[Cranial nerve palsies: ganglioside autoantibodies indicating an immunoneuropathy]. / Isolierte Hirnnerven-Läsionen: Gangliosid-Autoantikörper als Hinweis auf Immunneuropathie.

BACKGROUND: Cranial neuropathies are not infrequent and need a broad differential diagnostic approach. Etiologically autoimmune processes have to be considered. METHOD: In five patients with cranial neuropathy (in two cases lesion of the abducens nerve, in one case bilateral facial palsy, in one case abducens, facial and bilateral vestibular lesion, in one case bilateral glossopharyngeal lesion) IgG and IgM autoantibodies directed against most relevant gangliosides were quantitatively analyzed (Bühlmann Laboratories AG, Schönenbuch, Switzerland). All patients underwent lumbar puncture and cranial imaging. RESULTS: Trauma, tumor, elevated intracranial pressure and vascular lesion could be excluded. In one patient varicella infection as a cofactor was probable, in the remaining patients direct infection could be excluded. In one patient a prominent cyto-albumin dissociation of the CSF was found. In all patients autoantibodies directed against gangliosides were detected with positive antibodies against GD1a and GD1b in all patients. Prior to the cranial neuropathy one patient reported an infection of the upper airway and one reported an infection of the gastrointestinal tract. One patient was treated with steroids and one patient with intravenous immunoglobulin, the other patients were been carefully observed. All patients recovered well. CONCLUSION: Autoimmune processes with positive autoantibodies directed against gangliosides can be found in cranial neuropathy. Based on these observations an immunomodulating therapy should be considered.

Early Dynamics of P-selectin and Interleukin 6 Predicts Outcomes in Ischemic Stroke.

BACKGROUND: Thromboinflammatory molecules connect the prothrombotic state, endothelial dysfunction, and systemic/local inflammation in the acute phase of ischemic stroke. METHODS: We prospectively investigated (1) serial changes in the levels of thromboinflammatory biomarkers in 76 patients with acute ischemic stroke (6, 24, and 72 hours after onset); (2) compared with 44 patients with asymptomatic severe (≥70%) carotid stenosis and 66 patients with Parkinson disease; and (3) we applied multiple regression methods, relating biological biomarkers combined with demographic data and comorbidities to poststroke infection, death, and functional outcome, and assessed the ability of the models to predict each outcome. RESULTS: Interleukin 6 (IL-6) levels and change of IL-6 concentrations by 72 hours correlated with the size of tissue damage indicated by S100B titers. Levels of IL-6 and P-selectin at 72 hours were higher in patients with large-artery versus lacunar stroke. High concentration of IL-6, monocyte chemotactic protein 1, and S100B at 6 hours were associated with poststroke infections; high concentration of IL-6, S100B, and high-sensitivity C-reactive protein (hsCRP) correlated with death. Change of P-selectin from 6 to 72 hours by 1 unit increased the incidence of poststroke infections with an odds ratio of 22.7; each 100 units of IL-6 at baseline increased the odds of death by 9‰, and at 72 hours, the odds of poststroke infections by 4‰. Each unit of baseline hsCRP elevated the odds of death by 7%. CONCLUSIONS: In regression models, in which biological, demographic, and comorbid factors were combined, those biological biomarkers predicted poor outcome with high accuracy, which were characterized by an increasing concentration by 72 hours. Two particular biomarkers emerged to predict outcomes besides hsCRP: early dynamic changes in the systemic levels of P-selectin and IL-6.

Association of myasthenia gravis with polymorphisms in the gene of histamine N-methyltransferase.

INTRODUCTION: Histamine N-methyltransferase (HNMT) is the main metabolizing enzyme of histamine. Histamine modulates immune responses and plays a role in the pathogenesis of autoimmune disorders. METHODS: The non-synonymous HNMT C314T polymorphism and the A939G single-nucleotide polymorphism (SNP) influencing HNMT mRNA stability were genotyped in 213 patients with myasthenia gravis (MG) and 342 healthy controls. RESULTS: The carrier frequency of the A allele of the A939G SNP was over-represented among patients with anti-AchR and anti-Titin antibodies (P = 0.05 and P = 0.004, respectively); the presence of the minor G allele was protective against anti-AchR and anti-Titin positive MG (OR = 0.67 and OR = 0.54, respectively). The combination of the G allele carrier status with wild-type C314C homozygosity was also protective against MG (OR = 0.55, P = 0.008) and against the development of anti-AchR antibodies (OR = 0.37, P = 0.01). DISCUSSION: The A939G HNMT polymorphism is associated with autoimmune MG, while no association with C314T SNP was found.

Effective humoral immunity against diphtheria and tetanus in patients with systemic lupus erythematosus or myasthenia gravis.

INTRODUCTION: Controversy exists about the effectiveness of vaccine-induced immune response in patients with immunoregulatory disorders. Our aim was to determine the antibody titers to diphtheria and tetanus in patients with either of two autoimmune diseases. METHODS: 279 patients with SLE (205 females, aged 45.0 ± 13.8 years), 158 patients with myasthenia gravis (MG) (101 females, aged 55 ± 18.7 years) and 208 healthy subjects (122 females, aged 48 ± 14.6 years) were enrolled. Serum concentrations of diphtheria-antitoxin-IgG (A-DIPHTH) and tetanus-antitoxoid-IgG (A-TET) were determined with ELISA. RESULTS: Equal proportions of healthy subjects, as well as patients with SLE or MG exhibited proper antibody responses and immune protection against diphtheria and tetanus. In all three test groups, serum concentration of A-DIPHTH decreased significantly (p<0.001) with age throughout the study population, while titers of A-TET dropped only in the elderly (>60-years-old) subjects. There were no significant differences among the groups in the age-related changes of A-TET and A-DIPHTH except that in <40-years-old subjects, A-DIPHTH level was significantly (p=0.029) lower in SLE patients than in controls. CONCLUSIONS: Our findings suggest that the level of vaccine-induced immunity against diphtheria and tetanus infections in patients with SLE or MG is comparable to the healthy population.

Enzyme replacement therapy induces T-cell responses in late-onset Pompe disease.

INTRODUCTION: Enzyme replacement therapy (ERT) in ultra-orphan Pompe disease generates anti-rhGAA antibodies, which may interfere with efficacy. METHODS: rhGAA-specific T-cell responses were examined at different time-points in 6 Hungarian patients treated with rhGAA and compared with 1 untreated patient and 5 healthy controls. RESULTS: The ex vivo percentage of activated T cells was increased in treated patients. rhGAA stimulation in vitro generated a dose-dependent increase in intracellular interferon-gamma (IFN-γ) expression in CD4(+) and CD8(+) T cells. Isolated CD4(+) and CD8(+) T cells produced increased amounts of IFN-γ and tumor necrosis factor-alpha (TNF-α) in half of the patients after in vitro stimulation with rhGAA, whereas interleukin (IL)-4, IL-6, and IL-17 levels were not elevated. Expression of cytotoxic FasL and perforin molecules by natural killer (NK), NKT-like, and CD8(+) T cells were not increased ex vivo. CONCLUSIONS: We found that enzyme replacement therapy (ERT) induces pro-inflammatory T-cell responses in addition to the antibody response in Pompe disease.

Impaired function of innate T lymphocytes and NK cells in the acute phase of ischemic stroke.

BACKGROUND: Functional alterations of innate lymphocytes, which can mount rapid immune responses and shape subsequent T cell reactions, were examined in the acute phase of ischemic stroke. METHODS: Frequencies, intracellular perforin and interferon-gamma (IFN-gamma) expression of Vdelta2 T cells, CD3+ CD56+ natural killer T (NKT)-like and NK cells were examined in the peripheral blood of 20 healthy controls and 28 patients within 6 h of the onset of acute ischemic stroke and after 72 h by flow cytometry. Cytokine production of isolated NKT-like and NK cells following in vitro activation was measured by cytometric bead array. NK cytotoxicity was examined in the peripheral blood mononuclear cells. RESULTS: Percentages of Vdelta2, NKT-like and NK cells were constant, and similar to percentages in healthy subjects. In contrast, proinflammatory intracellularIFN-gamma expression by Vdelta2 T cells, NKT-like cells and NK cells and IFN-gamma production by isolated NK cells in culture was low at 6 h and reached the level of healthy subjects by 72 h after stroke. Production of anti-inflammatory cytokines was unaltered. Intracellular perforin expression by Vdelta2 T cells, NKT-like cells and NK cells, and NK cytotoxicity was low at 6 h, and reached the level of healthy subjects by 72 h. Increases in IFN-gamma and perforin expression by Vdelta2 T cells correlated with clinical improvement indicated by decreases in NIHSS scores. CONCLUSIONS: Pro-inflammatory and cytotoxic responses of NK, NKT-like and Vdelta2 T cells become acutely deficient in ischemic stroke, which may contribute to an increased susceptibility to infections.

Invariant Valpha7.2-Jalpha33 TCR is expressed in human kidney and brain tumors indicating infiltration by mucosal-associated invariant T (MAIT) cells.

The anti-tumor response of human invariant NKT (NKT) cells is well established. A novel T cell subset, mucosal-associated invariant T (MAIT) cells, possesses similar regulatory properties to NKT cells in autoimmune models and disease. Here, we examined the clonality of four T cell subsets expressing invariant alphaTCR, including Valpha7.2-Jalpha33 of MAIT cells, in 19 kidney and brain tumors. The MAIT clonotype was identified and co-expressed with NKT clonotype in half of the tumors. In contrast, two other invariant T cell clonotypes (Valpha4 and Valpha19) were not present in tumors. Such tumors also expressed Vbeta2 and Vbeta13, the restricted TCRbeta chain of MAIT cells and the antigen-presenting molecule MR1. A high percentage of infiltrating T cells was CD8+ and expressed HLA-DR suggesting activation. Although the MAIT alphaTCR was identified in both peripheral CD56+ and CD56- subsets, infiltrating lymphocytes were CD56 negative. The clonal presence of MAIT cells in tumors correlated with the expression of pro-inflammatory cytokines but no IL-4, IL-5 and IL-10, suggesting that a pro-inflammatory subset of human MAIT cells may exist. Our data imply that a CD56- subset of MAIT cells may participate in tumor immune responses similarly to NKT cells.