Modulation of galectin-9 mediated responses in monocytes and T-cells by pregnancy-specific glycoprotein 1.

Successful pregnancy relies on a coordinated interplay between endocrine, immune, and metabolic processes to sustain fetal growth and development. The orchestration of these processes involves multiple signaling pathways driving cell proliferation, differentiation, angiogenesis, and immune regulation necessary for a healthy pregnancy. Among the molecules supporting placental development and maternal tolerance, the families of pregnancy-specific glycoproteins and galectins are of great interest in reproductive biology. We previously found that PSG1 can bind to galectin-1 (GAL-1). Herein, we characterized the interaction between PSG1 and other members of the galectin family expressed during pregnancy, including galectin-3, -7, -9, and -13 (GAL-3, GAL-7, GAL-9, and GAL-13). We observed that PSG1 binds to GAL-1, -3, and -9, with the highest apparent affinity seen for GAL-9, and that the interaction of PSG1 with GAL-9 is carbohydrate-dependent. We further investigated the ability of PSG1 to regulate GAL-9 responses in human monocytes, a murine macrophage cell line, and T-cells, and determined whether PSG1 binds to both carbohydrate recognition domains of GAL-9. Additionally, we compared the apparent affinity of GAL-9 binding to PSG1 with other known GAL-9 ligands in these cells, Tim-3 and CD44. Lastly, we explored functional conservation between murine and human PSGs by determining that Psg23, a highly expressed member of the murine Psg family, can bind some murine galectins despite differences in amino acid composition and domain structure.

Perturbations of the T-cell receptor repertoire in response to SARS-CoV-2 in immunocompetent and immunocompromised individuals.

BACKGROUND: Functional T-cell responses are essential for virus clearance and long-term protection after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, whereas certain clinical factors, such as older age and immunocompromise, are associated with worse outcome. OBJECTIVE: We sought to study the breadth and magnitude of T-cell responses in patients with coronavirus disease 2019 (COVID-19) and in individuals with inborn errors of immunity (IEIs) who had received COVID-19 mRNA vaccine. METHODS: Using high-throughput sequencing and bioinformatics tools to characterize the T-cell receptor ß repertoire signatures in 540 individuals after SARS-CoV-2 infection, 31 IEI recipients of COVID-19 mRNA vaccine, and healthy controls, we quantified HLA class I- and class II-restricted SARS-CoV-2-specific responses and also identified several HLA allele-clonotype motif associations in patients with COVID-19, including a subcohort of anti-type 1 interferon (IFN-1)-positive patients. RESULTS: Our analysis revealed that elderly patients with COVID-19 with critical disease manifested lower SARS-CoV-2 T-cell clonotype diversity as well as T-cell responses with reduced magnitude, whereas the SARS-CoV-2-specific clonotypes targeted a broad range of HLA class I- and class II-restricted epitopes across the viral proteome. The presence of anti-IFN-I antibodies was associated with certain HLA alleles. Finally, COVID-19 mRNA immunization induced an increase in the breadth of SARS-CoV-2-specific clonotypes in patients with IEIs, including those who had failed to seroconvert. CONCLUSIONS: Elderly individuals have impaired capacity to develop broad and sustained T-cell responses after SARS-CoV-2 infection. Genetic factors may play a role in the production of anti-IFN-1 antibodies. COVID-19 mRNA vaccines are effective in inducing T-cell responses in patients with IEIs.

Management of Atopy with Dupilumab and Omalizumab in CADINS Disease.

The caspase activation and recruitment domain 11 (CARD11) gene encodes a scaffold protein required for lymphocyte antigen receptor signaling. Dominant-negative, loss-of-function (LOF) pathogenic variants in CARD11 result in CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) disease. Patients with CADINS suffer with severe atopic manifestations including atopic dermatitis, food allergy, and chronic spontaneous urticaria in addition to recurrent infections and autoimmunity. We assessed the response of dupilumab in five patients and omalizumab in one patient with CADINS for the treatment of severe atopic symptoms. CARD11 mutations were validated for pathogenicity using a T cell transfection assay to assess the impact on activation-induced signaling to NF-κB. Three children and three adults with dominant-negative CARD11 LOF mutations were included. All developed atopic disease in infancy or early childhood. In five patients, atopic dermatitis was severe and recalcitrant to standard topical and systemic medications; one adult suffered from chronic spontaneous urticaria. Subcutaneous dupilumab was initiated to treat atopic dermatitis and omalizumab to treat chronic spontaneous urticaria. All six patients had rapid and sustained improvement in atopic symptoms with no complications during the follow-up period. Previous medications used to treat atopy were able to be decreased or discontinued. In conclusion, treatment with dupilumab and omalizumab for severe, refractory atopic disease in patients with CADINS appears to be effective and well tolerated in patients with CADINS with severe atopy.