The Centenary of Immune Thrombocytopenia-Part 2: Revising Diagnostic and Therapeutic Approach

Primary immune thrombocytopenia (ITP) is the most common cause of thrombocytopenia in children and adolescents and can be considered as a paradigmatic model of autoimmune disease. This second part of our review describes the clinical presentation of ITP, the diagnostic approach and overviews the current therapeutic strategies. Interestingly, it suggests an algorithm useful for differential diagnosis, a crucial process to exclude secondary forms of immune thrombocytopenia (IT) and non-immune thrombocytopenia (non-IT), which require a different therapeutic management. Advances in understanding the pathogenesis led to new therapeutic targets, as thrombopoietin receptor agonists, whose role in treatment of ITP will be discussed in this work

The brain–heart interaction in epilepsy: implications fordiagnosis, therapy, and SUDEP prevention

Epilèpsia; Malalties cardiaques; Mort sobtadaEpilepsia; Enfermedades cardiacas; Muerte súbitaEpilepsy; Heart disease; Sudden deathThe influence of the central nervous system and autonomic system on cardiac activity is being intensively studied, as it contributes to the high rate of cardiologic comorbidities observed in people with epilepsy. Indeed, neuroanatomic connections between the brain and the heart provide links that allow cardiac arrhythmias to occur in response to brain activation, have been shown to produce arrhythmia both experimentally and clinically. Moreover, seizures may induce a variety of transient cardiac effects, which include changes in heart rate, heart rate variability, arrhythmias, asystole, and other ECG abnormalities, and can trigger the development of Takotsubo syndrome. People with epilepsy are at a higher risk of death than the general population, and sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. Although the cause of SUDEP is still unknown, cardiac abnormalities during and between seizures could play a significant role in its pathogenesis, as highlighted by studies on animal models of SUDEP and registration of SUDEP events. Recently, genetic mutations in genes co-expressed in the heart and brain, which may result in epilepsy and cardiac comorbidity/increased risk for SUDEP, have been described. Recognition and a better understanding of brain-heart interactions, together with new advances in sequencing techniques, may provide new insights into future novel therapies and help in the prevention of cardiac dysfunction and sudden death in epileptic individuals

Environmental Genomics: A Tale of Two Fishes

The influence of the environment on two congeneric fishes, Gillichthys mirabilis and Gillichthys seta, that live in the Gulf of California at temperatures of 10-25 degrees C, and up to 42-44 degrees C, respectively, was addressed by analyzing their genomes. Compared with G. mirabilis, G. seta showed some striking features. Substitution rates in the mitochondrial genes were found to be extremely fast, in fact faster than in noncoding control regions (D-loops), from which a divergence time of less than 0.66-0.75 Mya could be estimated. In the nuclear genome, 1) both AT --> GC/GC --> AT and transversion: transition ratios in coding sequences (CDSs) were relatively high; moreover, the ratios of nonsynonymous/synonymous changes (Ka/Ks) suggested that some genes were under positive selection; 2) DNA methylation showed a very significant decrease; and 3) a GC-rich minisatellite underwent a 4-fold amplification in the gene-rich regions. All these observations clearly indicate that the environment (temperature and the accompanying hypoxia) can rapidly mold the nuclear as well as the mitochondrial genome. The stabilization of gene-rich regions by the amplification of the GC-rich minisatellite and by the GC increase in nuclear CDSs is of special interest because it provides a model for the formation of the GC-rich and gene-rich isochores of the genomes of mammals and birds

Corneal epithelial wound healing promoted by verbascoside-based liposomal eyedrops

Different liposomal formulations were prepared to identify those capable of forming eyedrops for corneal diseases. Liposomes with neutral or slightly positive surface charge interact very well with the cornea. Then these formulations were loaded with verbascoside to heal a burn of corneal epithelium induced by alkali. The cornea surface affected involved in wound was monitored as a function of time. Experimental results were modeled by balance equation between the rate of healing, due to the flow of phenylpropanoid, and growth of the wound. The results indicate a latency time of only three hours and furthermore the corneal epithelium heals in 48 hours.Thus, the topical administration of verbascoside appears to reduce the action time of cells, as verified by histochemical and immunofluorescence assays

Therapeutic aspects of Sydenham's Chorea: an update

Sydenham's Chorea (SC) is a hyperkinetic movement disorder associated with neuropsychiatric manifestations. It is believed to be caused by the autoimmune response following a group A beta-hemolytic streptococcal (GABHS) pharyngitis, and it is one of the major diagnostic criteria for Acute Rheumatic Fever (ARF) diagnosis. Despite having been known and studied for centuries, there are still no standardized therapies or official guidelines for SC treatment, so that it is necessarily left to physicians' clinical experience. Antibiotic treatment, symptomatic therapies, and immunomodulatory treatment are the three pillars upon which SC patients' management is currently based, but they still lack a solid scientific basis. The aim of this writing is precisely to review the state of the art of SC's treatment, with an overview of the advances made in the last 5 years. However, since the therapeutic uncertainties are a mere reflection of the severe gap of knowledge that concerns SC's pathogenesis and manifestations, the importance of high-quality research studies based on homogenized methodologies, instruments, and measured outcomes will also be stressed

Lupus Eritematoso Sistemico in una coorte di pazienti in età pediatrica: valutazione del profilo clinico all'esordio e durante il follow-up

Il Lupus eritematoso sistemico è una patologia infiammatoria a patogenesi autoimmune con impegno sistemico multiorgano e decorso cronico-recidivante. Ad oggi si parla di Lupus in età pediatrica (pSLE) per una condizione caratterizzata da un’insorgenza della patologia ad età inferiore ai 18 anni, limite che riflette delle marcate differenze sia dal punto di vista epidemiologico e di prevalenza di genere sia dal punto di vista del fenotipo clinico e dell’aggressività di malattia. In questo studio retrospettivo sono stati valutati 25 pazienti affetti da pSLE provenienti dalle Unità Operative di Pediatria, Reumatologia ed Immunologia Clinica, analizzando nello specifico i sintomi di presentazione ed il fenotipo clinico all’esordio della patologia e durante un follow-up di 10 anni. I risultati dello studio confermano come il pSLE sia una patologia caratterizzata all’esordio da una alta percentuale di interessamento articolare (64% dei pazienti alla diagnosi), cutaneo (il 52% dei pazienti ha rash malare) ematologico (60%) e renale (36%). Si è evidenziata inoltre la comparsa di alterazioni renali in oltre il 68% dei pazienti durante il follow-up, con frequenza ancora maggiore (87,5%) nel sottogruppo di pazienti con età di esrdio inferiore a 15 anni, mentre sono risultati rari i sintomi di natura neurologica. Infine lo studio ha evidenziato l’alto livello di attività della malattia all’esordio, soprattutto nei pazienti con esordio precoce della nostra coorte (10.7 punti medi calcolato secondo l’indice SLEDAI)

Ruolo del fenotipo immunologico avanzato nell'approccio diagnostico alle citopenie in età pediatrica

Introduzione e obiettivi: Le citopenie rappresentano la più frequente causa di consulto ematologico in età pediatrica, e dato l’ampio numero di potenziali cause sottostanti, l’orientamento diagnostico è frequentemente complesso. Nelle principali cause di citopenia pediatrica è presente, seppure con modalità differenti, un coinvolgimento patogenetico del sistema immunitario. Difatti, sono meccanismi riconosciuti la distruzione immunomediata periferica nella citopenie autoimmuni, la disregolazione immunitaria estesa nei disordini congeniti dell’immunità, la ridotta produzione di precursori midollari nelle sindromi ereditarie da insufficienza midollare, e la distruzione immunomediata intramidollare di precursori emopoietici nelle aplasie midollari acquisite. Obiettivo principale del presente studio è l’identificazione di differenze nel fenotipo immunologico standard e avanzato nei pazienti con citopenie a differente eziologia, per la ricerca di elementi utili nella diagnosi differenziale delle citopenie pediatriche. Pazienti e metodi: Sono stati inclusi pazienti 36 seguiti presso l’Unità Operativa di Oncoematologia Pediatrica dell’Azienda ospedaliero Universitaria Pisana per citopenie di diversa diagnosi (23 con citopenia immunomediata, 5 dei quali con disordini congeniti dell’immunità, 10 con sindromi ereditarie da insufficienza midollare e 3 con aplasia midollare acquisita). Per ogni paziente sono stati eseguiti analisi dei linfociti totali, sottopopolazioni standard (CD3+, CD4+, CD8+, CD19+, CD16/56+) in valore percentuale e assoluto, immunoglobuline sieriche (IgA, IgG, IgM) e fenotipo immunologico avanzato, comprendente assetto B e T naïve e di memoria. Risultati: Dallo studio emerge come i pazienti con sindromi ereditarie da insufficienza midollare tendano a presentare, in confronto a pazienti con citopenia immunomediata primitiva, valori assoluti di linfociti inferiori, ridotti livelli di cellule B circolanti ed espansione compensatoria delle cellule NK, in associazione con la tendenza ad osservare una polarizzazione delle popolazioni dei linfociti T nei confronti delle cellule di memoria. Contrariamente, una polarizzazione verso le popolazioni T naïve, associata a livelli generalmente più elevati di cellule B e cellule T regolatorie caratterizza la maggior parte dei pazienti con citopenia immunomediata primitiva. Elevati livelli di linfociti totali e di IgA sieriche, unitamente a ridotti valori di cellule B circolanti, con bassa percentuale di cellule B switched memory, unitamente alla riduzione delle cellule T regolatorie e dell’output timico ed elevazione frequente dei linfociti T doppi negativi ab sono invece gli elementi principali descritti nel sottogruppo di pazienti con citopenia secondaria a disordini congeniti dell’immunità. Infine, nonostante il numero ridotto di pazienti analizzati, si è osservata una tendenza da parte dei pazienti con aplasia midollare acquisita ad avere un fenotipo immunologico ben distinto da quanto evidenziato nelle sindromi ereditarie da insufficienza midollare, con caratteristiche di parziale sovrapposizione nei confronti delle citopenie immunomediate primitive. Conclusioni: Pur con alcuni limiti derivanti dalla numerosità ridotta del campione e dell’eterogeneità delle patologie prese in esame, questo studio ha mostrato aspetti di potenziale utilità nella pratica clinica e nell’orientamento del processo di diagnosi differenziale del paziente pediatrico con citopenia. Inoltre, lo studio apre numerose prospettive future, comprendenti la potenziale utilità dell’analisi del repertorio di specificità recettoriale delle cellule T (repertorio TCR) e delle cellule B (repertorio BCR), unitamente allo studio della proliferazione linfocitaria in vitro, che potrebbero contribuire, in futuro, a migliorare l’approccio diagnostico al paziente citopenico

Piastrinopenia immunomediata in età adolescenziale ed evoluzione in lupus eritematoso sistemico il ragionamento critico attraverso la descrizione di tre casi clinici

Thrombocytopenia, defined by a platelet count lower than 100,000 mm3, in children and adolescents is more frequently ascribable to an immune pathogenesis (Immune Thrombocytopenia, or ITP). ITP is defined “persistent” if it is still present after three months from diagnosis, and “chronic” if remission is not reached after 12 months from the first finding. ITP in childhood usually follows infections of the upper respiratory tract, and presents a self-limiting clinical course, while in adolescents chronic forms are more frequent and require a complex clinical management. The present paper focuses on chronic ITP in adolescents, introducing three cases in which the finding of thrombocytopenia preceded by several years the diagnosis of Systemic Lupus Erythematosus. From the analysis of the presented cases and literature data appears that, even if it is not possible to predict the progression to SLE, patients not responsive to conventional therapies typically developed this condition. Furthermore, the paper suggests an approach that is useful for the confirmation of clinical suspect of ITP and for the surveillance of patients with a high risk of developing the chronic form, in order to identify among them those that will evolve to systemic autoimmune diseases

Autoimmunity in Primary Immunodeficiency Disorders: An Updated Review on Pathogenic and Clinical Implications

During the last years, studies investigating the intriguing association between immunodeficiency and autoimmunity led to the discovery of new monogenic disorders, the improvement in the knowledge of the pathogenesis of autoimmunity, and the introduction of targeted treatments. Autoimmunity is observed with particular frequency in patients with primary antibody deficiencies, such as common variable immunodeficiency (CVID) and selective IgA deficiency, but combined immunodeficiency disorders (CIDs) and disorders of innate immunity have also been associated with autoimmunity. Among CIDs, the highest incidence of autoimmunity is described in patients with autoimmune polyendocrine syndrome 1, LRBA, and CTLA-4 deficiency, and in patients with STAT-related disorders. The pathogenesis of autoimmunity in patients with immunodeficiency is far to be fully elucidated. However, altered germ center reactions, impaired central and peripheral lymphocyte negative selection, uncontrolled lymphocyte proliferation, ineffective cytoskeletal function, innate immune defects, and defective clearance of the infectious agents play an important role. In this paper, we review the main immunodeficiencies associated with autoimmunity, focusing on the pathogenic mechanisms responsible for autoimmunity in each condition and on the therapeutic strategies. Moreover, we provide a diagnostic algorithm for the diagnosis of PIDs in patients with autoimmunity