Massimo Ralli MD PhD, Alessandro Lambiase MD PhD, Marco Artico MD, Marco de Vincentiis MD and Antonio Greco MD
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive death of motor neurons leading to fatal paralysis. The causes of ALS remain unknown; however, evidence supports the presence of autoimmune mechanisms contributing to pathogenesis. Although several environmental factors have been proposed, the only established risk factors are older age, male gender, and a family history of ALS. To date, there are no diagnostic test for ALS, and clinicians rely on the combination of upper motor neuron and lower motor neuron signs in the same body region. The aim of this paper was to provide a comprehensive review of current clinical literature with special focus on the role of autoimmunity in ALS, differential diagnosis, and available therapeutic approaches. Current evidence suggests a contribution of the innate immune system in ALS, with a role of microglial cell activation at the sites of neurodegeneration. The median time from symptom onset to diagnosis of ALS is 14 months, and this time estimate is mainly based on specific clinical signs and exclusion of ALS-like conditions. Several therapeutic approaches have been proposed, including immunosuppressive drugs, to reduce disease progression. Riluzole has been established as the only, although modestly effective, disease modifying therapy, extending mean patient survival by 3to 6 months. Recent advances in understanding the pathophysiology mechanisms of ALS encourage realistic hope for new treatment approaches. To date, the cornerstones of the management of patients with ALS are focused on symptom control, maintaining quality of life and improving survival.
Darja Kanduc PhD
Background: Although cross-reactions between Epstein-Barr virus (EBV) and human systemic lupus erythematosus (SLE) autoantigens occur, a complete analysis of the potential EBV peptide cross-reactome has not been performed.
Objectives: To analyze the whole EBV proteome searching for peptides common to SLE-related proteins and endowed with an immunological potential.
Methods: Fifty-one SLE-related proteins were analyzed for hexapeptide sharing with EBV proteome using publicly available databases.
Results: An extremely high number of hexapeptides are shared between 34 human SLE autoantigens and EBV proteins. The peptide sharing mostly occurs with complement components C4 and Interleukin-10 (IL-10).
Conclusion: This study thoroughly describes the EBV vs. SLE autoantigens peptide overlap and powerfully supports cross-reactivity as a major mechanism in EBV-associated SLE etiopathogenesis.
Yarden Yavne MD, Anas Kabaha MD, Tsufit Rosen NDSF, Irit Avisar RN LLB MHA, Hedi Orbach MD, Daniela Amital MD MHA and Howard Amital MD MHA
Background: Fibromyalgia is a syndrome of unknown etiology that is characterized by widespread pain, which severely impairs quality of life. Several forms of occupational and alternative therapy have demonstrated beneficial effects in fibromyalgia patients.
Objective: To assess the effects of participation in a floral design course on physical and psychiatric symptoms in a cohort of fibromyalgia patients.
Methods: This study was conducted as an observational study. Women diagnosed with fibromyalgia over the age of 18 were recruited to participate in one of two 12-week flower design (floristry) courses. Demographic details, disease activity indices, and anxiety and depression scores were calculated for all participants at baseline, week 12, and study completion. Physical and mental health of the two groups were compared throughout the study time-points.
Results: The study was completed by 61 female fibromyalgia patients who were included in the final analyses; 31 patients participated in the first floristry course and 30 in the second. Significant improvements in the 36-Item Short Form Survey physical and mental health components, visual analog scale, Fibromyalgia Impact Questionnaire, Hamilton Anxiety Rating Scale, and Hamilton Depression Rating Scale scores for the entire study population and for each group separately could be seen following participation in each floristry course.
Conclusions: Participation in a floristry course may lead to a significant improvement in pain and psychiatric symptoms in fibromyalgia patients. These findings highlight the potential benefit of utilizing occupational therapy programs, such as a floristry course, for improving quality of life in fibromyalgia.
Giacomo Cafaro MD, Elena Bartoloni MD, Alessia Alunno MD PhD, Onelia Bistoni BSc, Sabrina Cipriani PhD, Fabiana Topini PhD and Roberto Gerli MD
Platelets have the ability to influence the immune system and the inflammatory process and may be strongly involved in the whole pathogenic process of chronic inflammatory joint diseases, such as rheumatoid arthritis. They may play a significant role even before the clinical onset of the disease, contributing to the loss of tolerance of the immune system and the induction of autoimmunity. Subsequently, they can interact with the most important cellular players involved in autoimmunity and inflammation, namely innate immunity cells and T cells and eventually contribute to the building of inflammation in the synovium, thus inducing the activation, migration, and proliferation of fibroblasts that eventually lead to joint damage. Due to their peculiar features, studying the behavior of platelets is a challenging task; however, platelets may prove to be valuable therapeutic targets in the future.
Laura Andreoli MD PhD, Antía García-Fernández MD, Maria Chiara Gerardi MD and Angela Tincani MD
Rheumatic diseases commonly affect women of childbearing age, when women may be contemplating pregnancy or they discover an unplanned pregnancy. Therefore, specific issues about pregnancy planning and management are commonly encountered in patients during these times. Knowledge of the effect of pregnancy on disease activity is important for counseling. This review summarizes recent data on the course of different rheumatic diseases during pregnancy and the postpartum period. Rheumatoid arthritis and systemic lupus erythematosus are the most commonly investigated diseases. Data are increasing about spondyloarthritis. Sparse data are available for other rheumatic diseases. Despite the differences in these diseases and the various courses these disease take during pregnancy, a common feature is that active maternal disease in the months prior to conception increases the risk of flares during pregnancy, which in turn can lead to adverse pregnancy outcomes. Therefore, maternal and fetal health can be optimized if conception is planned when disease is inactive so that a treatment regimen can be maintained throughout pregnancy.
Paola Di Benedetto PhD, Piero Ruscitti MD, Vasiliki Liakouli MD PhD, Paola Cipriani MD PhD and Roberto Giacomelli MD PhD
Microvascular damage, clinically expressed by Raynaud’s phenomenon, is generally the first symptom of the disease and the injured vascular cells, both endothelial and perivascular, may transdifferentiate to myofibroblasts, thus leading to collagen deposition in the tissue and consequent fibrosis. Systemic sclerosis (SSc, scleroderma) is complex disease characterized by autoimmunity, vasculopathy, and fibrosis. It has been shown that microvascular damage may be the first symptom of SSc. Injured endothelial cells and pericytes may transdifferentiate into myofibroblasts, the cells responsible for fibrosis and collagen deposition in the tissue. Based on these factors, the process of myofibroblast generation may link two pivotal events of SSc: microvascular damage and fibrosis. Understanding the development, differentiation, and function of myofibroblasts is therefore crucial to individuate early pathogenetic events and develop new therapeutic target for SSc, a condition in which no disease-modifying agents are available. The aim of this review was to discuss the possible origins of myofibroblasts in SSc, highlighting the process of endothelial mesenchymal transition and pericytes to myofibroblast transition and to show how these events may contribute to pathogenesis of the disease.
Lisa Gamalero MD, Gabriele Simonini MD, Giovanna Ferrara MD, Silvio Polizzi MD, Teresa Giani MD and Rolando Cimaz MD
Uveitis is an inflammatory disorder of the uveal tract of the eye that can affect both adults and children. Non-infectious uveitis can be an expression of a systemic autoimmune condition, or it can be idiopathic. It is a serious disease, associated with possible severe complications leading to visual impairment and blindness. For this reason, a prompt diagnosis and assessment of an appropriate treatment, with the collaboration of specialists such as ophthalmologists and rheumatologists, are extremely important. Many treatment options may be associated to side effects; therefore, clinicians should follow a stepladder approach starting with the least aggressive treatments to induce remission of inflammation. In this review, we reported the current evidence-based treatments for non-infectious uveitis in pediatric and adult patients with particular attention to the biologic response modifier treatment options. Important multicenter studies have demonstrated the efficacy of adalimumab, both in adults (VISUAL I, VISUAL II, VISUAL III) and in children (SYCAMORE, ADJUVITE), while for other agents data are still scarce.
Carlo Perricone MD PhD, Daphna Katz, Cinzia Ciccacci PhD, Fulvia Ceccarelli MD PhD, Guido Valesini MD, Yehuda Shoenfeld MD FRCP MaACR, Paola Borgiani PhD and Fabrizio Conti MD PhD
Recurrent pericarditis is a state of repetitive inflammation of the pericardium with intervals of remission. The etiology of recurrent pericarditis is still largely unknown, yet most causes are presumed to be immune mediated. Genetic factors, including human leukocyte antigen (HLA) haplotypes, can be involved in dysregulation of the immune system and as a predisposition to several autoimmune conditions, including recurrent pericarditis. Several diseases are frequently associated with such manifestations. They include systemic lupus erythematosus, familial Mediterranean fever, and tumor necrosis factor receptor-associated periodic syndrome. However, idiopathic recurrent pericarditis remains the most frequently observed clinical condition and the conundrum of this disease still needs to be solved.
Pier Luigi Meroni MD MACR, Elias Toubi MD and Yehuda Shoenfeld MD FRCP MACR
Maria Giovanna Danieli MD PhD, Denise Menghini MD, Cristina Mezzanotte MD, Chiara Gelardi MD, Veronica Pedini MD and Fernando Monteforte MD
Daniela Rossi MD, Savino Sciascia MD PhD and Dario Roccatello MD
Doron Rimar MD, Ori Rimar MD, Itzhak Rosner MD, Michael Rozenbaum MD, Lisa Kaly MD, Nina Boulman MD and Gleb Slobodin MD
Hadar Simchony, Gil Diamant PhD, Zvi Ram MD and Ilan Volovitz PhD
Background: Tumor treating fields (TTFields) are low-intensity, intermediate frequency electric fields that affect proliferating cells. TTFields are FDA approved for treatment of newly diagnosed and recurrent glioblastoma. Combining TTFields with immunotherapy is a rational approach due to their different mechanisms of action (MOA) and to the ability of TTFields to induce immunogenic cell death. Conversely, TTFields may interfere with immune functions critical for effective T-cell responses.
Objectives: To evaluate the effects of TTFields on pivotal antitumoral T-cell functions.
Methods: T-cells from healthy donor peripheral blood (PB) or from viably dissociated human glioblastoma samples were cultured under normal or TTFields conditions, with or without superantigen stimulation. Multiparametric flow cytometry (8-color) was used to assess T-cell responses by monitoring select pivotal functions: proliferation (CFSE), IFNγ secretion, cytotoxic degranulation (CD107a), and activation/exhaustion (PD-1). Cellular viability was assessed in a dedicated assay. A chimeric antigen receptor (CAR) T-cell-based assay directly evaluated cellular cytotoxicity.
Results: Activated PB T-cells and tumor-infiltrating T-cells (TILs) preserved all monitored anti- tumoral functions under TTFields, apart from proliferation. This finding also applied specifically to PD-1 + TILs, comprised predominantly of tumor antigen-specific cells. Activated T-cells that attempted to proliferate under TTFields demonstrated decreased viability, in line with TTField MOA. Small or no reduction in viability was found in T-cells that did not attempt to proliferate, whether activated or resting.
Conclusions: All monitored anti-tumoral T cell functions, except for proliferation, were unhindered by TTFields. Our results support further investigation into combinations of TTFields with T-cell based immunotherapeutic approaches.
Bar Davidov MD, Riva Shmulevich MSc, Ayelet Shabtay PhD, Tami Rubinek PhD and Ido Wolf MD
Background: Klotho is a transmembrane protein that can be shed and can act as a circulating hormone in three forms: soluble klotho (KL1 + KL2), KL1, and KL2. Klotho was discovered as a gene implicated in aging through inhibition of the IGF-I pathway. Our laboratory discovered the role of klotho as a tumor suppressor in breast cancer and other malignancies. Furthermore, we showed that the KL1 domain mediates this activity. Altered cancer cell metabolism is a hallmark of cancer and our lab demonstrated various effects of klotho on breast cancer cell metabolism. Thus, klotho inhibited glycolysis and activated adenosine monophosphate activating kinase (AMPK), an energy sensor pathway. Moreover, inhibition of AMPK reduced the tumor suppressor activity of klotho.
Objectives: To assess the effect of KL1 on breast tumor cells metabolism, as KL1 possesses the tumor suppressor activity of klotho.
Methods: We used MCF-7 breast cancer cells treated with soluble or over-expressed KL1 and klotho. Glycolysis was assessed by measuring mRNA levels of key glycolytic enzymes using reverse transcription polymerase chain reaction and by measuring lactate and glucose levels in media. The AMPK pathway was studied by monitoring AMPK phosphorylation as well as its down-stream target, acetyl-CoA carboxylase, using western blotting. Wound healing assay was used to assess cell migration.
Results: KL1 treatment reduced glycolytic enzymes mRNA levels and the activity of hexokinase, similar to klotho treatment. Furthermore, KL1 reduced glucose uptake and decreased lactate production. KL1 elevated phosphorylated acetyl-CoA carboxylase and phosphorylatedAMPK levels. Inhibition AMPK (using a mutant AMPK activator) stopped KL1 from inhibiting cell migration, suggesting AMPK underlies klotho’s tumor suppressor activity.
Conclusions: Our data indicate KL1 as a regulator of metabolic activity in breast cancer and suggest that metabolic alterations underlie KL1 tumor suppressor activities. Furthermore, as KL1 and klotho share a similar effect on cell metabolism, our results further support the central role KL1 domain plays in klotho’s tumor suppressor activity.