Reduced numbers of naïve CD4 + T cells and an altered CD4/CD8 balance in depressed common variable immune deficiency (CVID) patients. Is thymosin-α1 a possible treatment?

In the 1990's the macrophage-T-cell-theory of depression was posed stating that low grade inflammation and an abnormal T cell system destabilize the development and function of the emotional brain in such a way, that individuals become ultrasensitive to stress. Recently we gathered evidence that indeed higher frequencies of CD4+ memory T cells, lower frequencies of naive CD4 + T cells, higher frequencies of CD8 + T cells (the latter two in part elicited by Cytomegalovirus, CMV, infection) are a characteristic of Major Depressive Disorder (MDD). In MDD patients with a history of childhood trauma and severe depression monocytes are inflammatory activated. Low grade inflammation and T cell system defects have also been reported in patients with Common Variable Immune Deficiency (CVID) (next to antibody production defects). CVID patients show a higher prevalence of mild depression. The aim of this study was to determine T cell frequencies and monocyte inflammatory activation in CVID patients with and without depression. This study confirms that CVID patients have CMV independent decreases in the frequency of naïve CD4 + T cells and it de novo shows a CMV dependent increase in the expression of inflammatory genes in monocytes. CVID patients with depression are additionally characterized by a CMV independent increase in the frequency of naïve CD8 + T cells, while lacking monocyte inflammatory activation. In conclusion, depressed CVID patients have T cell abnormalities comparable to that of patients with regular MDD. These abnormalities are presently targeted by thymosin α1 in an open-label proof of concept trial.

Identification of ultra-rare genetic variants in pediatric acute onset neuropsychiatric syndrome (PANS) by exome and whole genome sequencing.

Abrupt onset of severe neuropsychiatric symptoms including obsessive-compulsive disorder, tics, anxiety, mood swings, irritability, and restricted eating is described in children with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS). Symptom onset is often temporally associated with infections, suggesting an underlying autoimmune/autoinflammatory etiology, although direct evidence is often lacking. The pathological mechanisms are likely heterogeneous, but we hypothesize convergence on one or more biological pathways. Consequently, we conducted whole exome sequencing (WES) on a U.S. cohort of 386 cases, and whole genome sequencing (WGS) on ten cases from the European Union who were selected because of severe PANS. We focused on identifying potentially deleterious genetic variants that were de novo or ultra-rare (MAF) < 0.001. Candidate mutations were found in 11 genes (PPM1D, SGCE, PLCG2, NLRC4, CACNA1B, SHANK3, CHK2, GRIN2A, RAG1, GABRG2, and SYNGAP1) in 21 cases, which included two or more unrelated subjects with ultra-rare variants in four genes. These genes converge into two broad functional categories. One regulates peripheral immune responses and microglia (PPM1D, CHK2, NLRC4, RAG1, PLCG2). The other is expressed primarily at neuronal synapses (SHANK3, SYNGAP1, GRIN2A, GABRG2, CACNA1B, SGCE). Mutations in these neuronal genes are also described in autism spectrum disorder and myoclonus-dystonia. In fact, 12/21 cases developed PANS superimposed on a preexisting neurodevelopmental disorder. Genes in both categories are also highly expressed in the enteric nervous system and the choroid plexus. Thus, genetic variation in PANS candidate genes may function by disrupting peripheral and central immune functions, neurotransmission, and/or the blood-CSF/brain barriers following stressors such as infection.

Activated PI3Kδ syndrome, an immunodeficiency disorder, leads to sensorimotor deficits recapitulated in a murine model.

The phosphoinositide-3-kinase (PI3K) family plays a major role in cell signaling and is predominant in leukocytes. Gain-of-function (GOF) mutations in the PIK3CD gene lead to the development of activated PI3Kδ syndrome (APDS), a rare primary immunodeficiency disorder. A subset of APDS patients also displays neurodevelopmental delay symptoms, suggesting a potential role of PIK3CD in cognitive and behavioural function. However, the extent and nature of the neurodevelopmental deficits has not been previously quantified. Here, we assessed the cognitive functions of two APDS patients, and investigated the causal role of the PIK3CD GOF mutation in neurological deficits using a murine model of this disease. We used p110δE1020K knock-in mice, harbouring the most common APDS mutation in patients. We found that APDS patients present with visuomotor deficits, exacerbated by autism spectrum disorder comorbidity, whereas p110δE1020K mice exhibited impairments in motor behaviour, learning and repetitive behaviour patterning. Our data indicate that PIK3CD GOF mutations increase the risk for neurodevelopmental deficits, supporting previous findings on the interplay between the nervous and the immune system. Further, our results validate the knock-in mouse model, and offer an objective assessment tool for patients that could be incorporated in diagnosis and in the evaluation of treatments.

Documentation of clinically relevant genomic biomarker allele frequencies in the next-generation FINDbase worldwide database.

FINDbase (http://www.findbase.org) is a comprehensive data resource recording the prevalence of clinically relevant genomic variants in various populations worldwide, such as pathogenic variants underlying genetic disorders as well as pharmacogenomic biomarkers that can guide drug treatment. Here, we report significant new developments and technological advancements in the database architecture, leading to a completely revamped database structure, querying interface, accompanied with substantial extensions of data content and curation. In particular, the FINDbase upgrade further improves the user experience by introducing responsive features that support a wide variety of mobile and stationary devices, while enhancing computational runtime due to the use of a modern Javascript framework such as ReactJS. Data collection is significantly enriched, with the data records being divided in a Public and Private version, the latter being accessed on the basis of data contribution, according to the microattribution approach, while the front end was redesigned to support the new functionalities and querying tools. The abovementioned updates further enhance the impact of FINDbase, improve the overall user experience, facilitate further data sharing by microattribution, and strengthen the role of FINDbase as a key resource for personalized medicine applications and personalized public health.

Dermatography (Medical Tattooing) for Scars and Skin Grafts in Head and Neck Patients to Improve Appearance and Quality of Life.

IMPORTANCE: Dermatography (medical tattooing) is often overlooked as an adjuvant procedure to improve color mismatch in the head and neck area, and its effect on patient satisfaction and quality of life has not been evaluated, to our knowledge. OBJECTIVE: To analyze the effect of dermatography on the subjective perception of the appearance of scars and skin grafts and the quality of life in head and neck patients. DESIGN, SETTING, AND PARTICIPANTS: Case series of patients undergoing dermatography at the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, between July 1, 2007, and April 1, 2015. Participants were invited to respond to 2 questionnaires measuring their scar or graft appearance and their quality of life before and after dermatography as an adjuvant treatment for benign or malignant head and neck tumors. INTERVENTION: Use of dermatography. MAIN OUTCOMES AND MEASURES: Two questionnaires evaluating a visual analog scale score (range, 0-10) and multiple questions on a 5-point scale focusing on satisfaction with the appearance and the quality of life. RESULTS: Among 76 patients, 56 (74%) were included in the study. The mean (SD) age of the study cohort was 56.5 (16.0) years, and 42 (75%) were female. The mean improvement in scar or skin graft perception on the visual analog scale of the modified Utrecht Questionnaire for Outcome Assessment in Aesthetic Rhinoplasty before and after dermatography was 4 points. On the modified Patient Scar Assessment Questionnaire, uniform improvement of approximately 1 point across 9 questions was observed. The answers to all patient satisfaction and quality-of-life questions on both questionnaires improved significantly after dermatography. CONCLUSIONS AND RELEVANCE: Dermatography is an effectual adjuvant procedure to improve the subjective perception of scar and skin graft appearance and the quality of life in head and neck patients. LEVEL OF EVIDENCE: 4.