Concept: Autoimmune disease
Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis
- Proceedings of the National Academy of Sciences of the United States of America
- Published almost 3 years ago
Rheumatoid arthritis (RA) is a heterogeneous, prevalent, chronic autoimmune disease characterized by painful swollen joints and significant disabilities. Symptomatic relief can be achieved in up to 50% of patients using biological agents that inhibit tumor necrosis factor (TNF) or other mechanisms of action, but there are no universally effective therapies. Recent advances in basic and preclinical science reveal that reflex neural circuits inhibit the production of cytokines and inflammation in animal models. One well-characterized cytokine-inhibiting mechanism, termed the “inflammatory reflex,” is dependent upon vagus nerve signals that inhibit cytokine production and attenuate experimental arthritis severity in mice and rats. It previously was unknown whether directly stimulating the inflammatory reflex in humans inhibits TNF production. Here we show that an implantable vagus nerve-stimulating device in epilepsy patients inhibits peripheral blood production of TNF, IL-1β, and IL-6. Vagus nerve stimulation (up to four times daily) in RA patients significantly inhibited TNF production for up to 84 d. Moreover, RA disease severity, as measured by standardized clinical composite scores, improved significantly. Together, these results establish that vagus nerve stimulation targeting the inflammatory reflex modulates TNF production and reduces inflammation in humans. These findings suggest that it is possible to use mechanism-based neuromodulating devices in the experimental therapy of RA and possibly other autoimmune and autoinflammatory diseases.
To determine whether feeding infants with hydrolysed formula reduces their risk of allergic or autoimmune disease.
Systemic sclerosis (scleroderma) is unique among the rheumatic diseases because it presents the challenge of managing a chronic multisystem autoimmune disease with a widespread obliterative vasculopathy of small arteries that is associated with varying degrees of tissue fibrosis. The hallmark of scleroderma is clinical heterogeneity with subsets that vary in the degree of disease expression, organ involvement, and ultimate prognosis. Thus, the term scleroderma is used to describe patients who have common manifestations that link them together, whereas a highly variable clinical course exists that spans from mild and subtle findings to aggressive, life-threatening multisystem disease. The physician needs to carefully characterize each patient to understand the specific manifestations and level of disease activity to decide appropriate treatment. This is particularly important in treating a patient with scleroderma because there is no treatment that has been proven to modify the overall disease course, although therapy that targets specific organ involvement early before irreversible damage occurs improves both quality of life and survival. This review describes our approach as defined by evidence, expert opinion, and our experience treating patients. Scleroderma is a multisystem disease with variable expression; thus, any treatment plan must be holistic, yet at the same time focus on the dominant organ disease. The goal of therapy is to improve quality of life by minimizing specific organ involvement and subsequent life-threatening disease. At the same time the many factors that alter daily function need to be addressed, including nutrition, pain, deconditioning, musculoskeletal disuse, comorbid conditions, and the emotional aspects of the disease, such as fear, depression, and the social withdrawal caused by disfigurement.
Celiac disease (CD) is an autoimmune condition affecting the small intestine, triggered by the ingestion of gluten, the protein fraction of wheat, barley, and rye. There is a strong linkage between CD and HLA-DQ2 and HLA-DQ8 haplotypes. Multiple case reports and small series suggest concordance between CD and other autoimmune disorders. This paper provides a brief overview of the pathogenesis of CD and reviews the literature regarding associations between CD and other autoimmune diseases, including the potential effects of gluten-free diet therapy on the prevention or amelioration of associated diseases.
Multiple myeloma (MM) and its precursor, monoclonal gammopathy of undetermined significance (MGUS), have been linked with several autoimmune conditions in the medical literature. Yet, significance of these associations is not well understood.
We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P < 5 × 10(-8)), increasing the number of known susceptibility loci to 25. The most associated variant at 19p12 is a low-frequency nonsynonymous SNP in TYK2, further implicating JAK-STAT and cytokine signaling in disease pathogenesis. An additional five loci contained nonsynonymous variants in high linkage disequilibrium (LD; r(2) > 0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non-human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r(2) > 0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up.
In autoimmune disease, a network of diverse cytokines is produced in association with disease susceptibility to constitute the ‘cytokine milieu’ that drives chronic inflammation. It remains elusive how cytokines interact in such a complex network to sustain inflammation in autoimmune disease. This has presented huge challenges for successful drug discovery because it has been difficult to predict how individual cytokine-targeted therapy would work. Here, we combine the principles of Chinese Taoism philosophy and modern bioinformatics tools to dissect multiple layers of arbitrary cytokine interactions into discernible interfaces and connectivity maps to predict movements in the cytokine network. The key principles presented here have important implications in our understanding of cytokine interactions and development of effective cytokine-targeted therapies for autoimmune disorders.
CD40-CD40 ligand (CD40L) interactions appear to play pathogenic roles in autoimmune disease. Here we quantify CD40 expression on fibrocytes, circulating, and bone marrow-derived progenitor cells. The functional consequences of CD40 ligation are determined since these may promote tissue remodeling linked with thyroid-associated ophthalmopathy (TAO).
SEC is an undifferentiated tumour used in tumour studies. MTX is an antimetabolite used in treatment of cancer, autoimmune diseases and induction of abortion. VPA is used as anticonvulsant and is under investigation for treatment of cancer. The aim of this work was to compare between the effect of each of MTX and VPA on solid Ehrlich tumour in mice.
Genetic profiling in Graves' disease: further evidence for lack of a distinct genetic contribution to Graves' ophthalmopathy.
- Thyroid : official journal of the American Thyroid Association
- Published almost 7 years ago
Graves' disease (GD), including Graves' ophthalmopathy or orbitopathy (GO), is an autoimmune disease with an environmental and genetic component to its etiology. The genetic contribution to the GO clinical phenotype remains unclear. Previous data from our laboratory and others have suggested that GO has no specific genetic component distinct from GD itself, while other reports have occasionally appeared suggesting that polymorphisms in genes such as CTLA4 and IL23R specifically increase the risk for GO. One of the criticisms of all these reports has been the clinical definition of the GO phenotype as distinct from hyperthyroid GD devoid of clinically significant eye involvement. The objective of this study was to take advantage of a phenotypically pure group of GD patients with GO and examine a series of genes associated with GD to determine if any were more definitively associated with GO rather than Graves' thyroid disease itself.