CD8 T Cell Avidity is Dependent on T Regulatory Cells

A review of Pace L., et al. Regulatory T Cells Increase the Avidity of Primary CD8+ T Cell Responses and Promote Memory. Science 338; 532-36, 2012. PMID: 23112334

T regulatory cells (Tregs) are necessary to prevent aberrant immune activation that can lead to autoimmunity. Interestingly however, Tregs do not appear to prevent immune activation in response to pathogens. In fact, in two separate reports, Tregs have been shown to contribute to the clearance of L. major and herpes simplex virus (Belkaid et al., 2002; Lund et al., 2008). The precise mechanisms as to how Tregs contribute to the priming of the immune response remain unclear. Here, Pace et al. utilize FoxP3 DTR mice, in which FoxP3+ cells express the human diphtheria toxin receptor, to eliminate Tregs via an injection of diphtheria toxin. They administered the toxin before administering a foreign antigen which activates CD8 T cells, and employed MHC-multimers to measure the frequency of antigen reactive T cells during the response. Their key findings were:

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Epigenetics and Chromatin Remodeling in Henoch-Schönlein Purpura

A review of Luo S., et al. Aberrant Histone Modifications in Peripheral Blood Mononuclear Cells from Patients with Henoch-Schönlein Purpura. Clinical Immunology (2013) 146:165-175. PMID: 23353785

Henoch-Schönlein purpura (HSP) is a systemic vasculitis that classically presents as palpable purpura with arthritis, abdominal pain, or kidney dysfunction in the weeks following an upper respiratory tract infection. The majority of cases of HSP occur in children, although it can affect adults as well, and the pathophysiology is thought to involve IgA-immune complex deposition, which leads to complement activation, neutrophil influx, and microvascular destruction. Despite much interest in HSP, its precise etiology remains unclear and a variety of host and environmental factors have been identified as potential contributors. One area that has not been previously explored in HSP is the role of epigenetics and histone remodeling, which can affect the transcriptional accessibility of specific genetic loci. This avenue of research is of particular interest in light of recent evidence supporting the notion that epigenetic regulation may influence T cell function and susceptibility to autoimmune diseases such as lupus, Sjögren’s syndrome, and rheumatoid arthritis. To test the hypothesis that epigenetic changes might contribute to HSP, Luo et al. analyzed histone modifications and gene expression in PBMCs collected from 24 adult patients with HSP and 22 healthy controls of similar age. The authors found that:

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Miniaturizing Immune Monitoring Assays

Holden T. Maecker, PhD, Stanford University

The most common immune monitoring assays are serological. This stems from the fact that antibody-based assays have a much longer history in immunology than do cellular assays, and because the technical demands for antibody assays tend to be lower. Because of their long history and widespread use, technological advances in antibody-based assays are many. Two of the main areas for advancement have been multiplexing (the ability to measure many analytes at once) and miniaturization (to allow use of smaller samples). Often, the two go hand in hand. Consider the following advances in multiplexing and/or miniaturization of antibody-based assays:

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A New Wave of Rational Therapeutics for Immunological Disorders: Small Molecule Signaling Inhibitors

Shiv Pillai, MD, PhD, Massachusetts General Hospital

History
For over two millenia, compounds with therapeutic efficacy have largely been discovered by chance - at best by a process of trial and error. In ancient Greece, India and China and later in the Islamic world and pre-Columbian America, arsenals of efficacious medicinal preparations were discovered centuries ago by physicians and herbalists and some of these preparations are still in use today. A little over a hundred years ago, Paul Ehrlich searched for drugs derived from dyes and related organic compounds and early in the 20th century gave us our first chemotherapeutic, Salvarsan. This opened the doors to more discoveries that helped bring synthetic chemists into the brave new world of pharmacology. Alexander Fleming's discovery in the 1940s of the first antibiotic derived from a fungal spore led to Ernst Boris Chain's chemical synthesis of penicillin. Organic chemists have since created large compendiums of compound libraries - these libraries as well as collections of molecules derived from natural products have long formed the core of large screens aimed at identifying random molecules that happen to possess some biological efficacy of relevance to the treatment of disease.

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Edited by Carla J. Greenbaum, MD, Benaroya Research Institute

Dimethyl Fumarate in Relapsing Multiple Sclerosis: The DEFINE and CONFIRM Studies

Clinical Trials:

Fox J. et al., Placebo-Controlled Phase 3 Study of Oral BG-12 or Glatiramer in Multiple Sclerosis. New England Journal of Medicine 2012; 367:1087-97.) PMID: 22992072

Gold R et al., Placebo-Controlled Phase 3 Study of Oral BG-12 for Relapsing Multiple Sclerosis. New England Journal of Medicine 2012; 367:10107. PMID: 22992073

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