TY  - JOUR
A1  - Postema, Merel C.
A1  - Hoogman, Martine
A1  - Ambrosino, Sara
A1  - Asherson, Philip
A1  - Banaschewski, Tobias
A1  - Bandeira, Cibele E.
A1  - Baranov, Alexandr
A1  - Bau, Claiton H.D.
A1  - Baumeister, Sarah
A1  - Baur‐Streubel, Ramona
A1  - Bellgrove, Mark A.
A1  - Biederman, Joseph
A1  - Bralten, Janita
A1  - Brandeis, Daniel
A1  - Brem, Silvia
A1  - Buitelaar, Jan K.
A1  - Busatto, Geraldo F.
A1  - Castellanos, Francisco X.
A1  - Cercignani, Mara
A1  - Chaim‐Avancini, Tiffany M.
A1  - Chantiluke, Kaylita C.
A1  - Christakou, Anastasia
A1  - Coghill, David
A1  - Conzelmann, Annette
A1  - Cubillo, Ana I.
A1  - Cupertino, Renata B.
A1  - de Zeeuw, Patrick
A1  - Doyle, Alysa E.
A1  - Durston, Sarah
A1  - Earl, Eric A.
A1  - Epstein, Jeffery N.
A1  - Ethofer, Thomas
A1  - Fair, Damien A.
A1  - Fallgatter, Andreas J.
A1  - Faraone, Stephen V.
A1  - Frodl, Thomas
A1  - Gabel, Matt C.
A1  - Gogberashvili, Tinatin
A1  - Grevet, Eugenio H.
A1  - Haavik, Jan
A1  - Harrison, Neil A.
A1  - Hartman, Catharina A.
A1  - Heslenfeld, Dirk J.
A1  - Hoekstra, Pieter J.
A1  - Hohmann, Sarah
A1  - Høvik, Marie F.
A1  - Jernigan, Terry L.
A1  - Kardatzki, Bernd
A1  - Karkashadze, Georgii
A1  - Kelly, Clare
A1  - Kohls, Gregor
A1  - Konrad, Kerstin
A1  - Kuntsi, Jonna
A1  - Lazaro, Luisa
A1  - Lera‐Miguel, Sara
A1  - Lesch, Klaus‐Peter
A1  - Louza, Mario R.
A1  - Lundervold, Astri J.
A1  - Malpas, Charles B
A1  - Mattos, Paulo
A1  - McCarthy, Hazel
A1  - Namazova‐Baranova, Leyla
A1  - Nicolau, Rosa
A1  - Nigg, Joel T.
A1  - Novotny, Stephanie E.
A1  - Oberwelland Weiss, Eileen
A1  - O'Gorman Tuura, Ruth L.
A1  - Oosterlaan, Jaap
A1  - Oranje, Bob
A1  - Paloyelis, Yannis
A1  - Pauli, Paul
A1  - Picon, Felipe A.
A1  - Plessen, Kerstin J.
A1  - Ramos‐Quiroga, J. Antoni
A1  - Reif, Andreas
A1  - Reneman, Liesbeth
A1  - Rosa, Pedro G.P.
A1  - Rubia, Katya
A1  - Schrantee, Anouk
A1  - Schweren, Lizanne J.S.
A1  - Seitz, Jochen
A1  - Shaw, Philip
A1  - Silk, Tim J.
A1  - Skokauskas, Norbert
A1  - Soliva Vila, Juan C.
A1  - Stevens, Michael C.
A1  - Sudre, Gustavo
A1  - Tamm, Leanne
A1  - Tovar‐Moll, Fernanda
A1  - van Erp, Theo G.M.
A1  - Vance, Alasdair
A1  - Vilarroya, Oscar
A1  - Vives‐Gilabert, Yolanda
A1  - von Polier, Georg G.
A1  - Walitza, Susanne
A1  - Yoncheva, Yuliya N.
A1  - Zanetti, Marcus V.
A1  - Ziegler, Georg C.
A1  - Glahn, David C.
A1  - Jahanshad, Neda
A1  - Medland, Sarah E.
A1  - Thompson, Paul M.
A1  - Fisher, Simon E.
A1  - Franke, Barbara
A1  - Francks, Clyde
T1  - Analysis of structural brain asymmetries in attention‐deficit/hyperactivity disorder in 39 datasets
JF  - Journal of Child Psychology and Psychiatry
N2  - Objective
Some studies have suggested alterations of structural brain asymmetry in attention‐deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left‐right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium.

Methods
We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries.

Results
There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen’s d from −0.18 to 0.18) and would not survive study‐wide correction for multiple testing.

Conclusion
Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.
KW  - attention‐deficit
KW  - hyperactivity disorder
KW  - brain asymmetry
KW  - brain laterality
KW  - structural MRI
KW  - large‐scale data
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239968
VL  - 62
IS  - 10
SP  - 1202
EP  - 1219
ER  - 
TY  - JOUR
A1  - Sadovnick, A. Dessa
A1  - Traboulsee, Anthony L.
A1  - Bernales, Cecily Q.
A1  - Ross, Jay P.
A1  - Forwell, Amanda L.
A1  - Yee, Irene M.
A1  - Guillot-Noel, Lena
A1  - Fontaine, Bertrand
A1  - Cournu-Rebeix, Isabelle
A1  - Alcina, Antonio
A1  - Fedetz, Maria
A1  - Izquierdo, Guillermo
A1  - Matesanz, Fuencisla
A1  - Hilven, Kelly
A1  - Dubois, Bénédicte
A1  - Goris, An
A1  - Astobiza, Ianire
A1  - Alloza, Iraide
A1  - Antigüedad, Alfredo
A1  - Vandenbroeck, Koen
A1  - Akkad, Denis A.
A1  - Aktas, Orhan
A1  - Blaschke, Paul
A1  - Buttmann, Mathias
A1  - Chan, Andrew
A1  - Epplen, Joerg T.
A1  - Gerdes, Lisa-Ann
A1  - Kroner, Antje
A1  - Kubisch, Christian
A1  - Kümpfel, Tania
A1  - Lohse, Peter
A1  - Rieckmann, Peter
A1  - Zettl, Uwe K.
A1  - Zipp, Frauke
A1  - Bertram, Lars
A1  - Lill, Christina M.
A1  - Fernandez, Oscar
A1  - Urbaneja, Patricia
A1  - Leyva, Laura
A1  - Alvarez-Cermeño, Jose Carlos
A1  - Arroyo, Rafael
A1  - Garagorri, Aroa M.
A1  - García-Martínez, Angel
A1  - Villar, Luisa M.
A1  - Urcelay, Elena
A1  - Malhotra, Sunny
A1  - Montalban, Xavier
A1  - Comabella, Manuel
A1  - Berger, Thomas
A1  - Fazekas, Franz
A1  - Reindl, Markus
A1  - Schmied, Mascha C.
A1  - Zimprich, Alexander
A1  - Vilariño-Güell, Carles
T1  - Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients
JF  - G3: Genes Genomes Genetics
N2  - Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93–1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.
KW  - multiple sclerosis
KW  - genetics
KW  - linkage
KW  - association
KW  - plasminogen
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165405
VL  - 6
IS  - 7
ER  - 
TY  - THES
A1  - Paul, Luisa
T1  - Charakterisierung von Individuen mit heterozygoter IGHD-Variante hinsichtlich B-Zell Differenzierung, Immunglobulin-Repertoire Entwicklung und Entstehung eines Antikörpermangels
T1  - Characterization of individuals with heterozygous IGHD variant regarding B cell differentiation, immunoglobulin repertoire development and development of an antibody deficiency
N2  - Die Expression eines funktionsfähigen BZR ist essentiell für die Entwicklung und Differenzierung von B-Zellen, für deren Toleranzinduktion und Sekretion protektiver Antikörper. 

Genetisch bedingte Defekte im BZR-Signaltransduktionsweg liegen den primären Immundefekten mit vorwiegendem Antikörpermangel („humoraler Immundefekt“) zu Grunde. Naive B-Zellen in der Peripherie exprimieren den BZR als zwei Isotypen (IgM und IgD), wohingegen unreife B-Zellen im Knochenmark nur IgM exprimieren. Die Bedeutung für diese differentielle IgM/IgD-Expression ist nicht bekannt. Es wird jedoch der Expression von IgD eine Rolle in der Generierung hochaffiner Antikörper und in der Regulation von B-Zell Toleranz zugeschrieben. 

In dieser Arbeit wurden die Familienmitglieder einer Indexpatientin klinisch, immunologisch und genetisch charakterisiert. Bei der Indexpatientin wurde ein Immundefekt im Sinne eines CVID diagnostiziert. Es zeigte sich eine auffällige Expression von IgD auf naiven B-Zellen, zudem konnte eine Variante in dem für IgD kodierenden IGHD-Gen nachgewiesen werden.
Es konnte keine Korrelation zwischen dem Auftreten des Immundefektes und der p.Pro6Leu IGHD-Variante nachgewiesen werden. Ebenso zeigte sich bei den Trägern der IGHD-Variante kein Hinweis auf eine Störung der B-Zell Differenzierung oder ein Defekt der spezifischen Antikörperproduktion. Somit scheint die untersuchte p.Pro6Leu IGHD-Variante nicht ursächlich für den klinischen und immunologischen Phänotyp der Indexpatientin zu sein. Inwieweit die Variante ein relatives Risiko für die Entwicklung eines CVID darstellt, kann aus der Untersuchung der Familie nicht beurteilt werden und müsste in einer größeren CVID-Kohorte evaluiert werden. 

Da aus Untersuchungen von transgenen/knock-out Mausmodellen eine Bedeutung von IgD für die Regulation der peripheren B-Zell Toleranz vermutet wird, nutzten wir in dieser Arbeit charakterisierte heterozygote Träger der IGHD-Variante als „genetisches Modell“ zur Analyse der Bedeutung von IgD für die Entwicklung des Immunglobulin-Repertoires naiver B-Zellen des Menschen. Die durch allelische Exklusion bedingte chimäre Situation der IgD-Expression naiver B-Zellen bei heterozygoten IGHD-Variantenträgern machte den direkten Vergleich zwischen IgD+ Wildtyp-Populationen und IgD- Mutante im gleichen Organismus möglich. 
In den Untersuchungen des Immunglobulin-Repertoires von transitionalen und reifen, naiven B-Zellen in diesen Individuen zeigten sich jedoch keine wegweisenden Unterschiede zwischen IgD+ und IgD- Populationen. Insbesondere auch charakteristische Motive des Immunglobulin-Repertoires, die auf eine Autoreaktivität des kodierten Immunglobulins hin¬weisen (VH4-34 Gensegment, lange CDR3-Region, positive Ladung und Hydrophobizität der CDR3-Region) waren nicht unterschiedlich zwischen beiden Zellpopulationen. 

Somit scheint entweder die Expression von IgD auf naiven B-Zellen beim Menschen keinen Einfluss auf die Immunglobulin-Repertoire Entwicklung und die Regulation der Toleranzinduktion zu haben oder die verwendete Methodik ist nicht sensitiv genug, um mögliche Auffälligkeiten zu detektieren. 
Hier würde sich für zukünftige Untersuchungen des Immunglobulin-Repertoires eine Hochdurchsatzsequenzierung mittels next-generation sequencing und für die Analyse der Autoreaktivität die Expression und Reaktivitätstestung monoklonaler Antikörper aus individuellen B-Zellen anbieten.
N2  - The expression of a functional BZR is essential for the development and differentiation of B-cells, for their tolerance induction and secretion of protective antibodies.

Genetic defects in the BZR signal transduction pathway are based on the primary immunodeficiencies with predominant antibody deficiency ("humoral immune deficiency"). Naive B-cells in the periphery express the BZR as two isotypes (IgM and IgD), whereas immature B-cells express only IgM in the bone marrow. The significance for this differential IgM / IgD expression is unknown. However, the expression of IgD is thought to play a role in the generation of high affinity antibodies and in the regulation of B cell tolerance.

In this study, the family members of an index patient were characterized clinically, immunologically and genetically. The index patient was diagnosed with an immunodeficiency in the sense of a CVID. There was a conspicuous expression of IgD on naive B-cells as well as a variant in the IGHD gene coding for IgD.

There was no correlation between the occurrence of the immunodeficiency and the p.Pro6Leu IGHD variant. Similary, the carriers of the IGHD Variant showed no evidence of a disturbance of the B-cell differentiation or a defect in the specific antibody production. Thus, the investigated p.Pro6Leu IGHD variant does not seem to be causative for the clinical and immunological phenotype of the index patient. The extent to which the variant poses a relative risk for the development of a CVID can not be assessed from the family examination and would have to be evaluated in a larger CVID cohort.

Since investigations of transgenic / knock-out mouse models suggest an interpretation of IgD for the regulation of peripheral B-cell tolerance, we used heterozygous carriers of the IGHD variant characterized in this work as a "genetic model" to analyze the significance of IgD for the development of the immunoglobulin repertoire of naive human B-cells. The chimeric situation of IgD expression of naive B-cells in heterozygous IGHD variant carriers caused by allelic exclusion made a direct comparison possible between IgD + wild-type populations and IgD mutants in the same organism.
However, studies of the immunoglobulin repertoire of transitional and mature, naive B cells in these individuals, did not reveal any landmark differences between IgD + and IgD populations were found. In particular, characteristic motifs of the immunoglobulin repertoire indicating autoreactivity of the encoded immunoglobulin (VH4-34 gene segment, long CDR3 region, positive charge and hydrophobicity of the CDR3 region) were not different between the two cell populations.

Thus, either the expression of IgD on naive B-cells in humans does not seem to have any effect on the immunoglobulin repertoire development and the regulation of tolerance induction or the methodology used is not sensitive enough to detect possible abnormalities.
For future investigations of the immunoglobulin repertoire a high-throughput sequencing by next-generation sequencing and for the analysis of autoreactivity the expression and reactivity testing of monoclonal antibodies from individual B-cells would be appropriate.
KW  - Immundefekt
KW  - Durchflusscytometrie
KW  - Immunglobulin D
KW  - IGHD-Variante
KW  - B-Zell Differenzierung
KW  - Immunglobulin-Repertoire
KW  - CVID
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-185210
ER  - 
TY  - JOUR
A1  - Dirks, Johannes
A1  - Andres, Oliver
A1  - Paul, Luisa
A1  - Manukjan, Georgi
A1  - Schulze, Harald
A1  - Morbach, Henner
T1  - IgD shapes the pre-immune naïve B cell compartment in humans
JF  - Frontiers in Immunology
N2  - B cell maturation and immunoglobulin (Ig) repertoire selection are governed by expression of a functional B cell receptor (BCR). Naïve B cells co-express their BCR as IgM and IgD isotype. However, the role of the additionally expressed IgD on naïve B cells is not known. Here we assessed the impact of IgD on naïve B cell maturation and Ig repertoire selection in 8 individuals from 3 different families with heterozygous loss-of-function or loss-of expression mutations in IGHD. Although naïve B cells from these individuals expressed IgM on their surface, the IGHD variant in heterozygous state entailed a chimeric situation by allelic exclusion with almost half of the naïve B cell population lacking surface IgD expression. Flow cytometric analyses revealed a distinct phenotype of IgD-negative naïve B cells with decreased expression of CD19, CD20 and CD21 as well as lower BAFF-R and integrin-β7 expression. IgD-negative B cells were less responsive in vitro after engaging the IgM-BCR, TLR7/9 or CD40 pathway. Additionally, a selective disadvantage of IgD-negative B cells within the T2 transitional and mature naïve B cell compartment as well as reduced frequencies of IgMlo/- B cells within the mature naïve B cell compartment lacking IgD were evident. RNA-Ig-seq of bulk sorted B cell populations showed an altered selection of distinct VH segments in the IgD-negative mature naïve B cell population. We conclude that IgD expression on human naïve B cells is redundant for generation of naïve B cells in general, but further shapes the naive B cell compartment starting from T2 transitional B cells. Our observations suggest an unexpected role of IgD expression to be critical for selection of distinct Ig VH segments into the pre-immune Ig repertoire and for the survival of IgMlo/- naïve B cells known to be enriched in poly-/autoreactive B cell clones.
KW  - B cell
KW  - IgD
KW  - IgM
KW  - immunoglobulin repertoire
KW  - B cell maturation
KW  - B cell receptor
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304758
VL  - 14
ER  -