Neuromyelitis optica spectrum disorders. Comparison according to the phenotype and serostatus

Objective: To (1) determine the value of the recently proposed criteria of neuromyelitis optica (NMO) spectrum disorder (NMOSD) that unify patients with NMO and those with limited forms (NMO/LF) with aquaporin-4 immunoglobulin G (AQP4-IgG) antibodies; and (2) investigate the clinical significance of the serologic status in patients with NMO. Methods: This was a retrospective, multicenter study of 181 patients fulfilling the 2006 NMO criteria (n = 127) or NMO/LF criteria with AQP4-IgG (n = 54). AQP4-IgG and myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) antibodies were tested using cell-based assays. Results: Patients were mainly white (86%) and female (ratio 6.5:1) with median age at onset 39 years (range 10-77). Compared to patients with NMO and AQP4-IgG (n = 94), those with NMO/LF presentedmore often with longitudinally extensive transverse myelitis (LETM) (p<0.001), and had lower relapse rates (p = 0.015), but similar disability outcomes. Nonwhite ethnicity and optic neuritis presentation doubled the risk for developing NMO compared with white race (p = 0.008) or LETM presentation (p = 0.008). Nonwhite race (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.4-13.6) and older age at onset were associated with worse outcome (for every 10-year increase, HR 1.7, 95% CI 1.3-2.2). Patients with NMO and MOG-IgG (n = 9) had lower female: male ratio (0.8:1) and better disability outcome than AQP4-IgG-seropositive or double-seronegative patients (p<0.001). Conclusions: In patients with AQP4-IgG, the similar outcomes regardless of the clinical phenotype support the unified term NMOSD; nonwhite ethnicity and older age at onset are associated with worse outcome. Double-seronegative and AQP4-IgG-seropositive NMO have a similar clinical outcome. The better prognosis of patients with MOG-IgG and NMO suggests that phenotypic and serologic classification is useful

San Sebastián, 1952

Dibujo de un hombre mirando al mar, para ilustrar un texto de Alfredo R. AntigüedadPublicaciones: Signatura MH-42/6 correspondiente a la caja y sobre de la Colección Mundo Hispánico‎Título tomado de la revistaPublicado en Mundo Hispánico, n. 52 (año 1952, julio), p. 26Dibujo a tinta negra sobre papelIndicación de datos para publicación a lápì

Fine mapping and functional analysis of the multiple sclerosis risk gene CD6.

Journal Article;CD6 has recently been identified and validated as risk gene for multiple sclerosis (MS), based on the association of a single nucleotide polymorphism (SNP), rs17824933, located in intron 1. CD6 is a cell surface scavenger receptor involved in T-cell activation and proliferation, as well as in thymocyte differentiation. In this study, we performed a haptag SNP screen of the CD6 gene locus using a total of thirteen tagging SNPs, of which three were non-synonymous SNPs, and replicated the recently reported GWAS SNP rs650258 in a Spanish-Basque collection of 814 controls and 823 cases. Validation of the six most strongly associated SNPs was performed in an independent collection of 2265 MS patients and 2600 healthy controls. We identified association of haplotypes composed of two non-synonymous SNPs [rs11230563 (R225W) and rs2074225 (A257V)] in the 2(nd) SRCR domain with susceptibility to MS (P max(T) permutation = 1×10(-4)). The effect of these haplotypes on CD6 surface expression and cytokine secretion was also tested. The analysis showed significantly different CD6 expression patterns in the distinct cell subsets, i.e. - CD4(+) naïve cells, P = 0.0001; CD8(+) naïve cells, P<0.0001; CD4(+) and CD8(+) central memory cells, P = 0.01 and 0.05, respectively; and natural killer T (NKT) cells, P = 0.02; with the protective haplotype (RA) showing higher expression of CD6. However, no significant changes were observed in natural killer (NK) cells, effector memory and terminally differentiated effector memory T cells. Our findings reveal that this new MS-associated CD6 risk haplotype significantly modifies expression of CD6 on CD4(+) and CD8(+) T cells.This work was supported from the European Community’s Seventh Framework Programme [FP7/2007–2013] under grant agreement no. 212877 (UEPHA*MS; www.reem.es/uepha-ms/) and from the Gobierno Vasco (Grupos de Investigación del Sistema Universitario Vasco; ref. IT512-10). UEPHA*MS (No 2121877). Ministerio de Ciencia e Innovación - FEDER (SAF2009-11491) and FIS_FEDER (CP10/00526), Junta de Andalucía-FEDER (P07-CVI-02551).Ye

Clinical characteristics of the MS patients included in the genetic study.

<p><i>Abbreviations</i>: RR = Relapsing-remitting, SP = Secondary progressive, PP = Primary progressive, PR = Primary relapsing, S.D. = Standard deviation.</p

Association analysis of 14 <i>CD6</i> SNPs in the northern Spanish-Basque dataset.

(1)<p>Power was calculated with an OR = 1.34 based on the original OR for rs17824933 in the Spanish-Basque dataset <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062376#pone.0062376-Swaminathan1" target="_blank">[18]</a> using the CEU frequencies (NCBI) for each SNP.</p>(2)<p>The risk alleles are underlined.</p>(3)<p>Values represented in terms of the risk allele.</p>(4)<p>Genotyping success rates were above 95% for all the SNPs typed.</p>(5)<p>rs650258 was included based on the association observed in a recent genome–wide screen in MS <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062376#pone.0062376-IMSGC3" target="_blank">[17]</a>.</p

CD6 expression on different cell types segregated by non-synonymous CD6 haplotypes, as analyzed by FACS.

<p>A total of 27 PBMC samples representing each of the three haplotypes from the two non-synonymous SNPs rs11230563 and rs2074225 were analysed for CD6 expression on the different cell subsets. The y-axis represents the median fluorescence intensity (MFI) while the x-axis represents the three different haplotypes; i.e. the CC haplotype that confers protection, CT associated with risk and TT conferring mild risk. The distinct subpopulations were identified using different surface markers as listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062376#pone.0062376.s009" target="_blank">Table S4</a>. The markers CD3 and CD56 were used to identify T cells (CD4+/CD8+ CD3⁺ CD56⁻), NK (CD3⁻ CD56⁺), and NKT (CD3⁺ CD56⁺) cell subsets; CD45RA, CD27 and CD28 were used to distinguish naïve (CD45RA⁺ CD27⁺ CD28⁺), central memory cells (CD45RA⁻ CD27⁺) and effector memory cells (CD45RA⁻ CD27⁻ CD28⁺), as well as the terminally differentiated effector memory cells (TEMRA, CD45RA⁺ CD27⁻ CD28⁻); while CD56 and CD16 were used to identify the NK CD56dim (CD56^int CD16⁺) and the CD56bright (CD56^hi CD16) cells.</p

LD values (<i>D</i>’/<i>r²</i> values) between each of the 14 SNP markers genotyped in the Spanish-Basque population.

<p>The figure represents a comparison of the LD values between the 14 SNPs genotyped in the northern Spanish-Basque population (<i>D</i>’/<i>r²</i> values) using the values from the CEU 1000 genomes project and from the data generated from the Spanish-Basque population (823 cases/814 controls). The values in white are the <i>D’</i>/<i>r²</i> values from the CEU 1000 Genomes Project, while the blue-shaded ones are generated for the northern Spanish-Basque dataset using Haploview software (version 4.2).</p

Locations of the 14 Stage 1 SNPs and their linkage disequilibrium (LD) patterns at the <i>CD6</i> locus.

<p>(A) LD block images with the approximate locations of the 14 SNP markers chosen for this study, recombination spots and LD patterns within the CEU LD plot (Hapmap, version 27) of the <i>CD6</i> gene, and (B) LD patterns in the northern Spanish-Basque population using the confidence interval method (Gabriel et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062376#pone.0062376-Gabriel1" target="_blank">[54]</a>; generated using the Haploview software).</p