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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.

Objective Bipolar Disorder (BD) is characterized by deregulated adaptive immune processes. Recent genome-wide association studies (GWAS) implicate the major histocompatibility complex (MHC) region in BD. The present study investigates the potential influence of variations in human leukocyte antigen (HLA) on BD risk and/or clinical presentations. This may have relevance to the dysregulated inflammatory processes commonly found in BD. Method DNAs from 475 BD patients and 195 healthy controls (HC) were genotyped for classical HLA class I and II loci. Results We found that: (i) the HLA-A*02~B*44~DRB1*07 sub-haplotype is less prevalent in BD, vs. HC (pc = 2.4 × 10-2 ); (ii) the 57.1 and the 8.1-derived ancestral haplotypes i.e. HLA-A*02~B*57~Cw*06~DRB1*07~DQB1*09 and HLA-A*02~B*08~Cw*07 are associated with rapid cycling (pc = 1.9 × 10-3 and 1.05 × 10-2 , respectively); (iii) the 8.1AH-derived HLA class II-DRB*03~HLA-DQB1*02 sub-haplotype is more frequent in BD patients with a history of suicidal behaviors (pc = 2.1 × 10-2 ); and (iv) disease onset by an hypomanic episode or by psychotic symptoms are, respectively, more frequent in BD patients bearing the 7.1 AH-derived A*03~B*07~DRB1*15 sub-haplotype (pc = 8.5 × 10-3 ) and the HLA-A*02~B*07~DRB1*15 sub-haplotype (pc = 4.0 × 10-2 ). Conclusion Corroborating the established link between these HLA haplotypes/sub haplotypes and common immune disorders, our findings suggest possible HLA-mediated proinflammatory processes operating in BD.

Infections and autoimmunity are associated with autism spectrum disorders (ASD), with both strongly influenced by the genetic regulation of the human leukocyte antigen (HLA) system. The relationship between ASD and the HLA genetic diversity requires further investigation. Using a case control design, the distribution of HLA class II-DRB1 and DQB1 alleles, genotypes and haplotypes were investigated in ASD patients, versus healthy controls (HC). ASD patients meeting DSM-IV TR criteria and HC (474 and 350 respectively) were genotyped at medium resolution using a Luminex-based SSO technology. Comparisons of genotypes, allele frequencies associated with a haplotype analysis were performed. Results indicate: (i) the HLA-DRB1 *11-DQB1*07 haplotype was more prevalent in ASD patients, versus HC (Pc = 0.001), partially replicating previous data and possibly linking to gastro-intestinal (GI)-related pro-inflammatory processes, given that this haplotype associates with pediatric celiac disorders; (ii) the HLA-DRB1 *17-DQB1*02 haplotype was higher in HC, versus ASD patients (Pc = 0.002), indicating that this is a protective haplotype. Using the Autism Diagnostic Interview to assess clinical dimensions, higher scores on social (Pc = 0.006) and non-verbal functioning (Pc = 0.004) associated with the DRB1 *11 DQB1*07 haplotype. Our results support HLA involvement in ASD, with possible relevance to GI and gut-brain axis dysregulation.

Background The Luminex bead-based multiplex assay is useful for quantifying immune mediators such as cytokines and chemokines. Cross-comparisons of reagents for this technique from different suppliers have already been performed using serum or plasma but rarely with supernatants collected from antigen-stimulated peripheral blood mononuclear cells (PBMC). Here, we first describe an optimization protocol for cell culture including quantity of cells and culture duration to obtain reproducible cytokine and chemokine quantifications. Then, we compared three different Luminex kit suppliers. Results Intraclass correlation coefficients (ICCs) for a 2-days stimulation protocol were >0.8 for IFNγ and Perforin. The specific concentration was maximal after two or five days of stimulation, depending on the analyte, using 0.5 million PBMC per well, a cell quantity that gave the same level of specific cytokine secretion as 1.0 million. In the second part of the study, Luminex kits from Millipore showed a better working range than Bio-Rad and Ozyme ones. For tuberculin purified protein derivative (PPD)-stimulated samples, the overall mean pooled coefficients of variation (CVs) for all donors and all cytokines was 17.2 % for Bio-Rad, 19.4 % for Millipore and 26.7 % for Ozyme. Although the different kits gave cytokine concentrations that were generally compatible, there were discrepancies for particular cytokines. Finally, evaluation of precision and reproducibility of a 15-plex Millipore kit using a “home-made” internal control showed a mean intra-assay CV

Background Genetic and clinical overlaps between Schizophrenia (SZ) and Bipolar disorder (BD) are remarkable with at least immune dysfunction as a common thread. Belonging to the innate arm of immune responses, the complement system encodes important molecules for: (i) immune surveillance and (ii) physiological synaptic pruning processes during childhood [1,2]. Recently, strong correlations between C4 copy number variations (CNVs) and SZ risk through complex gene rearrangements likely influencing the synaptic pruning were demonstrated [3]. The C4 component corresponds to the C4A and C4B protein isoforms encoded by loci differing only by five nucleotides and by distinct functions. The C4 genetic diversity, mainly represented by CNVs and structural size variations (long/short forms according to presence/absence of HERV-K), was demonstrated to influences the C4 protein expression [4]. Objective: We took advantage of phenotypically well-defined cohorts of BD and SZ patients to analyze the distribution of C4 structural variants as compared to healthy controls (HC). We also examined the presence of potential relationships between the C4 structural diversity and clinico-biological parameters. Methods: A total of 190 BD subjects, 97 SZ subjects and 132 HC were included in the study at Henri Mondor Hospital, Creteil, France. Digital Droplet PCR was used to determine the C4A, C4B, C4L and C4S CNVs as well as the exact C4AL, C4AS, C4BL and C4BS CNV types. The circulating serum levels of 44 cytokines and chemokines were quantified using electro-chemiluminescence. Results: We identified 44 different structural forms of C4 gene among which three were more represented: AL-AL-BL-BS (21.5 %), AL-AL-BL-BL (11.4 %) and AL-AL-BS-BS a (10.9 %). The C4 haplotypic analysis showed that the AL-AL-BL-BS haplotype was less frequent in SZ patients as compared to HC (p=0.017). We also observed in SZ patients that (i) high copy number of some C4 structural forms are correlated with a high level of some circulating cytokines (p

Background Genetic vulnerability to environmental stressors is yet to be clarified in bipolar disorder (BD), a complex multisystem disorder in which immune dysfunction and infectious insults seem to play a major role in the pathophysiology. Association between pattern-recognition receptor coding genes and BD had been previously reported. However, potential interactions with history of pathogen exposure are yet to be explored. Methods 138 BD patients and 167 healthy controls were tested for serostatus of Toxoplasma gondii, CMV, HSV-1 and HSV-2 and genotyped for TLR2 (rs4696480 and rs3804099), TLR4 (rs1927914 and rs11536891) and NOD2 (rs2066842) polymorphisms (SNPs). Both the pathogen-specific seroprevalence and the TLR/NOD2 genetic profiles were compared between patients and controls followed by modelling of interactions between these genes and environmental infectious factors in a regression analysis. Results First, here again we observed an association between BD and Toxoplasma gondii (p = 0.045; OR = 1.77; 95 % CI 1.01–3.10) extending the previously published data on a cohort of a relatively small number of patients (also included in the present sample). Second, we found a trend for an interaction between the TLR2rs3804099 SNP and Toxoplasma gondii seropositivity in conferring BD risk (p = 0.017, uncorrected). Conclusions Pathogen exposure may modulate the influence of the immunogenetic background on BD. A much larger sample size and information on period of pathogen exposure are needed in future gene–environment interaction studies.

Mesenchymal stem cells (MSC) are known to repair broken heart tissues primarily through a paracrine fashion while emerging evidence indicate that MSC can communicate with cardiomyocytes (CM) through tunneling nanotubes (TNT). Nevertheless, no link has been so far established between these two processes. Here, we addressed whether cell-to-cell communication processes between MSC and suffering cardiomyocytes and more particularly those involving TNT control the MSC paracrine regenerative function. In the attempt to mimic in vitro an injured heart microenvironment, we developed a species mismatch coculture system consisting of terminally differentiated CM from mouse in a distressed state and human multipotent adipose derived stem cells (hMADS). In this setting, we found that crosstalk between hMADS and CM through TNT altered the secretion by hMADS of cardioprotective soluble factors such as VEGF, HGF, SDF-1α, and MCP-3 and thereby maximized the capacity of stem cells to promote angiogenesis and chemotaxis of bone marrow multipotent cells. Additionally, engraftment experiments into mouse infarcted hearts revealed that in vitro preconditioning of hMADS with cardiomyocytes increased the cell therapy efficacy of naïve stem cells. In particular, in comparison with hearts treated with stem cells alone, those treated with cocultured ones exhibited greater cardiac function recovery associated with higher angiogenesis and homing of bone marrow progenitor cells at the infarction site. In conclusion, our findings established the first relationship between the paracrine regenerative action of MSC and the nanotubular crosstalk with CM and emphasize that ex vivo manipulation of these communication processes might be of interest for optimizing current cardiac cell therapies. Stem Cells 2014;32:216–230