Severance, E. G. | Search bioRxiv

bioRxiv2026

Blockade of Tim-3 pathway in a mouse model of Toxoplasmosis: impact on brain leukocyte infiltration, parasite burden, and neuroinflammation

Cell-mediated immune responses are crucial for protecting the host against Toxoplasma gondii infection. However, impaired immunity, such as T-cell exhaustion, is a common phenomenon during chronic infection. This may represent a strategy employed by T. gondii to evade host defenses. T-cell immunoglobulin and mucin-domain containing 3 (Tim-3) is an important regulatory molecule involved in cell-mediated immunity. This study examined the expression of Tim-3 and the effects of its blockade in a mouse model of toxoplasmosis. In mice with chronic T. gondii infection, we found that Tim-3 is highly expressed in both cyst-bearing and non-cyst-bearing tissues, and its expression correlates with the parasite burden. Blocking the Tim-3 pathway with an anti-Tim-3 antibody enhances the immune response, resulting in elevated levels of cytokines (IFN-{gamma}, IL-12p70, IL-2, IL-9) and the chemokine CXCL1 in the serum, increased leukocyte infiltration (CD3+, CD14+ cells) in the brain, and downregulation of Tim-3 expression in microglial cells. As a result, the anti-Tim-3 treatment resulted in a 62% reduction in the number of tissue cysts and a trend towards an increase in the homeostatic signature, P2RY12, in microglia. Our study provides proof of concept for an anti-Tim-3 approach in treating chronic T. gondii infection and potentially other brain-residing pathogens.

microbiology↗

bioRxiv2020

Maternal antibodies to gliadin and autism spectrum disorders in offspring - A population-based case-control study in Sweden

ObjectiveIndividuals diagnosed with autism spectrum disorders (ASD) are reported to have higher levels of antibodies directed towards gliadin, a component of wheat gluten. However, no study has examined such antibodies in etiologically-relevant periods before diagnosis. The objective of this study is to investigate if maternal levels of immunoglobulin G antibodies directed at gliadin, during pregnancy and at the time of birth, are associated with ASD in offspring. MethodsIn this population-based study set in Sweden with 921 ASD cases and 1090 controls, we analyzed levels of anti-gliadin antibodies (AGA) in archived neonatal dried blood spots (NDBS, as maternal IgG is transferred to the fetus) and in paired maternal sera collected earlier in pregnancy for a subset of 547 cases and 428 controls. We examined associations to any ASD diagnosis and considering common comorbidities (i.e. intellectual disability [ID] and attention-deficit/hyperactivity disorder [ADHD]). We compared 206 ASD cases to their unaffected siblings to examine the potential for confounding by shared familial factors. ResultsHigh levels ([≥]90th percentile) of maternal AGA were associated with decreased odds of ASD, particularly ASD with comorbid ID, when measured in NDBS (OR 0.51, 95% CI 0.30-0.87) with a similar trend in maternal sera (0.55, 0.24-1.29). High levels of maternal AGA were similarly associated with lower odds of ASD with ID in the sibling comparison. ConclusionsThis first study of exposure to AGA in the pre- and perinatal periods suggests that high levels of maternal AGA are associated with lower odds of ASD with ID.

molecular biology↗