EditorialImmune and Inflammatory-Mediated Disorders: FromBench to Bedside

Marcella Reale ,1 Lucia Conti ,2 and Diana Velluto3

1University of G. D’Annunzio, Chieti, Italy2Istituto Superiore di Sanità, Rome, Italy3University of Miami, Miami, FL, USA

Correspondence should be addressed to Marcella Reale; mreale@unich.it

Received 15 July 2018; Accepted 15 July 2018; Published 3 September 2018

Copyright © 2018 Marcella Reale et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Immune responses play a key role in maintaining tissuehomeostasis, influencing nearly all organs and systems ofthe body including skin, gut, lungs, brain, and the cardiovas-cular system. Excessive or dysregulated immune responsesand chronic inflammation represent a central driving forcein many disorders, including infectious, inflammatory, andautoimmune diseases, as well as cancer. Cells of the mononu-clear phagocyte lineage act as innate sentinels and are activelyinvolved in regulating the balance between homeostasis andinflammation, thus ultimately contributing to the mainte-nance of the health condition. Age- and gender-related dif-ferences in immune response as well as in gut microbiotaare emerging as important contributors in increasing thecomplexity in the diagnosis, treatment, and prevention ofimmune-mediated disorders.

In four original investigation articles, different autoim-mune diseases were studied to find new biomarkers thatcould help explain the aetiology and pathogenesis of the dis-eases and be useful for new targeted therapy.

Myasthenia gravis (MG) is an antibody-mediated dis-ease affecting the neuromuscular junction, caused by anti-bodies against the nicotinic acetylcholine receptor (AChR,AChR-Ab). Thanks to short half-life serum levels, freeimmunoglobulin light chains (FLCs) can be considered aninstantaneous marker of B cell activity. In their study, U.Basile et al. showed an increase in free k chains in bothAChR- and muscle-specific tyrosine kinase (MuSK-) MGwhile free λ chain levels were increased only in AChR-MG. Thus, they suggest that at least k chains can beconsidered a very sensitive circulating biomarker of B cell

activation and humoral autoimmune response. This mayrepresent a preliminary important study for a more detailedmulticenter analysis.

It is clinically known that patients with one autoimmunedisease tend to develop additional autoimmune diseases, andrecently an increased prevalence of neuromyelitis optica(NMO) in patients with MG has been reported. To explainthe exacerbation or increased susceptibility of patients withone autoimmune disease to developing an additional autoim-mune syndrome, T. Mizrachi et al. established an animalmodel for both NMO and MG, using EAMG mice immu-nized with Torpedo AChR and then subjected to passivetransfer of NMO-IgG or to immunization with AQP4-derived peptide. This study shows that injection of eitherAQP4 peptide or NMO-Ig to naïve mice caused increasedfatigability and when the same molecules were injected intoEAMG mice, the disease severity mediated by muscle weak-ness significantly increased.

In the course of primary Sjögren’s syndrome (pSS),inflammatory cell infiltration consists mainly of lymphocytesinfiltrating exocrine glands, which leads to their impairedfunction. The characteristic feature is generalized dryness.The disease develops slowly, and months can pass before apatient presents full spectrum of clinical symptoms. Insuffi-cient treatment without inhibiting the autoimmune responseleads to severe complications. A. Sebastian et al. attempted toanswer the question whether it is possible to distinguishbetween patients with pSS and individuals with drynesscaused by other pathologies without applying invasive diag-nostic methods. The study included 68 patients with pSS

HindawiJournal of Immunology ResearchVolume 2018, Article ID 7197931, 3 pageshttps://doi.org/10.1155/2018/7197931

and 43 healthy controls with dryness. They found that chronicfatigue syndrome is more common in pSS patients and canbe a subjective distinguishing factor in the group of peoplewith dryness.

E. Dziadkowiak et al. have planned their study to estab-lish whether in patients with pSS without central nervous sys-tem (CNS) involvement, the function of the central portionof the sensory pathway can be challenged. The authors, bymeasuring somatosensory evoked potentials (SEP) to evalu-ate the function of afferent sensory pathways, confirmed dys-function of the central sensory neuron, which indicatessubclinical damage to the CNS in pSS patients.

Behcet’s disease (BD) is an autoimmune and autoin-flammatory disorder which origin is unknown, althoughboth genetic and environmental factors play a role. Severalgenes have been found to be associated with the disease.Transcriptional profiling of PBCs, obtained from patientswith active BD, to evaluate the role of the immune systemin the pathogenesis of the disease was performed by A.Puccetti et al. The authors found up- and downregulatedtranscripts. By performing Gene Ontology analysis, theyevidenced that most of the regulated transcripts can berelated to inflammation, immune response, apoptosis,blood coagulation, vascular damage, and cell proliferationpathways, all playing a key role in BD.

The mechanisms contributing to the chronic inflamma-tory condition underlying some immunomediated disordershave been investigated or reviewed in a number of articles.

Lobular inflammation and mixed portal/periportalinflammation were observed in recurrent hepatitis C virus(HCV) infection and in acute cellular rejection (ACR),respectively. The aim of the research by A. I. Gomaa et al.was to evaluate whether the origin of macrophages and theimmune mediator CXCR3 could help in differentiatingbetween acute recurrent HCV infection and ACR after livertransplantation. Analyzing the expression of CD68 andCXCR3 in the postliver transplant biopsy in cases of recur-rent HCV infection and cases of ACR, the authors found thatCD68 was expressed in both recurrent HCV infection andACR, and in patients suffering from recurrent HCV, strongerCD11b deposits in liver biopsies were also detected. On theother hand, CXCR3 is a marker and plays a considerablerole in acute rejection following liver transplantation. Theauthors concluded that macrophages infiltrating the livertissue after transplantation can distinguish between ACRby upregulation of CXCR3 and recurrent HCV infectionby predominantly expressing CD11b.

H. Li et al. have reviewed the role of the innate immunesystem, inflammatory cells, immunoglobulins, immune-mediated mechanisms, and key cytokines in the pathogenesisof abdominal aortic aneurysm (AAA), a common degenera-tive cardiovascular disease. Reviewed studies demonstratethat immune-inflammatory reactions play a key role inAAA formation, development, and progression opening thedoor to the individuation of molecular targets and that,although a good deal of strategies have been proposed, theclinical practice is still lacking a valuable test.

G. Gelders et al. have reported current concepts of neuro-inflammation and its involvement in Parkinson’s disease-

(PD-) associated neurodegeneration and interventions thatcould modify the pathological immune response in PD. Inparticular, the potential link among α-synuclein, activatedmicroglia, increased expression of Toll-like receptors(TLRs), and several proinflammatory mediators, whichconsequently activate peripheral immune response, mightopen novel therapeutic options to modulate disease pro-gression and outcome.

Among the recognized chronic inflammatory disorders isatherosclerosis, that represents a major threat to publichealth worldwide as is the main cause of cardiovascular dis-eases. Atherosclerosis is induced by oxidized low-densitylipoprotein (ox-LDL) accumulation in the arterial intimaunder hypercholesterolemic conditions, which generates astate of chronic vascular inflammation. Multiple innate celltypes contribute to this pathophysiological process, withmacrophages playing a major role. In their original researchpaper, Y.Wu et al. reported, in the mouse macrophage modelRAW264.7, that Toll/IL-1R domain-containing adaptor-inducing IFN-β (TRIF), a key adaptor of TLR3/TLR4-medi-ated signaling, plays an important role in regulating the ox-LDL-induced inflammatory response. They specifically dem-onstrated that TRIF modulates the expression of BIC/miR-155 and the downstream SOCS1-STAT3-NF-κB signalingpathway via ERK1/2 activation, highlighting the potentialrole of TRIF as a novel therapeutic target for atherosclerosis.Y. Hao et al. investigated the mechanisms of the chronicinflammatory response contributing to visceral hyperalgesia(VH), providing new insight into the mechanisms involvedin the antinociceptive effect of protease-activated receptor 4(PAR4) activation. VH characterizes subjects with irritablebowel syndrome (IBS) who perceive excessive pain duringabdominal distension. Activated colonic mucosal mast cells(MC) have been shown to play a crucial role in this process,through the release of proinflammatory mediators like tryp-tase, iNOS, IL-1β, and P2X7. The authors confirmed theexpression of PAR4 in this cell type in a rat model of VHand its role in blocking the induction of proinflammatorymediators, suggesting that, in the gastrointestinal tract, theantinociceptive effects of PAR4 activation are mediated,directly or indirectly, by MC. They also hypothesized thatnociceptive receptors could represent additional targets formodifying pain in gastrointestinal disorders such as IBSand inflammatory bowel diseases.

Myocarditis, mostly induced by viral infections, is animmune-mediated disorder resulting from both directvirus-triggered damage and indirect lesions induced by thehost immune system. In particular, dilated cardiomyopathy,a complication of myocarditis, results from host immuneresponse-induced killing of virus-infected and virus-uninfected cardiomyocytes and can lead to death. L. Zhaoand Z. Fu summarized in their review article the specific roleof host immunity (autoimmunity) in the development ofviral myocarditis and in dilated cardiomyopathy.

Regarding cardiovascular diseases, in another reviewarticle, W. Zhou et al. reported on a novel mediator, theNLRP3. The NLRP is a subfamily of the nucleotide-bindingand oligomerization domain- (NOD-) like receptors (NLRs)containing a pyrin domain. The NLRP mainly participates

2 Journal of Immunology Research

in inflammasome formation that is linked to many cardio-vascular diseases. In this review, the authors presented thecurrent knowledge about the function of NLRP in vasculardisease, ischemic and nonischemic heart disease, and theydiscussed the potential therapeutic options targeting theNLRP3 inflammasome.

Human gut microbiota, as well as microbiota associatedwith other body sites (i.e., oral cavity, airways, and skin), isincreasingly recognized for its important role in health.Microbiota and host mutually affect each other, and this inti-mate relationship strongly contributes to the maintenance ofhomeostasis. Disruption of this equilibrium has been associ-ated with several chronic inflammatory diseases.

In this special issue, F. A. Salzano et al. have reviewedrecent studies documenting the emerging role of nasal micro-biota in reactive nasal inflammatory conditions, where theeffects of allergens and environmental agents are mediatedby host factors, including innate and adaptive immuneresponses. The critical role of nasal microbiota in coordinat-ing these components and the contribution of microbialcomposition in affecting the onset and progression of allergicor nonallergic inflammation were discussed. Likewise, R.Yang et al. discussed the role of structural changes in gutmicrobiota composition in inducing immunological changesand in sustaining chronic hepatitis B virus infection and liverinflammation. The role of innate immunity componentssuch as TLRs in linking intestinal flora and liver immunityis also reviewed.

Given the need of improving cancer prognosis, Y. Gidronet al. have studied the influence of the vagus nerve on tumor-igenesis and observed that the vagus nerve may slow tumorprogression because it inhibits inflammation. They haveexamined the relationship between a new vagal neuroimmu-nomodulation (NIM) index and survival in pancreatic cancerand in non-small-cell lung cancer. They found that the NIMindex, reflecting vagal modulation of inflammation, may be anew independent prognostic biomarker in fatal cancers.

An interesting study on ventilator-induced lung injury(VILI) in preterm newborns has been also published in thisissue. Here, the authors, C. Gutiérrez Carvalho et al., ana-lyzed any association between the oxygen levels at bloodsampling and plasma levels of the interleukins IL-6, IL-1β,IL-10, and IL-8 and TNF-α in preterm newborns undermechanical ventilation (MV) in their first two days. Thestudy was conducted on 20 neonates (gestational age 32.2± 3 weeks) with severe respiratory distress. Blood sampleswere collected right before and 2 hours after invasive MV.The newborns were separated according to oxygen require-ment: low-oxygen (≤30%) and high-oxygen (>30%) groups.In the high-oxygen group, IL-6, IL-8, and TNF-α plasmalevels increased significantly after two hours under MV.Despite the small sample studied, data showed that there issome relationship between VILI, proinflammatory cytokines,and oxygen-induced lung injury, but a study consideringoxidative marker measurements is needed. It seems that lessoxygen may keep safer saturation targets playing a lessharmful role.

Finally, a large amount of evidence has demonstratedthat neuroinflammation plays a significant role in both acute

and chronic neurodegenerative disorders including Parkin-son’s disease, Alzheimer’s disease, multiple sclerosis, stroke,and traumatic brain injury. Y. Fu et al. reviewed the role ofexcessive microglial activation inducing inflammation-mediated neuronal damage and degeneration. They explorednew herbal compounds that are able to suppress neurotoxic-ity via inhibiting microglial activation. The therapeutic tar-gets and pharmacological mechanisms of these compoundshave also been discussed in the review.

This special issue is a collection of original or review arti-cles submitted by investigators representing eight countriesacross Europe, Asia, Africa, and South America, to highlightsome of the objectives achieved in basic, translational, andclinical immunology. It provides a glimpse on some selectedimmune-mediated disorders highlighting the cell types andmolecular mechanisms involved in the damage triggered byhost immune responses either directly or following virusinfections or changes in commensal flora composition.

Authors’ Contributions

Marcella Reale and Lucia Conti contributed equally to thiswork.

Acknowledgments

We would like to thank all the authors who contributed tothis special issue and also thank all the expert reviewerswho provided vital constructive feedback and criticismthroughout the review process and editors whose effortssubstantially contributed to the improvement of the overallquality of this special issue.

Marcella RealeLucia Conti

Diana Velluto

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