A role for pathogen risk factors and autoimmunity in encephalitis lethargica?

The encephalitis lethargica (EL) epidemic swept the world from 1916 to 1926 and is estimated to have afflicted between 80,000 to one million people. EL is an unusual neurological illness that causes profound sleep disorders, devastating neurological sequalae and, in many cases, death. Though uncommon, EL is still occasionally diagnosed today when a patient presents with an acute or subacute encephalitic illness, where all other known causes of encephalitis have been excluded and criteria for EL are met. However, it is impossible to know whether recent cases of EL-like syndromes result from the same disease that caused the epidemic. After more than 100 years of research into potential pathogen triggers and the role of autoimmune processes, the aetiology of EL remains unknown. The epidemic approximately coincided with the 1918 H1N1 influenza pandemic but the evidence of a causal link is inconclusive. This article reviews the literature on the causes of EL with a focus on autoimmune mechanisms. In light of the current pandemic, we also consider the parallels between the EL epidemic and neurological manifestations of COVID-19. Understanding how pathogens and autoimmune processes can affect the brain may well help us understand the conundrum of EL and, more importantly, will guide the treatment of patients with suspected COVID-19-related neurological disease, as well as prepare us for any future epidemic of a neurological illness.

Immunoglobulin use in immune deficiency and autoimmune disease states.

Although immunoglobulin (Ig) has been available since the 1950s for replacement therapy in primary immune deficiency, many other effective uses of this class of biologics have been investigated and evolved over recent decades. Ig administration has become common practice in the treatment of the immunocompromised patient and has recently expanded into the treatment of those patients with an inflammatory disease and autoimmune neuropathies per established clinical guidelines. As research into the genetic basis of disease advances, clinicians should better assess complex data surrounding safe and effective uses of Ig to treat patients who present with B-cell and T-cell deficiencies, along with those harboring gene deletions or genetic anomalies who may potentially benefit from Ig therapy. Evidence-based clinical indications for the use of Ig include idiopathic thrombocytopenic purpura, B-cell chronic lymphocytic leukemia, Kawasaki disease, chronic idiopathic demyelinating polyneuropathy, multifocal motor neuropathy, bone marrow transplantation, and pediatric HIV infection, among others, and have evolved over time. Ig is also often tried in refractory cases that might benefit from its anti-inflammatory effects or empirically in off-label situations. Due to its anti-inflammatory effects, high-dose Ig has been used for numerous off-label indications with varying levels of effectiveness and evidence to support its use. A review of all autoimmune conditions for which Ig has been used is beyond the scope of this article and newer treatments are available for many of these disorders. Here the focus will be on selected conditions in which Ig has clear benefit. Because there is a limited supply of Ig and a need for further research into optimal use, it is important for healthcare professionals to better understand current and developing indications and data/levels of evidence to support Ig therapy as its role continues to evolve.

Pancreatitis crónica. Algunos aspectos históricos relevantes / Chronic pancreatitis. Some important historical aspects

Desde la antigüedad había llamado la atención el aumento de tamaño y dureza que, en ocasiones, presentaba la estructura abdominal que recibió el nombre de páncreas. Portal en 1803 describió por primera vez los signos clínicos de la pancreatitis crónica. En 1815 Fleischman especuló sobre el posible papel del consumo exagerado de alcohol. Comfort en 1946 acuñó el término «pancreatitis crónica recidivante» y 6 años más tarde refirió lo que se llamaría pancreatitis hereditaria. Zuidema en 1959 definió la pancreatitis tropical y 2 años después Sarles puntualizó sobre otra forma de pancreatitis que en 1995 Yoshida denominaría pancreatitis autoinmune. La pancreatitis del surco era descrita en 1970 por Potet. En 1984 se definió la pancreatitis obstructiva y en 1987 Ammann refirió la pancreatitis idiopática. En este artículo se hace un recuerdo histórico de los pioneros que supieron valorar determinadas características que permitieron definir diferentes formas de pancreatitis crónicas

Since ancient times the increase of size and hardness sometimes presented by the abdominal structure known as the pancreas has attracted attention. Portal was the first to describe the clinical signs of chronic pancreatitis in 1803. In 1815, Fleischman speculated about the potential role of excessive alcohol consumption. Comfort coined the term "chronic relapsing pancreatitis" in 1946 and described hereditary pancreatitis 6 years later. Zuidema defined tropical pancreatitis in 1959 and 2 years later Sarles described another form of pancreatitis to which Yoshida gave the name autoimmune pancreatitis in 1995. Groove pancreatitis was described by Potet in 1970. Obstructive pancreatitis was defined in 1984 and Ammann identified idiopathic pancreatitis 3 years later. This article gives a historical account of the pioneers who developed the knowledge of how to assess the characteristics that allowed the different forms of chronic pancreatitis to be defined

Chronic pancreatitis. Some important historical aspects. / Pancreatitis crónica. Algunos aspectos históricos relevantes.

Since ancient times the increase of size and hardness sometimes presented by the abdominal structure known as the pancreas has attracted attention. Portal was the first to describe the clinical signs of chronic pancreatitis in 1803. In 1815, Fleischman speculated about the potential role of excessive alcohol consumption. Comfort coined the term "chronic relapsing pancreatitis" in 1946 and described hereditary pancreatitis 6 years later. Zuidema defined tropical pancreatitis in 1959 and 2 years later Sarles described another form of pancreatitis to which Yoshida gave the name autoimmune pancreatitis in 1995. Groove pancreatitis was described by Potet in 1970. Obstructive pancreatitis was defined in 1984 and Ammann identified idiopathic pancreatitis 3 years later. This article gives a historical account of the pioneers who developed the knowledge of how to assess the characteristics that allowed the different forms of chronic pancreatitis to be defined.

Interview with Amr H Sawalha: epigenetics and autoimmunity.

Amr H Sawalha is Professor of Internal Medicine and Marvin and Betty Danto Research Professor of Connective Tissue Research at the University of Michigan, Department of Internal Medicine, Division of Rheumatology. He also holds faculty appointments at the Center for Computational Medicine and Bioinformatics and the Graduate Program in Immunology at the University of Michigan. He was recently appointed as Guest Professor at Central South University in Changsha, China. He received his medical degree from Jordan University of Science and Technology and completed his residency training in internal medicine at the University of Oklahoma Health Sciences Center, and his fellowship in rheumatology at the University of Michigan. His research focus is the genetics and epigenetics of complex autoimmune and inflammatory diseases, including lupus and systemic vasculitis. He has authored over 100 peer-reviewed manuscripts, book chapters and review articles, and is on the editorial board of several journals in his field. He has been elected as a member of the American Society for Clinical Investigation, and has received numerous awards, including the Edmund L Dubois, MD, Memorial Lectureship Award from the American College of Rheumatology in recognition for his work in lupus. He is Chair of the Lupus Foundation of America research subcommittee and is a member of the Vasculitis Foundation Medical and Scientific Advisory Board. He also provides clinical care and teaching in the rheumatology outpatient and inpatient services, and he is the director of the NIH-funded rheumatology training grant at the University of Michigan.

Dr Eng M. Tan: a tribute to an enduring legacy in autoimmunity.

At the age of ninety years, Dr Eng Meng Tan has had a remarkable impact on the accumulated knowledge of autoimmune diseases, including seminal findings in systemic lupus erythematosus (SLE) and a wide range of other autoimmune diseases. Dating to the first description of the Sm (Smith) autoantibody in SLE, his focus has been the use of autoantibodies as probes to identify and elucidate novel cellular molecules and then translating these discoveries into biomarkers and immunoassays for a wide range of these diseases and, later, cancer. He led efforts to standardize autoantibody nomenclature and testing protocols. Through his mentorship a great number of trainees and collaborators have had remarkably successful careers, and by that virtue he has garnered a remarkable continuing legacy.

The type I interferons: Basic concepts and clinical relevance in immune-mediated inflammatory diseases.

There is increasing scientific and clinical interest in elucidating the biology of type I Interferons, which began approximately 60 years ago with the concept of "viral interference", a property that reduces the ability of a virus to infect cells. Although our understanding of the multiple cellular and molecular functions of interferons has advanced significantly, much remains to be learned and type I Interferons remain an active and fascinating area of inquiry. In this review, we cover some general aspects of type I interferon genes, with emphasis on interferon-alpha, and various aspects of molecular mechanisms triggered by type I interferons and toll-like receptor signaling by the Janus activated kinase/signal transducer activation of transcription (JAK-STAT) pathway and interferon regulatory factor pathway. We will also describe the role of type I interferons in autoimmune and inflammatory diseases, and its potential use as therapeutic agent.

Importancia del patrón moteado fino denso y de los anticuerpos anti-DFS70 en el diagnóstico de enfermedades autoinmunitarias del tejido conectivo / Importance of the dense fine speckled pattern and anti-DFS70 antibodies for the diagnosis of systemic autoimmune rheumatic diseases

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History and milestones of mouse models of autoimmune diseases.

Autoimmune diseases are a group of disorders mediated by self-reactive T cells and/or autoantibodies. Mice, as the most widely used animal for modeling autoimmune disorders, have been extensively used in the investigation of disease pathogenesis as well as in the search for novel therapeutics. Since the first mouse model of multiple sclerosis was established more than 60 years ago, hundreds of mouse models have been established for tens of autoimmune diseases. These mouse models can be divided into three categories based on the approaches used for disease induction. The first one represents the induced models in which autoimmunity is initiated in mice by immunization, adoptive transfer or environmental factors. The second group is formed by the spontaneous models where mice develop autoimmune disorders without further induction. The third group refers to the humanized models in which mice bearing humanized cells, tissues, or genes, develop autoimmune diseases either spontaneously or by induction. This article reviews the history and highlights the milestones of the mouse models of autoimmune diseases.

Autoimmunity: from black water fever to regulatory function.

Autoimmunity is a field that has only been around for a little over a century. Initially, it was thought that autoimmunity could not happen, that the body would never turn on itself (i.e. "horror autotoxicus"). It was only around the First World War that autoimmunity was recognized as the pathogenesis of various diseases, including rheumatoid arthritis. The discovery of Compound E led to successful treatment of patients with autoimmune diseases, but it was not till later that the adverse effects of this class of drugs were elucidated. The "modern" age of autoimmunity began around 1945 with the description of blackwater fever, and most of the subsequent research on hemolytic anemia and the role of an autoantibody in its pathogenesis led to a description of the anti-globulin reaction. The lupus erythematous (LE) cell was recognized in the mid-1940s by Hargreaves. His research carried on into the 1960s. Rheumatoid factor was also first described in the 1940s as yet another serum factor with activity against globulin-coated sheep red blood cells. The concept of autoimmunity really gained a foothold in the 1950s, when autoimmune thyroid disease and idiopathic thrombocytopenia were first described. Much has happened since then, and our understanding of autoimmunity has evolved now to include mechanisms of apoptosis, signaling pathway derangements, and the discovery of subsets of T cells with regulatory activity. The modern day study of autoimmunity is a fascinating area of research, and full understanding of the pathogenesis of autoimmune diseases is far from being completely elucidated.

Sjögren's syndrome: a forty-year scientific journey.

My long scientific journey studying as a disease model Sjogren's syndrome (SS) gave me the opportunity to uncover the mysteries of systemic autoimmune diseases. After an extensive training, under the supervision of the major autoimmune disease investigators, I was able to convey and expand the acquired knowledge through inspiring my students and collaborators. Our research enriches the understanding of the wide clinical spectrum of the syndrome and the clinical, laboratory and molecular events predicting or being responsible for lymphomagenesis. Our molecular and cellular studies indicated that the target of autoimmunity in SS, the activated glandular epithelial cells, play significant role in the initiation and perpetuation of the autoimmune process. Furthermore, discovery of the epitopes on autoantigens where the autoimmune humoral reactivity is directed against, provided us tools to develop specific and sensitive diagnostic assays, to unmask similarities of the epitope sequence with infectious agents and gave us the potential to use them as therapeutic modalities.

Subcutaneous immunoglobulin replacement therapy: the European experience.

PURPOSE OF REVIEW: Rapid subcutaneous immunoglobulin (SCIg) infusions have been used as an important method of delivering replacement immunoglobulin (Ig) to patients with primary immune deficiencies (PIDs) in Europe over the last 25 years. This review provides a comprehensive interpretation of the literature relating to the administration of SCIg and the services that have been developed alongside. RECENT FINDINGS: Using rates of at least 20 ml/h per infusion site and simultaneous sites, the infusion time once per week is short (1-2 h in adults) and using small portable pumps, the child or adult is free for other activities during the therapy. The rapid SCIg infusions have been documented as well tolerated, efficacious and acceptable to infants and their parents, children, adults and elderly patients, and more recently to patients with autoimmunity requiring immunomodulatory Ig doses. SUMMARY: As part of PID diagnostic and management services, educational programmes for self-infusion of both intravenous Ig and SCIg at home have been developed throughout Europe, resulting in increased patient compliance and patient empowerment as well as cost-savings for healthcare providers.

Immunoregulatory dendritic cells to treat autoimmunity are ready for the clinic. Interview by Katie Lockwood.

Nick Giannoukakis began his medical career at McGill University (Montreal, Canada), receiving his BSc and PhD in 1992 and 1997, respectively. From there, he went on to study a postdoctoral fellowship at the University of Pittsburgh School of Medicine (PA, USA) where he now holds the position of Associate Professor of Pathology and Immunology. He is a current member of the Division of Experimental Pathology and a member of the Cellular and Molecular Pathology Graduate Training Program. He teaches topics on pancreas and thyroid development and pathology, as well as cell and gene therapy approaches in diabetes mellitus in a number of courses offered by the department and also directs the 'Introduction to Immunobiotherapeutics' course in the Department of Immunology. He has mentored graduate, MD/PhD students, as well as clinical fellows. Giannoukakis is also one of the founders of DiaVacs(®) (NJ, USA), a biotechnology entity leveraging dendritic cell therapy for autoimmunity.