Individual and stable autoantibody repertoires in healthy individuals

In the era towards precision medicine, we here present the individual specific autoantibody signatures of 193 healthy individuals. The self-reactive IgG signatures are stable over time in a way that each individual profile is recognized in longitudinal sampling. The IgG autoantibody reactivity towards an antigen array comprising 335 protein fragments, representing 204 human proteins with potential relevance to autoimmune disorders, was measured in longitudinal plasma samples from 193 healthy individuals. This analysis resulted in unique autoantibody barcodes for each individual that were maintained over one year's time. The reactivity profiles, or signatures, are person specific in regards to the number of reactivities and antigen specificity. Two independent data sets were consistent in that each healthy individual displayed reactivity towards 0-16 antigens, with a median of six. Subsequently, four selected individuals were profiled on in-house produced high-density protein arrays containing 23,000 protein fragments representing 14,000 unique protein coding genes. Based on a unique, broad and deep longitudinal profiling of autoantibody reactivities, our results demonstrate a unique autoreactive profile in each analyzed healthy individual. The need and interest for broad-ranged and high-resolution molecular profiling of healthy individuals is rising. We have here generated and assessed an initial perspective on the global distribution of the self-reactive IgG repertoire in healthy individuals, by investigating 193 well-characterized healthy individuals.Peer reviewe

Integration of molecular profiles in a longitudinal wellness profiling cohort

An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, we sample a longitudinal wellness cohort with 100 healthy individuals and analyze blood molecular profiles including proteomics, transcriptomics, lipidomics, metabolomics, autoantibodies and immune cell profiling, complemented with gut microbiota composition and routine clinical chemistry. Overall, our results show high variation between individuals across different molecular readouts, while the intra-individual baseline variation is low. The analyses show that each individual has a unique and stable plasma protein profile throughout the study period and that many individuals also show distinct profiles with regards to the other omics datasets, with strong underlying connections between the blood proteome and the clinical chemistry parameters. In conclusion, the results support an individual-based definition of health and show that comprehensive omics profiling in a longitudinal manner is a path forward for precision medicine

Neolithic hydroclimatic change and water resources exploitation in the Fertile Crescent

Abstract In the first millennia of the Holocene, human communities in the Fertile Crescent experienced drastic cultural and technological transformations that modified social and human-environments interactions, ultimately leading to the rise of complex societies. The potential influence of climate on this “Neolithic Revolution” has long been debated. Here we present a speleothem record from the Kurdistan Region of Iraq, covering from Early Neolithic to Early Chalcolithic periods (~ 11 to 7.3 ka, 9000–5300 BCE). The record reveals the influence of the Siberian High on regional precipitation, and shows large hydroclimatic variability at the multicentennial scale. In particular, it highlights wetter conditions between 9.7 and 9.0 ka, followed by an abrupt reduction of precipitation between 9.0 and 8.5 ka, and a wetter interval between 8.5 and 8.0 ka. A comparison with regional and local archaeological data demonstrates an influence of recorded hydroclimatic changes on settlement patterns (size, distribution, permanent vs. seasonal occupation) and on the exploitation of water resources by Neolithic to Chalcolithic populations. Our record does not show prominent hydroclimatic changes at 9.3 and 8.2 ka, thus not supporting direct influence of such rapid and widespread events on the process of Neolithization and its cultural dispersal

Expression of LRIG proteins as possible prognostic factors in primary vaginal carcinoma

Background Primary vaginal carcinoma (PVC) is a rare malignancy. Established prognostic factors include tumour stage and age at diagnosis. The leucine-rich repeats and immunoglobuline-like domains (LRIG)-1 protein functions as a tumour suppressor, but less is known about the functions of LRIG2 and LRIG3. The present study aimed to evaluate the expression of LRIG proteins and analyse their possible associations with clinical characteristics and survival in a cohort of PVC patients. Methods We used immunohistochemistry to investigate LRIG1, LRIG2, and LRIG3 expression in tumour samples from a consecutive cohort of 70 PVC patients. The association between LRIG protein expression and clinical characteristics and cancer-specific survival was investigated using univariate and multivariate analyses. Results The majority of PVC patients (72%) had > 50% LRIG1-and LRIG2-positive cells, and no or low LRIG3-positive cells. HPV status was significantly correlated with LRIG1 expression (p = 0.0047). Having high LRIG1 expression was significantly correlated with superior cancer-specific survival in univariate and multivariate analyses. LRIG2 and LRIG3 expression did not significantly correlate with clinical characteristics or survival. Conclusion LRIG1 expression might be of interest as a prognostic marker in PVC patients, whereas the role of LRIG2 and LRIG3 expression remains to be clarified

SARS-CoV-2 induces a durable and antigen specific humoral immunity after asymptomatic to mild COVID-19 infection

Current SARS-CoV-2 serological assays generate discrepant results, and the longitudinal characteristics of antibodies targeting various antigens after asymptomatic to mild COVID-19 are yet to be established. This longitudinal cohort study including 1965 healthcare workers, of which 381 participants exhibited antibodies against the SARS-CoV-2 spike antigen at study inclusion, reveal that these antibodies remain detectable in most participants, 96%, at least four months post infection, despite having had no or mild symptoms. Virus neutralization capacity was confirmed by microneutralization assay in 91% of study participants at least four months post infection. Contrary to antibodies targeting the spike protein, antibodies against the nucleocapsid protein were only detected in 80% of previously anti-nucleocapsid IgG positive healthcare workers. Both anti-spike and anti-nucleocapsid IgG levels were significantly higher in previously hospitalized COVID-19 patients four months post infection than in healthcare workers four months post infection (p = 2*10(-23) and 2*10(-13) respectively). Although the magnitude of humoral response was associated with disease severity, our findings support a durable and functional humoral response after SARS-CoV-2 infection even after no or mild symptoms. We further demonstrate differences in antibody kinetics depending on the antigen, arguing against the use of the nucleocapsid protein as target antigen in population-based SARS-CoV-2 serological surveys

A Pharmacokinetic and Dosing Study of Intravenous Insulin-Like Growth Factor-I and IGF-Binding Protein-3 Complex to Preterm Infants.

In preterm infants, low levels of Insulin like growth factor 1 (IGF-I) have been associated with impaired growth and retinopathy of prematurity. Our objective was to study safety and pharmacokinetics of intravenously administered rhIGF-I with its binding protein 3 (rhIGFBP-3) to preterm infants. At 3 days chronological age, an intravenous 3 hours infusion of rhIGF-I/rhIGFBP-3 was administered followed by serial measurements of IGF-I and IGFBP-3. Infants were evaluated for physiological safety measurements. The individual dose of rhIGF-I ranged from 1 to 12 mug/kg. The study was conducted at Queen Silvia Children's Hospital, Gothenburg, Sweden, between January and November 2007. Five patients (3F) with mean (range) PMA 27 weeks (26-29) and birth weight 1022 grams (810-1310) participated. IGF-I and IGFBP-3 levels before infusion were median (range) 18 (12-28) and 771 (651-1047) ng/ml, respectively. Immediately after study drug infusion, serum IGF-I and IGFBP-3 levels were 38 (25-59) and 838 (754-1182) ng/ml, respectively. Median (range) half-life for IGF-I and IGFBP-3 was 0.79 (0.59-1.42) and 0.87 (0.85-0.94) hours, respectively. Blood glucose, insulin, sodium, potassium and physiological safety measures were within normal ranges. The rhIGF-I/rhIGFBP-3 equimolar proportion was effective in increasing serum IGF-I levels and administration under these study conditions was safe and well tolerated

Identification of four novel T cell autoantigens and personal autoreactive profiles in multiple sclerosis

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), in which pathological T cells, likely autoimmune, play a key role. Despite its central importance, the autoantigen repertoire remains largely uncharacterized. Using a novel in vitro antigen delivery method combined with the Human Protein Atlas library, we screened for T cell autoreactivity against 63 CNS-expressed proteins. We identified four previously unreported autoantigens in MS: fatty acid-binding protein 7, prokineticin-2, reticulon-3, and synaptosomal-associated protein 91, which were verified to induce interferon-gamma responses in MS in two cohorts. Autoreactive profiles were heterogeneous, and reactivity to several autoantigens was MS-selective. Autoreactive T cells were predominantly CD4(+) and human leukocyte antigen-DR restricted. Mouse immunization induced antigen-specific responses and CNS leukocyte infiltration. This represents one of the largest systematic efforts to date in the search for MS autoantigens, demonstrates the heterogeneity of autoreactive profiles, and highlights promising targets for future diagnostic tools and immunomodulatory therapies in MS