Although the disorder is not very well known, narcolepsy is thought to affect 1 in 2000 individuals and this figure may be higher as a consequence of under-reporting and under-diagnosis. The most common symptom is excessive daytime sleepiness (EDS), which may be accompanied by sudden loss of muscular control (cataplexy) triggered by strong emotions. Narcoleptics may also experience sleep paralysis (short periods of paralysis when waking or falling asleep), hypnagogic or hypnopompic hallucinations (vivid images or sounds, respectively, when waking or falling asleep) or automatic behaviour (when routine activities are continued during a sleep episode).

For the last ten years it has been known that narcoleptics have a deficiency in hypocretin (orexin), a neurotransmitter involved in control of sleep/wakefulness. In parallel with the neurotransmitter deficiency there is a massive loss of hypothalamic neurons that produce hypocretin and it has been hypothesised that this results from an autoimmune response.

Swiss scientists have now identified autoantibodies to Tribbles homolog 2 (Trib2), an autoantigen previously identified in autoimmune uveitis, in narcolepsy patients. The team developed a transgenic mouse model to identify peptides enriched within hypocretin-producing neurons that could serve as potential autoimmune targets. Having identified enrichment of Trib2 in the mouse hypocretin neurons, the team went on to analyse sera from narcoleptics. Narcolepsy patients with cataplexy had higher Trib2-specific antibody titres compared with either normal controls or patients with other inflammatory neurological disorders. Trib2-specific antibody titres were highest early after narcolepsy onset, sharply decreased within 2–3 years, and then stabilized at levels substantially higher than that of controls for up to 30 years. Additionally, high Trib2-specific antibody titres correlated with the severity of cataplexy.

The study, published in the Journal of Clinical Investigation, provides the first evidence that narcolepsy is an autoimmune disorder.

Systemic lupus erythematosus (SLE or lupus) is a chronic autoimmune disease that can affect any part of the body. Lupus cannot be cured, although symptoms can be managed and the risk of organ damage minimised by treatment with immunosuppressants, NSAIDS and corticosteroids. Lupus is a complex disease but, although the cause is unknown, a number of genetic susceptibilities and environmental triggers have been proposed.

Deficient phagocytic clearance of apoptotic cells by macrophages is one pathway that has been suggested to contribute to the pathogenesis of lupus. In healthy individuals, macrophages rapidly engulf apoptotic cells to limit the release of noxious cellular contents and to restrict autoimmune responses to apoptotic debris. Scientists at Stanford University School of Medicine have now shown that the nuclear receptor, peroxisome proliferator-activated receptor-δ (PPAR-δ) plays a pivotal role in orchestrating phagocytosis. Genetically engineered mice lacking PPAR-δ showed decreased expression of opsonins, resulting in impaired clearance of apoptotic cells and reduced levels of anti-inflammatory cytokines. Both global and macrophage-specific Ppard^-/- mice showed increased production of autoantibodies and were predisposed to autoimmune kidney disease, a condition resembling one of the manifestations of human lupus. PPAR-δ agonists are being investigated for the treatment of metabolic disorders such as hyperlipidemia, diabetes and obesity and the authors suggest that such compounds could also potentially benefit lupus sufferers.

The study was published online on October 18^th in the journal Nature Medicine.

Crohn’s disease is an inflammatory disease of the gastrointestinal tract that causes abdominal pain, diarrhea and vomiting. First described by Burrill Bernard Crohn and co-workers in 1932, the disease is believed to be an autoimmune disorder but the precise causes are unknown. Treatment options focus on management of acute symptoms and maintenance of remission, since no known cure is available.

Crohn himself was convinced that the disease was caused by Mycobacterium paratuberculosis (MAP), the same pathogen responsible for the related Johne’s disease in cattle. Whilst his research was unable to establish the involvement of MAP, the theory has received more attention in recent years.

New research from McGill University Health Centre (MUHC), Quebec, has established a link between the human NOD2 gene and mycobacteria. Mutations in NOD2 have been observed in approximately 25% of Crohn’s disease patients, but the nature of the effect of these mutations has not been understood. Normally, NOD2 codes for a receptor that recognises invading bacteria, triggering an immune response. The MUHC study demonstrates that the NOD2 receptor preferentially recognises a peptide, N-glycolylated peptidoglycan-derived muramyl dipeptide (MDP), which is only found in mycobacteria. When mycobacteria invade the human body, they cause an immediate and very strong immune response via the NOD2 receptor. This new discovery, published in the Journal of Experimental Medicine, associates the predisposition for Crohn’s disease with both the NOD2 mutation and the presence of mycobacteria, but researchers must still determine the precise combination of these factors to understand how the disease develops.

In a separate study, researchers from Case Western Reserve University School of Medicine have identified a novel link between ITCH, a gene known to regulate inflammation in the body and NOD2. ITCH,which encodes an E3 ubiquitin ligase, can cause a variety of inflammatory diseases when malfunctioning. The team at Case Western found that ITCH also influences NOD2-induced inflammation. These findings, to be published in the August 11^th issue of Current Biology, suggest a common pathophysiology exists between multiple inflammatory diseases. The unexpected finding of the interaction between these genes offers the possibility of new drug targets for intervention in Crohn’s disease.

Lupus erythematosus is a chronic autoimmune disease that, worldwide, is more common than leukaemia, multiple sclerosis, and muscular dystrophy. There are three recognised forms of lupus: discoid (cutaneous) lupus which affects the skin, systemic lupus (SLE) which attacks multiple organ systems, and drug-induced lupus which generally resolves once the drug is discontinued. The symptoms of lupus, which can flare and subside, vary from patient to patient but include severe fatigue, joint pain, muscle aches, anaemia, and general malaise. Approximately 10% of discoid lupus cases develop into systemic lupus which can result in the destruction of vital organs.

The causes of lupus are poorly understood, but researchers at the Scripps institute have now shown that specific Toll-like receptors (TLRs) play a key role in the development of this disease. One of the principal diagnostic indicators of lupus is a high level of self-recognising antinuclear antibodies. Antinuclear antibodies normally form part of the immune response and are produced when bacteria or viruses are degraded in the endolysosome. TLRs inside this compartment specifically detect viral RNA and viral and bacterial DNA and stimulate immune cells to produce antibodies against these molecules.

Writing in the Proceedings of the National Academy of Sciences, the Scripps team have shown that three TLRs in the endolysosome are necessary for the generation of antinuclear antibodies in mice. Previous studies had pointed to endolysosomal TLRs – TLR3, TLR7, TLR8 (in humans but not mice) and TLR9 – as important for the production of antinuclear antibodies but, in mouse models of lupus, knocking out only TLR 7 or TLR9 had not dramatically reduced symptoms. The Scripps team wanted to eliminate all three TLRs in mice and achieved this by knocking out a transmembrane endoplasmic reticulum protein, UNC-93B, which is necessary for correct functioning of the endolysosomal TLRs. Knocking out UNC-93B in strains of laboratory mice that spontaneously develop many of the same symptoms as human lupus sufferers produced animals with fewer antinuclear antibodies and fewer and less severe symptoms of lupus. Even lipid A stimulation of TLR4 – which is known to promote production of autoantibodies – did not produce symptoms of lupus in the knockout animals. Nucleic acid-sensing TLRs may thus provide a critical pathway in the development of systemic autoimmunity by reducing tolerance to nucleic acid-containing antigens.

Rheumatoid arthritis (RA) is a chronic, typically progressive, autoimmune disease that primarily affects the joints although it can damage other tissues, including heart, lung, and eyes. There is currently no cure for RA and the goal of treatment is reduce joint pain and inflammation, maximise function, and minimise joint destruction and deformity. Newer biological treatments targeting components of the immune system in combination with disease-modifying antirheumatic drugs (DMARDs) are effective in preventing joint damage in some patients, but not all sufferers respond to these treatments and some may relapse despite treatment. The cause of RA remains unknown but both genetic and environmental factors are suspected to play a role.

Researchers at Imperial College have now identified a new immune trigger that may contribute to the pathology of RA. Tenascin-C is an extracellular matrix glycoprotein specifically expressed at areas of inflammation and tissue damage in inflamed rheumatoid joints. The team found that injection of tenascin-C into the joint cavity in mice caused severe joint inflammation and damage and, in a separate experiment, that mice lacking tenascin-C were protected from erosive arthritis. In cultures of cells from rheumatoid arthritis patients, tenascin-C induced synthesis of pro-inflammatory cytokines via activation of Toll-like receptor 4 (TLR4). TLR4 is one of a family of receptors that play a key role in pathogen recognition and activation of innate immunity. Stimulation of TLR4 is known to activate macrophages leading to release of TNF-α, one of the targets of existing biological agents used to treat RA patients. Previous studies had shown that mice lacking TLR4 do not show chronic joint inflammation, and blocking the interaction between tenascin-C and TLR4 may provide a new way to combat RA.

The study is published in the journal Nature Medicine.

Proteasomes are abundant and ubiquitous multi-protein complexes capable of degrading almost any protein into oligopeptides. The 20S proteasome is composed of 14 subunits (seven α and seven β) arranged in four rings to form a barrel, the ends of which can open to accept substrates. Catalytic activity is confined to three of the β-subunits, all of which are N-terminal threonine proteases. The addition of 19S regulatory complexes at the ends of the 20S multimer creates the 26S proteasome and confers the ability to process ubiquitylated substrates in an ATP-dependent manner.

Proteasomes chomp their way through a huge number of proteins including defective ribosomal products that arise from imperfections in the conversion of genetic information into proteins. The oligopeptides that result are then rapidly processed to constituent amino acids by endo- and amino-peptidases. Some oligopeptides, however, escape further processing and are presented on the cell surface by MHC Class I molecules. This provides a mechanism for the immune system to monitor the gene products that a particular cell is processing.

A variant of the proteasome, the immunoproteasome, is constitutively expressed in immune tissues and can be induced in other cell types in response to cytokines such as γ-interferon and TNF-α. The immunoproteasome differs from the proteasome at the level of the catalytic β-subunits and generates alternate peptides that modify the antigens presented by MHC class I.

The proteasome has been validated as a target in oncology and bortezomib was the first proteasome inhibitor approved in the US (2003). Until now, however, utility of proteasome inhibitors in auto-immune diseases has been hampered by the higher doses of conventional inhibitors required and the consequently smaller therapeutic window. This situation has potentially changed with results from Proteolix using their immunoproteasome-selective inhibitor, PR-957.

PR-957 is a peptide epoxy-ketone that selectively inhibits the LMP7 catalytic subunit of the immunoproteasome. Inhibition of this subunit modulates immune cell signalling and blocks production of cytokines associated with autoimmune inflammation, without affecting proteasome function in non-immune cells. In mouse models of rheumatoid arthritis, PR-957 treatment reversed signs of disease and reduced cellular infiltration, cytokine production and autoantibody levels. The study is published in the journal Nature Medicine.

Proteolix plans to file an Investigational New Drug Application for PR-957 in mid-2010.

A major challenge in treating autoimmune disease is to prevent tissue damage without generalised immunosuppression. US researchers now suggest that selective damping down of the T_H17 response using compounds such as halofuginone may provide an answer to this challenge.

Writing in the June 5^th edition of the journal Science, they show that halofuginone specifically inhibits the development of T_H17 cells which are believed to play a key role in tissue injury in autoimmune diseases such as inflammatory bowel disease, multiple sclerosis, type 1 diabetes, eczema and psoriasis. When halofuginone was added to cultures of naïve mouse CD4⁺ T-cells containing cytokines that would normally induce differentiation into T_H17 cells, the number of T_H17 cells – but not T_H1, T_H2 or T regulatory cells – was substantially reduced. In cultured human CD4⁺ T-cells, halofuginone also selectively suppressed levels of IL-17, the main cytokine produced by T_H17 cells. In mice with experimental autoimmune encephalitis (EAE), an artificially-induced immune disease resembling multiple sclerosis and marked by infiltration of T_H17 cells into the central nervous system, treatment with low doses of halofuginone significantly reduced both the development of EAE and its severity.

To understand how halofuginone works, the researchers looked at alterations in gene expression in response to drug treatment and found that a cytoprotective signalling pathway, the amino acid starvation response (AAR), was activated. Inhibition of T_H17 differentiation by halofuginone could be overcome by the addition of excess amino acids and was mimicked by AAR activation in response to selective amino acid depletion.

Halofuginone is a synthetic analogue of febrifugine, the active principal of the Chinese herb, chang shan (Dichroa febrifuga), which has been used to treat fever and malaria for more than 2000 years. Febrifugine itself causes severe emesis and gastrointestinal irritation and, in the 1960s, a number of analogues – including halofuginone – were synthesized by U.S. Army scientists looking for novel antimalarials. Halofuginone also inhibits synthesis of collagenase and collagen type 1 and underwent clinical trials for the treatment of scleroderma, a chronic, autoimmune condition of the connective tissue. In animal husbandry, halofuginone (as Stenerol®) is used prophylactically to control coccidial infection in poultry flocks.