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Bridging the divide between academia and industry is the sacred goal of many researchers, but few are equipped to take their ideas from the bench to the boardroom.
Bridging science and accessibility: a tactile journey from gluten through to coeliac disease.
As part of the Monash Sensory Science Exhibition, our team guided participants through a multisensory journey unraveling coeliac disease development and pathology. Through tactile and sensory exhibits, we showed how benign dietary gluten can be transformed into a harmful entity for the 1 in 70 Australians with this illness. In contrast to the common misconception of coeliac disease as a food allergy, our exhibits revealed its closer association with autoimmune diseases such as type 1 diabetes, involving genetic susceptibility linked to specific human leukocyte antigens, crucial antigen-specific T- and B-cell responses and autoantibody production. Tactile models underscored the severe consequences of the proinflammatory immune response to gluten on patient health and quality of life. This educational event affirmed to us the value and importance of fostering inclusivity in science education.
Access all areas: multisensory science exhibitions tailored toward blind, low-vision and diverse-needs communities.
Monash Sensory Science is a scientific outreach initiative specifically tailored to members of the community who are blind, have low vision and have diverse needs. The purpose of this initiative is to showcase Australian science and encourage greater participation in science from these often-overlooked communities. This article presents our experience in establishing Monash Sensory Science at Monash University and inspiring other institutions to launch similar outreach events.
Conveying the pathogenesis of type 1 diabetes to the blind, low-vision and diverse needs communities through sensory stimulation.
To educate members of the blind, low-vision and diverse needs communities on the pathogenesis of the chronic autoimmune disease, type 1 diabetes, members of our team with research expertise in immune-mediated diseases, participated in the 2023 Monash Sensory Science (MSS) Exhibition. Using QR code linked audio commentary, participants were guided through tactile displays demonstrating normal insulin action in the regulation of blood glucose levels and its vital role in providing energy to tissues, followed by displays describing the various stages of the immune system's aberrant attack and the eventual complete destruction of the insulin producing beta-cells of the pancreatic islets in type 1 diabetes. These models conveyed to the participants the huge effect that this autoimmune-mediated disease has on the quality of life of affected individuals including the subsequent lifelong reliance on insulin injections to maintain glucose homeostasis. This MSS Exhibition provided a unique opportunity for our researchers to engage with under-represented members of the community and to raise awareness about such a debilitating and common autoimmune disease.
Structural bases of T cell antigen receptor recognition in celiac disease.
Celiac disease (CeD) is a human leukocyte antigen (HLA)-linked autoimmune-like disorder that is triggered by the ingestion of gluten or related storage proteins. The majority of CeD patients are HLA-DQ2.5+, with the remainder being either HLA-DQ8+ or HLA-DQ2.2+. Structural studies have shown how deamidation of gluten epitopes engenders binding to HLA-DQ2.5/8, which then triggers an aberrant CD4+ T cell response. HLA tetramer studies, combined with structural investigations, have demonstrated that repeated patterns of TCR usage underpins the immune response to some HLADQ2.5/8 restricted gluten epitopes, with distinct TCR motifs representing common landing pads atop the HLA-gluten complexes. Structural studies have provided insight into TCR specificity and cross-reactivity towards gluten epitopes, as well as cross-reactivity to bacterial homologues of gluten epitopes, suggesting that environmental factors may directly play a role in CeD pathogenesis. Collectively, structural immunology-based studies in the CeD axis may lead to new therapeutics/diagnostics to treat CeD, and also serve as an exemplar for other T cell mediated autoimmune diseases.
Structural basis of T cell receptor specificity and cross-reactivity of two HLA-DQ2.5-restricted gluten epitopes in celiac disease.
Celiac disease is a T cell-mediated chronic inflammatory condition often characterized by human leukocyte antigen (HLA)-DQ2.5 molecules presenting gluten epitopes derived from wheat, barley, and rye. Although some T cells exhibit cross-reactivity toward distinct gluten epitopes, the structural basis underpinning such cross-reactivity is unclear. Here, we investigated the T-cell receptor specificity and cross-reactivity of two immunodominant wheat gluten epitopes, DQ2.5-glia-α1a (PFPQPELPY) and DQ2.5-glia-ω1 (PFPQPEQPF). We show by surface plasmon resonance that a T-cell receptor alpha variable (TRAV) 4+-T-cell receptor beta variable (TRBV) 29-1+ TCR bound to HLA-DQ2.5-glia-α1a and HLA-DQ2.5-glia-ω1 with similar affinity, whereas a TRAV4- (TRAV9-2+) TCR recognized HLA-DQ2.5-glia-ω1 only. We further determined the crystal structures of the TRAV4+-TRBV29-1+ TCR bound to HLA-DQ2.5-glia-α1a and HLA-DQ2.5-glia-ω1, as well as the structure of an epitope-specific TRAV9-2+-TRBV7-3+ TCR-HLA-DQ2.5-glia-ω1 complex. We found that position 7 (p7) of the DQ2.5-glia-α1a and DQ2.5-glia-ω1 epitopes made very limited contacts with the TRAV4+ TCR, thereby explaining the TCR cross-reactivity across these two epitopes. In contrast, within the TRAV9-2+ TCR-HLA-DQ2.5-glia-ω1 ternary complex, the p7-Gln was situated in an electrostatic pocket formed by the hypervariable CDR3β loop of the TCR and Arg70β from HLA-DQ2.5, a polar network which would not be supported by the p7-Leu residue of DQ2.5-glia-α1a. In conclusion, we provide additional insights into the molecular determinants of TCR specificity and cross-reactivity to two closely-related epitopes in celiac disease.
T cell receptor cross-reactivity between gliadin and bacterial peptides in celiac disease.
The human leukocyte antigen (HLA) locus is strongly associated with T cell-mediated autoimmune disorders. HLA-DQ2.5-mediated celiac disease (CeD) is triggered by the ingestion of gluten, although the relative roles of genetic and environmental risk factors in CeD is unclear. Here we identify microbially derived mimics of gliadin epitopes and a parental bacterial protein that is naturally processed by antigen-presenting cells and activated gliadin reactive HLA-DQ2.5-restricted T cells derived from CeD patients. Crystal structures of T cell receptors in complex with HLA-DQ2.5 bound to two distinct bacterial peptides demonstrate that molecular mimicry underpins cross-reactivity toward the gliadin epitopes. Accordingly, gliadin reactive T cells involved in CeD pathogenesis cross-react with ubiquitous bacterial peptides, thereby suggesting microbial exposure as a potential environmental factor in CeD.
Discriminative T-cell receptor recognition of highly homologous HLA-DQ2-bound gluten epitopes.
Celiac disease (CeD) provides an opportunity to study the specificity underlying human T-cell responses to an array of similar epitopes presented by the same human leukocyte antigen II (HLA-II) molecule. Here, we investigated T-cell responses to the two immunodominant and highly homologous HLA-DQ2.5-restricted gluten epitopes, DQ2.5-glia-α1a (PFPQPELPY) and DQ2.5-glia-ω1 (PFPQPEQPF). Using HLA-DQ2.5-DQ2.5-glia-α1a and HLA-DQ2.5-DQ2.5-glia-ω1 tetramers and single-cell αβ T-cell receptor (TCR) sequencing, we observed that despite similarity in biased variable-gene usage in the TCR repertoire responding to these nearly identical peptide-HLA-II complexes, most of the T cells are specific for either of the two epitopes. To understand the molecular basis of this exquisite fine specificity, we undertook Ala substitution assays revealing that the p7 residue (Leu/Gln) is critical for specific epitope recognition by both DQ2.5-glia-α1a- and DQ2.5-glia-ω1-reactive T-cell clones. We determined high-resolution binary crystal structures of HLA-DQ2.5 bound to DQ2.5-glia-α1a (2.0 Å) and DQ2.5-glia-ω1 (2.6 Å). These structures disclosed that differences around the p7 residue subtly alter the neighboring substructure and electrostatic properties of the HLA-DQ2.5-peptide complex, providing the fine specificity underlying the responses against these two highly homologous gluten epitopes. This study underscores the ability of TCRs to recognize subtle differences in the peptide-HLA-II landscape in a human disease setting.
Sideways lipid presentation by the antigen-presenting molecule CD1c.
For the MHC, MR1 and CD1 systems, antigen recognition involves contact of the membrane distal surfaces of both the αβ T cell receptor (TCR) and the antigen-presenting molecule. Whether other antigen display mechanisms by antigen-presenting molecules operate remains unknown. Here, we report mass spectrometry analyses of endogenous lipids captured by CD1c when bound to an autoreactive αβ TCR. CD1c binds twenty-six lipid species with bulky headgroups that cannot fit within the tight TCR-CD1c interface. We determined the crystal structures of CD1c presenting several gangliosides, revealing a general mechanism whereby two lipids, rather than one, are bound in the CD1c cleft. Bulky lipids are oriented sideways so that their polar headgroups protrude laterally through a side portal of the CD1c molecule - an evolutionarily conserved structural feature. The sideways-presented ganglioside headgroups do not hinder TCR binding and so represent a mechanism that allows autoreactive TCR recognition of CD1c. In addition, ex vivo studies showed that the sideways-presented gangliosides can also represent TCR recognition determinants. These findings reveal that CD1c simultaneously presents two lipid antigens from the top and side of its cleft, a general mechanism that differs markedly from other antigen-presenting molecules.
Multi-organ abnormalities assessed by a single MRI scan in individuals with blood cancer.
BACKGROUND: During the COVID-19 pandemic individuals with all blood cancers were classified as clinically vulnerable and at high risk of complications and death. Our study sought to determine if individuals with specific blood cancers were at a heightened risk of longer term organ impairment, secondary to SARS-CoV-2 infection. METHODS: We set up a prospective observational study, utilising quantitative multi-parametric MRI to determine organ health over time in patients with specific blood cancers who had recovered from COVID-19. RESULTS: Multi-organ abnormality was more prevalent in blood cancer patients than in healthy controls (42 % vs 6 % p < 0.001) but comparable to the long COVID controls (42 % vs 33 %, p > 0.05). At 6 month follow up scans, organ abnormalities persisted in most individuals with blood cancer (71 % ≥1 organ and 52 % multi-organ). CONCLUSION: A multi-organ MRI platform offers the capacity to accurately evaluate organ health dynamically in blood cancers and detect asymptomatic organ impairment. The application of multi-organ MRI could aid early detection and longitudinal monitoring of organ impairment, potentially guiding more personalised treatment strategies and improving clinical outcomes in many rare diseases.
FLT3-ITDs instruct a myeloid differentiation and transformation bias in lymphomyeloid multipotent progenitors.
Whether signals mediated via growth factor receptors (GFRs) might influence lineage fate in multipotent progenitors (MPPs) is unclear. We explored this issue in a mouse knockin model of gain-of-function Flt3-ITD mutation because FLT3-ITDs are paradoxically restricted to acute myeloid leukemia even though Flt3 primarily promotes lymphoid development during normal hematopoiesis. When expressed in MPPs, Flt3-ITD collaborated with Runx1 mutation to induce high-penetrance aggressive leukemias that were exclusively of the myeloid phenotype. Flt3-ITDs preferentially expanded MPPs with reduced lymphoid and increased myeloid transcriptional priming while compromising early B and T lymphopoiesis. Flt3-ITD-induced myeloid lineage bias involved upregulation of the transcription factor Pu.1, which is a direct target gene of Stat3, an aberrantly activated target of Flt3-ITDs, further establishing how lineage bias can be inflicted on MPPs through aberrant GFR signaling. Collectively, these findings provide new insights into how oncogenic mutations might subvert the normal process of lineage commitment and dictate the phenotype of resulting malignancies.
Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo.
Evidence for distinct human cancer stem cells (CSCs) remains contentious and the degree to which different cancer cells contribute to propagating malignancies in patients remains unexplored. In low- to intermediate-risk myelodysplastic syndromes (MDS), we establish the existence of rare multipotent MDS stem cells (MDS-SCs), and their hierarchical relationship to lineage-restricted MDS progenitors. All identified somatically acquired genetic lesions were backtracked to distinct MDS-SCs, establishing their distinct MDS-propagating function in vivo. In isolated del(5q)-MDS, acquisition of del(5q) preceded diverse recurrent driver mutations. Sequential analysis in del(5q)-MDS revealed genetic evolution in MDS-SCs and MDS-progenitors prior to leukemic transformation. These findings provide definitive evidence for rare human MDS-SCs in vivo, with extensive implications for the targeting of the cells required and sufficient for MDS-propagation.
Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo
Evidence for distinct human cancer stem cells (CSCs) remains contentious and the degree to which differentcancer cells contribute to propagating malignancies in patients remains unexplored. In low- to intermediate-risk myelodysplastic syndromes (MDS), we establish the existence of rare multipotent MDS stem cells (MDS-SCs), and their hierarchical relationship to lineage-restricted MDS progenitors. All identified somatically acquired genetic lesions were backtracked to distinct MDS-SCs, establishing their distinct MDS-propagating function invivo. In isolated del(5q)-MDS, acquisition of del(5q) preceded diverse recurrent driver mutations. Sequential analysis in del(5q)-MDS revealed genetic evolution in MDS-SCs and MDS-progenitors prior to leukemic transformation. These findings provide definitive evidence for rare human MDS-SCs invivo, with extensive implications for the targeting of the cells required and sufficient for MDS-propagation. © 2014 Elsevier Inc.
Platelet-biased stem cells reside at the apex of the haematopoietic stem-cell hierarchy
The blood system is maintained by a small pool of haematopoietic stem cells (HSCs), which are required and sufficient for replenishing all human blood cell lineages at millions of cells per second throughout life. Megakaryocytes in the bone marrow are responsible for the continuous production of platelets in the blood, crucial for preventing bleeding - a common and life-threatening side effect of many cancer therapies - and major efforts are focused at identifying the most suitable cellular and molecular targets to enhance platelet production after bone marrow transplantation or chemotherapy. Although it has become clear that distinct HSC subsets exist that are stably biased towards the generation of lymphoid or myeloid blood cells, we are yet to learn whether other types of lineage-biased HSC exist or understand their inter-relationships and how differently lineage-biased HSCs are generated and maintained. The functional relevance of notable phenotypic and molecular similarities between megakaryocytes and bone marrow cells with an HSC cell-surface phenotype remains unclear. Here we identify and prospectively isolate a molecularly and functionally distinct mouse HSC subset primed for platelet-specific gene expression, with enhanced propensity for short- and long-term reconstitution of platelets. Maintenance of platelet-biased HSCs crucially depends on thrombopoietin, the primary extrinsic regulator of platelet development. Platelet-primed HSCs also frequently have a long-term myeloid lineage bias, can self-renew and give rise to lymphoid-biased HSCs. These findings show that HSC subtypes can be organized into a cellular hierarchy, with platelet-primed HSCs at the apex. They also demonstrate that molecular and functional priming for platelet development initiates already in a distinct HSC population. The identification of a platelet-primed HSC population should enable the rational design of therapies enhancing platelet output. © 2013 Macmillan Publishers Limited. All rights reserved.
Platelet-biased stem cells reside at the apex of the haematopoietic stem-cell hierarchy.
The blood system is maintained by a small pool of haematopoietic stem cells (HSCs), which are required and sufficient for replenishing all human blood cell lineages at millions of cells per second throughout life. Megakaryocytes in the bone marrow are responsible for the continuous production of platelets in the blood, crucial for preventing bleeding--a common and life-threatening side effect of many cancer therapies--and major efforts are focused at identifying the most suitable cellular and molecular targets to enhance platelet production after bone marrow transplantation or chemotherapy. Although it has become clear that distinct HSC subsets exist that are stably biased towards the generation of lymphoid or myeloid blood cells, we are yet to learn whether other types of lineage-biased HSC exist or understand their inter-relationships and how differently lineage-biased HSCs are generated and maintained. The functional relevance of notable phenotypic and molecular similarities between megakaryocytes and bone marrow cells with an HSC cell-surface phenotype remains unclear. Here we identify and prospectively isolate a molecularly and functionally distinct mouse HSC subset primed for platelet-specific gene expression, with enhanced propensity for short- and long-term reconstitution of platelets. Maintenance of platelet-biased HSCs crucially depends on thrombopoietin, the primary extrinsic regulator of platelet development. Platelet-primed HSCs also frequently have a long-term myeloid lineage bias, can self-renew and give rise to lymphoid-biased HSCs. These findings show that HSC subtypes can be organized into a cellular hierarchy, with platelet-primed HSCs at the apex. They also demonstrate that molecular and functional priming for platelet development initiates already in a distinct HSC population. The identification of a platelet-primed HSC population should enable the rational design of therapies enhancing platelet output.