Rabbit Anti-Human FUM Polyclonal Antibody Knockout Validated

Rare genetic lipid disorders comprise all the monogenic disorders of lipoprotein metabolism with the exception of heterozygous familial hypercholesterolaemia (FH). The creation and maintenance of patient registries is critical for disease monitoring, improving clinical best practice, facilitating research and enabling the development of novel therapeutics, but very few disease-specific rare genetic lipid disorder registries currently exist. Our aim was to design, develop and deploy a web-based patient registry for rare genetic lipid disorders. The Rare Genetic Lipid Disorders Registry is based on the FH Australasia Network (FHAN) Registry, which has been operating since 2015. The Rare Genetic Lipid Disorders Registry was deployed utilising the open-source Rare Disease Registry Framework (RDRF), which enables the efficient customisation and sustainable deployment of web-based registries. The Registry has been designed to capture longitudinal data on 13 rare genetic lipid disorders, with the ability to add more if required in the future. Recruitment of volunteers into the Registry is currently through the Royal Perth Hospital Lipid Disorders Clinic in Western Australia. Although in essence a clinic-based patient registry, the web-based design allows for expansion and distribution across Australia and beyond. Data collated by the Registry may ultimately improve the diagnosis, management and treatment of these conditions.

Background: Pemphigus vulgaris (PV) is an autoimmune bullous disease mediated by autoantibodies against desmoglein 3 (DSG3). Inducible costimulator (ICOS) is a costimulatory receptor expressed on T cells and influences the activity of T follicular helper (T-FH) cells in various autoimmune diseases, but the roles of ICOS and T-FH cells in PV remain unclear. Objective: We examined the immunological characteristics, antigen specificity, and pathogenicity of CD4(+) T-cell subpopulations, as well as the therapeutic effect of anti-ICOS blocking antibodies in PV. Methods: A mouse model of PV was established by adoptive transfer of immune cells from the skin-draining lymph nodes or spleens of DSG3-expressing skin-grafted Dsg3(-/-) mice into Rag1(-/-) mice. The T-FH cells and CD4(+) T cells in PBMCs from PV patients were examined by flow cytometry. Results: Among CD4(+) T cells from the mouse model, ICOS-positive T-FH cells were associated with B-cell differentiation and were required for disease induction. Using an MHC class II tetramer, DSG3-specific ICOS+ T-FH cells were found to be associated with anti-DSG3 antibody production and expanded in the absence of B cells. In human PV, the frequency of ICOS1 CXCR5(+) PD-1(+) memory CD4(+) T cells correlated with the autoantibody level. Treatment with anti-ICOS blocking antibodies targeting ICOS+ T-FH cells decreased the anti-DSG3 antibody level and delayed disease progression in vivo. Conclusions: Mouse Dsg3-specific ICOS+ T-FH cells and human ICOS(+)CXCR5(+)PD-1(+) T-H cells are associated with the anti-DSG3 antibody response in PV. ICOS expressed on CXCR5(+)PD-1(+) T-H cells may be a therapeutic target for PV.