Background Progranulin is a widely expressed pleiotropic growth factor with a central regulatory effect during the early immune response in sepsis. Progranulin signaling has not been systematically studied and compared between sepsis, community-acquired pneumonia (CAP), COVID-19 pneumonia and a sterile systemic inflammatory response (SIRS). We delineated molecular networks of progranulin signaling by next-generation sequencing (NGS), determined progranulin plasma concentrations and quantified the diagnostic performance of progranulin to differentiate between the above-mentioned disorders using the established biomarkers procalcitonin (PCT), interleukin-6 (IL-6) and C-reactive protein (CRP) for comparison. Methods The diagnostic performance of progranulin was operationalized by calculating AUC and ROC statistics for progranulin and established biomarkers in 241 patients with sepsis, 182 patients with SIRS, 53 patients with CAP, 22 patients with COVID-19 pneumonia and 53 healthy volunteers. miRNAs and mRNAs in blood cells from sepsis patients ( n = 7) were characterized by NGS and validated by RT-qPCR in an independent cohort ( n = 39) to identify canonical gene networks associated with upregulated progranulin at sepsis onset. Results Plasma concentrations of progranulin (ELISA) in patients with sepsis were 57.5 (42.8–84.9, Q25–Q75) ng/ml and significantly higher than in CAP (38.0, 33.5–41.0 ng/ml, p < 0.001), SIRS (29.0, 25.0–35.0 ng/ml, p < 0.001) and the healthy state (28.7, 25.5–31.7 ng/ml, p < 0.001). Patients with COVID-19 had significantly higher progranulin concentrations than patients with CAP (67.6, 56.6–96.0 vs. 38.0, 33.5–41.0 ng/ml, p < 0.001). The diagnostic performance of progranulin for the differentiation between sepsis vs. SIRS ( n = 423) was comparable to that of procalcitonin. AUC was 0.90 (95% CI = 0.87–0.93) for progranulin and 0.92 (CI = 0.88–0.96, p = 0.323) for procalcitonin. Progranulin showed high discriminative power to differentiate bacterial CAP from COVID-19 (sensitivity 0.91, specificity 0.94, AUC 0.91 (CI = 0.8–1.0) and performed significantly better than PCT, IL-6 and CRP. NGS and partial RT-qPCR confirmation revealed a transcriptomic network of immune cells with upregulated progranulin and sortilin transcripts as well as toll-like-receptor 4 and tumor-protein 53, regulated by miR-16 and others. Conclusions Progranulin signaling is elevated during the early antimicrobial response in sepsis and differs significantly between sepsis, CAP, COVID-19 and SIRS. This suggests that progranulin may serve as a novel indicator for the differentiation between these disorders. Trial registration : Clinicaltrials.gov registration number NCT03280576 Registered November 19, 2015.

BACKGROUND:There is evidence for a relevant role of inflammation in the pathogenesis of Parkinson's disease (PD). Mutations in the LRRK2 gene represent the most frequent genetic cause for autosomal dominant PD. LRRK2 is highly expressed in macrophages and microglia suggesting an involvement in inflammatory pathways. The objectives are to test (1) whether idiopathic PD and LRRK2-associated PD share common inflammatory pathways or present distinct profiles and (2) whether non-manifesting LRRK2 mutation carriers present with similar aspects of inflammatory profiles as seen in PD-affected patients.METHODS:We assessed serum profiles of 23 immune-associated markers and the brain-derived neurotrophic factor in 534 individuals from the MJFF LRRK2 consortium.RESULTS:A large proportion of inflammatory markers were gender-dependent. Both PD-affected cohorts showed increased levels of the pro-inflammatory marker fatty-acid-binding protein. Additionally, idiopathic PD but not LRRK2-associated PD patients showed increased levels of the pro-inflammatory marker interleukin-12-p40 as well as the anti-inflammatory species interleukin-10, brain-derived neurotrophic factor, and stem cell factor. Non-manifesting LRRK2 mutation carriers including those with prodromal characteristics of PD presented with control-like inflammatory profiles.CONCLUSIONS:Concomitant inflammation seems to be associated with idiopathic and LRRK2-associated PD. Identifying PD patients in whom inflammatory processes play a major role in their pathophysiology might offer a new therapeutic window at least for a subgroup of patients. Since non-manifesting LRRK2 mutation carriers with symptoms of the prodromal phase of PD did not show inflammatory profiles, activation of the immune system seems not an early event in the disease cascade.

Naturally occurring autoantibodies (NAbs) against a number of potentially disease-associated cellular proteins, including Amyloid-beta1-42 (Abeta1-42), Alpha-synuclein (Asyn), myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), and S100 calcium binding protein B (S100B) have been suggested to be associated with neurodegenerative disorders, in particular Alzheimer's (AD) and Parkinson's disease (PD). Whereas the (reduced) occurrence of specific NAbs in AD is widely accepted, previous literature examining the relation of these NAb titres between PD patients and controls, as well as comparing these levels with demographic and clinical parameters in PD patients have produced inconsistent findings. We therefore aimed, in a cross-sectional approach, to determine serum titres of the above NAbs in a cohort of 93 PD patients (31 of them demented) and 194 controls. Levels were correlated with demographic and clinical variables, cerebrospinal fluid Abeta1-42, total tau and phospho-tau levels, as well as with single nucleotide polymorphisms (SNPs) of genes which either have been reported to influence the immune system, the amyloid cascade or the occurrence of PD (ApoE, GSK3B, HLA-DRA, HSPA5, SNCA, and STK39). The investigated NAb titres were neither significantly associated with the occurrence of PD, nor with demographic and clinical parameters, neurodegenerative markers or genetic variables. These results argue against a major potential of blood-borne parameters of the adaptive immune system to serve as trait or state markers in PD.

Reduced levels of naturally occurring autoantibodies against amyloid-β (Aβ) have been described in Alzheimer's disease (AD). Lifetime depression doubles the risk of AD, thus these autoantibodies may also be reduced in this group. We measured serum IgG autoantibody titers against Aβ1-42, S100b and α-synuclein in 214 individuals with depression and 419 controls. Titers against Aβ1-42 were lower in individuals with lifetime depression (5544.6 ± 389.3) compared to controls (7208.7 ± 482.4; p = 0.048). Titers against S100b and α-synuclein were comparable between the cohorts. These data suggest an AD-like impairment of the humoral immune response in a relevant proportion of individuals with depression.

There is increasing evidence that in Lewy body-associated dementias (encompassing Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB)), the adaptive immune system is altered and the degenerative process includes glial cells in addition to neuronal structures. We therefore aimed to determine levels of autoantibodies against amyloid and glial-derived structures in these dementia types. Using a newly developed Enzyme-linked immunosorbent assay (ELISA), we measured levels of IgG autoantibodies against neuronal and glial structures in serum and cerebrospinal fluid of a total of 91 subjects (13 PDD, 14 DLB, 11 Alzheimer's disease (AD), 11 frontotemporal dementia (FTD), 11 vascular dementia patients (VaD), and 31 healthy controls). Autoantibody levels against α-synuclein, amyloid-β₄₂ (Aβ₄₂), myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), and S100B were determined. In all groups, autoantibody levels were about three magnitudes higher in serum than in CSF. Serum autoantibody levels against α-synuclein, Aβ₄₂, MOG, MBP, and S100B were higher in PDD/DLB compared to tau-associated dementias (AD, FTD), VaD, and controls, respectively, with most of them reaching highly significant p-values. In cerebrospinal fluid (CSF), levels of antibodies against oligodendrocyte-derived antigens (MOG, MBP) were significantly increased in PDD/DLB. Increased levels of autoantibodies against both neuronal- and glial-derived antigens in serum and CSF of Lewy body-associated dementias indicate an altered activity of the adaptive immune system in these dementia types. The potential of neural-derived IgG autoantibodies as part of a biomarker panel for the diagnosis of Lewy body-associated dementias should be further evaluated.

BACKGROUND:Multiple sclerosis (MS) is a frequent and often severe autoimmune disease of the central nervous system. We describe a newly developed enzyme-linked immunosorbent assay (ELISA)-based test system for the assessment of neuronal autoantibodies in serum and cerebrospinal fluid (CSF). This tool could help define autoimmune status and thus be a potential means of therapeutic surveillance. METHODS:We used an assay system (ELISA, E100, Mediagnost) based on purified bovine antigens [myelin-oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), myelin-associated glycoprotein (MAG), proteolipid protein (PLP) and alpha-B-crystalline (CRY)] antibodies for the measurement of specific immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies. Assay characteristics and preliminary validation were conducted by measurement of serum and CSF samples from 41 MS patients and 128 patients with other neurological diseases (OND). RESULTS:We measured the inter- (17.8/10.1%) and intra-assay variability (5.5/6.7%); linearity (1:250- 1:16,000), and specificity of IgG and IgM. We demonstrate that by the results of this test system MS patients can be differentiated from patients with OND. CONCLUSIONS:The ELISA kit we evaluated is suitable for the measurement of neuronal autoantibodies. The initial validation demonstrates its potential use in the differential diagnosis of central neuronal system diseases.

BACKGROUND Formula milk-fed infants show faster rates of growth and weight gain than do breastfed infants, and they have higher concentrations of insulin-like growth factor I (IGF-I). OBJECTIVE Our objective was to determine the influence of IGF-I concentrations on gains in weight, length, body mass index (BMI), and adiposity in the first year of life. DESIGN IGF-I concentrations were measured in 953 capillary blood samples from 675 unselected infants at ages 3 and 12 mo. These infants were born between 2002 and 2008 in one center and were participating in a prospective longitudinal birth cohort. Weight, length, and 4 skinfold thicknesses as an indicator of adiposity were measured at ages 0, 3, and 12 mo. Analyses were adjusted for age and sex. RESULTS Infants who were formula milk-fed had higher IGF-I concentrations at 3 mo, and they showed greater gains in weight, length, BMI, and adiposity between age 3 and 12 mo. IGF-I concentrations at 3 mo were unrelated to subsequent overall weight gain (P = 0.5). However, higher IGF-I concentrations at age 3 mo predicted greater subsequent gains in body length (P < 0.001 and P = 0.007 in formula milk-fed and breastfed infants, respectively) and slower gains in BMI (P < 0.001 and P = 0.004, respectively) and adiposity (P = 0.03 and P = 0.003, respectively). CONCLUSIONS Our findings support a key role for IGF-I in the partitioning of overall infant weight gain into statural growth compared with adiposity. In formula milk-fed infants, higher IGF-I concentrations may lead to faster gains in length; however, other mechanisms likely explain their faster gains in weight, BMI, and adiposity.

Many cancers produce high amounts of the insulin-like growth factor binding protein (IGFBP)-2, which can influence the tumorigenicity and growth of tumor cells. In order to study the possible cause of elevated expression of IGFBP-2 in tumors, we investigated the transcriptional regulation by IGF of a 633-bp fragment of the human IGFBP-2 promoter in a transiently transfected choriocarcinoma (JAR) and a leukemic T-cell line (Molt-4) that express IGFBP-2 highly, and in a leukemic B-cell line (Raji) that expresses little IGFBP-2. Strong basal promoter activity, i.e. luciferase activity was measurable in all of the tumor cell lines. The introduction of equal amounts of normal IGF-I and IGF-II stimulated the transcription of IGFBP-2 only slightly. Synthetic IGF analogues with increased biological activity, however, caused a specific 2.0–3.3-fo1d transactivation of the promoter, as well as a 25% increase in IGFBP-2 mRNA. Synchronously, IGF analogues caused a decrease in the level of IGFBP-3 mRNA of about 45%, while the production of IGFBP-2 as measured by RIA increased in relation to IGFBP-3 by up to 15 times. Blocking with the IGF antagonist JB1 revealed partial involvement of the IGF-I receptor in the regulation of IGFBP-2 expression by locally produced IGF. We conclude, that the reduced ability of IGF analogues to form complexes with locally produced IGFBP may account for their increased biological activity in the stimulation of expression of IGFBP-2 and of cell growth. Since increased biological activity had also been demonstrated for natural pro-IGF forms often produced by tumors, pro-IGFs may be involved in the mechanism leading to elevated IGFBP-2 expression of tumors in vivo.