Biology subjects

Goh, S.

Publications and source records attributed to Goh, S..

4 recordsLinked to original sources

bioRxiv2026

Unconventional presentation of an immunodominant HLA-DR15-restricted nephritogenic proteinase 3 epitope implicated in vasculitis

Proteinase 3 (PR3) anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is associated with HLA-DR15, implicating HLA-DR15-restricted CD4 T cell autoimmunity in the disease. However, the PR3 epitopes presented by HLA-DR15 and the autoreactive CD4 T cell responses they elicit are undefined. Using humanized hPR3.DR15+ mice, we identified PR3216-231 as an immunodominant human PR3-derived CD4 T cell epitope presented by HLA-DR15. Immunopeptidomic profiling confirmed the natural processing and HLA-DR15-restricted presentation of PR3216-231. Structural analyses of HLA-DR15-PR3216-231 complexes revealed an unconventional mode of HLA class II antigen presentation, in which a 10 amino acid peptide core occupies the 9 amino acid binding groove, causing a central kink in the bound peptide. PR3216-231-specific CD4 T cells from both hPR3.DR15+ mice and patients with PR3-ANCA-associated vasculitis exhibited convergent T cell receptor features, and patients with active vasculitis displayed a clonally expanded, PR3216-231-specific CD4 TCR repertoire. Immunization of hPR3.DR15 mice with PR3216-231 induced cell-mediated glomerulonephritis characterized by increased renal infiltration of CD4 T cells and macrophages together with segmental glomerular necrosis. These findings identify a nephritogenic PR3-derived CD4 T cell epitope presented by HLA-DR15 in ANCA-associated vasculitis and define a new extended core binding pattern, broadening our understanding of HLA class II peptide presentation.

immunology↗

bioRxiv2025

Clinical relevance of zebrafish for gene variants testing. Proof-of-principle with SMN1/SMA.

Spinal muscular atrophy (SMA) results from SMN1 gene loss-of-function (LOF), with disease severity directly linked to the level of remaining SMN protein. Nusinersen, risdiplam and onasemnogene abeparvovec are revolutionary treatments but should ideally be implemented before clinical symptoms appear. Because of this, prenatal and newborn screenings are increasingly used to identify common SMN1 mutations and patients requiring therapy. However, for novel mutations, clinicians lack robust analytic tools to predict pathogenicity before irreversible damage occurs. To address this gap, we deployed a zebrafish model presenting smn1-LOF, exhibiting progressive motor defects and death by only six days of age. We evaluated two SMN1-variants (VUS) identified in newborn patients awaiting definite diagnosis and treatment recommendations. We demonstrated that while known pathogenic variants did not change the disease course, wild-type SMN1 and both patient variants rescued SMA hallmarks in zebrafish, demonstrating the relevance of this approach for VUS-testing within a crucial timeframe for patients. Both VUS turned out to be non-pathogenic, and therapeutic costs of >US$2 million per child were avoided. Beyond SMA, this study provides robust proof-of-principle that the zebrafish represents a powerful translational tool for VUS-analysis, and that such approaches should be considered in clinical settings for supporting diagnosis and treatment decisions.

neuroscience↗

bioRxiv2021

Development of a yeast-based vaccine for Theileria parva infection in cattle

East Coast Fever (ECF), caused by the tick-borne apicomplexan parasite Theileria parva, remains one of the most important livestock diseases in sub-Saharan Africa with more than 1 million cattle dying from infection every year. Disease prevention relies on the so-called "Infection and Treatment Method" (ITM), which is costly, complex, laborious, difficult to standardise on a commercial scale and results in a parasite strain specific, MHC class I restricted cytotoxic T cell response. We therefore attempted to develop a safe, affordable, stable, orally applicable and potent subunit vaccine for ECF using five different T. parva schizont antigens (Tp1, Tp2, Tp9, Tp10 and N36) and Saccharomyces cerevisiae as an expression platform. Full-length native Tp2 and Tp9 as well as fragments of native Tp1 were successfully expressed on the surface of S. cerevisiae. In vitro analyses highlighted that recombinant yeast expressing Tp2 can elicit IFNy responses using PBMCs from ITM-animals, while Tp2 and Tp9 induced IFNy responses from enriched bovine CD8+ T cells. A subsequent in vivo study showed that oral administration of heat-inactivated, freeze-dried yeast stably expressing Tp2 increased total murine serum IgG over time, but more importantly, induce Tp2 specific serum IgG antibodies in individual mice compared to the control group. While these results will require subsequent experiments to verify induction of protection in neonatal calves, our data indicates that oral application of yeast expressing Theileria antigens could provide an affordable and easy vaccination platform for sub-Saharan Africa. Evaluation of antigen specific cellular immune responses, especially cytotoxic CD8+ T cell immunity in cows will further contribute to the development of a yeast-based vaccine for ECF.

immunology↗

bioRxiv2019

CD38 is a good predictor of anti-PD-1 immunotherapy responsiveness in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated mortality in the world. However, with the associated low five-year survival and high recurrence rates, alternative treatment modalities specifically immunotherapy have been researched. A correlation between CD38+ tumour-infiltrating leukocyte (TIL) density and improved prognosis was found in a recent study. However, studies relating to CD38 expression in immune infiltrates within tumours are limited. In the present study, we confirmed the expression of CD38 on macrophages in HCC and determined the relationship between CD38+ leukocytes and lymphocytes and patient response to immunotherapy. Using immunohistochemistry, we analysed tissue samples obtained from 20 patients from Singapore with HCC prior to immunotherapy. Tumour infiltrating leukocytes expression within tumour were correlated to the responsiveness of patients to immunotherapy.\n\nExpression of CD38 was found within the tumour cells and surrounding immune infiltrates including lymphocytes and macrophages. We then ask whether CD38 expression by the distinct cell populations may acquire theranostic relevance. Patients with higher level of CD38+ immune infiltrate subsets had significantly better response to anti-PD-1 immunotherapy, and this is also true for CD38+ lymphocytes within the tumour microenvironment. In particular, a cut-off of 13.0% positive out of total leukocytes and 12.4% positive out of total lymphocytes is found to be of strong predictive value of responsiveness to immunotherapy treatment, thus a strong theranostic impact is seen by using CD38 as a biomarker for anti-PD-1 therapy.\n\nThe establishment of an association between CD38 expression and the response to anti-PD-1 immunotherapy in HCC, could be applied to a larger cohort outside Singapore. These may eventually change the routine testing in clinical practice to identify HCC patients suitable for immunotherapy.

cancer biology↗