Alemtuzumab-related eosinophilic central nervous system vasculitis.

A 36-year-old woman with relapsing remitting multiple sclerosis (MS) presented with right-sided spasms, focal seizures and neuropsychiatric symptoms 10 months after her first course of alemtuzumab. Magnetic resonance imaging (MRI) brain imaging revealed multiple foci of T2 hyperintensity. Subsequent blood and cerebrospinal fluid (CSF) testing for progressive multifocal leukoencephalopathy (PML), vasculitis and infective causes was negative. A brain biopsy was performed, revealing a prominent perivascular inflammatory infiltrate with multiple immune cells including eosinophils, suggesting eosinophilic vasculitis. The patient was treated successfully with cyclophosphamide. The potential sequelae of alemtuzumab treatment are discussed; this treatable complication should be considered when tests for JC virus are negative.

Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity.

Thousands of genetic variants have been identified, which contribute to the development of complex diseases, but determining how to elucidate their biological consequences for translation into clinical benefit is challenging. Conflicting evidence regarding the functional impact of genetic variants in the tyrosine kinase 2 (TYK2) gene, which is differentially associated with common autoimmune diseases, currently obscures the potential of TYK2 as a therapeutic target. We aimed to resolve this conflict by performing genetic meta-analysis across disorders; subsequent molecular, cellular, in vivo, and structural functional follow-up; and epidemiological studies. Our data revealed a protective homozygous effect that defined a signaling optimum between autoimmunity and immunodeficiency and identified TYK2 as a potential drug target for certain common autoimmune disorders.

CD8⁺ MAIT cells infiltrate into the CNS and alterations in their blood frequencies correlate with IL-18 serum levels in multiple sclerosis.

Recent findings indicate a pathogenic involvement of IL-17-producing CD8(+) T cells in multiple sclerosis (MS). IL-17 production has been attributed to a subset of CD8(+) T cells that belong to the mucosal-associated invariant T (MAIT) cell population. Here, we report a reduction of CD8(+) MAIT cells in the blood of MS patients compared with healthy individuals, which significantly correlated with IL-18 serum levels in MS patients. In vitro stimulation of peripheral blood mononuclear cells from healthy individuals and MS patients with IL-18 specifically activated CD8(+) MAIT cells. Moreover, IL-18 together with T-cell receptor stimulation induced, specifically on CD8(+) MAIT cells, an upregulation of the integrin very late antigen-4 that is essential for the infiltration of CD8(+) T cells into the CNS. Notably, we were able to identify CD8(+) MAIT cells in MS brain lesions by immunohistochemistry while they were almost absent in the cerebrospinal fluid (CSF). In summary, our findings indicate that an IL-18-driven activation of CD8(+) MAIT cells contributes to their CNS infiltration in MS, in turn leading to reduced CD8(+) MAIT-cell frequencies in the blood. Therefore, CD8(+) MAIT cells seem to play a role in the innate arm of immunopathology in MS.

TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis.

Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS), it has been difficult to demonstrate which variants are causal and what role they have in disease. Moreover, the modest contribution that these variants make to disease risk has raised questions regarding their medical relevance. Here we have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes tumour necrosis factor receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS), but not with other autoimmune conditions such as rheumatoid arthritis, psoriasis and Crohn's disease. By analysing MS GWAS data in conjunction with the 1000 Genomes Project data we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF-blocking drugs can promote onset or exacerbation of MS, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF-blocking drugs. Hence, our study demonstrates that clinical practice can be informed by comparing GWAS across common autoimmune diseases and by investigating the functional consequences of the disease-associated genetic variation.

Subarachnoid haemorrhage in undiagnosed secondary hypertension: back to basics.

Aortic coarctation (AC) is a significant cause of secondary hypertension and is diagnosed in childhood in the vast majority of patients. Mild or moderate coarctation may exist undetected into adult life, when it usually presents due to its sequelae. The authors present the case of a 20-year-old woman, previously extensively investigated for severe hypertension, who was admitted following sever, sudden-onset headache. CT scanning of the head showed the presence of subarachnoid blood (SAH), with subsequent CT angiography revealing two intracerebral aneurysms as the source. On attempting to catheterise the femoral artery her pulses were noted to be weak and during passage of the catheter she was found to have significant AC. The aneurysms were duly treated with detachable coils and the clinical course with regard to the SAH was unremarkably safe for high-pressure headache.