HLA-DRB1 15:01 and Epstein-Barr virus in a multiple sclerosis patient with psoriasis, nasopharyngeal and breast cancers. Lessons for possible hidden links for autoimmunity and cancer.

BACKGROUND: Multiple sclerosis (MS) patients have a low general cancer risk and cases of neoplastic comorbidity are attributed by many researchers in chance, or therapeutical side-effects. Human leucocyte antigen (HLA) class II allele DRB1 15:01 is considered the main genetic factor independently associated with increased susceptibility for MS in Caucasians. Epstein-Barr virus (EBV) has also been proven to be a core triggering factor in MS initiation and progress, mainly in HLA-DRB1 15:01 positive MS patients. CASE REPORT: We present an exceptional case of a Greek-origin woman, carrying a distinct immunogenetic profile (HLA-A 26:01-Cw 06:02-DRB1 15:01), which gradually developed psoriasis, nasopharyngeal carcinoma (NPC), MS, breast cancer, uterine leiomyoma and other neoplasms. DISCUSSION: EBV plays a fundamental role in the pathogenesis of both autoimmunity (i.e. MS) and cancer (i.e. NPC). Our patient's immunogenetic profile included HLA alleles which are associated with psoriasis (Cw 06:02), NPC (A 26:01), MS (DRB1 15:01) and increased risk of MS, in patients carrying EBV (DRB1 15:01). We made a targeted review of the literature finding data supporting an EBV-HLA interaction mechanism behind our patient's unique combination of disorders, suggesting that beyond the standard role of each factor, their combination could act as the hidden link, in initiation or/and comorbidity of autoimmunity and cancer.

Body Mass Index in Multiple Sclerosis: Associations with CSF Neurotransmitter Metabolite Levels.

Body weight and height of patients with relapsing-remitting multiple sclerosis (RRMS) or clinically isolated syndrome suggesting MS (CIS) in the age range 18 to 60 years (154 males and 315 females) were compared with those of subjects (146 males and 212 females) free of any major neurological disease. In drug-free patients, CSF levels of the metabolites of noradrenaline (MHPG), serotonin (5-HIAA), and dopamine (HVA), neurotransmitters involved in eating behavior, were estimated in searching for associations with body mass index (BMI). Statistical evaluations were done separately for males and females. Lower BMI was found in female MS patients compared to female controls, more pronounced in RRMS. BMI was not associated with duration of illness, smoking, present or previous drug treatment, or disability score. Body height showed a shift towards greater values in MS patients compared to controls. Patients in the lower BMI quartile (limits defined from control subjects) had lower 5-HIAA and HVA compared to patients in the upper quartile. The results provide evidence for weight reduction during disease process in MS, possibly related to deficits in serotoninergic and dopaminergic activities that develop during disease course, resulting in impairments in food reward capacity and in motivation to eat.

Rare association of polyneuropathy and Crohn's disease: a clinicopathological study of 4 cases.

The purpose of this study is to investigate the clinical, electrophysiological and pathological features of neuropathy in patients with Crohn's disease. Biopsies were selected from over 700 sural nerve biopsies. The diagnosis of Crohn's disease was based on established clinicopathological criteria. Complete laboratory, clinical, electrophysiological and pathological studies were performed in all cases. Nerve biopsies of 4 patients were diagnosed as neuropathy and Crohn's disease. Distal symmetrical sensorimotor polyneuropathy was the pattern of neuropathy. The pathological features were mixed, demyelination with predominant axonal degeneration and a varying pattern of myelinated fiber loss. There were no vasculitic changes found. We conclude that patients with Crohn's disease are complicated frequently with polyneuropathy, and as remission depends on immunosuppressive therapy, it is important to recognise it in the early stage. The diagnosis of polyneuropathy is based on clinical and electrophysiological studies, but precise histology, immunohistochemistry and morphometric studies of the peripheral nerve biopsy may be decisive in establishing the diagnosis.

Nonsystemic vasculitic neuropathy: a clinicopathological study of 22 cases.

OBJECTIVE: The involvement of the peripheral nervous system in patients with systemic vasculitis has been reported, but nonsystemic peripheral nervous system vasculitis is not so well known. We investigated the clinical, electrophysiological, and pathological features of nonsystemic vasculitic neuropathy (NSVN) in order to establish the clinical and histological manifestations and to promote the earlier diagnosis of the syndrome. METHODS: Biopsies were selected from over 700 sural nerve biopsies performed at the Section of Neuropathology, Neurological Clinic of Athens University Hospital. The diagnosis of vasculitis was based on established clinicopathological criteria. Other causes of peripheral neuropathy were excluded. Complete laboratory, clinical, electrophysiological, and pathological studies were performed in all cases. RESULTS: Nerve biopsies of 22 patients were diagnosed as NSVN. The pathological features were vasculitis and predominant axonal degeneration with a varying pattern of myelinated fiber loss. The vasculitic changes were found mainly in small epineural blood vessels. Mononeuritis multiplex and distal symmetrical sensorimotor neuropathy were equally frequent. CONCLUSION: NSVN should be suspected in a case of unexplained polyneuropathy without evidence of systemic involvement. Clinical and neurophysiological studies are essential for the detection of nerve involvement, but the specific diagnosis of NSVN may be missed unless a biopsy is performed.

Modulation of voltage-gated potassium channels in human T lymphocytes by extracellular glutamate.

Glutamate is present in the plasma under tightly regulated concentrations. However, under conditions of immune deficiency, such as AIDS and malignancy, its plasma levels are highly elevated. In vitro, glutamate interacts with T lymphocytes, affecting mitogen-induced calcium responses, whereas at high doses, it impairs T lymphocyte proliferation, a process strongly dependent on the activity of voltage-gated potassium channels. In this study, we demonstrate novel dose-related effects of the endogenous ligand glutamate and its metabotropic and non-N-methyl-D-aspartic acid receptor agonists on the electrophysiological properties of native Kv1.3 channels of human T lymphocytes. Glutamate, at concentrations within normal plasma levels, positively modulates Kv1.3 channel gating, causing currents to activate faster and at significantly more hyperpolarized potentials, hence rendering the T lymphocyte readily responsive to immune stimuli. This effect is maximal at 1 microM Glu and is fully mimicked by a 100 microM concentration of the metabotropic receptor agonist trans-(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid. Most importantly, Glu, at concentrations > or =100 microM, which in vitro produce suppression of mitogen-induced proliferation, significantly decreases whole-cell potassium currents by increasing current and steady-state inactivation. This effect saturates at 1000 microM and seems to result from the subsequent activation of low-affinity metabotropic Glu receptors, as suggested by specific agonist data. Therefore, the antiproliferative effects of high glutamate may, at least in part, result from its inhibitory effect on the potassium current, suggesting an in vivo immunosuppressive role of elevated plasma glutamate.