activation is necessarily required for the processing and secretion of proinflammatory cytokines, such as interleukin (IL)-1b, IL-18, and IL-33. Therefore, the inflammasomes are critical regulators of the inflammatory response. Dysregulation of such a versatile sentry system is involved in the pathogenesis of human autoinflammatory diseases, autoimmune disorders, and microcrystalline arthritides. A better knowledge of the inflammasome crucial role in the immune response may provide possible future therapeutic improvements in protection against invading pathogens and in vaccine efficacy, as well as in the treatment of human inflammatory diseases.