Publications by authors named "Ryad Tamouza"

112 Publications

Chemoinformatic Analysis of Psychotropic and Antihistaminic Drugs in the Light of Experimental Anti-SARS-CoV-2 Activities.

Adv Appl Bioinform Chem 2021 12;14:71-85. Epub 2021 Apr 12.

INSERM U1138, Centre de Recherche des Cordeliers, Université de Paris, Paris, 75006, France.

Introduction: There is an urgent need to identify therapies that prevent SARS-CoV-2 infection and improve the outcome of COVID-19 patients.

Objective: Based upon clinical observations, we proposed that some psychotropic and antihistaminic drugs could protect psychiatric patients from SARS-CoV-2 infection. This observation is investigated in the light of experimental in vitro data on SARS-CoV-2.

Methods: SARS-CoV-2 high-throughput screening results are available at the NCATS COVID-19 portal. We investigated the in vitro anti-viral activity of many psychotropic and antihistaminic drugs using chemoinformatics approaches.

Results And Discussion: We analyze our clinical observations in the light of SARS-CoV-2 experimental screening results and propose that several cationic amphiphilic psychotropic and antihistaminic drugs could protect people from SARS-CoV-2 infection; some of these molecules have very limited adverse effects and could be used as prophylactic drugs. Other cationic amphiphilic drugs used in other disease areas are also highlighted. Recent analyses of patient electronic health records reported by several research groups indicate that some of these molecules could be of interest at different stages of the disease progression. In addition, recently reported drug combination studies further suggest that it might be valuable to associate several cationic amphiphilic drugs. Taken together, these observations underline the need for clinical trials to fully evaluate the potentials of these molecules, some fitting in the so-called category of broad-spectrum antiviral agents. Repositioning orally available drugs that have moderate side effects and should act on molecular mechanisms less prone to drug resistance would indeed be of utmost importance to deal with COVID-19.
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http://dx.doi.org/10.2147/AABC.S304649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051956PMC
April 2021

Clinical and Prognostic Value of Immunogenetic Characteristics in Anti-LGI1 Encephalitis.

Neurol Neuroimmunol Neuroinflamm 2021 05 5;8(3). Epub 2021 Mar 5.

From the French Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., L.T., A.V., A.-L.P., G.P., C.B., L.-D.D., B.J., V.R., J. Honnorat), Hospices Civils de Lyon, Hôpital Neurologique, Bron, France; SynatAc Team (S.M.-C., L.T., A.V., A.-L.P., G.P., C.B., L.-D.D., B.J., V.R., J. Honnorat), Institut NeuroMyoGène, INSERM U1217/CNRS UMR 5310, Université de Lyon, Université Claude Bernard Lyon 1, France; Clinic Research and Epidemiology Department (J. Haesebaert), Hospices Civils de Lyon, Lyon, France, HESPER Team, EA 7425, Medicine School, Université Claude Bernard Lyon 1, France; Neurology Department 2-Mazarin (G.B., D.P., A. Alentorn), Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, APHP; Brain and Spinal Cord Institute (G.B., D.P., A. Alentorn), INSERM U1127/CNRS UMR 7255, Université Pierre-et-Marie-Curie, Universités Sorbonnes, Paris, France; HLA Laboratory (V.D.), French Blood Service, EFS Auvergne-Rhône-Alpes, Lyon, France; Stanford University Center for Sleep Sciences and Medicine (A. Ambati, E.M.), Palo Alto, CA; and Department of Psychiatry (R.T.), Hôpitaux Universitaires Henri Mondor, Créteil, France, Mondor Institute for Biomedical Research, INSERM U955, Université de Paris-Est-Créteil, France.

Objective: Antibodies against leucine-rich glioma-inactivated 1 (LGI1-Abs) characterize a limbic encephalitis (LE) strongly associated with HLA-DRB1*07:01, although some patients lack LGI1-Abs in CSF or do not carry this allele. Whether they represent a different subtype of disease or have different prognoses is unclear.

Methods: Retrospective analysis of clinical features, IgG isotypes, and outcome according to LGI1-Ab CSF positivity and DRB1*07:01 in a cohort of anti-LGI1 LE patients.

Results: Patients with LGI1-Abs detected in both CSF and serum (105/134, 78%) were compared with those who were CSF negative (29/134, 22%). Both groups had similar clinical features and serum levels, but CSF-positive patients had shorter diagnostic delay, more frequently hyponatremia, inflammatory CSF, and abnormal MRI ( < 0.05). Human leukocyte antigen (HLA) genotyping was performed in 72/134 (54%) patients and 63/72 (88%) carried DRB1*07:01. Noncarriers (9/72, 12%) were younger, more commonly women, and had less frequently psychiatric and frontal symptoms ( < 0.05). No difference in IgG isotypes according to CSF positivity or HLA was found ( > 0.05). HLA and IgG isotypes were not associated with poor outcome (mRS >2 at last follow-up) in univariate analyses; CSF positivity was only identified as a poor outcome predictor in the multivariate analysis including the complete follow-up, whereas age and female sex also remained when just the first year was considered.

Conclusions: LE without CSF LGI1-Abs is clinically indistinguishable and likely reflects just a lesser LGI1-Ab production. HLA association is sex and age biased and presents clinical particularities, suggesting subtle differences in the immune response. Long-term outcome depends mostly on demographic characteristics and the intensity of the intrathecal synthesis.
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http://dx.doi.org/10.1212/NXI.0000000000000974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938443PMC
May 2021

Elevated expression of complement C4 in the mouse prefrontal cortex causes schizophrenia-associated phenotypes.

Mol Psychiatry 2021 Apr 9. Epub 2021 Apr 9.

INSERM UMR-S 1270, Paris, France.

Accumulating evidence supports immune involvement in the pathogenesis of schizophrenia, a severe psychiatric disorder. In particular, high expression variants of C4, a gene of the innate immune complement system, were shown to confer susceptibility to schizophrenia. However, how elevated C4 expression may impact brain circuits remains largely unknown. We used in utero electroporation to overexpress C4 in the mouse prefrontal cortex. We found reduced glutamatergic input to pyramidal cells of juvenile and adult, but not of newborn C4-overexpressing (C4-OE) mice, together with decreased spine density, which mirrors spine loss observed in the schizophrenic cortex. Using time-lapse two-photon imaging in vivo, we observed that these deficits were associated with decreased dendritic spine gain and elimination in juvenile C4-OE mice, which may reflect poor formation and/or stabilization of immature spines. In juvenile and adult C4-OE mice, we found evidence for NMDA receptor hypofunction, another schizophrenia-associated phenotype, and synaptic accumulation of calcium-permeable AMPA receptors. Alterations in cortical GABAergic networks have been repeatedly associated with schizophrenia. We found that functional GABAergic transmission was reduced in C4-OE mice, in line with diminished GABA release probability from parvalbumin interneurons, lower GAD67 expression, and decreased intrinsic excitability in parvalbumin interneurons. These cellular abnormalities were associated with working memory impairment. Our results substantiate the causal relationship between an immunogenetic risk factor and several distinct cortical endophenotypes of schizophrenia and shed light on the underlying cellular mechanisms.
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http://dx.doi.org/10.1038/s41380-021-01081-6DOI Listing
April 2021

DNA hydrolysing IgG catalytic antibodies: an emerging link between psychoses and autoimmunity.

NPJ Schizophr 2021 Feb 26;7(1):13. Epub 2021 Feb 26.

Centre for BioSeparation Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India.

It is not uncommon to observe autoimmune comorbidities in a significant subset of patients with psychotic disorders, namely schizophrenia (SCZ) and bipolar disorder (BPD). To understand the autoimmune basis, the DNA abyzme activity mediated by serum polyclonal IgG Abs were examined in psychoses patients, quantitatively, by an in-house optimized DNase assay. A similar activity exhibited by IgG Abs from neuropsychiatric-systemic lupus erythematosus (NP-SLE) patients was used as a comparator. Our data revealed that the IgG DNase activity of SCZ was close to that of NP-SLE and it was twofold higher than the healthy controls. Interestingly, the association between DNase activity with PANSS (positive, general and total scores) and MADRS were noted in a subgroup of SCZ and BPD patients, respectively. In our study group, the levels of IL-6 and total IgG in BPD patients were higher than SCZ and healthy controls, indicating a relatively inflammatory nature in BPD, while autoimmune comorbidity was mainly observed in SCZ patients.
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http://dx.doi.org/10.1038/s41537-021-00143-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910540PMC
February 2021

Severe mental illness and European COVID-19 vaccination strategies.

Lancet Psychiatry 2021 05 17;8(5):356-359. Epub 2021 Feb 17.

IMRB Translational Neuropsychiatry Lab, Université Paris Est Creteil, Creteil, France; Department of Psychiatry and Addictology, Hôpitaux Universitaires Henri Mondor, Créteil, France; Fondation FondaMental, Creteil, France.

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http://dx.doi.org/10.1016/S2215-0366(21)00046-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906735PMC
May 2021

Viewpoint | European COVID-19 exit strategy for people with severe mental disorders: Too little, but not yet too late.

Brain Behav Immun 2021 05 23;94:15-17. Epub 2021 Jan 23.

Translational Neuropsychiatry Lab, Université Paris Est Creteil (UPEC), INSERM U955, IMRB, F-94010 Creteil, France; Département Medico-Universitaire de Psychiatrie et d'Addictologie (DMU ADAPT), AP-HP, Hopital Henri Mondor, F-94010 Creteil, France; Fondation FondaMental, Creteil, France. Electronic address:

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http://dx.doi.org/10.1016/j.bbi.2021.01.008DOI Listing
May 2021

Natural killer cells in first-episode psychosis: an innate immune signature?

Mol Psychiatry 2021 Jan 17. Epub 2021 Jan 17.

Sorbonne Université, Inserm U1135, CNRS ERL 8255, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), F-75013, Paris, France.

Accumulating evidence majorly implicates immune dysfunction in the etiology of psychotic disorders. In particular, altered numbers and functions of natural killer (NK) cells have been described in psychosis, but interpretation has often been confounded by a number of biases, including treatment. Eighty-one first-episode psychosis (FEP) patients who subsequently received a diagnosis of either schizophrenia (SZ; n = 30) or bipolar disorder (BP; n = 31) over a five-year follow-up period were investigated for their NK cell phenotype and compared to 61 healthy controls (HCs). We found a similar proportion of CD3CD56 NK cells in FEP patients and HCs. The frequency of NK cells expressing the late cell activation marker HLA-DR was significantly increased in FEP patients compared to HCs, especially in patients with BP (p < 0.0001) and, to a lesser degree, in patients with SZ (p = 0.0128). Interestingly, the expression of the activating NKG2C receptor, known to be associated with infections, was higher in patients with SZ and BP than in HCs (p < 0.0001) and correlated with HLA-DR expression, altogether defining adaptive NK cells. In terms of NK cell function, we observed a suppressed capacity of SZ-derived NK cells to mount cytotoxic responses in the presence of target cells, while NK cells from patients with BP show an inability to produce IFN-γ, a cytokine pivotal to NK function. This study strongly suggests major dysfunction of NK cells in FEP with functioning impairment correlated with psychotic, manic, and depressive symptoms in subsequently diagnosed patients with SZ and BP.
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http://dx.doi.org/10.1038/s41380-020-01008-7DOI Listing
January 2021

Brain-immune crosstalk in the treatment of major depressive disorder.

Eur Neuropsychopharmacol 2021 Apr 29;45:89-107. Epub 2020 Dec 29.

Département Medico-Universitaire de Psychiatrie et d'Addictologie (DMU ADAPT), Laboratoire Neuro-psychiatrie translationnelle, AP-HP, Université Paris Est Créteil, INSERM U955, IMRB, Hôpital Henri Mondor, Fondation FondaMental, F-94010 Créteil, France.

A growing number of studies are pointing out the need for a conceptual shift from a brain-centered to a body-inclusive approach in mental health research. In this perspective, the link between the immune and the nervous system, which are deeply interconnected and continuously interacting, is one of the most important novel theoretical framework to investigate the biological bases of major depressive disorder and, more in general, mental illness. Indeed, depressed patients show high levels of inflammatory markers, administration of pro-inflammatory drugs triggers a depressive symptomatology and antidepressant efficacy is reduced by excessive immune system activation. A number of molecular and cellular mechanisms have been hypothesized to act as a link between the immune and brain function, thus representing potential pharmacologically targetable processes for the development of novel and effective therapeutic strategies. These include the modulation of the kynurenine pathway, the crosstalk between metabolic and inflammatory processes, the imbalance in acquired immune responses, in particular T cell responses, and the interplay between neural plasticity and immune system activation. In the personalized medicine approach, the assessment and regulation of these processes have the potential to lead, respectively, to novel diagnostic approaches for the prediction of treatment outcome according to the patient's immunological profile, and to improved efficacy of antidepressant compounds through immune modulation.
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http://dx.doi.org/10.1016/j.euroneuro.2020.11.016DOI Listing
April 2021

Disruption of Conscious Access in Psychosis Is Associated with Altered Structural Brain Connectivity.

J Neurosci 2021 01 23;41(3):513-523. Epub 2020 Nov 23.

Université Paris Saclay, CEA, Neurospin, F-91191, Gif-sur-Yvette, France

According to global neuronal workspace (GNW) theory, conscious access relies on long-distance cerebral connectivity to allow a global neuronal ignition coding for conscious content. In patients with schizophrenia and bipolar disorder, both alterations in cerebral connectivity and an increased threshold for conscious perception have been reported. The implications of abnormal structural connectivity for disrupted conscious access and the relationship between these two deficits and psychopathology remain unclear. The aim of this study was to determine the extent to which structural connectivity is correlated with consciousness threshold, particularly in psychosis. We used a visual masking paradigm to measure consciousness threshold, and diffusion MRI tractography to assess structural connectivity in 97 humans of either sex with varying degrees of psychosis: healthy control subjects ( = 46), schizophrenia patients ( = 25), and bipolar disorder patients with ( = 17) and without ( = 9) a history of psychosis. Patients with psychosis (schizophrenia and bipolar disorder with psychotic features) had an elevated masking threshold compared with control subjects and bipolar disorder patients without psychotic features. Masking threshold correlated negatively with the mean general fractional anisotropy of white matter tracts exclusively within the GNW network (inferior frontal-occipital fasciculus, cingulum, and corpus callosum). Mediation analysis demonstrated that alterations in long-distance connectivity were associated with an increased masking threshold, which in turn was linked to psychotic symptoms. Our findings support the hypothesis that long-distance structural connectivity within the GNW plays a crucial role in conscious access, and that conscious access may mediate the association between impaired structural connectivity and psychosis.
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http://dx.doi.org/10.1523/JNEUROSCI.0945-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821858PMC
January 2021

Use of the HLA-B leader to optimize cord-blood transplantation.

Haematologica 2020 10 29;Online ahead of print. Epub 2020 Oct 29.

Eurocord, Hôpital Saint Louis APHP, Institut de Recherche de Saint-Louis (IRSL) EA3518, Université de Paris, Paris, France; Monacord, International Observatory on Sickle Cell Disease, Centre Scientifique de Monaco.

Cord-blood transplantation (CBT) can cure life-threatening blood disorders. The HLA-B leader affects the success of unrelated donor transplantation but its role in CBT is unknown. We tested the hypothesis that the HLA-B leader influences CBT outcomes in unrelated single-unit cord-blood transplants performed by Eurocord/European Blood and Marrow Transplant (EBMT) centers between 1990 and 2018 with data reported to Eurocord. Among 4822 transplants, 2178 had one HLA-B mismatch of which 1013 were HLA-A and HLA-DRB1-matched. The leader (M or T) was determined for each HLA-B allele in patients and units to define the genotype. Among single HLA-B-mismatched transplants, the patient/unit mismatched alleles were defined as leader-matched if they encoded the same leader, or leader-mismatched if they encoded different leaders; the leader encoded by the matched (shared) allele was determined. The risks of GVHD, relapse, non-relapse mortality and overall mortality were estimated for various leaderdefined groups using multivariable regression models. Among the 1013 HLA-A, -DRB1- matched transplants with one HLA-B mismatch, increasing numbers of cord-blood unit M-leader alleles was associated with increased risk of relapse (hazard ratio [HR] for each increase in one M-leader allele 1.30, 95% confidence interval [CI] 1.05 to 1.60, P 0.02). Furthermore, leader mismatching together with an M-leader of the shared HLA-B allele lowered non-relapse mortality (HR 0.44, 95% CI 0.23 to 0.81; P 0.009) relative to leader-matching and a shared T-leader allele. The HLA-B leader may inform relapse and non-relapse mortality risk after CBT. Future patients might benefit from the appropriate selection of units that consider the leader.
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http://dx.doi.org/10.3324/haematol.2020.264424DOI Listing
October 2020

High-Sensitive c-Reactive Protein Levels in Euthymic Bipolar Patients: Case-Control Study.

Psychiatr Q 2021 Jun 22;92(2):803-811. Epub 2020 Oct 22.

Faculty of Medicine of Tunis, El Manar University, Tunis, Tunisia.

Bipolar disorder is a chronic, disabling disease that is characterized by the recurrence of thymic episodes. The role of the immune-inflammatory system in the etiopathogenesis of this affection arouses the interest of research. The aim of this work was to determine the plasma levels of the high sensitivity C reactive protein (hs-CRP) in patients with bipolar disorder in remission phase by comparing them to a control group.A case-control cross-sectional study was conducted from 56 subjects with bipolar disorder in clinical remission, and 56 volunteers and healthy control subjects.Mean plasma hs-CRP was significantly higher in patients with bipolar disorder than control subjects. In bipolar patients, a hs-CRP elevation was significantly associated with the disease severity item mean score.Through this study, bipolar disorder appears to be associated with a state of chronic inflammation. This should lead to randomized controlled trials evaluating the value of anti-inflammatory drugs in the management of bipolar disorder.
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http://dx.doi.org/10.1007/s11126-020-09854-yDOI Listing
June 2021

Understanding the genetic contribution of the human leukocyte antigen system to common major psychiatric disorders in a world pandemic context.

Brain Behav Immun 2021 01 5;91:731-739. Epub 2020 Oct 5.

Université Paris Est Créteil, INSERM U955, IMRB, Laboratoire Neuro-Psychiatrie Translationnelle, F-94010 Creteil, France; AP-HP, Hopital Henri Mondor, Département Medico-Universitaire de Psychiatrie et d'Addictologie (DMU ADAPT), F-94010, France; Fondation FondaMental, Créteil, France.

The human leukocyte antigen (HLA) is a complex genetic system that encodes proteins which predominantly regulate immune/inflammatory processes. It can be involved in a variety of immuno-inflammatory disorders ranging from infections to autoimmunity and cancers. The HLA system is also suggested to be involved in neurodevelopment and neuroplasticity, especially through microglia regulation and synaptic pruning. Consequently, this highly polymorphic gene region has recently emerged as a major player in the etiology of several major psychiatric disorders, such as schizophrenia, autism spectrum disorder and bipolar disorder and with less evidence for major depressive disorders and attention deficit hyperactivity disorder. We thus review here the role of HLA genes in particular subgroups of psychiatric disorders and foresee their potential implication in future research. In particular, given the prominent role that the HLA system plays in the regulation of viral infection, this review is particularly timely in the context of the Covid-19 pandemic.
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http://dx.doi.org/10.1016/j.bbi.2020.09.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534661PMC
January 2021

Polymorphisms in Inflammatory Genes Modulate Clinical Complications in Patients With Sickle Cell Disease.

Front Immunol 2020 4;11:2041. Epub 2020 Sep 4.

INSERM U955, CHU Henri Mondor, Créteil, France.

Sickle cell disease (SCD), the most common monogenic disease worldwide, is marked by a phenotypic variability that is, to date, only partially understood. Because inflammation plays a major role in SCD pathophysiology, we hypothesized that single nucleotide polymorphisms (SNP) in genes encoding functionally important inflammatory proteins might modulate the occurrence of SCD complications. We assessed the association between 20 SNPs in genes encoding Toll-like receptors (TLR), NK cell receptors (NKG), histocompatibility leukocyte antigens (HLA), major histocompatibility complex class I polypeptide-related sequence A (MICA) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and the occurrence of six SCD clinical complications (stroke, acute chest syndrome (ACS), leg ulcers, cholelithiasis, osteonecrosis, or retinopathy). This study was performed in a cohort of 500 patients. We found that the 4696480 3804099 , and HLA-G, 9380142 genotypes were more frequent in patients who had fewer complications. Also, in logistic regression, the HLA-G 9380142 allele increased the risk of cholelithiasis ( vs. , OR 1.57, 95%CI 1.16-2.15; vs. , OR 2.47, 95%CI 1.34-4.64; = 0.02). For SNPs located in the loci, in logistic regression, the A allele in three SNPs was associated with a lower frequency of retinopathy, namely, 2246809 ( vs. : OR 0.22, 95%CI 0.09-0.50; vs. : OR 0.47, 95%CI 0.31-0.71; = 0.004, for patients of same origin), 2617160 ( vs. : OR 0.67, 95%CI 0.48-0.92; vs. : OR 0.45, 95%CI 0.23-0.84; = 0.04), and 2617169 ( vs. : OR 0.33, 95%CI 0.13-0.82; vs. : OR 0.58, 95%CI 0.36-0.91, = 0.049, in patients of same SCD genotype). These results, by uncovering susceptibility to, or protection against SCD complications, might contribute to a better understanding of the inflammatory pathways involved in SCD manifestations and to pave the way for the discovery of biomarkers that predict disease severity, which would improve SCD management.
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http://dx.doi.org/10.3389/fimmu.2020.02041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510050PMC
April 2021

Overexpression of complement component C4 in the dorsolateral prefrontal cortex, parietal cortex, superior temporal gyrus and associative striatum of patients with schizophrenia.

Brain Behav Immun 2020 11 19;90:216-225. Epub 2020 Aug 19.

Fondation FondaMental, Créteil, France; Department of Psychiatry and Addictology, Mondor University Hospital, AP-HP, DMU IMPACT, France; University Paris-Est-Créteil, UPEC, Créteil, France; Inserm U955, Mondor Institute for Biomedical Research, IMRB, Translational Neuropsychiatry Team, Créteil, France.

Background: In schizophrenia, abnormal synaptic pruning during adolescence may be due to altered expression of the Complement component 4 (C4). Overexpression of C4 genes has been identified in the total cerebral cortex and in 6 different brain regions of schizophrenic patients compared to controls. These alterations should be replicated and extended to other brain regions relevant to schizophrenia. Moreover, it remains unknown whether cerebral and peripheral C4 expression levels are related.

Methods: We explored C4 genes expression both at the cerebral and peripheral levels. Using shinyGEO application we analyzed C4 expression from eight Gene Expression Omnibus datasets obtained from 196 schizophrenic patients and 182 control subjects. First, we compared C4 expression between schizophrenic patients and controls in postmortem cerebral samples from 7 different brain regions. Then, we compared C4 expression between schizophrenic patients and controls in 4 peripheral tissues.

Results: At the cerebral level, we provide further evidence of C4 overexpression in schizophrenic patients. Consistently with a previous report, we found C4 overexpression in the dorsolateral prefrontal cortex and in the parietal cortex of schizophrenic patients. The observation of C4 overexpression was further extended to the superior temporal cortex and the associative striatum of schizophrenic patients. Conversely, no significant alteration of C4 expression was observed in peripheral tissues.

Conclusions: Our results support the hypothesis of an excessive Complement activity in various brain regions of schizophrenic patients which may disrupt the synaptic pruning process occurring during adolescence. C4 overexpression may be specific to the cerebral tissue while other alterations of the Complement system may be detected at the systemic level.
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http://dx.doi.org/10.1016/j.bbi.2020.08.019DOI Listing
November 2020

HLA-Matched Unrelated Donors for Patients with Sickle Cell Disease: Results of International Donor Searches.

Biol Blood Marrow Transplant 2020 11 23;26(11):2034-2039. Epub 2020 Jul 23.

Monacord, Centre Scientifique de Monaco, Principauté de Monaco, Monaco; Eurocord, Hôpital Saint Louis, Institut de recherche Saint Louis, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.

Sickle cell disease (SCD) is the most common inherited hemoglobinopathy. Hematopoietic stem cell transplantation (HCT) is the sole curative therapy for SCD, but few patients will have a matched sibling donor. Patients with SCD are mostly of African origin and thus are less likely to find a matched unrelated donor in international registries. Using HaploStats, we estimated HLA haplotypes for 185 patients with SCD (116 from a Brazilian center and 69 from European Society for Blood and Marrow Transplantation [EBMT] centers) and classified the ethnic origin of haplotypes. Then we assessed the probability of finding an HLA-matched unrelated adult donor (MUD), considering loci A, B, and DRB1 (6/6), in international registries. Most haplotypes were African, but Brazilians showed a greater ethnic admixture than EBMT patients. Nevertheless, the chance of finding at least one 6/6 potential allelic donor was 47% for both groups. Most potential allelic donors were from the US National Marrow Donor Program registry and from the Brazilian REDOME donor registry. Although the probability of finding a donor is higher than previously reported, strategies are needed to improve ethnic diversity in registries. Moreover, predicting the likelihood of having an MUD might influence SCD management.
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http://dx.doi.org/10.1016/j.bbmt.2020.07.015DOI Listing
November 2020

Anti-CASPR2 clinical phenotypes correlate with HLA and immunological features.

J Neurol Neurosurg Psychiatry 2020 10 10;91(10):1076-1084. Epub 2020 Jul 10.

French National Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hôpital Neurologique, Hospices Civils de Lyon, Bron, France

Objective: Antibodies against contactin-associated protein-like 2 (CASPR2-Abs) have been described in acquired neuromyotonia, limbic encephalitis (LE) and Morvan syndrome (MoS). However, it is unknown whether these constitute one sole spectrum of diseases with the same immunopathogenesis or three distinct entities with different mechanisms.

Methods: A cluster analysis of neurological symptoms was performed in a retrospective cohort of 56 CASPR2-Abs patients. In parallel, immunological features and human leucocyte antigen (HLA) were studied.

Results: Cluster analysis distinguished patients with predominant limbic symptoms (n=29/56) from those with peripheral nerve hyperexcitability (PNH; n=27/56). In the limbic-prominent group, limbic features were either isolated (LE/-; 18/56, 32.1%), or combined with extralimbic symptoms (LE/+; 11/56, 19.6%). Those with PNH were separated in one group with severe PNH and extralimbic involvement (PNH/+; 16/56, 28.6%), resembling historical MoS descriptions; and one group with milder and usually isolated PNH (PNH/-; 11/56, 19.6%). LE/- and LE/+ patients shared immunogenetic characteristics demonstrating a homogeneous entity. HLA-DRB1*11:01 was carried more frequently than in healthy controls only by patients with LE (94.1% vs 18.3%; p=1.3×10). Patients with LE also had serum titres (median 1:40 960) and rates of cerebrospinal fluid positivity (93.1%) higher than the other groups (p<0.05). Conversely, DRB1*11:01 association was absent in PNH/+ patients, but only they had malignant thymoma (87.5%), serum antibodies against leucine-rich glioma-inactivated 1 protein (66.7%) and against netrin-1 receptor deleted in colorectal carcinoma (53.8%), and myasthenia gravis (50.0%).

Interpretation: Symptoms' distribution supports specific clinical phenotypes without overlap between LE and MoS. The distinct immunogenetic characteristics shared by all patients with LE and the particular oncological and autoimmune associations of MoS suggest two very different aetiopathogenesis.
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http://dx.doi.org/10.1136/jnnp-2020-323226DOI Listing
October 2020

Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders.

Drug Discov Today 2020 08 25;25(8):1287-1290. Epub 2020 Jun 25.

Université Paris Est Créteil, INSERM U955, IMRB, Laboratoire Neuro-psychiatrie translationnelle, AP-HP, Département Medico-Universitaire de Psychiatrie et d'Addictologie (DMU ADAPT), Hôpital Henri Mondor, Fondation FondaMental, F-94010 Créteil, France. Electronic address:

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http://dx.doi.org/10.1016/j.drudis.2020.06.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315962PMC
August 2020

Precision psychiatry with immunological and cognitive biomarkers: a multi-domain prediction for the diagnosis of bipolar disorder or schizophrenia using machine learning.

Transl Psychiatry 2020 05 24;10(1):162. Epub 2020 May 24.

AP-HP, Université Paris Est Créteil, Department of Psychiatry and Addictology, Mondor University Hospital, DMU IMPACT, Translational Neuro-Psychiatry laboratory, INSERM U955, Créteil, France.

Precision psychiatry is attracting increasing attention lately as a recognized priority. One of the goals of precision psychiatry is to develop tools capable of aiding a clinically informed psychiatric diagnosis objectively. Cognitive, inflammatory and immunological factors are altered in both bipolar disorder (BD) and schizophrenia (SZ), however, most of these alterations do not respect diagnostic boundaries from a phenomenological perspective and possess great variability in different individuals with the same phenotypic diagnosis and, consequently, none so far has proven to have the ability of reliably aiding in the differential diagnosis of BD and SZ. We developed a probabilistic multi-domain data integration model consisting of immune and inflammatory biomarkers in peripheral blood and cognitive biomarkers using machine learning to predict diagnosis of BD and SZ. A total of 416 participants, being 323, 372, and 279 subjects for blood, cognition and combined biomarkers analysis, respectively. Our multi-domain model performances for the BD vs. control (sensitivity 80% and specificity 71%) and for the SZ vs. control (sensitivity 84% and specificity 81%) pairs were high in general, however, our multi-domain model had only moderate performance for the differential diagnosis of BD and SZ (sensitivity 71% and specificity 73%). In conclusion, our results show that the diagnosis of BD and of SZ, and that the differential diagnosis of BD and SZ can be predicted with possible clinical utility by a computational machine learning algorithm employing blood and cognitive biomarkers, and that their integration in a multi-domain outperforms algorithms based in only one domain. Independent studies are needed to validate these findings.
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http://dx.doi.org/10.1038/s41398-020-0836-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246255PMC
May 2020

Compatibility at amino acid position 98 of MICB reduces the incidence of graft-versus-host disease in conjunction with the CMV status.

Bone Marrow Transplant 2020 07 14;55(7):1367-1378. Epub 2020 Apr 14.

Department of Hematology and ErasmusMC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.

Graft-versus-host disease (GVHD) and cytomegalovirus (CMV)-related complications are leading causes of mortality after unrelated-donor hematopoietic cell transplantation (UD-HCT). The non-conventional MHC class I gene MICB, alike MICA, encodes a stress-induced polymorphic NKG2D ligand. However, unlike MICA, MICB interacts with the CMV-encoded UL16, which sequestrates MICB intracellularly, leading to immune evasion. Here, we retrospectively analyzed the impact of mismatches in MICB amino acid position 98 (MICB98), a key polymorphic residue involved in UL16 binding, in 943 UD-HCT pairs who were allele-matched at HLA-A, -B, -C, -DRB1, -DQB1 and MICA loci. HLA-DP typing was further available. MICB98 mismatches were significantly associated with an increased incidence of acute (grade II-IV: HR, 1.20; 95% CI, 1.15 to 1.24; P < 0.001; grade III-IV: HR, 2.28; 95% CI, 1.56 to 3.34; P < 0.001) and chronic GVHD (HR, 1.21; 95% CI, 1.10 to 1.33; P < 0.001). MICB98 matching significantly reduced the effect of CMV status on overall mortality from a hazard ratio of 1.77 to 1.16. MICB98 mismatches showed a GVHD-independent association with a higher incidence of CMV infection/reactivation (HR, 1.84; 95% CI, 1.34 to 2.51; P < 0.001). Hence selecting a MICB98-matched donor significantly reduces the GVHD incidence and lowers the impact of CMV status on overall survival.
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http://dx.doi.org/10.1038/s41409-020-0886-5DOI Listing
July 2020

MICA-129 Met/Val polymorphism could be a genetic biomarker for Familial Breast Cancer in the Tunisian population.

Int J Immunogenet 2020 Oct 11;47(5):406-413. Epub 2020 Feb 11.

INSERM U955, Translational Psychiatry, Creteil, France.

Identification of candidate genes associated with susceptibility of breast cancer can have a significant impact at a cancer management national healthcare systems level, making genetic testing more affordable and cost-effective. We have previously shown that the major histocompatibility complex class I-related chain A (MICA) was related to breast cancer and plays an important role in modulating immune response mechanisms through NKG2D receptor activation. Compared to our previous study, in this work, we recruited a new cohort composed of 354 unrelated Tunisian women affected by breast cancer and 380 age-matched women as controls, all genotyped for MICA-129 Met/Val (rs 1051792). Subsequently, we exanimated the distribution of this polymorphism in ten families. As a result, an association was found between the Val allele and Val/Val genotype and the risk of breast cancer (p = 2.5 × 10 ; OR = 2.40; p = 6.5 × 10 ; OR = 3.03, respectively). Stratified analysis with age and family history of cancer revealed an association between the Val/Val genotype and younger patients <40 years (p = .003; OR = 2.03). Among those patients having a family history of cancer, 68% had a Val/Val genotype (p = .02; OR = 1.82). In the family study, an analyse of pedigrees revealed that the majority of families showed the development of breast cancer at a young age. Moreover, all patients diagnosed with early-onset breast cancer had a Val/Val genotype. Our results lead us to propose that this polymorphism may be an inherited genetic biomarker contributing to an increased breast cancer risk in Tunisian women.
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http://dx.doi.org/10.1111/iji.12480DOI Listing
October 2020

Soluble MICA and anti-MICA Antibodies as Biomarkers of Nasopharyngeal Carcinoma Disease.

Immunol Invest 2020 Jul 9;49(5):498-509. Epub 2019 Dec 9.

INSERM, U955, Translational Psychiatry, Paris-East University , Creteil, France.

The MHC class I chain-related molecule A (MICA) is a ligand for the activating natural killer (NK) cell receptor NKG2D. A part from its genetic diversity, MICA is characterized by the presence of membrane-bound and soluble isoform (sMICA) and by the propensity to elicit antibody-mediated allogeneicity (MICA Abs). Altogether such properties are important in the cancer setting. Here, we investigated whether MICA polymorphism, serum level of sMICA and MICA antibodies (Abs) may influence nasopharyngeal carcinoma (NPC) risk. 274 NPC naïve of treatment patients and 275 healthy individuals, all originating from Tunisia were included and genotyped. Among them, 160 sera from patients and 51 from controls were analyzed for the sMICA level by ELISA and were tested for the presence of MICA Abs by Luminex assay. The statistical analysis showed that: (1) we extend and confer our previous finding concerning Val/Val association with risk of NPC ( = .02, OR = 1.56; 95%CI [1.12-2.11]). (2) The higher level of sMICA characterized patients advanced stage of the disease. (3) The 18 (78%) of patients having MICA Abs exhibit all a non-advanced stage of the tumor extension at presentation. MICA129 Met /Val, sMICA and MICA Abs could be potential biomarkers of prediction, the diverse staging of NPC and hence prognostic and treatment.
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http://dx.doi.org/10.1080/08820139.2019.1690506DOI Listing
July 2020

HLA Polymorphism in Regressive and Non-Regressive Autism: A Preliminary Study.

Autism Res 2020 02 8;13(2):182-186. Epub 2019 Oct 8.

Gillberg Neuropsychiatry Centre, Institute of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska Academy, Gothenburg, Sweden.

Autism spectrum disorders (ASD) comprises heterogeneous neurodevelopmental conditions with symptom onset usually during infancy. However, about 10%-30% of affected cases experience a loss of language and social skills around 18-30 months, so-called regressive autism. In this subset with regression, immune dysfunctions including inflammation and autoimmunity have been proposed to be at risk factors. Given the implication of the human histocompatibility antigens (HLA) system in various aspects of immune responses, including autoimmunity, and in ASD, we investigate here the distribution of the HLA Class I and Class II haplotypes in 131 children with ASD meeting DSM-IV TR criteria, with and without regression. We found that 62 of the 98 non-regressive ASD patients carry the HLA-DPA1*01-DPB1*04 sub-haplotype as compared to 14 of the 33 patients with regression (63% vs. 43% respectively, Pc = 0.02), suggesting that this HLA haplotype may exert a protective effect against regression. Similarly, the HLA-DPA1*01-DPB1*04 has also been found to be more represented in healthy controls as compared to patients affected with common nonpsychiatric autoimmune disorders. Overall our findings suggest a possible involvement of HLA polymorphism in the context of regressive ASD. Autism Res 2020, 13: 182-186. © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: Immune dysfunctions including inflammatory and autoimmune processes have been reported in autism, particularly in regressive forms. In this study, we analyzed the distribution of HLA haplotypes among children with autism spectrum disorder (ASD), with and without regression from Sweden and observed that HLA-DPA1*01-DPB1*04 sub-haplotype was less represented in patients with regressive autism as compared with those without regression. Such possible protective effect, also observed in other common autoimmune disorders, may constitute a link between HLA-mediated immune processes and regressive ASD.
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http://dx.doi.org/10.1002/aur.2217DOI Listing
February 2020

Human Autoantibodies Against N-Methyl-D-Aspartate Receptor Modestly Alter Dopamine D1 Receptor Surface Dynamics.

Front Psychiatry 2019 13;10:670. Epub 2019 Sep 13.

Université de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, Bordeaux, France.

Circulating autoantibodies directed against extracellular domains of the glutamatergic N-methyl-D-aspartate receptors (NMDAR-Ab) elicit psychotic symptoms in humans and behavioral deficits in animal models. Recent advances suggest that NMDAR-Ab exert their pathogenic action by altering the trafficking of NMDAR, which results in a synaptic NMDAR hypofunction consistent with the consensual glutamatergic hypothesis of psychotic disorders. Yet, dysfunction in the dopaminergic signaling is also proposed to be at the core of psychotic disorders. Since NMDAR and dopamine D1 receptors (D1R) form membrane signaling complexes, we investigated whether NMDAR-Ab purified from patients with NMDAR-encephalitis or schizophrenia impaired D1R surface dynamics. As previous data demonstrated that NMDAR-Ab, at least from NMDAR-encephalitis patients, mainly bind to hippocampal NMDAR, we used single nanoparticle imaging to track D1R specifically at the surface of hippocampal neurons that were exposed to either purified G type immunoglobulins (IgGs) from NMDAR-Ab seropositive patients suffering from NMDAR-encephalitis or schizophrenia, or control IgGs from healthy NMDAR-Ab seropositive or seronegative subjects. We report that overnight incubation with NMDAR-Ab from patients, but not from healthy carriers, decreased the surface dynamics of D1R compared with NMDAR-Ab seronegative IgGs. This decrease was abolished, and even reversed, in D1R mutant that cannot physically interact with NMDAR. Overall, our data indicate that NMDAR-Ab from patients with psychotic symptoms alter the trafficking of D1R, likely through the surface crosstalk between NMDAR and D1R.
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http://dx.doi.org/10.3389/fpsyt.2019.00670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754069PMC
September 2019

Obsessive-Compulsive Disorder: Autoimmunity and Neuroinflammation.

Curr Psychiatry Rep 2019 08 1;21(8):78. Epub 2019 Aug 1.

Inserm U955, Team 15, Genetic Psychiatry, 94000, Creteil, France.

Purpose Of Review: Here, we propose to review the immuno-inflammatory hypothesis in OCD given the concurrent incidence of autoimmune comorbidities, infectious stigma, and raised levels of inflammatory markers in a significant subset of patients. A better understanding of the immune dysfunction in OCD may allow stratifying the patients in order to design personalized pharmaco/psychotherapeutic strategies.

Recent Findings: A persistent low-grade inflammation involving both innate and adaptive immune system with coexisting autoimmune morbidities and stigma of infectious events has been prominently observed in OCD. Hence, specific treatments targeting inflammation/infection are a feasible alternative in OCD. This review highlights that OCD is associated with low-grade inflammation, neural antibodies, and neuro-inflammatory and auto-immune disorders. In some subset of OCD patients, autoimmunity is likely triggered by specific bacterial, viral, or parasitic agents with overlapping surface epitopes in CNS. Hence, subset-profiling in OCD is warranted to benefit from distinct immune-targeted treatment modalities.
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http://dx.doi.org/10.1007/s11920-019-1062-8DOI Listing
August 2019

Persistence of dysfunctional natural killer cells in adults with high-functioning autism spectrum disorders: stigma/consequence of unresolved early infectious events?

Mol Autism 2019 15;10:22. Epub 2019 May 15.

3Sorbonne Université, UPMC, INSERM U1135, CNRS ERL8255, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France.

Background: Autism spectrum disorders (ASD) are characterized by abnormal neurodevelopment, genetic, and environmental risk factors, as well as immune dysfunctions. Several lines of evidence suggest alterations in innate immune responses in children with ASD. To address this question in adults with high-functioning ASD (hf-ASD), we sought to investigate the role of natural killer (NK) cells in the persistence of ASD.

Methods: NK cells from 35 adults with hf-ASD were compared to that of 35 healthy controls (HC), selected for the absence of any immune dysfunctions, at different time-points, and over a 2-year follow-up period for four patients. The phenotype and polyfunctional capacities of NK cells were explored according to infectious stigma and clinical parameters (IQ, social, and communication scores).

Results: As compared to HC, NK cells from patients with hf-ASD showed a high level of cell activation ( < 0.0001), spontaneous degranulation ( < 0.0001), and interferon-gamma production ( = 0.0004), whereas they were exhausted after in vitro stimulations ( = 0.0006). These data yielded a specific HLA-DRKIR2DL1NKG2C NK-cell signature. Significant overexpression of NKG2C in hf-ASD patients ( = 0.0005), indicative of viral infections, was inversely correlated with the NKp46 receptor level ( = - 0.67;  < 0.0001), regardless of the IgG status of tested pathogens. Multivariate linear regression analysis also revealed that expression of the late-activating HLA-DR marker was both associated with structural language ( = 0.48;  = 0.007) and social awareness ( = 0.60;  = 0.0007) scores in adult patients with hf-ASD, while KIR2DL1 expression correlated with IQ scores ( = 0.0083).

Conclusions: This study demonstrates that adults with hf-ASD have specific NK-cell profile. Presence of NKG2C overexpression together with high-level activation of NK cells suggest an association with underlying pathogens, a hypothesis warranting further exploration in future studies.
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http://dx.doi.org/10.1186/s13229-019-0269-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521549PMC
June 2020

Immunoneuropsychiatry - novel perspectives on brain disorders.

Nat Rev Neurol 2019 06;15(6):317-328

Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

Immune processes have a vital role in CNS homeostasis, resilience and brain reserve. Our cognitive and social abilities rely on a highly sensitive and fine-tuned equilibrium of immune responses that involve both innate and adaptive immunity. Autoimmunity, chronic inflammation, infection and psychosocial stress can tip the scales towards disruption of higher-order networks. However, not only classical neuroinflammatory diseases, such as multiple sclerosis and autoimmune encephalitis, are caused by immune dysregulation that affects CNS function. Recent insight indicates that similar processes are involved in psychiatric diseases such as schizophrenia, autism spectrum disorder, bipolar disorder and depression. Pathways that are common to these disorders include microglial activation, pro-inflammatory cytokines, molecular mimicry, anti-neuronal autoantibodies, self-reactive T cells and disturbance of the blood-brain barrier. These discoveries challenge our traditional classification of neurological and psychiatric diseases. New clinical paths are required to identify subgroups of neuropsychiatric disorders that are phenotypically distinct but pathogenically related and to pave the way for mechanism-based immune treatments. Combined expertise from neurologists and psychiatrists will foster translation of these paths into clinical practice. The aim of this Review is to highlight outstanding findings that have transformed our understanding of neuropsychiatric diseases and to suggest new diagnostic and therapeutic criteria for the emerging field of immunoneuropsychiatry.
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http://dx.doi.org/10.1038/s41582-019-0174-4DOI Listing
June 2019

Increased and Decreased Superficial White Matter Structural Connectivity in Schizophrenia and Bipolar Disorder.

Schizophr Bull 2019 10;45(6):1367-1378

INSERM U955 Unit, Mondor Institute for Biomedical Research, Team 15 "Translational Psychiatry", Créteil, France.

Schizophrenia (SZ) and bipolar disorder (BD) are often conceptualized as "disconnection syndromes," with substantial evidence of abnormalities in deep white matter tracts, forming the substrates of long-range connectivity, seen in both disorders. However, the study of superficial white matter (SWM) U-shaped short-range tracts remained challenging until recently, although findings from postmortem studies suggest they are likely integral components of SZ and BD neuropathology. This diffusion weighted imaging (DWI) study aimed to investigate SWM microstructure in vivo in both SZ and BD for the first time. We performed whole brain tractography in 31 people with SZ, 32 people with BD and 54 controls using BrainVISA and Connectomist 2.0. Segmentation and labeling of SWM tracts were performed using a novel, comprehensive U-fiber atlas. Analysis of covariances yielded significant generalized fractional anisotropy (gFA) differences for 17 SWM bundles in frontal, parietal, and temporal cortices. Post hoc analyses showed gFA reductions in both patient groups as compared with controls in bundles connecting regions involved in language processing, mood regulation, working memory, and motor function (pars opercularis, insula, anterior cingulate, precentral gyrus). We also found increased gFA in SZ patients in areas overlapping the default mode network (inferior parietal, middle temporal, precuneus), supporting functional hyperconnectivity of this network evidenced in SZ. We thus illustrate that short U-fibers are vulnerable to the pathological processes in major psychiatric illnesses, encouraging improved understanding of their anatomy and function.
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http://dx.doi.org/10.1093/schbul/sbz015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811818PMC
October 2019

The Impact of 3'UTR Polymorphisms in Breast Cancer in a Tunisian Population.

Immunol Invest 2019 Jul 4;48(5):521-532. Epub 2019 Apr 4.

d INSERM, U955, Translational Psychiatry , Paris-East University , Creteil , France.

Human leukocyte antigens G and E (HLA-G and HLA-E) are nonclassical major histocompatibility complex (MHC) class I molecules. These molecules play an important role in immune surveillance by inhibiting natural killer and cytotoxic T cells responsible for immune escape. The expression of HLA-G and HLA-E has been associated with several diseases including tumor. The main objective of the study is to evaluate the impact of three 3'UTR potential polymorphisms: +3187 A > G (rs9380142), +3142 G > C (rs1063320), +2960 14-base pair (bp) Insertion/Deletion (Ins/Del) (rs66554220), and the HLA-E*01:01/01:03 A > G (rs1264457) polymorphism in Tunisian breast cancer population. A total of 355 patients and 381 controls were genotyping for and polymorphisms using a Taq Man assay. +3142  allele and +3142  genotype were significantly associated with increased risk of breast cancer (p = 0.00002; OR = 1.58; 95% CI = 27-1.97) (49% versus 35%; p = 0.0001; OR = 1.79; 95% CI = 1.32-2.44). In addition, allele and the homozygous state for genotype confer a risk for breast cancer (52% versus 45%, p = 0.006; OR = 1.33, 95% CI = 1.08-1.64) (28% versus 22%, p = 0.039; OR = 1.43, 95% CI = 0.90-2.25). However, no statistical significant differences were reported for  + 3187 A > G and variations and breast cancer in a Tunisian population. The found results indicate that HLA-G may play an important role in the breast cancer.
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http://dx.doi.org/10.1080/08820139.2019.1569043DOI Listing
July 2019

A Toll-like receptor 2 genetic variant modulates occurrence of bacterial infections in patients with sickle cell disease.

Br J Haematol 2019 06 25;185(5):918-924. Epub 2019 Mar 25.

INSERM U955, Centre Hospitalier Universitaire Henri Mondor, Créteil, France.

Despite adequate immunization and penicillin prophylaxis, bacterial infections remain a leading cause of morbidity and mortality in patients with sickle cell disease (SCD). Besides hyposplenism, inflammatory and genetic factors might modulate their susceptibility to bacterial infections. We performed a candidate gene association of single nucleotide polymorphisms (SNPs) located in Toll-like receptor (TLR) genes, encoding prominent molecules for innate immune responses, with the occurrence of bacterial infections in patients with SCD. A cohort followed in centres in Brazil, France and Senegal (n = 430) was divided in two groups: patients who presented at least one episode of bacterial infection (n = 235) and patients who never had bacterial infections (n = 195). There were no differences in gender or age distribution among the groups. The frequency of the TLR2 rs4696480 TA genotype was significantly lower in the infected group (50% vs. 67%, odds ratio [OR] = 0·50, 95% confidence interval [CI] 0·34-0·75, P < 0·001), and the TT genotype was significantly higher in the infected group (15% vs. 5%, OR = 3·18, 95% CI 1·53-6·61, P < 0·001). Previous reports demonstrated higher secretion of inflammatory factors in cells from AA individuals, lower occurrence and severity of immune diseases in T carriers. The rs4696480 TA genotype might stand between deleterious effects of over inflammatory response (AA genotype) and inefficient responses (TT genotype) to infectious agents in SCD settings.
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http://dx.doi.org/10.1111/bjh.15875DOI Listing
June 2019