Genetic associations in type I interferon related pathways with autoimmunity

Type I interferons play an outstanding role in innate and adaptive immunity by enhancing functions of dendritic cells, inducing differentiation of monocytes, promoting immunoglobulin class switching in B cells and stimulating effector functions of T cells. The increased production of IFNα/β by plasmacytoid dendritic cells could be responsible for not only efficient antiviral defence, but it also may be a pathological factor in the development of various autoimmune disorders. The first evidence of a genetic link between type I interferons and autoimmune diseases was the observation that elevated IFNα activity is frequently detected in the sera of patients with systemic lupus erythematosus, and that this trait shows high heritability and familial aggregation in their first-degree healthy relatives. To date, a number of genes involved in interferon signalling have been associated with various autoimmune diseases. Patients with systemic lupus erythematosus, Sjögren's syndrome, dermatomyositis, psoriasis, and a fraction of patients with rheumatoid arthritis display a specific expression pattern of interferon-dependent genes in their leukocytes, termed the interferon signature. Here, in an attempt to understand the role of type I interferons in the pathogenesis of autoimmunity, we review the recent advances in the genetics of autoimmune diseases focusing on the association of genes involved in type I interferon pathways.     

TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity

We formulate a two-phase paradigm of autoimmunity associated with systemic lupus erythematosus, the archetypal autoimmune disease. The initial Toll-like receptor (TLR)-independent phase is mediated by dendritic cell uptake of apoptotic cell debris and associated nucleic acids, whereas the subsequent TLR-dependent phase serves an amplification function and is mediated by uptake of TLR ligands derived from self-antigens (principally nucleic acids) complexed with autoantibodies. Both phases depend on elaboration of type I interferons (IFNs), and therapeutic interruption of induction or activity of these cytokines in predisposed individuals might have a substantial mitigating effect in lupus and other autoimmune diseases.     

Acetylation-dependent signal transduction for type I interferon receptor

Cytokine-activated receptors initiate intracellular signaling by recruiting protein kinases that phosphorylate the receptors on tyrosine residues, thus enabling docking of SH2 domain-bearing activating factors. Here we report that in response to type 1 interferon (IFNalpha), IFNalpha receptors recruit cytoplasmic CREB-binding protein (CBP). By binding to IFNalphaR2 within the region where two adjacent proline boxes bear phospho-Ser364 and phospho-Ser384, CBP acetylates IFNalphaR2 on Lys399, which in turn serves as the docking site for interferon regulatory factor 9 (IRF9). IRF9 interacts with the acetyl-Lys399 motif by means of its IRF homology2 (IH2) domain, leading to formation of the ISGF3 complex that includes IRF9, STAT1, and STAT2. All three components are acetylated by CBP. Remarkably, acetylation within the DNA-binding domain (DBD) of both IRF9 and STAT2 is critical for the ISGF3 complex activation and its associated antiviral gene regulation. These results have significant implications concerning the central role of acetylation in cytokine receptor signal transduction.     

Receptor dimerization dynamics as a regulatory valve for plasticity of type I interferon signaling

Type I interferons (IFNs) activate differential cellular responses through a shared cell surface receptor composed of the two subunits, IFNAR1 and IFNAR2. We propose here a mechanistic model for how IFN receptor plasticity is regulated on the level of receptor dimerization. Quantitative single-molecule imaging of receptor assembly in the plasma membrane of living cells clearly identified IFN-induced dimerization of IFNAR1 and IFNAR2. The negative feedback regulator ubiquitin-specific protease 18 (USP18) potently interferes with the recruitment of IFNAR1 into the ternary complex, probably by impeding complex stabilization related to the associated Janus kinases. Thus, the responsiveness to IFNα2 is potently down-regulated after the first wave of gene induction, while IFNβ, due to its ∼100-fold higher binding affinity, is still able to efficiently recruit IFNAR1. Consistent with functional data, this novel regulatory mechanism at the level of receptor assembly explains how signaling by IFNβ is maintained over longer times compared with IFNα2 as a temporally encoded cause of functional receptor plasticity.     

Is interferon effective after oral administration? The state of the art.

At present the evidence that interferon can be effective when administered by oral route is tenous and the purpose of this minireview is to focus attention on this problem. Interferon may act on the oral-associated lymphoid tissue and trigger a cascade of events leading to activation of the immune system with little or no presence of interferons in body fluids and lack of toxicity. If this is true, the oral administration could be the ideal route for the treatment of some viral diseases and immunodeficiencies.     

Fine tuning type I interferon responses

Interferon responses are balanced between protection against pathogens and other disease agents versus toxicity and development of chronic diseases. Optimal outcomes are achieved by regulating the nature, strength and duration of Interferon (IFN) production, IFN-receptor interaction and signalling pathways modulated in a manner appropriate for particular target cells. Modification of cell behaviour is mediated by regulation of positive and negative signalling pathways and by proteins encoded by selected groups of IFN-regulated genes. Understanding how these pathways are regulated and how to measure them by biomarkers or gene signatures will enable us to better understand the role of IFN pathways in the pathogenesis of infectious and inflammatory diseases and cancer. This will lead to improved patient stratification and disease treatment.     

Pidotimod: the state of art

Despite the use of antibiotics and vaccines, the frequency of respiratory tract infections is still high and these infections interest a wide range of patients, from children to aged people, including in particular these extreme categories because of the deficiency of their immune system, due to immaturity in the former case and to “immunosenescence” in the latter. For that reason immunostimulant drugs are getting more important to prevent and to attenuate infections. Pidotimod (3-L-pyroglutamyl-L-thiazolidine-4carboxylic acid) is a synthetic dipeptide with immunomodulatory properties. We reviewed studies conducted on different categories of patients, with particular attention on children and senile patients suffering from recurrent respiratory tract infections, associated, or not, with asthma or COPD. The outcomes considered are both clinical and laboratory parameters. The common end-point of these studies is that Pidotimod has an immunomodulatory activity which is able both to improve the clinical conditions of patients and to enhance and stimulate their immunity cells (lymphocytes but not only) functions acting on adaptive and innate immunity. Pidotimod is also able to increase the concentration of salivary IgA directed against bacteria; furthermore, it can modulate airway epithelial cells functions up-regulating the expression of toll-like receptors and acting on adhesion molecules. According to studies conducted on patients with atopic asthma, it seems that Pidotimod could affect T-lymphocytes balance with a possible addictional anti-allergic activity. Furthermore, it has been demonstrated an improvement of FEV1 and PEF in asthmatic patients treated with Pidotimod. Main clinical outcomes are the reduction of the number of infectious episodes, lesser severity of signs and symptoms and, consequently, a reduction in use of antibiotics and symptomatic drugs, less working and school days lost, less mortality and morbidity. The studies considered give positive results, confirming Pidotimod’s efficacy. Furthermore, many studies show a good safety profile of the drug, without recording serious adverse events and mutagenic potential, and a very low incidence of side effects. Pidotimod is also a more safe solution in patients subjected to vaccination, if compared to lyophilized polibacterial, which can’t be administered for thirty days before vaccination.     

Virus-induced expression of type I interferon genes

Intracellular double-stranded (ds) RNA is a major sign of replication for many viruses. Host mechanisms detect the dsRNA and provoke antiviral responses. Recently, we identified retinoic acid inducible gene-I (RIG-I), which encodes a DExD/H box RNA helicase containing the caspase recruitment domain (CARD) as a critical regulator for dsRNA-induced signaling. The helicase domain with intact ATPase activity is responsible for recognition of dsRNA, and the CARD transmits downstream signals, resulting in the activation of genes including type I interferons. In this review, we discuss the function of RIG-I in antiviral innate immunity.     

Type I interferon as a stimulus for cross-priming

Type I interferon (IFN-alpha/beta) is induced rapidly by infection and is well recognised for its crucial role in innate defence. However, it is evident that IFN-alpha/beta also serves as a signal for the generation of adaptive immune responses. In this review, we focus on the involvement of IFN-alpha/beta in the induction of CD8+ T cell responses by cross-priming.     

Botulinum toxin for the treatment of idiopathic and neurogenic overactive bladder: state of the art

The pharmacologic treatment of overactive bladder and detrusor overactivity, whether idiopathic or neurogenic, has centered around blocking muscarinic receptors on the detrusor muscle. Although newer agents have been developed with better tolerability and safety, the basic mechanism by which the "irritable" detrusor is treated has not changed in decades. Although effective in many cases of idiopathic and neurogenic detrusor overactivity and overactive bladder, antimuscarinic agents fall short in many other cases because of lack of efficacy and/or tolerability. For the past several years, there has been increasing evidence to support the use of botulinum toxin for the treatment of detrusor overactivity and overactive bladder syndrome not effectively treated by anticholinergics. From early open-label studies to the more recent randomized, controlled trials, efficacy and tolerability data have been very encouraging. Botulinum toxin is not yet approved by the US Food and Drug Administration for the treatment of detrusor overactivity and overactive bladder, but the positive results seen thus far cannot be ignored.     

The human type I interferon gene cluster

The human type I interferon genes are clustered on the short arm of chromosome 9, at band 9p21. The structure of this gene cluster has been recently determined, and is described. The organization of the genes, and their divergence in sequence give clues about the possible mechanisms that were involved in the evolution of the type I interferons. TheIFNAgenes andIFNWpseudogenes can be separated in two groups: a distal group of 10 genes and pseudogenes, that has a more recent origin, and a proximal group of 13 genes and pseudogenes, which expanded earlier in the evolution of the cluster.     

Hematopoietic stem cell transplantation for the treatment of autoimmunity in type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease that leads to the destruction of the insulin-producing pancreatic b cells. While there is no current cure, recent work in the field of allogeneic hematopoietic stem cell transplantation (HSCT) and the induction of mixed chimerism, a state in which multilineage hematopoietic populations of both recipient and donor co-exist, has demonstrated that it is possible to provide protection from disease onset, as well as reverse the autoimmune state in spontaneously diabetic mice. Furthermore, the establishment of mixed chimerism induces donor-specific tolerance, providing the potential to normalize glucose regulation via pancreatic islet transplantation without the requirement of life-long immunosuppression. Current studies are aimed at understanding the mechanisms involved in both the reversal of autoimmunity and the induction of tolerance, with the aim of moving this promising approach to curing T1D into the clinic.     

Systemic lupus erythematosus and the type I interferon system

Patients with systemic lupus erythematosus (SLE) have ongoing interferon-α (IFN-α) production and serum IFN-α levels are correlated with both disease activity and severity. Recent studies of patients with SLE have demonstrated the presence of endogenous IFN-α inducers in such individuals, consisting of small immune complexes (ICs) containing IgG and DNA. These ICs act specifically on natural IFN-α-producing cells (NIPCs), often termed plasmacytoid dendritic cells (PDCs). Given the fact that the NIPC/PDC has a key role in both the innate and adaptive immune response, as well as the many immunoregulatory effects of IFN-α, these observations might be important for the understanding of the etiopathogenesis of SLE. In this review we briefly describe the biology of the type I IFN system, with emphasis on inducers, producing cells (especially NIPCs/PDCs), IFN-α actions and target immune cells that might be relevant in SLE. On the basis of this information and results from studies in SLE patients, we propose a hypothesis that explains how NIPCs/PDCs become activated and have a pivotal etiopathogenic role in SLE. This hypothesis also indicates new therapeutic targets in this autoimmune disease.     

Endogenous, or therapeutically induced, type I interferon responses differentially modulate Th1/Th17-mediated autoimmunity in the CNS

Different viruses trigger pattern recognition receptor systems, such as Toll-like receptors or cytosolic RIG-I like helicases (RLH), and thus induce early type I interferon (IFN-I) responses. Such responses may confer protection until adaptive immunity is activated to an extent that the pathogen can be eradicated. Interestingly, the same innate immune mechanisms that are relevant for early pathogen defense have a role in ameliorating experimental autoimmune encephalomyelitis (EAE), a rodent model of human multiple sclerosis. We and others found that mice devoid of a component of the IFN-I receptor (Ifnar1(-/-)) showed significantly enhanced autoimmune disease of the central nervous system (CNS). A detailed analysis revealed that in wild-type mice IFN-I triggering of myeloid cells was instrumental in reducing brain damage. A more recent study indicated that similar to Ifnar1(-/-) mice, RLH-signaling-deficient mice showed enhanced autoimmune disease of the CNS as well. Moreover, when peripherally treated with synthetic RLH ligands wild-type animals with EAE disease showed reduced clinical scores. Under such conditions, IFN-I receptor triggering of dendritic cells had a crucial role. The therapeutic effect of treatment with RLH ligands was associated with negative regulation of Th1 and Th17 T-cell responses within the CNS. These experiments are consistent with the hypothesis that spatiotemporal conditions of, and cell types involved in, disease-ameliorating IFN-I responses differ significantly, depending on whether they were endogenously induced in the context of EAE pathogenesis within the CNS or upon therapeutic RLH triggering in the periphery. It is attractive to speculate that RLH triggering represents a new strategy to treat multiple sclerosis by stimulating endogenous immunoregulatory IFN-I responses.     

Modulation of T-cell function by type I interferon

Production of type I interferon (IFN-α/β) is a common cellular response to virus infection. IFN-α/β has a dual role in combating infection, triggering innate antiviral mechanisms and stimulating the generation of an adaptive immune response. This review focuses on the effects of IFN-α/β on one particular immune cell type, the T cell, and the impact of IFN-α/β-mediated signalling in T cells on the immune response. The critical role of T-cell responsiveness to IFN-α/β for the generation of productive T-cell responses after infections with certain viruses in vivo is discussed in the context of in vitro experiments investigating the mechanisms by which IFN-α/β modifies T-cell function. These studies reveal complex effects of IFN-α/β on T cells, with the consequences of exposure to IFN-α/β depending on the context of other signals received by the T cell.     

Surgical treatment of liver metastases of gastric cancer: state of the art

ABSTRACT: BACKGROUND: The prognosis of patients with liver metastases from gastric cancer (LMGC) is dismal, and little is known about prognostic factors in these patients; so justification for surgical resection is still controversial. Furthermore the results of chemotherapy for these patients are disappointing. The purpose of this study was to review recent outcomes of hepatectomy for LMGC and to determine the suitable candidates for surgery, assessing the surgical results and clinicopathologic features. Moreover we compare these results with those obtained with alternative treatments.