Publications by authors named "A Richard Kitching"

217 Publications

Recurrent membranous nephropathy after transplantation: donor antigen and HLA converge in defining risk.

Kidney Int 2021 03;99(3):545-548

Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Monash University, Clayton, Victoria, Australia; Department of Nephrology, Monash Health, Clayton, Victoria, Australia; Department of Pediatric Nephrology, Monash Health, Clayton, Victoria, Australia. Electronic address:

Membranous nephropathy, like many forms of glomerulonephritis, is an HLA-associated autoimmune disease that can recur in the transplanted kidney. In this issue of Kidney International, Berchtold and colleagues publish an intriguing and important paper on risk factors for recurrent post-transplant membranous nephropathy due to autoimmunity to PLA2R1. They found that the genetics of both the autoantigen and donor HLA are important determinants of the risk of recurrent disease in the graft.
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http://dx.doi.org/10.1016/j.kint.2020.10.044DOI Listing
March 2021

vLUME: 3D virtual reality for single-molecule localization microscopy.

Nat Methods 2020 11 12;17(11):1097-1099. Epub 2020 Oct 12.

Department of Chemistry, University of Cambridge, Cambridge, UK.

vLUME is a virtual reality software package designed to render large three-dimensional single-molecule localization microscopy datasets. vLUME features include visualization, segmentation, bespoke analysis of complex local geometries and exporting features. vLUME can perform complex analysis on real three-dimensional biological samples that would otherwise be impossible by using regular flat-screen visualization programs.
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http://dx.doi.org/10.1038/s41592-020-0962-1DOI Listing
November 2020

ANCA-associated vasculitis.

Nat Rev Dis Primers 2020 08 27;6(1):71. Epub 2020 Aug 27.

Department of Pathology, Medical University Vienna, Vienna, Austria.

The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are a group of disorders involving severe, systemic, small-vessel vasculitis and are characterized by the development of autoantibodies to the neutrophil proteins leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). The three AAV subgroups, namely granulomatosis with polyangiitis (GPA), microscopic polyangiitis and eosinophilic GPA (EGPA), are defined according to clinical features. However, genetic and other clinical findings suggest that these clinical syndromes may be better classified as PR3-positive AAV (PR3-AAV), MPO-positive AAV (MPO-AAV) and, for EGPA, by the presence or absence of ANCA (ANCA or ANCA, respectively). Although any tissue can be involved in AAV, the upper and lower respiratory tract and kidneys are most commonly and severely affected. AAVs have a complex and unique pathogenesis, with evidence for a loss of tolerance to neutrophil proteins, which leads to ANCA-mediated neutrophil activation, recruitment and injury, with effector T cells also involved. Without therapy, prognosis is poor but treatments, typically immunosuppressants, have improved survival, albeit with considerable morbidity from glucocorticoids and other immunosuppressive medications. Current challenges include improving the measures of disease activity and risk of relapse, uncertainty about optimal therapy duration and a need for targeted therapies with fewer adverse effects. Meeting these challenges requires a more detailed knowledge of the fundamental biology of AAV as well as cooperative international research and clinical trials with meaningful input from patients.
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http://dx.doi.org/10.1038/s41572-020-0204-yDOI Listing
August 2020

Tertiary lymphoid tissue in kidneys: understanding local immunity and inflammation.

Kidney Int 2020 08;98(2):280-283

Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia; Department of Nephrology, Monash Health, Clayton, Victoria, Australia; Department of Pediatric Nephrology, Monash Health, Clayton, Victoria, Australia. Electronic address:

Tertiary lymphoid tissues are peripheral foci of immune activity that develop in kidneys and other peripheral organs in the context of chronic inflammation. In this issue of Kidney International, Sato and colleagues present a detailed characterization of tertiary lymphoid tissues in mouse and human kidneys in the context of acute kidney injury, chronic pyelonephritis, aging, and chronic kidney disease, showing the importance of nontraditional roles of B cells in the inflamed kidney microenvironment.
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http://dx.doi.org/10.1016/j.kint.2020.04.026DOI Listing
August 2020

Atypical clinical presentation of Ebola virus disease in pregnancy: Implications for clinical and public health management.

Int J Infect Dis 2020 Aug 22;97:167-173. Epub 2020 May 22.

Ministry of Health and Sanitation, Youyi Building, Freetown, Sierra Leone.

Background: Between December 2013 and June 2016, West Africa experienced the largest Ebola virus disease (EVD) outbreak in history. Understanding EVD in pregnancy is important for EVD clinical screening and infection prevention and control.

Methods: We conducted a review of medical records and EVD investigation reports from three districts in Sierra Leone. We report the clinical presentations and maternal and fetal outcomes of six pregnant women with atypical EVD, and subsequent transmission events from perinatal care.

Results: The six women (ages 18-38) were all in the third trimester. Each presented with signs and symptoms initially attributed to pregnancy. None met EVD case definition; only one was known at presentation to be a contact of an EVD case. Five women died, and all six fetuses/neonates died. These cases resulted in at least 35 additional EVD cases.

Conclusions: These cases add to the sparse literature focusing on pregnant women with EVD, highlighting challenges and implications for outbreak control. Infected newborns may also present atypically and may shed virus while apparently asymptomatic. Pregnant women identified a priori as contacts of EVD cases require special attention and planning for obstetrical care.
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http://dx.doi.org/10.1016/j.ijid.2020.05.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383225PMC
August 2020

Experimental Antiglomerular Basement Membrane GN Induced by a Peptide from .

J Am Soc Nephrol 2020 06;31(6):1282-1295

Renal Division, Peking University First Hospital, Beijing, PR China.

Background: Antiglomerular basement membrane (anti-GBM) disease is associated with HLA-DRB1*1501 (the major predisposing genetic factor in the disease), with 3 as a nephritogenic T and B cell epitope. Although the cause of disease remains unclear, the association of infections with anti-GBM disease has been long suspected.

Methods: To investigate whether microbes might activate autoreactive T and B lymphocytes molecular mimicry in anti-GBM disease, we used bioinformatic tools, including BLAST, SYFPEITHI, and ABCpred, for peptide searching and epitope prediction. We used sera from patients with anti-GBM disease to assess peptides recognized by antibodies, and immunized WKY rats and a humanized mouse model (HLA-DR15 transgenic mice) with each of the peptide candidates to assess pathogenicity.

Results: On the basis of the critical motif, the bioinformatic approach identified 36 microbial peptides that mimic human 3. Circulating antibodies in sera from patients with anti-GBM recognized nine of them. One peptide, B7, derived from species, induced proteinuria, linear IgG deposition on the GBM, and crescent formation when injected into WKY rats. The antibodies to B7 also targeted human and rat 3. B7 induced T cell activation from human 3-immunized rats. T cell responses to B7 were detected in rats immunized by lysate proteins or recombinant proteins. We confirmed B7's pathogenicity in HLA-DR15 transgenic mice that developed kidney injury similar to that observed in 3-immunized mice.

Conclusions: Sera from patients with anti-GBM disease recognized microbial peptides identified through a bioinformatic approach, and a peptide from induced experimental anti-GBM GN by T and B cell crossreactivity. These studies demonstrate that anti-GBM disease may be initiated by immunization with a microbial peptide.
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http://dx.doi.org/10.1681/ASN.2019060619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269348PMC
June 2020

Animal Models of ANCA Associated Vasculitis.

Front Immunol 2020 9;11:525. Epub 2020 Apr 9.

Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC, Australia.

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a rare and severe autoimmune multisystemic disease. Its pathogenesis involves multiple arms of the immune system, as well as complex interactions between immune cells and target organs. Experimental animal models of disease can provide the crucial link from human disease to translational research into new therapies. This is particularly true in AAV, due to low disease incidence and substantial disease heterogeneity. Animal models allow for controlled environments in which disease mechanisms can be defined, without the clinical confounders of environmental and lifestyle factors. To date, multiple animal models have been developed, each of which shed light on different disease pathways. Results from animal studies of AAV have played a crucial role in enhancing our understanding of disease mechanisms, and have provided direction toward newer targeted therapies. This review will summarize our understanding of AAV pathogenesis as has been gleaned from currently available animal models, as well as address their strengths and limitations. We will also discuss the potential for current and new animal models to further our understanding of this important condition.
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http://dx.doi.org/10.3389/fimmu.2020.00525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179669PMC
April 2020

Identifying Outcomes Important to Patients with Glomerular Disease and Their Caregivers.

Clin J Am Soc Nephrol 2020 05 30;15(5):673-684. Epub 2020 Apr 30.

Sydney School of Public Health, The University of Sydney, Sydney, New South Wales, Australia.

Background And Objectives: Shared decision making in patients with glomerular disease remains challenging because outcomes important to patients remain largely unknown. We aimed to identify and prioritize outcomes important to patients and caregivers and to describe reasons for their choices.

Design: We purposively sampled adult patients with glomerular disease and their caregivers from Australia, Hong Kong, the United Kingdom, and the United States. Participants identified, discussed, and ranked outcomes in focus groups using the nominal group technique; a relative importance score (between zero and one) was calculated. Qualitative data were analyzed thematically.

Results: Across 16 focus groups, 134 participants (range, 19-85 years old; 51% women), including 101 patients and 33 caregivers, identified 58 outcomes. The ten highest-ranked outcomes were kidney function (importance score of 0.42), mortality (0.29), need for dialysis or transplant (0.22), life participation (0.18), fatigue (0.17), anxiety (0.13), family impact (0.12), infection and immunity (0.12), ability to work (0.11), and BP (0.11). Three themes explained the reasons for these rankings: constraining day-to-day experience, impaired agency and control over health, and threats to future health and family.

Conclusions: Patients with glomerular disease and their caregivers highly prioritize kidney health and survival, but they also prioritize life participation, fatigue, anxiety, and family impact.
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http://dx.doi.org/10.2215/CJN.13101019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269216PMC
May 2020

Molecular Analysis of Goodpasture's Disease Following Hematopoietic Stem Cell Transplant in a Pediatric Patient, Recalls the Conformeropathy of Wild-Type Anti-GBM Disease.

Front Immunol 2019 14;10:2659. Epub 2019 Nov 14.

Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States.

Goodpasture's disease (GP) is mediated by autoantibodies that bind the glomerular and alveolar basement membrane, causing rapidly progressive glomerulonephritis with or without pulmonary hemorrhage. The autoantibodies bind neoepitopes formed upon disruption of the quaternary structure of α345NC1 hexamer, a critical structural domain of α345 collagen IV scaffolds. Hexamer disruption leads to a conformational changes that transitions α3 and α5NC1 subunits into immunogens, however, the trigger remains unknown. This contrasts with another anti-GBM disease, Alports' post-transplant nephritis (APTN), where the pathogenic alloantibody binds directly to native NC1 hexamer. The current report includes the first study of antigenic specificity and allo-incompatability in anti-GBM disease occurring after allogeneic haematopoietic stem cell transplant (HSCT). The anti-GBM antibodies were found to be directed predominantly against the E epitope of the α3 NC1 monomer of collagen IV and developed rapidly in patient serum reaching peak level within 5 weeks. Autoantibody binding to native α345NC1 hexamer was minimal; however, binding was greatly increased upon dissociation of the native hexamer. There were no polymorphic genetic differences between donor and recipient collagen IV genes which would be predicted to cause a significant NC1 conformational change or to provide a target for antibody binding. Both patient and donor possessed the Goodpasture's susceptibility HLA-allele . The current report includes the first in-depth study of allo-incompatability and antigenic specificity in anti-GBM disease occurring after allogeneic haematopoietic stem cell transplant (HSCT). No polymorphic genetic differences were identified between donor and recipient collagen IV genes which would be predicted to provide a target for antibody binding. Furthermore, autoantibody binding to native α345NC1 hexamer was minimal, increasing greatly upon dissociation of the native hexamer, resembling wild-type GP diseases and marking this as the first example of a post-HSCT conformeropathy.
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http://dx.doi.org/10.3389/fimmu.2019.02659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868084PMC
November 2020

PD-L1- and calcitriol-dependent liposomal antigen-specific regulation of systemic inflammatory autoimmune disease.

JCI Insight 2019 09 19;4(18). Epub 2019 Sep 19.

The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Queensland, Australia.

Autoimmune diseases resulting from MHC class II-restricted autoantigen-specific T cell immunity include the systemic inflammatory autoimmune conditions rheumatoid arthritis and vasculitis. While currently treated with broad-acting immunosuppressive drugs, a preferable strategy is to regulate antigen-specific effector T cells (Teffs) to restore tolerance by exploiting DC antigen presentation. We targeted draining lymph node (dLN) phagocytic DCs using liposomes encapsulating 1α,25-dihydroxyvitamin D3 (calcitriol) and antigenic peptide to elucidate mechanisms of tolerance used by DCs and responding T cells under resting and immunized conditions. PD-L1 expression was upregulated in dLNs of immunized relative to naive mice. Subcutaneous administration of liposomes encapsulating OVA323-339 and calcitriol targeted dLN PD-L1hi DCs of immunized mice and reduced their MHC class II expression. OVA323-339/calcitriol liposomes suppressed expansion, differentiation, and function of Teffs and induced Foxp3+ and IL-10+ peripheral Tregs in an antigen-specific manner, which was dependent on PD-L1. Peptide/calcitriol liposomes modulated CD40 expression by human DCs and promoted Treg induction in vitro. Liposomes encapsulating calcitriol and disease-associated peptides suppressed the severity of rheumatoid arthritis and Goodpasture's vasculitis models with suppression of antigen-specific memory T cell differentiation and function. Accordingly, peptide/calcitriol liposomes leverage DC PD-L1 for antigen-specific T cell regulation and induce antigen-specific tolerance in inflammatory autoimmune diseases.
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http://dx.doi.org/10.1172/jci.insight.126025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795297PMC
September 2019

Tolerogenic Dendritic Cells Attenuate Experimental Autoimmune Antimyeloperoxidase Glomerulonephritis.

J Am Soc Nephrol 2019 11 23;30(11):2140-2157. Epub 2019 Aug 23.

Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Australia.

Because of their capacity to induce antigen-specific immunosuppression, tolerogenic dendritic cells are a promising tool for treatment of autoimmune conditions, such as GN caused by autoimmunity against myeloperoxidase (MPO).

Methods: We sought to generate tolerogenic dendritic cells to suppress anti-MPO GN by culturing bone marrow cells with an NFB inhibitor (BAY 11-7082) and exposing them to a pulse of MPO. After administering these MPO/BAY dendritic cells or saline to mice with established anti-MPO or anti-methylated BSA (mBSA) immunity, we assessed immune responses and GN. We also examined mechanisms of action of MPO/BAY dendritic cells.

Results: MPO/BAY dendritic cells decreased anti-MPO immunity and GN without inhibiting immune responses against mBSA; they also induced IL-10-producing regulatory T cells in MPO-immunized mice without affecting IL-10 CD4Foxp3 type 1 regulatory T cells or regulatory B cells. MPO/BAY dendritic cells did not inhibit anti-MPO immunity when CD4Foxp3 cells were depleted , showing that regulatory T cells are required for their effects. Coculture experiments with dendritic cells and CD4Foxp3 or CD4Foxp3 cells showed that MPO/BAY dendritic cells generate Foxp3 regulatory T cells from CD4Foxp3 cells through several pathways, and induce IL-10 regulatory T cells inducible costimulator (ICOS), which was confirmed . Transfer of MPO/BAY dendritic cell-induced regulatory T cells , with or without anti-IL-10 receptor antibody, demonstrated that they suppress anti-MPO immunity and GN IL-10.

Conclusions: MPO/BAY dendritic cells attenuate established anti-MPO autoimmunity and GN in an antigen-specific manner through ICOS-dependent induction of IL-10-expressing regulatory T cells. This suggests that autoantigen-loaded tolerogenic dendritic cells may represent a novel antigen-specific therapeutic option for anti-MPO GN.
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http://dx.doi.org/10.1681/ASN.2019030236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830784PMC
November 2019

Biologicals targeting T helper cell subset differentiating cytokines are effective in the treatment of murine anti-myeloperoxidase glomerulonephritis.

Kidney Int 2019 11 27;96(5):1121-1133. Epub 2019 May 27.

Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, Victoria, Australia; Department of Nephrology, Monash Health, Monash Medical Centre, Clayton, Victoria, Australia; Department of Immunology, Monash Health, Monash Medical Centre, Clayton, Victoria, Australia.

Anti-myeloperoxidase nephritogenic autoimmunity induces severe glomerulonephritis. To assess the therapeutic potential of monoclonal antibodies targeting T helper (Th) subset differentiation determining cytokines, we studied a murine model of anti-myeloperoxidase glomerulonephritis. The temporal participation of T helper subsets was determined by quantitating gene expression of CD4 T-cells isolated from nephritic kidneys and cytokine production by lymphocytes from nodes draining myeloperoxidase immunization sites. Th17 cytokines (IL-17A and IL-6) rose rapidly but declined as autoimmunity matured when Th1 cytokines (IL-12 and TNF) predominated. Therefore, T helper subset participation in anti-myeloperoxidase autoimmunity is biphasic, with Th17 early and Th1 late. To confirm the functional relevance of this biphasic pattern, we compared systemic anti-myeloperoxidase autoimmunity in wild type, Th17 deficient and Th1 deficient mice. Early, Th1 deficient mice developed similar autoimmunity and glomerulonephritis to wild type mice. However, Th17 deficient mice had significantly reduced anti-myeloperoxidase autoimmunity. In late autoimmunity, Th1 deficient mice developed reduced autoimmunity and were protected from anti-myeloperoxidase glomerulonephritis. The therapeutic potential of these findings were demonstrated by neutralizing monoclonal antibodies. Targeting IL-23p19 attenuated early Th17 dominated anti-myeloperoxidase autoimmunity and glomerulonephritis but not late phase disease. Targeting IL-12p35 attenuated late phase Th1 dominated anti-myeloperoxidase autoimmunity and glomerulonephritis but not early autoimmunity or glomerulonephritis. Targeting both T helper subsets with an anti-IL-12p40 monoclonal antibody was effective during both early and late phases of anti-myeloperoxidase glomerulonephritis. Thus, definition of dominant T helper differentiating subsets in anti-myeloperoxidase glomerulonephritis by renal CD4 T-cell cytokine gene expression allows effective proper phase monoclonal antibody treatment of anti-myeloperoxidase glomerulonephritis.
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http://dx.doi.org/10.1016/j.kint.2019.05.012DOI Listing
November 2019

A plasmid-encoded peptide from Staphylococcus aureus induces anti-myeloperoxidase nephritogenic autoimmunity.

Nat Commun 2019 07 29;10(1):3392. Epub 2019 Jul 29.

Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC, 3168, Australia.

Autoreactivity to myeloperoxidase (MPO) causes anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), with rapidly progressive glomerulonephritis. Here, we show that a Staphylococcus aureus peptide, homologous to an immunodominant MPO T-cell epitope (MPO), can induce anti-MPO autoimmunity. The peptide (6PGD) is part of a plasmid-encoded 6-phosphogluconate dehydrogenase found in some S. aureus strains. It induces anti-MPO T-cell autoimmunity and MPO-ANCA in mice, whereas related sequences do not. Mice immunized with 6PGD, or with S. aureus containing a plasmid expressing 6PGD, develop glomerulonephritis when MPO is deposited in glomeruli. The peptide induces anti-MPO autoreactivity in the context of three MHC class II allomorphs. Furthermore, we show that 6PGD is immunogenic in humans, as healthy human and AAV patient sera contain anti-6PGD and anti-6PGD antibodies. Therefore, our results support the idea that bacterial plasmids might have a function in autoimmune disease.
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http://dx.doi.org/10.1038/s41467-019-11255-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662820PMC
July 2019

Apoptotic Cell-Induced, Antigen-Specific Immunoregulation to Treat Experimental Antimyeloperoxidase GN.

J Am Soc Nephrol 2019 08 23;30(8):1365-1374. Epub 2019 Jul 23.

Department of Medicine, Centre for Inflammatory Diseases, Monash University, Clayton, Victoria, Australia; and Departments of.

Background: Myeloperoxidase (MPO)-ANCA-associated GN is a significant cause of renal failure. Manipulating autoimmunity by inducing regulatory T cells is potentially a more specific and safer therapeutic option than conventional immunosuppression.

Methods: To generate MPO-specific regulatory T cells, we used a modified protein-conjugating compound, 1-ethyl-3-(3'dimethylaminopropyl)-carbodiimide (ECDI), to couple the immunodominant MPO peptide (MPO) or a control ovalbumin peptide (OVA) to splenocytes and induced apoptosis in the conjugated cells. We then administered MPO- and OVA-conjugated apoptotic splenocytes (MPO-Sps and OVA-Sps, respectively) to mice and compared their effects on development and severity of anti-MPO GN. We induced autoimmunity to MPO by immunizing mice with MPO in adjuvant; to trigger GN, we used low-dose antiglomerular basement membrane globulin, which transiently recruits neutrophils that deposit MPO in glomeruli. We also compared the effects of transferring CD4 T cells from mice treated with MPO-Sp or OVA-Sp to recipient mice with established anti-MPO autoimmunity.

Results: MPO-Sp but not OVA-Sp administration increased MPO-specific, peripherally derived CD4Foxp3 type 1 regulatory T cells and reduced anti-MPO autoimmunity and GN. However, in mice depleted of regulatory T cells, MPO-Sp administration did not protect from anti-MPO autoimmunity or GN. Mice with established anti-MPO autoimmunity that received CD4 T cells transferred from mice treated with MPO-Sp (but not CD4 T cells transferred from mice treated with OVA-Sp) were protected from anti-MPO autoimmunity and GN, confirming the induction of therapeutic antigen-specific regulatory T cells.

Conclusions: These findings in a mouse model indicate that administering apoptotic splenocytes conjugated with the immunodominant MPO peptide suppresses anti-MPO GN by inducing antigen-specific tolerance.
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http://dx.doi.org/10.1681/ASN.2018090955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683705PMC
August 2019

Key aspects for the sustainable coordination of a process to facilitate holistic well-being in South African schools.

Health Promot Int 2020 Aug;35(4):692-701

COMBER (Community-Based Educational Research), Educational Psychology, Faculty of Education, North-West University, Potchefstroom, South Africa.

A holistic well-being approach, understood as an approach that pays attention to the promotion of individual, relational and collective well-being in a particular context, is proposed as a way to address the fragmented nature in which mental health and well-being programmes are implemented in school communities in South Africa. The goal of this paper is to indicate key aspects for sustainable coordination of a process to facilitate holistic well-being in South African schools. Research was conducted in six South African schools with the aim of developing an integrated, multilevel process to facilitate holistic well-being in these contexts. A participatory action learning and action research approach was applied. As part of this research, key aspects that could contribute to the sustainable coordination of holistic well-being were identified. The research comprised a cross-case analysis of the data gathered, as well as a focus group that was held with the coordinators who facilitated the development of the process in each school. In addition, the school principals completed a semi-structured questionnaire, and Skype interviews were conducted with four international experts. The five aspects identified as key to the sustainable coordination of well-being are: that ownership and responsibility should reside in the school context; that there should be a clear vision for the promotion of holistic well-being; that the connections between all involved should be deepened; that all efforts to promote holistic well-being should be integrated, and that the complexity of the process should be acknowledged.
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http://dx.doi.org/10.1093/heapro/daz060DOI Listing
August 2020

HLA-DR15-specific inhibition attenuates autoreactivity to the Goodpasture antigen.

J Autoimmun 2019 09 16;103:102276. Epub 2019 May 16.

Centre for Inflammatory Diseases, Monash University, Clayton, Victoria, 3168, Australia. Electronic address:

Goodpasture's disease manifests as rapidly progressive glomerulonephritis. Current immunosuppressive treatments do not specifically target the pathological immune response and have significant side effects. Like most autoimmune diseases, the strongest genetic association is with the HLA alleles. Inheritance of HLA-DR15 confers susceptibility, and structure-function studies have shown that HLA-DR15 plays a causative role in activating autoreactive pro-inflammatory T cells. Thus, specific inhibition of HLA-DR15 would provide a targeted therapeutic approach. We hypothesised that PV-267, an HLA-DR15-specific inhibitor, would effectively block HLA-DR15 presentation of the dominant epitope, attenuate the activation of autoreactive T cells, and limit disease. Using humanised HLA-DR15 transgenic mice, α3-specific, pro-inflammatory T cell recall responses were measured using IFN-γ and IL-17A ELISPOTs and by proliferation assay. To determine if PV-267 could limit disease, experimental autoimmune anti-GBM glomerulonephritis was induced in HLA-DR15 transgenic mice (on an Fcgr2b background), and functional and histological disease endpoints were measured. PV-267 effectively inhibited α3-specific immune responses and disease development. Mice treated prior to immunization with α3 had reduced α3-specific recall responses, and limited disease by albuminuria, histological glomerular injury, IgG deposition, and inflammatory cell infiltrates. PV-267 treatment commencing after the onset of active anti-α3(IV)NC1 autoimmunity attenuated functional and histological renal injury. When treatment was administered after disease was established, PV-267 limited the severity of histological injury. In conclusion, HLA-DR15 inhibition attenuates α3(IV)NC1-specific pro-inflammatory responses and could be used as an adjunct therapy for anti-GBM disease.
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http://dx.doi.org/10.1016/j.jaut.2019.05.004DOI Listing
September 2019

Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus.

Nat Commun 2019 05 17;10(1):2201. Epub 2019 May 17.

Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Acton, 2601, ACT, Australia.

Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.
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http://dx.doi.org/10.1038/s41467-019-10242-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525203PMC
May 2019

The renal draining lymph nodes in acute inflammatory kidney disease.

Kidney Int 2019 02;95(2):254-256

Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia; Department of Nephrology, Monash Health, Clayton, Victoria, Australia; Department of Clinical Immunology, Monash Health, Clayton, Victoria, Australia.

Renal lymphatics are implicated in renal disease, but their function in inflammatory kidney diseases is relatively poorly defined. In the current issue, Kasinath et al. examine the role of the kidney draining lymph node in experimental glomerulonephritis, as well the role of fibroblastic reticular cells within lymph nodes. Removing the kidney-draining lymph nodes prior to the induction of glomerulonephritis attenuated disease, as did interventions that affected the function of lymph nodes in general.
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http://dx.doi.org/10.1016/j.kint.2018.10.011DOI Listing
February 2019

Platelet retention in inflamed glomeruli occurs via selective prolongation of interactions with immune cells.

Kidney Int 2019 02 3;95(2):363-374. Epub 2018 Dec 3.

Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia. Electronic address:

Platelet-leukocyte interactions promote acute glomerulonephritis. However, neither the nature of the interactions between platelets and immune cells nor the capacity of platelets to promote leukocyte activation has been characterized in this condition. We used confocal intravital microscopy to define the interactions of platelets with neutrophils, monocytes, and endothelial cells in glomerular capillaries in mice. In the absence of inflammation, platelets underwent rapid on/off interactions with immune cells. During glomerulonephritis induced by in situ immune complex formation, platelets that interacted with neutrophils or monocytes, but not with other intraglomerular cells, were retained in the glomerulus for prolonged durations. Depletion of platelets inhibited both neutrophil recruitment and activation. Inhibition of platelet activating factor reduced neutrophil recruitment without impacting reactive oxygen species generation, while blocking CXC chemokine ligand 7 (CXCL7) reduced both responses. In contrast, inhibition of the adenosine diphosphate and thromboxane A2 pathways inhibited neutrophil reactive oxygen species generation without affecting neutrophil adhesion. Thus, platelet retention in glomerular capillaries following immune complex deposition stems from prolongation of platelet interactions with immune cells but not other substrates. Pro-inflammatory mediators play divergent roles in promoting neutrophil retention and activation in glomerular capillaries.
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http://dx.doi.org/10.1016/j.kint.2018.08.042DOI Listing
February 2019

Inflammasomes in the Kidney.

Exp Suppl 2018;108:177-210

Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC, Australia.

Inflammasomes influence a diverse range of kidney disease, including acute and chronic kidney diseases, and those mediated by innate and adaptive immunity. Both IL-18 and in particular IL-1β are validated therapeutic targets in several kidney diseases. In addition to leukocyte-derived inflammasomes, renal tissue cells express functional inflammasome components. Furthermore, a range of endogenous substances that directly activate inflammasomes also mediate kidney injury. Many of the functional studies have focussed on the NLRP3 inflammasome, and there is also evidence for the involvement of other inflammasomes in some conditions. While, at least in some disease, the mechanistic details of the involvement of the inflammasome remain to be elucidated, therapies focussed on inflammasomes and their products have potential in treating kidney disease in the future.
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http://dx.doi.org/10.1007/978-3-319-89390-7_8DOI Listing
May 2019

Analysis of urinary macrophage migration inhibitory factor in systemic lupus erythematosus.

Lupus Sci Med 2018 19;5(1):e000277. Epub 2018 Oct 19.

Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.

Objective: To characterise the clinical relevance of urinary macrophage migration inhibitory factor (uMIF) concentrations in patients with systemic lupus erythematosus (SLE).

Methods: MIF, adjusted for urine creatinine, was quantified by ELISA in urine samples from 64 prospectively recruited patients with SLE. Serum MIF and urinary monocyte chemoattractant protein 1 (uMCP-1) were quantified by ELISA in a subset of patients (n = 39). Disease activity was assessed using the SLE Disease Activity Index-2000 (SLEDAI-2K) score.

Results: uMIF was detectable in all patients with SLE. uMIF was positively correlated with overall SLEDAI-2K, was significantly higher in patients with SLE with high disease activity (SLEDAI-2K≥10) compared with those with inactive disease (SLEDAI-2K<4), and this association remained significant after adjusting for ethnicity, flare and use of immunosuppressants. uMIF was also significantly higher in SLE patients with flare of disease, although not confirmed in multivariable analysis. No significant differences in uMIF levels were observed according to the presence of renal disease activity, as assessed by renal SLEDAI-2K or biopsy-confirmed lupus nephritis. In contrast, uMCP-1 was significantly higher in SLE patients with active renal disease. uMIF expression was not associated with irreversible organ damage accrual or glucocorticoid use.

Conclusions: These data suggest uMIF as a potential overall but not renal-specific SLE biomarker, whereas uMCP-1 is a renal-specific SLE biomarker.
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http://dx.doi.org/10.1136/lupus-2018-000277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203042PMC
October 2018

Urinary B-cell-activating factor of the tumour necrosis factor family (BAFF) in systemic lupus erythematosus.

Lupus 2018 Nov 9;27(13):2029-2040. Epub 2018 Oct 9.

1 Centre for Inflammatory Diseases, Monash University School of Clinical Sciences at Monash Health, Melbourne, Victoria, Australia.

Introduction: We examined the clinical relevance of urinary concentrations of B-cell-activating factor of the tumour necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) in systemic lupus erythematosus (SLE).

Methods: We quantified urinary BAFF (uBAFF) by enzyme-linked immunosorbent assay in 85 SLE, 28 primary Sjögren syndrome (pSS), 40 immunoglobulin A nephropathy (IgAN) patients and 36 healthy controls (HCs). Urinary APRIL (uAPRIL) and monocyte chemoattractant protein 1 (uMCP-1) were also quantified. Overall and renal SLE disease activity were assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000.

Results: uBAFF was detected in 12% (10/85) of SLE patients, but was undetectable in HCs, IgAN and pSS patients. uBAFF was detectable in 28% (5/18) of SLE patients with active nephritis vs 5/67 (7%) of those without ( p = 0.03), and uBAFF was significantly higher in active renal patients ( p = 0.02) and more likely to be detected in patients with persistently active renal disease. In comparison, uAPRIL and uMCP-1 were detected in 32% (25/77) and 46% (22/48) of SLE patients, respectively. While no difference in proportion of samples with detectable uAPRIL was observed between SLE, HCs and IgAN patients, both uAPRIL and uMCP-1 were significantly detectable in higher proportions of patients with active renal disease.

Conclusions: uBAFF was detectable in a small but a significant proportion of SLE patients but not in other groups tested, and was higher in SLE patients with active renal disease.
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http://dx.doi.org/10.1177/0961203318804885DOI Listing
November 2018

HLA and kidney disease: from associations to mechanisms.

Nat Rev Nephrol 2018 10;14(10):636-655

Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.

Since the first association between HLA and diseases of native kidneys was described almost 50 years ago, technological and conceptual advances in HLA biology and typing, together with better case ascertainment, have led to an improved understanding of HLA associations with a variety of renal diseases. A substantial body of evidence now supports the existence of HLA genetic associations in the field of renal disease beyond the role of HLA in allogeneic responses in transplant recipients. Allomorphs of HLA have emerged as important risk factors in most immune-mediated renal diseases, which, together with other genetic and environmental factors, lead to loss of tolerance and autoimmune-mediated renal inflammation. HLA associations have also been described for renal diseases that are less traditionally seen as autoimmune or immune-mediated. Here, we review essential concepts in HLA biology and the association of HLA with diseases of the native kidneys, and describe the current understanding of the epistatic and mechanistic bases of HLA-associated kidney disease. Greater understanding of the relationship between HLA and kidney function has the potential not only to further the understanding of immune renal disease at a fundamental level but also to lead to the development and application of more effective, specific and less toxic therapies for kidney diseases.
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http://dx.doi.org/10.1038/s41581-018-0057-8DOI Listing
October 2018

CD8+ cells and glomerular crescent formation: outside-in as well as inside-out.

J Clin Invest 2018 08 9;128(8):3231-3233. Epub 2018 Jul 9.

Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.

Crescentic glomerulonephritis, a complication of severe immune glomerular injury, is the pathological correlate of rapidly progressive glomerulonephritis, mediated by both humoral and cellular effectors. In the current issue of the JCI, Chen et al. have implicated Bowman's capsule in functionally isolating potentially immune effectors, specifically antigen-specific CD8+ T lymphocytes, from podocytes. They suggest that, in crescentic glomerulonephritis, immune-mediated glomerular endothelial injury results in inside-out injury to the glomerulus, with subsequent leukocyte migration through a weakened or ruptured Bowman's capsule, resulting in outside-in injury. Effector T cells then recognize nephritogenic antigens presented by podocytes or other cells within the urinary space, enhancing injury and crescent formation.
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http://dx.doi.org/10.1172/JCI122045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063495PMC
August 2018

OX40 ligand is inhibitory during the effector phase of crescentic glomerulonephritis.

Nephrol Dial Transplant 2019 03;34(3):429-441

Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Victoria, Australia.

Background: The functional relevance of OX40 ligand (OX40L) in the effector phase of crescentic glomerulonephritis (GN) is unknown. These studies defined the role of endogenous OX40L during the effector stage of murine crescentic GN.

Methods: GN was induced by immunization with sheep globulin/adjuvant on Day 0 and injection of sheep anti-mouse glomerular basement membrane immunoglobulin (Ig) on Day 10. Rat IgG or neutralizing anti-OX40L antibody was administered on Days 10-18 and immune responses and renal injury assessed on Day 20.

Results: Compared with naïve animals, OX40L was upregulated in the lymph nodes (LNs) and on leucocytes and resident non-immune cells in the kidneys of mice with GN. Inhibition of OX40L in GN augmented renal injury, as indicated by increased crescent formation, proteinuria and glomerular leucocyte accumulation. In line with increased injury, anti-OX40L treatment increased proliferation and decreased apoptosis of CD4 T cells in the LNs, without affecting LN CD4 cytokine production and CD8 T-cell responses. Blockade of OX40L decreased LN regulatory T-cell (Treg) proliferation, transforming growth factor β production and foxp3 expression. OX40L inhibition did not affect B cell expansion or circulating antibody levels. In the kidney, neutralization of OX40L augmented interferon γ (IFNγ) expression by CD4 and CD8 T cells and shifted macrophage polarization towards the pro-inflammatory M1 phenotype.

Conclusions: OX40L is protective during the effector phase of murine crescentic GN by reducing the expansion of CD4 T cells and enhancing Treg responses in the LNs, and by locally inhibiting T-cell IFNγ production and pro-inflammatory macrophage phenotype in the kidney.
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http://dx.doi.org/10.1093/ndt/gfy177DOI Listing
March 2019

Chimeric antigen receptor T (CAR T) cells: another cancer therapy with potential applications in kidney disease and transplantation?

Kidney Int 2018 07;94(1):4-6

Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia; Department of Nephrology, Monash Health, Clayton, Victoria, Australia.

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http://dx.doi.org/10.1016/j.kint.2018.05.006DOI Listing
July 2018

Intrarenal Toll-like receptor 4 and Toll-like receptor 2 expression correlates with injury in antineutrophil cytoplasmic antibody-associated vasculitis.

Am J Physiol Renal Physiol 2018 11 20;315(5):F1283-F1294. Epub 2018 Jun 20.

Centre for Inflammatory Diseases, Monash University Department of Medicine , Clayton, Victoria , Australia.

In antineutrophil cytoplasmic antibody-associated vasculitis (AAV), Toll-like receptors (TLRs) may be engaged by infection-associated patterns and by endogenous danger signals, linking infection and innate inflammation with this autoimmune disease. This study examined intrarenal TLR2, TLR4, and TLR9 expression and renal injury in AAV, testing the hypothesis that increased TLR expression correlates with renal injury. Patients with AAV exhibited both glomerular and tubulointerstitial expression of TLR2, TLR4, and TLR9, with TLR4 being the most prominent in both compartments. Glomerular TLR4 expression correlated with glomerular segmental necrosis and cellular crescents, with TLR2 expression correlating with glomerular segmental necrosis. The extent and intensity of glomerular and tubulointerstitial TLR4 expression and the intensity of glomerular TLR2 expression inversely correlated with the presenting estimated glomerular filtration rate. Although myeloid cells within the kidney expressed TLR2, TLR4, and TLR9, TLR2 and TLR4 colocalized with endothelial cells and podocytes, whereas TLR9 was expressed predominantly by podocytes. The functional relevance of intrarenal TLR expression was further supported by the colocalization of TLRs with their endogenous ligands high-mobility group box 1 and fibrinogen. Therefore, in AAV, the extent of intrarenal TLR4 and TLR2 expression and their correlation with renal injury indicates that TLR4, and to a lesser degree TLR2, may be potential therapeutic targets in this disease.
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http://dx.doi.org/10.1152/ajprenal.00040.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293285PMC
November 2018

Formyl peptide receptor activation inhibits the expansion of effector T cells and synovial fibroblasts and attenuates joint injury in models of rheumatoid arthritis.

Int Immunopharmacol 2018 Aug 4;61:140-149. Epub 2018 Jun 4.

Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia.

The effects of formyl peptide receptors (FPRs) on effector T cells and inflammation-causing tissue-resident cells are not well known. Here, we explored the effect of FPR activation on efferent T cell responses in models of rheumatoid arthritis (RA) and on the expansion of fibroblast-like synoviocytes (FLS). Compound 43 (Cpd43; FPR1/2 agonist) was administered to mice with collagen-induced arthritis (CIA) or antigen-induced arthritis (AIA) after disease onset. Joint inflammation/damage and immunity were assessed. FLS were cultured with Cpd43 to test its effects on cell apoptosis and proliferation. To explore the effects of endogenous FPR2 ligands on FLS proliferation, FLS FPR2 was blocked or Annexin A1 (AnxA1) expression silenced. Cpd43 reduced arthritis severity in both models. In CIA, Cpd43 decreased CD4 T cell proliferation and survival and increased the production of the protective cytokine, IFNγ, in lymph nodes. In AIA, Cpd43 increased CD4 apoptosis and production of the anti-inflammatory IL-4, while augmenting the proportion of splenic regulatory T cells and their expression of IL-2Rα. In both models, Cpd43 increased CD4 IL-17A production, without affecting humoral immunity. FPR2 inhibitors reversed Cpd43-mediated effects on AIA and T cell immunity. Cpd43 decreased TNF-induced FLS proliferation and augmented FLS apoptosis in association with intracellular FPR2 accumulation, while endogenous AnxA1 and FPR2 reduced FLS proliferation via the ERK and NFκB pathways. Overall, FPR activation inhibits the expansion of arthritogenic effector CD4 T cells and FLS, and reduces joint injury in experimental arthritis. This suggests the therapeutic potential of FPR ligation for the treatment of RA.
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http://dx.doi.org/10.1016/j.intimp.2018.05.028DOI Listing
August 2018

Goodpasture's autoimmune disease - A collagen IV disorder.

Matrix Biol 2018 10 12;71-72:240-249. Epub 2018 May 12.

Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, United States; Center for Matrix Biology, Department of Biochemistry, Department of Pathology, Microbiology and Immunology, Department of Cell and Developmental Biology, Vanderbilt Ingram Cancer Center, Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN, United States.

Goodpasture's (GP) disease is an autoimmune disorder characterized by the deposition of pathogenic autoantibodies in basement membranes of kidney and lung eliciting rapidly progressive glomerulonephritis and pulmonary hemorrhage. The principal autoantigen is the α345 network of collagen IV, which expression is restricted to target tissues. Recent discoveries include a key role of chloride and bromide for network assembly, a novel posttranslational modification of the antigen, a sulfilimine bond that crosslinks the antigen, and the mechanistic role of HLA in genetic susceptibility and resistance to GP disease. These advances provide further insights into molecular mechanisms of initiation and progression of GP disease and serve as a basis for developing of novel diagnostic tools and therapies for treatment of Goodpasture's disease.
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http://dx.doi.org/10.1016/j.matbio.2018.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482832PMC
October 2018