Howard W Davidson's research while affiliated with University of Colorado and other places
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Publications (78)
Objective
Zinc transporter 8 (ZnT8) is a major humoral target in human type 1 diabetes (T1D). Polymorphic variants of Slc30A8, which encodes ZnT8, are also associated with protection from type 2 diabetes (T2D). The current study examined whether ZnT8 might play a role beyond simply being a target of autoimmunity in the pathophysiology of T1D.
Meth...
Background
Corpus atrophic gastritis (CAG) may lead to intrinsic factor (IF) deficiency and vitamin B12 malabsorption. Intrinsic factor autoantibodies (IFA) are considered markers of pernicious anemia, but their clinical utility in CAG has not been evaluated. This study aimed to assess IFA in CAG patients and controls using a luciferase immunopreci...
The pancreatic beta cell is a highly specialized cell type whose primary function is to secrete insulin in response to nutrients to maintain glucose homeostasis in the body. As such, the beta cell has developed unique metabolic characteristics to achieve functionality; in healthy beta cells, the majority of glucose-derived carbons are oxidized and...
Activation of T cells specific for insulin B chain amino acids 9 to 23 (B:9–23) is essential for the initiation of type 1 diabetes (T1D) in non-obese diabetic mice. We previously reported that peptide/MHC complexes containing optimized B:9–23 mimotopes can activate most insulin-reactive pathogenic T cells. A monoclonal antibody (mAb287) targeting t...
Introduction:
Noninvasive assessment of corpus atrophic gastritis (CAG), a condition at increased risk of gastric cancer, is based on the measurement of pepsinogens, gastrin, and Helicobacter pylori antibodies. Parietal cell autoantibodies (PCAs) against the gastric proton pump (ATP4) are potential serological biomarkers of CAG. The purpose of thi...
At present, there is no cure for type 1A diabetes (T1D), a T cell-mediated autoimmune disease. Monoclonal antibodies (mAbs) are used to treat a wide number of diseases. For treating T1D, mAbs that target major immune cell subsets show considerable promise, but so far, when used at doses that do not cause unacceptable adverse reactions, have only be...
Numerous mammalian cells contain abundant Zn²⁺ in their secretory granules, yet available Zn²⁺ sensors lack the desired specificity and sensitivity for imaging granular Zn²⁺. We developed a fluorescent zinc granule indicator, ZIGIR, that possesses numerous desired properties for live cell imaging, including >100-fold fluorescence enhancement, membr...
We identified autoantibodies reacting with a variant IA-2 molecule (IA-2var) that has 3 amino acid substitutions (Cys27, Gly608 and Pro671) within the full length molecule. We examined IA-2var autoantibodies (AAb) in first-degree relatives of T1D probands from the TrialNet Pathway to Prevention Study. The presence of IA-2var-specific AAb in relativ...
In type 1 diabetes (T1D), proinsulin is a major autoantigen and the insulin B:9-23 peptide contains epitopes for CD4 ⁺ T cells in both mice and humans. This peptide requires carboxyl-terminal mutations for uniform binding in the proper position within the mouse IA g7 or human DQ8 major histocompatibility complex (MHC) class II (MHCII) peptide groov...
The Luciferase Immuno Precipitation System (LIPS) enables the detection of specific serum antibodies by immunoprecipitation of recombinant antigens tagged with a luciferase reporter. Here we describe LIPS assays for the quantification of autoantibodies to the H+, K+-ATPase A (ATP4A) and B (ATP4B) subunits, two serological markers of autoimmune atro...
A primary initiating epitope in the NOD mouse model of Type 1 Diabetes (T1D) lies between residues 9 and 23 of the insulin B chain. The B:9-23 peptide can bind to the NOD MHC class II molecule (I-Ag7) in multiple registers, but only one, (register 3, R3), creates complexes able to stimulate the majority of pathogenic B:9-23-specific CD4+ T cells. P...
Immortalized T cells such as T cell hybridomas, transfectomas, and transductants are useful tools to study tri-molecular complexes consisting of peptide, MHC, and T cell receptor (TCR) molecules. These cells have been utilized for antigen discovery studies for decades due to simplicity and rapidness of growing cells. However, responsiveness to anti...
Aims/hypothesis:
Validated biomarkers are needed to monitor the effects of immune intervention in individuals with type 1 diabetes. Despite their importance, few options exist for monitoring antigen-specific T cells. Previous reports described a combinatorial approach that enables the simultaneous detection and quantification of multiple islet-spe...
Individuals with type 1 diabetes (T1D) are at increased risk of coeliac disease (CD), autoimmune thyroiditis and autoimmune gastritis, but the absolute risks are unclear. The aim of this study was to investigate the prevalence of autoantibodies to tissue transglutaminase (TGA), thyroid peroxidase (TPOA), and gastric H⁺/K⁺-ATPase (ATPA) and their ge...
The human leukocyte antigen–A2 (HLA-A2)–restricted zinc transporter 8186–194 (ZnT8186–194) and other islet epitopes elicit interferon-γ secretion by CD8⁺ T cells preferentially in type 1 diabetes (T1D) patients compared with controls. We show that clonal ZnT8186–194-reactive CD8⁺ T cells express private T cell receptors and display equivalent funct...
Objective:
We aimed to assess the prevalence of autoantibodies against the 4A subunit of the gastric proton pump (ATP4A) in pediatric type 1 diabetes (T1D) patients and explore the relationship between ATP4A positivity and blood cell count, iron turnover, and vitamin B12 concentration.
Subjects:
The study included 94 (59% female) T1D children (a...
Objectives
Circulating autoantibodies targeting the H+/K+-ATPase proton pump of gastric parietal cells are considered markers of autoimmune gastritis, whose diagnostic accuracy in atrophic body gastritis, the pathological lesion of autoimmune gastritis, remains unknown. This study aimed to assess autoantibodies against ATP4A and ATP4B subunits of p...
Objective:
ZnT8-specific CD8+ T cells in human type 1 diabetes (T1D) have been reported recently, although the results from different laboratories are inconsistent. We aimed to characterize these ZnT8 specific CD8+ T cells and to validate assays to screen peptide libraries.
Methods:
We screened HLA-A2-restricted T cell candidate peptides of ZnT8...
Zinc transporter 8 autoantibodies (ZnT8A) were analyzed in sera from 1,504 subjects as part of the Type 1 Diabetes Genetics Consortium (T1DGC) Autoantibody Workshop. For these participants with type 1 diabetes (T1D), samples were collected within 3 years of T1D diagnosis. ZnT8A were detected in 862 subjects (57.3%), with the highest frequencies and...
Described is the identification of ZnT8 as an autoantigen target in type I autoimmune diabetes (T1D), other autoimmune disease, and other diabetes-linked diseases and conditions. Also described are a variety of therapeutic, diagnostic, and prognostic tools and methods based on this discovery. The identification of genetic variation in ZnT8 as an im...
Significance
Certain class II major histocompatibility alleles confer disease risk for type 1 diabetes (T1D). Insulin-specific and other autoantibodies often precede T1D development, but major efforts at disease prevention using insulin preparations (subcutaneous, oral, and intranasal) to induce tolerance have not been effective. Measuring insulin-...
OBJECTIVE
Immune intervention trials in recent-onset type 1 diabetes would benefit from biomarkers associated with good therapeutic response. In the previously reported randomized placebo-controlled anti-CD3 study (otelixizumab; GlaxoSmithKline), we tested the hypothesis that specific diabetes autoantibodies might serve this purpose.RESEARCH DESIGN...
Significance
The importance of antigenic peptides with low-affinity HLA binding in human autoimmune disease remains unclear. Studies in the nonobese diabetic mouse demonstrate recognition of a crucial insulin epitope presented in a weakly bound register. This work details a direct study of responses to this insulin B-chain peptide in humans. Respon...
Human pancreatic β cells have exceptionally high zinc content. In β cells the highest zinc concentration is in insulin secretory granules, from which it is cosecreted with the hormone. Uptake of zinc into secretory granules is mainly mediated by zinc transporter 8 (ZnT8), the product of the SLC30A8 [solute carrier family 30 (zinc transporter), memb...
Significance
Antigen-specific therapies are lacking for autoimmunity diseases. The recent discovery of the nature of the IA g7 –insulin complex that drives type 1 diabetes in nonobese diabetic (NOD) mice has allowed us to create a monoclonal antibody specific for this complex. This antibody delays diabetes development in NOD mice. Given the similar...
G6PC2, also known as islet-specific glucose 6-phosphatase catalytic subunit-related protein (IGRP), is a major target of autoreactive CD8(+) T cells in both diabetic human subjects and the non-obese diabetic (NOD) mouse. However, in contrast to the abundant literature regarding the CD8(+) response to this antigen, much less is known about the poten...
Anti-zinc transporter (ZnT)8 autoantibodies are commonly detected in type 1 diabetic patients. We hypothesised that ZnT8 is also recognised by CD8(+) T cells and aimed to identify HLA-A2 (A*02:01)-restricted epitope targets.
Candidate epitopes were selected by ZnT8 plasmid DNA immunisation of HLA-A2/DQ8 transgenic mice and tested for T cell recogni...
In type 1 diabetes, diabetes-associated autoantibodies, including islet cell antibodies (ICAs), reflect adaptive immunity, while increased serum N(ε)-carboxymethyl-lysine (CML), an advanced glycation end product, is associated with proinflammation. We assessed whether serum CML and autoantibodies predicted type 1 diabetes and to what extent they we...
Identification of the major humoral epitopes in zinc transporter 8 (ZnT8) will expand the range of biomarkers for human type 1 diabetes and may provide clues to the mechanisms governing disease progression. Our initial studies suggested that most ZnT8-reactive sera recognize conformational epitopes in the final 100aa region of the molecule. Subsequ...
Autoimmune atrophic body gastritis (ABG) and pernicious anaemia are prototypical, organ-specific autoimmune diseases whose prevalence in the general population is 2.0 vs 2 and 0.15-1%, respectively. The incidence of disease increases with age and is frequently associated with other autoimmune disorders such as type 1 diabetes mellitus (T1DM). Early...
Recently we demonstrated that zinc transporter 8 (ZnT8) is a major target of autoantibodies in human type 1 diabetes (T1D). Because the molecules recognized by T1D autoantibodies are typically also targets of autoreactive T cells, we reasoned that this would likely be the case for ZnT8. To test this hypothesis, IFN-γ-producing T cells specific for...
Zinc transporter 8 (ZnT8) is a newly discovered islet autoantigen in human type 1A diabetes (T1D).
The objective was to document changes in ZnT8 autoantibody (ZnT8A) titer and prevalence after onset of disease in relationship to 65 kDa glutamate decarboxylase antibody (GADA) and islet cell antigen antibody (IA2A).
Autoantibody radioimmunoprecipitat...
Zinc transporter-8 (ZnT8) was recently identified as a novel autoantigen in human type 1 diabetes (T1D). Autoantibody to ZnT8 (ZnT8A) was detected in up to 80% of patients with new-onset T1D and 26% of patients with T1D otherwise classified as negative on the basis of existing markers. As no data of ZnT8A in Chinese have been reported, we aim to ev...
to explore the application significance of zinc transporter 8 autoantibody (ZnT8A) in the diagnostic classification of acute-onset diabetics.
according to the status of glutamic acid decarboxylase antibody (GADA) and tyrosine phosphatase antibody (IA2-A), 453 acute-onset diabetics were divided into A+ subgroup (any antibody positive) and A- subgrou...
Type 1A diabetes is strongly associated with the presence of islet autoantibodies. Large scale population screening of islet autoantibodies is essential for many different national and international studies related to defining subtypes of diabetes, the natural history of the disease, and for trials of prevention. Testing for relevant autoantibodies...
Objective:
The objective of this study was to define the spectrum of TCR beta chains permissive for T cells with alpha chains containing the conserved TRAV5D-4*04 sequence to target the insulin B:9-23 peptide, a major epitope for initiation of diabetes in the NOD mouse.
Materials and methods:
We produced T cell hybridomas from mice with single T...
The presence of circulating islet cell autoantibodies distinguishes type 1A diabetes (T1D) from other diabetic syndromes and determination of autoantigen genes and proteins is instrumental in understanding T1D as a clinical entity and in investigating the pathogenesis of the disease. ZnT8 was recently defined as a candidate autoantigen based on a -...
The destruction of pancreatic beta cells leading to type 1 diabetes in humans is thought to occur mainly through apoptosis and necrosis induced by activated macrophages and T cells, and in which secreted cytokines play a significant role. The transcription factor nuclear factor kappa-B (NF-kappaB) plays an important role in mediating the apoptotic...
Methods are presented for the separation of dense core secretory vesicles from insulin-secreting tissues (insulin granules) based on a combination of differential and density gradient centrifugation on various media. Emphasis is given to the use of transplantable tumors, tissue culture cell lines, and pancreatic islets as a tissue source.
IA2 and phogrin are important targets of humoral and cell-mediated autoimmunity in type 1 diabetes in man. They belong to a conserved subfamily of transmembrane protein tyrosine phosphatases (PTPs) associated with the regulatory pathway of secretion. To examine potential cross-reactivity between PTP family members we tested sera from T1D patients f...
The human zinc transporter Slc30A8 (ZnT8) is a major target of humoral autoimmunity in human type 1A diabetes. However, despite extensive conservation, the majority of human autoimmune sera fail to recognize the murine ortholog. Moreover, Slc30A8 appears not to be a significant target of humoral autoimmunity in the NOD mouse. We therefore "humanize...
Type 1A diabetes (T1D) results from autoimmunity targeted at a limited number of molecules that are expressed in the pancreatic beta cell. Putative novel autoantigen candidates were identified from microarray expression profiling of human and rodent islet cells. The highest ranking candidate was Slc30A8 (zinc transporter 8; ZnT8), which was screene...
Aims/hypothesis
We analysed the association between humoral autoreactivity to zinc transporter-8 (ZnT8) and the SLC30A8 rs13266634 polymorphism (Arg325Trp), which is located at the most distal loop in the ZnT8 protein.
Methods
Autoantibodies to ZnT8 were determined by RIA in 270 patients with type 1 diabetes using ZnT8 carboxy-terminal constructs (...
The beta-cell-specific zinc transporter isoform 8 (SLC30A8) has recently emerged both as a major autoantigenic target of type 1 diabetes and also as a genetic marker for type 2 diabetes. We examine the hypothesis that the cell specificity and cellular localization of this granule membrane protein are significant factors in its contribution to the p...
Zinc transporter eight (SLC30A8) is a major target of autoimmunity in human type 1A diabetes and is implicated in type 2 diabetes in genome-wide association studies. The type 2 diabetes nonsynonymous single nucleotide polymorphism (SNP) affecting aa(325) lies within the region of highest ZnT8 autoantibody (ZnT8A) binding, prompting an investigation...
Type 1 diabetes (T1D) results from progressive loss of pancreatic islet mass through autoimmunity targeted at a diverse, yet limited, series of molecules that are expressed in the pancreatic β cell. Identification of these molecular targets provides insight into the pathogenic process, diagnostic assays, and potential therapeutic agents. Autoantige...
Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial, rate-limiting step of tryptophan (Trp) catabolism along the kynurenine (KYN) pathway, and its induction in cells of the immune system in response to cytokines has been implicated in the regulation of antigen presentation and responses to cell-mediated immune attack. Microarray and quantitativ...
Integral membrane proteins of neuroendocine dense-core vesicles (DCV) appear to undergo multiple rounds of exocytosis; however, their trafficking and site of incorporation into nascent DCVs is unclear. Previous studies with phogrin (IA-2beta) identified sorting signals in the luminal domain that is cleaved post-translationally; we now describe an i...
The precise trafficking routes followed by newly synthesized lysosomal membrane proteins after exit from the Golgi are unclear. To study these events we created a novel chimera (YAL) having a lumenal domain comprising two tyrosine sulfation motifs fused to avidin, and the transmembrane and cytoplasmic domains of lysosome associated membrane protein...
Susceptibility to type 1A autoimmune diabetes is linked to expression of particular MHC class II molecules, notably HLA-DQ8 in man and the orthologous I-Ag7 in the nonobese diabetic mouse. In the present study, we analyzed two peptide epitopes (peptides 2 and 7) from the diabetes autoantigen phogrin (IA-2beta), in the context of their presentation...
Insulin, the major secreted product of the beta-cells of the islets of Langerhans, is initially synthesized as a precursor (preproinsulin), from which the mature hormone is excised by a series of proteolytic cleavages. This review provides a personal narrative of some of the key research projects leading to the identification of the central process...
Salmonella typhimuriuminvades mammalian cells and replicates within a vacuole that protects it from the host's microbicidal weapons. TheSalmonella-containing vacuole (SCV) undergoes a remodelling akin to that of the host cell's endocytic pathway, but SCV progression is
arrested prior to fusion with lysosomes. We studied the role of phosphatidylinos...
Phagosomes acquire their microbicidal properties by fusion with lysosomes. Products of phosphatidylinositol 3-kinase (PI 3-kinase) are required for phagosome formation, but their role in maturation is unknown. Using chimeric fluorescent proteins encoding tandem FYVE domains, we found that phosphatidylinositol 3-phosphate (PI[3]P) accumulates greatl...
Lipid kinases and their phosphorylated products are important regulators of many cellular processes, including intracellular membrane traffic. The best example of this is provided by the class III phosphoinositide 3-kinase (PI-3K), Vps34p, which is required for correct targeting of newly synthesized carboxypeptidase Y to the yeast vacuole. A probab...
Movement of proteins and lipids between the various compartments of eukaryotic cells is fundamental to the maintenance of cellular homeostasis, and an understanding of the molecular mechanisms that govern these processes remains a key goal of cell biological research. This aim has been greatly facilitated by the development of assays that recapitul...
A number of recent studies have highlighted the importance of lipid domains within endocytic organelles in the sorting and movement of integral membrane proteins. In particular, considerable attention has become focussed upon the role of the unusual phospholipid lysobisphosphatidic acid (LBPA). This lipid appears to be directly involved in the traf...
Binding of antigenic peptides to major histocompatibility complex (MHC) class II glycoproteins occurs in specialized endocytic compartments of antigen-presenting cells, which in man are termed MIICs. Newly synthesized MHC class II molecules are transported from the trans-Golgi network to MIICs, but previous studies of this important step in antigen...
Phosphoinositide 3-kinases (PI 3-kinases) and their 3-phosphoinositide products were identified initially as components of intracellular signalling pathways emanating from cell surface receptors. A new role for 3-phosphoinositides in the constitutive movement o f proteins from one intracellular compartment to another was proposed with the discovery...
Citations
... The consequences of such changes in α-cells to the intercellular homeostatic regulation in the pancreatic islet microenvironment will be important to investigate. Wider processes in α-cells would also seem relevant, including the glutamate efflux in the course of GSH generation by system χ c allowing α-cells antioxidant regulation to drive mGluR5 activation in pancreatic β-cells, thereby leading to the 'backward' conversion of melatonin to NAS and thereafter to the trophic and metabolic benefits of TrkB activation; see Figure 4. Intra-islet zinc homeostasis and zinc transporter 8 may also be an important variable in determining the homeostatic interactions among cells in the pancreatic islet [142]. The intercellular interactions of cells in the pancreatic islet microenvironment add a further layer of complexity to the pathoetiology of T1DM. ...
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... Notably, partial ROC-pAUC90 analysis indicated a superior diagnostic performance for the ATP4B assay. In contrast, luciferase immunoprecipitation assays directed against intrinsic factor antibodies exhibited a diagnostic sensitivity of 32% and specificity of 95% in identifying autoimmune gastritis [46]. ...
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... Cellular senescence involves fundamental changes in gene expression and proliferative arrest. Senescence may be caused by stresses, such as DNA damage, telomere shortening, oncogenic mutations, metabolic and mitochondrial dysfunction, inflammation, and autoimmune conditions [46,78,79]. The mass of senescent cells increases in many tissues with age, in pathological loci during various chronic diseases, and after irradiation or chemotherapy [80]. ...
... Monoclonal antibody (mAbs) against IA g7 -Ins B:10-23 can modulate the onset of T1D (17,18). Dahan et al. found that the antibody against DR4/GAD-555-567 complexes significantly inhibited GAD-555-567-specific T-cell responses in vitro and in vivo (19). ...
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... Researchers have developed luciferase immunoprecipitation assays targeting ATP4A and ATP4B and have demonstrated favorable diagnostic accuracy in patients with histologically confirmed autoimmune gastritis [44]. The sensitivities of the ATP4A and ATP4B assays were 75% and 77%, respectively, with corresponding specificities of 88% for both tests [45]. Notably, partial ROC-pAUC90 analysis indicated a superior diagnostic performance for the ATP4B assay. ...
... 12 Immunological research at DUs has led to many immunotherapies. 13 Thus, exploring the impact and role of metabolic trends on immune infiltration in the DU microenvironment may lead to novel heterogeneous wound healing strategies. ...
... Such reduction in ISG content upon exposure to cytokines was confirmed by independent Western-Blot (WB) analysis of the total insulin content in cell lysates (Fig. 4F, see also Fig. S7 for uncropped WB) and supports the current model of aberrant insulin secretion induced by cytokines [7][8][9][10] . Please note that in the specific case of ISGs, the ExM-derived information on ISG density and localization was complemented with dynamic information on the population of residual ISGs labelled using ZIGIR (a fluorescent granule indicator with Zn 2+ -chelating properties 43 These data suggest that the residual granule population after 24-h exposure to cytokines is less prone to perform active transport as compared to granules from untreated cells. ...