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.

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.

Cognition: neurobiological correlates and dynamics.

Human brain constructs knowledge, elaborates thought and promotes goal-directed behavior, organizing memories of past experience and information from the environment, perceived by senses. Cognition entails all these mental processes. Neuroscience has attempted to explore the architecture of cognition, whose neurobiological substrates are provided by widely distributed neural networks, interacting through complex connections, including sensory-fugal (inward or forward) and sensory-petal (outward or backward) projections, running in opposite direction. The iterative dialogue between inward circuits (conveying information that reflect the physical nature of perceptive stimuli) and outward ones (inferring the nature of percepts based on empirical accounts of past experiences) allows the unimodal (modality-selective) and multimodal/supramodal elaboration of sensory information. Moreover, top-down projections from high-order associative cortices confer the ability to transcend experience-based representations, promoting individually-sculpted interpretations, as well as mental imagery, thought, and abstraction.

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)

The neurobiology of the human memory.

Memory can be defined as the ability to acquire, process, store, and retrieve information. Memory is indispensable for learning, adaptation, and survival of every living organism. In humans, the remembering process has acquired great flexibility and complexity, reaching close links with other mental functions, such as thinking and emotions. Changes in synaptic connectivity and interactions among multiple neural networks provide the neurobiological substrates for memory encoding, retention, and consolidation. Memory may be categorized as short-term and long-term memory (according to the storage temporal duration), as implicit and explicit memory (with respect to the consciousness of remembering), as declarative (knowing that [fact]) and procedural (knowing how [skill]) memory, or as sensory (echoic, iconic and haptil), semantic, and episodic memory (according to the various remembering domains). Significant advances have been obtained in understanding memory neurobiology, but much remains to be learned in its cognitive, psychological, and phenomenological aspects.

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.

The immunosenescence.

Aging is a post-maturational process, biologically characterized by the progressive failure to maintain or restore the physiologic homeostasis. Such a complex phenomenon is influenced by the interaction among genetic, epigenetic, environmental, behavioral and socio-economic factors and involves the whole body, including immune system. The age-related immune system changes, collectively termed immunosenescence and historically defined as a state of immunodeficiency, actually represent a complex remodeling that entails the increase of some immune functions and the decrease or invariability of others. These adjustments may either successfully result in a longstanding active immune system with a greater chance of long survival, or unsuccessfully lead to a dysregulated immunity with a higher risk of infections, malignancies and autoimmune diseases. Revealing the complete scenario of the biological events occurring in the immune system with advancing age might allow to identify immunosupportive treatments and/or behaviors direct to positively modulate the immunosenescence process.

Life-or-death fate in the adaptive immune system.

The tissue homeostasis is essentially realized through a precise control of cellular proliferation and death. The constant balance between expansion and contraction of different cell populations is a critical hallmark of the mammalian adaptive immune system. Immune-competent cells have to confront the survival-or-demise dilemma in primis during ontogenesis and, thereafter, in their mature life in order to maintain homeostasis, since the cellular proliferation occurring during the immune response must be counterbalanced by programmed death as the immune reaction attenuates. The programmed cell death is mainly realized through apoptosis. Perturbations in precise control of lymphocyte life-or-death balance may lead to pathological processes, such as immunodeficiencies, autoimmunity or lymphoproliferative disorders. The life-or-death fate in the human adaptive immune system is reviewed and discussed.

Fibromyalgia and psychiatric disorders.

Fibromyalgia (FM) is a common and polymorphic syndrome, characterized by long-lasting, widespread musculoskeletal pain, in the presence of 11 or more tender points located at specific anatomical sites. A heterogeneous series of disturbances, mainly involving autonomic, neuroendocrine and neuropsychic systems, is usually present. Even if subjective, the chronic psychophysical suffering state of FM adversely affects the patient's quality of life, performance and mood. Cognitive behavioural therapy and antidepressant drugs are useful in FM treatment, suggesting a close link between the syndrome and psychiatric, psychological and behavioural factors. Our aim was to evaluate the personality profiles of FM patients, as well as the aggregation and relationships between FM and psychiatric disorders (PD), reviewing the available evidences in current literature on this comorbidity. Personality variables associated with psychological vulnerability are frequent in FM patients. Personality disorders are rarely reported. Compared with controls, FM patients show a significantly higher prevalence of depressive and anxiety disorders, reported in 20-80% and 13-63.8% of cases, respectively. This high variability may depend on the psychosocial characteristics of patients, since most of the studies were performed on tertiary care consulting patients, however, even referring to the lower percentages, the occurrence of PD is significantly higher in FM subjects compared to the general population (7%). Moreover, elevated frequencies of PD have been detected in relatives of FM patients. The FM/PD aggregation suggests a common physiopathology, and alterations of neurotransmitter systems may constitute the shared underlying factor.

Carnitine: a therapeutic option for childhood psoriatic onycho-pachydermo-periostitis (POPP).

Psoriatic onycho-pachydermo-periostitis (POPP)is a rare subset of psoriatic arthritis, characterized by onychopathy, painful thickening of the periungual soft tissues, and radiological features consisting of an exuberant periosteal reaction of the terminal phalanx. The POPP treatment is debated, and side effect risk of therapies may not be offset by their benefits. We report on a successful treatment with carnitine in a 15-year old boy suffering from POPP.

Glucocorticoids and brain functions.

Natural glucocorticoids are essential components of the body neuroendocrine system, modulating the physiological homeostasis and coordinating the adaptive responses to stressors. The complex activity of glucocorticoids involves almost all organs and tissues, including brain. Their effects on central nervous system vary with species, gender, age, hormone concentrations, timing, and duration of exposure. In humans, the glucocorticoid effects on brain functions entail influences on arousal, sleep, behaviour, cognition, memory, mood and affect. Two types of cytoplasmic receptors, namely mineralcorticoid and glucocorticoid receptors, having different brain distribution and functional pattern, mediate the hormonal activity through the stimulation or suppression of target gene transcription, depending on cell type. Synthetic glucocorticoids substantially share the same mechanisms of action, however, with different kinetics and/or receptor affinities In this paper, the main effects of glucocorticoids on brain functions are reviewed and discussed.