Volume Articles

The Role of TET Proteins in B Cell Biology

Shinya Tanaka^1*, Wataru Ise², Yoshihiro Baba¹, Tomohiro Kurosaki^2,3#

¹Division of Immunology and Genome Biology, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka, 812-0054, Japan

²Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Osaka, Suita, 565-0871,Japan

³Laboratory of Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan

Gene expression must be strictly controlled during cell differentiation and function in mammalian systems. DNA methylation plays an important role in this process, and its pattern is shaped by balancing the activity of methyltransferases and demethylases. Ten-eleven translocation (TET) was identified as a demethylase that catalyzes the oxidation reaction of the methyl group of 5-methylcytosine (5mC), converting it to 5-hydroxymethylcytosine (5hmC). Recently, indispensable roles of TET proteins in the regulation of immune cells have been identified. Here, we review recent studies on the biological consequences of dysregulation of TET proteins in the immune system, with a particular focus on B cell biology. Finally, we discuss future perspectives in this research field.

Commentary: The Impact of Regional Astrocyte Interferon-γ Signaling During Chronic Autoimmunity: A Novel Role for the Immunoproteasome

Brandon C. Smith^1,2 & Jessica L. Williams^1*

¹Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

²Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH, USA

Despite an increase in approved therapies for treating the inflammatory and neurodegenerative disease multiple sclerosis (MS), many of which have efficacy in the early, acute phases, there are no reliable treatments for the chronic, progressive stages of the disease. A deeper understanding of the biological underpinnings that govern differences between acute and chronic stages of MS and an animal model of MS, experimental autoimmune encephalomyelitis, will inform therapeutic development and personalized treatment strategies. It is well-known that the effects of inflammation are complex and the implications vary between stages. Complimentary to our recent publication, we will discuss here the pleiotropic effects of the cytokine interferonγ across disease states, along with the implications of downstream mechanisms of action.

MHC-1 Mediated Antigen Presentation Machinery as a Key of Tumor Cells Immune Escape Control

Christian B. Auclair^* & Annette Ives^#

AC BioScience SA, Biopôle, Route de la Corniche 4 – Lysine, 1066 Epalinges, Switzerland

Lupus Anticoagulant in Gulf War Illness and Autoimmune Disorders: A Common Pathway Toward Autoimmunity

Lisa M. James^1,2,3, Rachel A. Johnson¹, Scott M. Lewis^1,4, Adam F. Carpenter^1,4, Brian E. Engdahl^1,2,5, Hollis E. Krug^6,7, Apostolos P. Georgopoulos^1,2,3,4*

¹Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA

²Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA

³Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, USA

⁴Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

⁵Department of Psychology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

⁶Department of Rheumatology, Department of Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA

⁷Department of Rheumatology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

Mounting evidence suggests that autoimmune mechanisms may underlie the chronic symptoms characteristic of Gulf War Illness (GWI). The presence of antiphospholipid antibodies including Lupus Anticoagulant (LA) are often associated with autoimmune disorders. Here we evaluated and compared blood samples from veterans with GWI and veterans with other autoimmune conditions including relapsing remitting multiple sclerosis, rheumatoid arthritis, Sjögren’s syndrome, and lupus for the presence of LA using Silica Clotting Time and dilute Russell’s Viper Venom Time assays. Positive LA was identified in one-quarter of veterans with GWI; this proportion was not statistically different from the proportion of positive LA identified in patients diagnosed with the other autoimmune conditions. The present findings add to the literature implicating autoimmune mechanisms in GWI and point to the presence of prothrombotic antiphospholipid antibodies as a common contributing factor in GWI and other autoimmune disorders. Furthermore, activation of the coagulation system suggests new potential avenues for treatment for LA-positive Gulf War veterans.

The Impact of Nanoparticles on the Immune System: A Gray Zone of Nanomedicine

Priyanka Ray¹, Noor Haideri², Inamul Haque², Omar Mohammed², Saborni Chakraborty², Snigdha Banerjee^2,3#, Mohiuddin Quadir^1#, Amanda E. Brinker ^4,5, and Sushanta K. Banerjee^2,3*

¹Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, ND

²Cancer Research Unit, VA Medical Center, Kansas City, MO

³Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS

⁴Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS

⁵Institute for Advancing Medical Innovation, University of Kansas Cancer Center, Kansas City, KS

Since the early days marking the first use of nanomedicine in the early 80s, there has been a meaningful change in the scientific field involving the Fabrication, characterization, and application of nanomaterials to treat many diseases, including cancers and genetic disorders. As unique and attractive properties of this novel class of materials unraveled, significant advances and discoveries were made over time. Addressing several challenges posed by conventional therapy, which were the only available treatment option for ailing patients, nanomedicine provided enhanced benefits, including reduced dosing, improved pharmacokinetics, and superior targeting efficiency. Several such formulations have successfully made their way to clinics and have shown promise in prolonging terminally ill patient populations' survival rates. However, the complex immune system and its various components, including various proteins and surface receptors, have made nanomaterials' journey from benchtop to the bedside a treacherous one. The innate and adaptive immune system interactions with nanomaterials are still under investigation and full of mysteries. This review highlights the various aspects of therapeutic nanocarriers and their current understanding of their immune systems' interactions.

Commentary: Role of Tocilizumab in Hospitalized COVID-19 Patients: A Pragmatic Guide for Clinicians

Vijairam Selvaraj^1,2*, Anneliese Beaubrun^1,2, Shenjun Zhu^1,2, Kwame Dapaah-Afriyie^1,2

¹Division of Hospital Medicine, The Miriam Hospital, Providence, Rhode Island.

²Warren Alpert Medical School of Brown University, Providence, Rhode Island.

Anti-inflammatory Effects of Naïve Stem Cells Dampen Systemic/Compartmental Overreactive Immune Responses

Wolters ECh¹, de Hoo K², Kramer BW³, de Munter JPJM^2,4

¹Department of Neurology, UniversitatsSpital Zurich, Zurich, Switzerland

²Neuroplast BV, Urmond, The Netherlands

³Department of Paediatrics, Maastricht University Medical Centre, Maastricht, The Netherlands

⁴School for Mental Health and NeuroScience, Maastricht University, Maastricht, The Netherlands 

A cytokine release syndrome (CRS), associated with elevated circulating levels of several cytokines including interleukin (IL)-6 and interferon (IFN)-γ, might be seen in some infectious insults, for instance in severe acute respiratory syndrome (SARS) induced by Coronavirus (Cov)-2, as well as following administration of natural and bispecific antibodies and, more recently, following adoptive T-cell therapies for cancer. Normally, inflammatory conditions activate the innate and adaptive immune systems, which results in the release of cytokines, responsible for the phagocytosis of apoptotic vesicles and resolution of inflammation. Pro-inflammatory cytokines such as IL-1β, tumor necrosis factor alpha (TNFα) and, especially in chronic inflammatory diseases, autoimmune diseases, cancer and cytokine storms, IL-6 play crucial roles in inflammation. In some instances, however, this release gets out of hand, and features of overzealous immune responses (macrophage activation syndromes) might occur, leading to cytokine release syndromes (CRS) with inflammatory signs such as fever, fatigue, nausea, and sometimes secondary organ dysfunction or multi-organ failure. Apart from specific vaccines and maybe the anti-viral remdesivir and/or dexamethasone for treatment of CRS, there are no convincing disease-modifying interventions. So far, though, non-antiviral and immune-targeted interventions, also affecting non-target cells, were found associated with many side effects. A more targeted or focused approach is thus needed. Pending the site of the CRS-inducing insult, CRSs may occur systemic or compartmental. Recently, preclinical research yielded a beneficial anti-inflammatory effect of fresh naive bone marrow-derived stem cells (bm-SCs) in the treatment of various compartmental CRSs in the immune-privileged central nervous system (CNS). Therefore, it is argued that bm-SCs might also play a disease-modifying role in the systemic CRS. Bm-SCs have the advantage of targeting only the cells of interest as they are very selective in their actions. In addition, they actively move to the sight of inflammation.