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HLA-B*53:64 differs from HLA-B*53:01:01:01 by one nucleotide substitution at position 1617 in exon 4.

HLA-C*03:04:94 differs from HLA-C*03:04:01:01 by one nucleotide substitution at position 737 in exon 4.

HLA-C*06:317 differs from HLA-C*06:02:01:01 by one nucleotide substitution at position 921 in exon 3.

HLA-C*07:1001N differs from HLA-C*07:01:01:01 by a deletion of 17 nucleotides in exon 1.

HLA-C*05:255 differs from HLA-C*05:01:01:02 by one nucleotide substitution at position 2013 in exon 5.

IntroductionAnti-glomerular basement membrane (GBM) antibodies are pathogenic antibodies first detected in renal-limited anti-GBM disease and in Goodpasture disease, the latter characterized by rapidly progressive crescentic glomerulonephritis combined with intra-alveolar hemorrhage. Studies have suggested that anti-GBM antibody positivity may be of interest in lupus nephritis (LN). Moreover, severe anti-GBM vasculitis cases in patients with systemic lupus erythematosus (SLE) have been described in the literature, but few studies have assessed the incidence of anti-GBM antibodies in SLE patients.ObjectiveThe main study objective was to determine if positive anti-GBM antibodies were present in the serum of SLE patients with or withoutproliferativerenal damage and compared to a healthy control group.MethodologyThis retrospective study was performed on SLE patients’ sera from a Franco-German European biobank, developed between 2011 and 2014, from 17 hospital centers in the Haut-Rhin region. Patients were selected according to their renal involvement, and matched by age and gender. The serum from healthy voluntary blood donors was also tested. Anti-GBM were screened by fluorescence enzyme immunoassay (FEIA), and then by indirect immunofluorescence (IIF) in case of low reactivity detection (titer >6 U/ml).ResultsThe cohort was composed of 100 SLE patients withproliferativeLN (27% with class III, 67% with class IV, and 6% with class V), compared to 100 SLE patients without LN and 100 controls. Patients were mostly Caucasian and met the ACR 1997 criteria and/or the SLICC 2012 criteria. Among the 300 tested sera, no significant levels of anti-GBM antibodies were detected (>10 U/ml) by the automated technique, three sera were found “ambivalent” (>7 U/ml): one in the SLE with LN group and two in the SLE without LN group. Subsequent IIF assays did not detect anti-GBM antibodies.ConclusionAnti-GBM antibodies were not detected in the serum of Caucasian patients with SLE, even in case of renal involvement, a situation favoring the antigenic exposure of glomerular basement membranes. Our results reaffirm the central role of anti-GBM antibodies as a specific diagnostic biomarker for Goodpasture vasculitis and therefore confirm that anti-GBM antibody must not be carried out in patients with SLE (with or without LN) in the absence of disease-suggestive symptoms.

Introduction Les patients presentant un deficit immunitaire humoral primitif (DIHP) ont un risque accru d’infection potentiellement grave a pneumocoque. La prevention de telles infections est essentielle. Cependant, le defaut de reponse vaccinale fait partie du tableau des DIHP, notamment avec les vaccins polysaccharidiques. Les societes savantes francaises et europeennes recommandent ainsi la vaccination par le vaccin antipneumococcique conjugue 13-valent (PCV13) puis par le vaccin polysaccharidique 23-valent (PPV23), malgre l’absence de donnees sur l’immunogenicite du vaccin conjugue chez ces patients. Les objectifs de ce travail etaient donc d’etablir la reponse a un mois apres vaccination par PCV13 et le maintien de la protection a un, six et douze mois chez des patients adultes suivis pour DIHP, ainsi que de determiner les facteurs associes au maintien de la protection vaccinale. Patients et methodes Les patients etaient vaccines a l’inclusion avec le vaccin conjugue 13-valent (Prevenar13®; Pfizer). Les concentrations seriques des IgG diriges contre les serotypes 4, 6B, 7F, 9 V, 14, 18 C, 19F, et 23F etaient mesurees par ELISA. La reponse vaccinale etait evaluee un mois apres vaccination et consideree comme atteinte si les concentrations d’IgG diriges contre au moins 5 serotypes testes etaient au moins doublees par rapport a l’inclusion. La protection etait egalement evaluee a l’inclusion puis a un, six et douze mois apres vaccination et considerees comme obtenue si les concentrations d’IgG contre au moins 5 serotypes testes etaient ≥ 1 μg/mL. L’activite d’opsonophagocytose des anticorps diriges contre les serotypes 4, 6B, 9 V, 14, 18 C, 19F, et 23F etaient egalement evaluee, par MOPA. De la meme facon, la reponse vaccinale a un mois etait obtenue si les titres d’opsonophagocytose pour les anticorps contre au moins 5 serotypes testes etaient au moins quadruples. La protection etait consideree comme atteinte si les titres d’opsonophagocytose des anticorps diriges contre au moins 5 serotypes etaient superieurs aux limites basses de quantification. Resultats Vingt-neuf patients ont ete inclus, d’âge moyen 44,4 ± 15,7 ans. Vingt-et-un (72,4 %) etaient des femmes. Quinze patients avaient un Deficit Immun Commun Variable (DICV) et quatorze un deficit en sous-classes d’IgG ; 79,3 % des patients avaient une supplementation par immunoglobulines polyvalentes. En considerant les concentrations seriques d’IgG diriges contre les serotypes vaccinaux, la moitie des patients etaient consideres comme proteges a l’inclusion. A un mois, 35,7 % des patients avaient repondus au vaccin et 71,4 % etaient consideres comme proteges. Cette protection etait maintenue a 6 mois (66,7 %) mais diminuee a un an (56,0 %). A l’inverse, en considerant l’activite d’opsonophagocytose de ces anticorps, seulement 3,4 % des patients etaient proteges a l’inclusion et 10,7 % presentaient une reponse vaccinale a un mois. Toutefois, la protection etait nettement amelioree a un, six et douze mois (28,6 %, 48,2 % and 33,3 %). Les facteurs associes au maintien de la protection a 1, 6 et 12 mois (definie par les concentrations d’IgG) etaient des concentrations seriques initiales d’IgG1 plus elevees (3,56 ± 0,70 g/L vs 2,58 ± 1,03 g/L, p = 0,02), le deficit en sous-classe d’IgG ainsi que l’immunosubstitution, et des concentrations seriques initiales d’IgG2 plus elevees (1,30 ±0,71 g/L vs 0,63 ± 0,53 g/L, p = 0,04), respectivement. Discussion La proportion elevee de patients proteges a l’inclusion est probablement liee a la presence d’anticorps anti-pneumococcique dans les IgIV/SC, expliquant peut-etre la discordance avec leur faible capacite d’opsonophagocytose. Cette disparite entre concentration serique d’Ig et capacite d’opsonophagocytose n’etait pas observee chez d’autres patients immunodeprimes (myelome indolent) [1] , laissant suggerer une diversite ou avidite des anticorps produits chez les DIHP diminuees (defaut des GC ?). Bien que le taux de reponse vaccinale dans cette population ne soit pas tres eleve, la vaccination avec le PCV13 semble apporter une protection durable, bien que diminuee a 1 an, et semble augmenter les capacites d’opsonophagocytose des anticorps ainsi obtenus. La diminution de l aprotection a 1 an est egalement observee chez les sujets sains [2] et chez les patients avec myelome indolent [1] et n’est donc pas specifique des DIHP. Enfin, il est interessant de noter qu’une concentration serique d’IgG2 plus elevee etait egalement associee a une protection vaccinale plus longue dans une population de patients lupiques [3] . Les IgG2 sont connus pour jouer un role important dans la reponse anti-pneumococcique, la vaccination par PCV13 permettant peut-etre la mobilisation de cellules B memoire specifiques pre-existantes. Conclusion Ce travail confirme l’interet de la vaccination par PCV13 dans une population de patients DIHP. L’interet d’une strategie Prime-Boost avec un vaccin PPV23 doit encore etre evaluee.

Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease of the skin. Investigation of the BP-associated pathophysiological processes during the last decades showed that the generation of autoantibodies directed against the hemidesmosome proteins BP180 and BP230, a hallmark of the BP-associated autoimmune response, leads to the recruitment of inflammatory immune cells at the dermal-epidermal junction, and subsequently to the release of a large amount of inflammatory molecules involved in blister formation. Analysis in transversal and longitudinal studies of autoantibodies and inflammatory molecules production both at the time of diagnosis and under treatment was mainly performed within the serum but also in the blister fluid. Some autoimmune or inflammatory molecules expression was related to the presence of clinical signs, while others were mere bystanders. In this review, we focused on the autoimmune and inflammatory molecules that have been identified as potential biomarkers of BP development and outcome.

Introduction La sclerodermie systemique (ScS) est une connectivite rare caracterisee par une forte heterogeneite. La plupart des patients presentent des lesions de microangiopathie, de fibrose cutanee et viscerale, et des auto-anticorps. Pour des raisons inconnues, certains patients vont developper une extension de la fibrose cutanee plus importante ainsi que des atteintes d’organes pouvant menacer le pronostic vital comme les pneumopathies interstitielles diffuses (PID) ou encore l’hypertension arterielle pulmonaire (HTAP). Actuellement la physiopathologie exacte de la ScS est encore debattue mais l’implication du stress oxydatif semble importante, a la croisee des dysfonctions endotheliales, fibroblastiques et immunitaires caracterisant cette maladie. Recemment, une nouvelle forme d’activation des polynucleaires neutrophiles (PNN) dependante du stress oxydatif, appelee NETose (NET pour neutrophil extracellular traps) a ete decrite. Dans cette etude, nous emettons l’hypothese que ce phenomene pourrait etre present dans la ScS, a l’instar d’autres maladies auto-immunes comme le lupus, et qu’il pourrait egalement etre different selon le phenotype de ScS (cutane, complications viscerales et profile immunologique), refletant ainsi la forte heterogeneite de cette maladie. Materiels et methodes Les PNN de 35 patients ScS et de 26 donneurs de sang (en tant que controle) ont ete isoles et stimules de facon autologue. Les NETs etaient visualises via un microscope a epifluorescence apres marquage de l’ADN (via Sytox orange et Hoechst 33342), de la myeloperoxydase et de l’histone citrulline H3. Les donnees de chaque patient concernant la duree d’evolution de la maladie, le phenotype cutane, les complications viscerales et le type d’auto-anticorps etaient recueillis. L’aire et le nombre de NETs etaient quantifies via un programme original du logiciel Image J®. Resultats Les PNN de ScS etaient significativement plus preactives que ceux des controles a generer des NETs qu’ils soient stimules par du serum de patient ou meme par du serum de controle. Au sein des ScS, il n’existait pas de difference selon le phenotype cutane (diffus ou limite) ou selon le type d’auto-anticorps. En revanche, les PNN de patients atteints de complications vasculaires produisaient plus de NETs que ceux de patients sans complication viscerale mais egalement ceux avec complications fibrosantes. De plus, ce phenomene etait important chez les patients recemment diagnostiques et avait tendance a s’estomper dans le temps chez les patients atteints de complications fibrosantes. Conclusion Les PNN de patients ScS peuvent generer une importante quantite de NETose avec une forte heterogeneite. Ce phenomene est particulierement associe aux complications vasculaires, ainsi qu’aux formes precoces de ScS, suggerant un role potentiel de la NETose dans la physiopathologie encore incompletement elucidee de cette maladie.

Background An autopsy case of a two-month-old male infant who suddenly and unexpectedly died during his sleep, eight days after the onset of benign varicella. Objectives To describe post-mortem combined histological and tissue molecular biological techniques for the diagnosis of cytomegalovirus and varicella zoster virus co-infection as a cause of death. Study design Real-time quantitative PCR and RT-PCR assays for Herpesviruses, respiratory viruses, Adenovirus, Enterovirus and Parvovirus B19 were performed on multi-organ frozen samples and paraffin-embedded tissues in combination with histology. Results Cytomegalovirus and varicella zoster virus were detected by molecular biology with highest viral loads detected in the lungs (4.6 × 10 7 and 1.9 × 10 5 genome copies per million of cells, respectively). Pulmonary extensive necrotizing inflammation and immunohistochemistry correlated to virological data. Virological molecular biology was negative on paraffin-embedded tissues. Conclusions This case shows that thorough quantitative virological investigations on frozen tissues must be performed in combination with histology and immunohistochemistry for the determination of the cause of a sudden unexplained infant death.

Checkpoint inhibitor (CPI) blockade is considered to be a revolution in cancer therapy, although most patients (70%–80%) remain resistant to this therapy. It has been hypothesized that only tumors with high mutation rates generate a natural antitumor T cell response, which could be revigorated by this therapy. In patients with no pre-existing antitumor T cells, a vaccine-induced T cell response is a rational option to counteract clinical resistance. This hypothesis has been validated in preclinical models using various cancer vaccines combined with inhibitory pathway blockade (PD-1-PDL1-2, CTLA-4-CD80-CD86). Enhanced T cell infiltration of various tumors has been demonstrated following this combination therapy. The timing of this combination appears to be critical to the success of this therapy and multiple combinations of immunomodulating antibodies (CPI antagonists or costimulatory pathway agonists) have reinforced the synergy with cancer vaccines. Only limited results are available in humans and this combined approach has yet to be validated. Comprehensive monitoring of the regulation of CPI and costimulatory molecules after administration of immunomodulatory antibodies (anti-PD1/PD-L1, anti-CTLA-4, anti-OX40, etc.) and cancer vaccines should help to guide the selection of the best combination and timing of this therapy.

Algorithms for celiac disease diagnosis provided by guidelines are based primarily on anti-tissue transglutaminase 2 (TG2) antibodies and/or anti-endomysium antibodies. The place of anti-deamidated gliadin peptide (DGP) antibodies is less well established. This study was designed to assess the clinical relevance of anti-DGP antibodies. Two thousand and twenty-six consecutive unselected patients systematically tested for anti-TG2, endomysium, gliadin, DGP antibodies and IgA dosage were investigated. The serological interpretation was assessed by analyzing the medical records of patients. From the 1984 newly investigated patients suspected of celiac disease, 10% had at least one celiac marker. Anti-TG2, anti-endomysium, anti-gliadin and anti-DGP antibodies were found in 1.1%, 0.6%, 6.8% and 4.1% of cases respectively, with different combinations. The diagnosis of celiac disease was retained in 0.45% of patients. When using the duodenal biopsies as a gold standard, analysis of the anti-DGP diagnosis performance showed that the specificity and the predictive positive value (PPV) were lower than that of the anti-TG2 assay. The combined detection of anti-TG2 and anti-DGP antibodies had a lower PPV than that of anti-TG2 and anti-endomysium antibodies (p = 0.04). When analyzing the contribution of anti-DGP antibodies as an additional marker to both anti-TG2 and anti-endomysium antibodies, the PPV of the three associated antibodies was shown to be significantly lower than the PPV of the both anti-TG2 and anti-endomysium antibodies (p = 0.04). As a conclusion, anti-DGP antibodies may not have the diagnosis value required as an additional screening test to anti-TG2 antibodies for identifying celiac disease patients in medical centers where anti-endomysium detection is available.

Introduction La pemphigoide bulleuse (PB) est une maladie auto-immune caracterisee par la fixation d’auto-anticorps anti-BP180 et anti-BP230 sur les hemidesmosomes des keratinocytes. Les formes atypiques comprennent souvent des atteintes muqueuses, evocatrices d’une epidermolyse bulleuse acquise (EBA), dermatose bulleuse auto-immune caracterisee par la presence d’auto-anticorps anti-collagene 7 (col7). Dans cette etude, nous avons recherche si la detection d’anticorps anti-col7 etait utile pour exclure une EBA au moment du diagnostic ou lors d’une de rechute eventuelle de PB. Patients et methodes Les anticorps anti-BP180, -BP230 et -col7 etaient recherches par Elisa dans 71 serums de PB consecutives presentant les criteres de diagnostic cliniques et immunopathologiques usuels (Vaillant et al., 1998), au moment du diagnostic et dans 24 serums de patients lors d’une rechute. Resultats L’âge moyen des patients PB avec atteinte muqueuse (PB-M) etait plus bas que celui des patients sans atteinte muqueuse (PB-ssM) (75 ± 12 ans vs 82 ± 7 ans, p Discussion Dans la PB, la presence d’une atteinte muqueuse apparait davantage comme un marqueur clinique de la severite et de l’activite de la maladie, plutot que d’une forme atypique de PB. Au diagnostic, la recherche d’anticorps anti-col7 ne permet pas de depister precocement une EBA si les criteres cliniques de PB sont presents. En revanche, l’apparition secondaire d’anticorps anti-col7 chez des malades presentant une rechute de PB pourrait temoigner d’un phenomene « d’epitope spreading » chez des malades ayant deja au diagnostic des anticorps anti-PB180 ou anti-PB230 detectables. Conclusion La recherche d’anticorps anti-col7 n’est pas utile au moment du diagnostic dans la PB. Leur apparition tardive est rare et liee a la persistance de l’activite de la maladie, et non a une transformation secondaire en EBA.

Measles is a highly contagious viral infection causing congenital infections with a risk of neurological complications in the newborn. Two cases of measles, which occurred in pregnant women within 14 days before the delivery, are described. Mother-to-child transmission of the virus was documented in the newborns either by RT-PCR in saliva or by IgM detection in blood. The measles strains evidenced in saliva samples were genotyped and belonged to the D4 Genotype. An early viral RT-PCR detection allowed successful immunoglobulin prophylaxis in one newborn taking into account that the duration between the onset of the skin rash in the mother and the delivery was less than 6 days. Twenty-four months later, none of the newborns developed classical or neurological clinical signs of measles infection. Measles RT-PCR assay in salivary samples can be used before symptoms develop in the infant to confirm early mother-to-child transmission, therefore permitting the use of an immunoglobulin prophylaxis in the newborn. J. Med. Virol. 85:2136–2138, 2013. © 2013 Wiley Periodicals, Inc.

Introduction Dans la pemphigoide bulleuse (PB), le decollement dermo-epidermique se developpe de facon preponderante sur des lesions erythemateuses et/ou urticariennes. Les eosinophiles sont majoritairement presents au niveau des lesions et l’eosinophilie a ete correlee a l’activite et a l’etendue de la maladie, mais sans signification pronostique reconnue a ce jour. Apres activation, les eosinophiles relarguent des granules secondaires contenant des proteines cationiques comme la major basic protein (MBP), l’eosinophil derived neurotoxin (EDN) et l’eosinophil cationic protein (ECP). Des travaux precedents ont montre la presence de ces proteines inflammatoires dans le serum des malades atteints de PB sans definir leur relation avec la maladie. Materiel et methodes Soixante et un malades avec PB etaient inclus dans une etude prospective, observationnelle, multicentrique avec une etude ancillaire des variations des proteines MBP, EDN et ECP entre le diagnostic et apres 2 mois de traitement. L’analyse etait realisee en fonction de la survenue de recidives durant la 1re annee de suivi. Au moment du diagnostic, des correlations etaient aussi recherchees entre les concentrations seriques et des liquides de bulles. Resultats Les concentrations seriques de MBP, EDN et ECP etaient significativement elevees au diagnostic chez les malades PB versus des temoins sains (n = 20) apparies en sexe et en âge. Les concentrations d’EDN et d’ECP etaient encore plus elevees dans le liquide de bulle (respectivement p Conclusion Notre etude confirme le role important des eosinophiles dans le processus inflammatoire lie a la PB et met en evidence des profils de concentrations seriques et tissulaires specifiques pour chacune de ces trois proteines cationiques. Ces profils suggerent que ces proteines pourraient etre secretees a des phases distinctes de la maladie ou impliquees dans differents processus pathophysiologiques associes a la PB. De plus, l’etude des variations des concentrations seriques de l’ECP presente un interet clinique majeur puisque qu’elle permet d’identifier les malades a risque de rechute dans la 1re annee de traitement.

Measles is a highly contagious viral infection causing congenital infections with a risk of neurological complications in the newborn. Two cases of measles, which occurred in pregnant women within 14 days before the delivery, are described. Mother-to-child transmission of the virus was documented in the newborns either by RT-PCR in saliva or by IgM detection in blood. The measles strains evidenced in saliva samples were genotyped and belonged to the D4 Genotype. An early viral RT-PCR detection allowed successful immunoglobulin prophylaxis in one newborn taking into account that the duration between the onset of the skin rash in the mother and the delivery was less than 6 days. Twenty-four months later, none of the newborns developed classical or neurological clinical signs of measles infection. Measles RT-PCR assay in salivary samples can be used before symptoms develop in the infant to confirm early mother-to-child transmission, therefore permitting the use of an immunoglobulin prophylaxis in the newborn.