Christopher Lock

Inhibitory role for GABA in autoimmune inflammation

GABA, the principal inhibitory neurotransmitter in the adult brain, has a parallel inhibitory role in the immune system. We demonstrate that immune cells synthesize GABA and have the machinery for GABA catabolism. Antigen-presenting cells (APCs) express functional GABA receptors and respond electrophysiologically to GABA. Thus, the immune system harbors all of the necessary constituents for GABA signaling, and GABA itself may function as a paracrine or autocrine factor. These observations led us to ask further whether manipulation of the GABA pathway influences an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Increasing GABAergic activity ameliorates ongoing paralysis in EAE via inhibition of inflammation. GABAergic agents act directly on APCs, decreasing MAPK signals and diminishing subsequent adaptive inflammatory responses to myelin proteins.

Janus-like opposing roles of CD47 in autoimmune brain inflammation in humans and mice

CD47 exerts different effects on disease in distinct cell types and locations and during different stages of experimental autoimmune encephalomyelitis.

MHC class II sequences of an HLA-DR2 narcoleptic

Narcolepsy has a 98% association with the DR2-Dw2/DQw1 haplotype. To establish if a disease-specific allele is present in narcolepsy, a cDNA library was made from a B-cell line from a DR2,4/DQw1,3 narcoleptic. Clones encoding the two expressed DR2β chains, along with DQw1 α and β chains, were isolated and completely sequenced. The coding regions of these four genes were similar to published nucleotide and protein sequences from corresponding healthy controls, with some minor exceptions. The 3′ untranslated region of one of the DR2β genes in the narcoleptic was extended by 42 bp. Complete sequences were not available for DQw1.2 α or β from healthy individuals, but first domain nucleotide sequences showed only a single nonproductive difference in DQα. Partial protein sequences of both DQ α and β from published data were identical. Although the effects of minor differences cannot be ruled out completely, it is concluded that there are probably no narcolepsy-specific DRβ or DQ α/β sequences, and that the alleles found in narcolepsy are representative of those found in the healthy population.

Antigen recognition and peptide-mediated immunotherapy in autoimmune disease.

Autoimmune disease occurs when the immune system of an individual is triggered to recognize self components. The immune system then proceeds to attack these self components with a destructive fury normally reserved for foreign invaders. CD4+ helper T lymphocytes and CD8+ cytotoxic T lymphocytes play a major role in the normal immune response to foreign antigens. These cells are activated when their specific T-cell receptors (TCR) recognize foreign antigenic peptide fragments bound to major histocompatibility complex (MHC) molecules. CD8 + T cells usually recognize peptides complexed to class I MHC molecules. In contrast, CD4+ T cells recognize peptides complexed to class II MHC molecules (AaAP and EaEy? in the mouse, and DRaDR;5, DQaDQy?, and DPaDP/? in humans). Activated CD4 + helper T cells consequently secrete a variety of lymphokines which then influence the activity of other cells in the immune system. Any given MHC molecule must be capable of binding to a variety of antigenic peptides in order to generate TCR recognition structures from all foreign proteins. Nevertheless, it has been shown that each class II MHC molecule maintains a certain degree of specificity, binding only to very characteristic antigenic peptides (Babbitt et al. 1985, Schwartz 1986, Buus et al. 1987). This binding specificity is conferred by the polymorphic amino acid residues which are clustered around

Genetic factors in sleep disorders.

Several sleep disorders have a genetic basis. These conditions include the narcoleptic syndrome, sleep walking, periodic movements in sleep, circadian delay syndromes and familial insomnia. These disorders illustrate different control mechanisms involved in sleep and wakefulness, including those determining the prevalence and timing of NREM and REM activity, somatomotor inhibition and excitation, autonomic discharge, and the circadian framework of sleep. The genetic defect in narcolepsy has been localised to the short arm of chromosome 6, but the chromosomal localisations of the genetic basis for the other disorders are not known. Also, with the possible exception of acetylcholine, no definite neurotransmitter involved in any aspect of sleep regulation has been positively identified and the biochemical defect in narcolepsy is not known.

Are “statins” beneficial or harmful in multiple sclerosis?

In this issue of Neurology ®, Dr. Birnbaum and co-authors study whether cholesterol medications called statins are helpful or harmful when combined with common multiple sclerosis (MS) treatments called interferons in patients who have MS.1 Interferons are drugs often used for treating MS, and they include interferon beta-1b (Betaseron) and interferon beta-1a (Rebif, Avonex). Statins are drugs given by doctors to lower cholesterol. Statins do more than lower cholesterol (figure). They also affect the body’s immune system (the system that helps the body fight infection and sickness) and decrease inflammation. The anti-inflammatory effects may partly explain why these medications protect patients against heart attacks and strokes. Some studies have suggested that these effects of statins might help patients with MS. Animals with a disease similar to MS did better when a statin was combined with MS therapy.2 Small studies in patients with MS or at risk for developing MS suggested a possible benefit of statins.3 Could a benefit of statins when added to interferons be confirmed? Figure Effects of statins Dr. Birnbaum and co-authors asked whether a high dose of a statin—atorvastatin—can be given safely to MS patients taking an interferon. Twenty-six patients with relapsing-remitting MS who were taking interferon beta-1a three times a week entered the study. All patients had to have stable disease activity for 6 months before the study began. The MS patients stayed on interferon, and then started on atorvastatin (40 or 80 mg) or placebo (a “sugar pill”) for 6 months. Patients were examined and had pictures of the brain (magnetic resonance images or MRIs) done at 0, 3, and 6 months, and after stopping the statin at 9 months. Patients were monitored for …

Fluorescence-Activated Cell Sorter Analysis of Peptide–Major Histocompatibility Complex

Publisher Summary In recent years it has become clear that the primary function of major histocompatibility complex (MHC) class I and class II molecules is to bind peptide fragments of protein antigens for their presentation to peptide-specific, MHC-restricted T cells. This chapter discusses fluorescence-activated cell sorter analysis (FACS) of peptide-major histocompatibility complex (MHC). Using FACS analysis, a large number of samples can be tested for binding in a very short period of time. This method can be used to assess peptide-MHC binding on a variety of live cell types. The exact molecular nature of the association of peptides and MHC proteins remains to be fully elucidated. It also remains to be determined exactly which residues of Ia make contact with antigen and which ones make contact with the T-cell receptor.