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2.
PLoS One ; 15(6): e0233957, 2020.
Article in English | MEDLINE | ID: mdl-32555697

ABSTRACT

INTRODUCTION: Autoantibodies (autoAbs) against desmoglein-1 (DSG1) and desmoglein-3 (DSG3) have conventionally been studied and well accepted in the pathogenesis of pemphigus vulgaris (PV) and foliaceus (PF). Recent studies have suggested that non-DSG autoAbs may contribute to the pathogenesis of pemphigus, including autoAbs directed at acetylcholine receptors (AChR) and thyroid peroxidase (TPO). The purpose of this study is to retrospectively analyze PV and PF patient sera to better understand the relationship between anti-AChR and -TPO Abs to disease activity and DSG reactivity between patients treated with prednisone and steroid sparing agents (SSA; n = 22) or prednisone and rituximab (n = 21). METHODS: Patients were evaluated at 2 time points, T1 and T2, for disease activity using the Pemphigus Disease Area Index (PDAI), and sera were tested for the presence of TPO, DSG1, DSG3, muscarinic (M3) and nicotinic (n) AChR IgG autoAbs, as well as antibodies against Varicella Zoster Virus (VZV) by ELISA. RESULTS: Disease activity significantly decreased in patients from T1 to T2 (p < .0001). A significant difference was seen in IgG anti-DSG1 (p < .0001) and anti-DSG3 (p = .0049) levels when T1 was compared to T2 in both treatment groups. A significant increase was found between pemphigus patients and normal subjects with nAChR (p < .0001) at T1 but not with m3AChR, TPO or VZV Abs. No significant difference was seen between T1 and T2 values in patients with pemphigus for the non-desmoglein Abs TPO (p = .7559), M3AChR (p = .9003), nAChR (p = .5143) or VZV (p = .2454). These findings demonstrate that although an increase in IgG anti-nAChR autoAbs was found in PV and PF subjects, these Abs did not decrease with treatment. No other non-DSG Abs were increased or significantly changed over time in patients with pemphigus. This suggests that anti -AChR and -TPO Abs may not play a direct role in the pathogenesis of most patients with pemphigus, but does not rule out a role for non-DSG auto antibodies in distinct subsets of pemphigus patient.


Subject(s)
Autoantibodies/blood , Desmoglein 1/immunology , Desmoglein 3/immunology , Immunoglobulin G/blood , Pemphigus/immunology , Receptor, Muscarinic M3/immunology , Receptors, Nicotinic/immunology , Adult , Aged , Autoantigens/immunology , Female , Humans , Iodide Peroxidase/immunology , Iron-Binding Proteins/immunology , Male , Middle Aged , Pemphigus/drug therapy , Prednisone/therapeutic use , Retrospective Studies , Rituximab/therapeutic use , Young Adult
3.
Hepatol Commun ; 2(11): 1344-1355, 2018 Nov.
Article in English | MEDLINE | ID: mdl-30411081

ABSTRACT

The severity of hepatic fibrosis is the primary predictor of liver-related morbidity and mortality in patients with nonalcoholic fatty liver disease (NAFLD). Unfortunately, noninvasive serum biomarkers for NAFLD-associated fibrosis are limited. We analyzed baseline serum samples for 24 cytokines of 97 patients with biopsy-proven NAFLD. These patients were prospectively enrolled in a clinical study (ClinicalTrials.gov NCT00794716) to identify cytokines associated with liver fibrosis in patients with nonalcoholic steatohepatitis. Patients were stratified according to severity of hepatic fibrosis (mild, stage 0-1, n = 37; moderate, stage 2, n = 40; and advanced, stage 3-4, n = 20) while controlling for age, race, sex, body mass index, and diabetes mellitus. Interleukin-8 (IL-8), osteopontin (OPN), and monocyte chemoattractant protein 1 (MCP1) were associated with liver fibrosis (P < 0.001, P = 0.005, P = 0.016, respectively). After controlling for steatosis, lobular inflammation, hepatocyte ballooning, age, sex, body mass index, diabetes mellitus, hypertension, and metabolic syndrome status, IL-8 remained strongly associated with fibrosis (P = 0.001). Furthermore, IL-8 was also a strong predictor of increased fibrotic liver injury compared to established markers of hepatic fibrosis. Hepatic gene expression from 72 patients with NAFLD (n = 40 mild fibrosis; n = 32 advanced fibrosis) from the Duke University Health System NAFLD Clinical Database and Biorepository revealed IL-8, MCP1, and OPN gene expression to be increased and differentially expressed in patients with advanced hepatic fibrosis. Thus, serum IL-8, MCP1, and OPN may reflect up-regulated gene expression during liver fibrosis in NAFLD. Conclusion: Serum IL-8, MCP1, and OPN may serve as a test for advanced hepatic fibrosis in NAFLD and thus reveal novel targets for antifibrotic therapies. The increased serum IL-8, MCP1, and OPN that correspond with associated hepatic gene expression lend strength to such analytes as ideal surrogate serum biomarkers for severity of hepatic fibrosis.

4.
Psychosom Med ; 77(7): 808-15, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26186432

ABSTRACT

BACKGROUND: Major depressive disorder (MDD) and chronic heart failure (CHF) have in common heightening states of inflammation, manifested by elevated inflammation markers such as C-reactive protein. This study compared inflammatory biomarker profiles in patients with CHF and MDD to those without MDD. METHODS: The study recruited patients admitted to inpatient care for acute heart failure exacerbations, after psychiatric diagnostic interview. Patients with Beck Depression Inventory (BDI) scores lower than 10 and with no history of depression served as the nondepressed reference group (n = 25). MDD severity was defined as follows: mild (BDI 10-15; n = 48), moderate (BDI 16-23; n = 51), and severe (BDI ≥ 24; n = 33). A Bio-Plex assay measured 18 inflammation markers. Ordinal logistic models were used to examine the association of MDD severity and biomarker levels. RESULTS: Adjusting for age, sex, statin use, body mass index, left ventricular ejection fraction, tobacco use, and New York Heart Association class, the MDD overall group variable was significantly associated with elevated interleukin (IL)-2 (p = .019), IL-4 (p = .020), IL-6 (p = .026), interferon-γ (p = .010), monocyte chemoattractant protein 1 (p = .002), macrophage inflammatory protein 1ß (p = .003), and tumor necrosis factor α (p = .004). MDD severity subgroups had a greater probability of elevated IL-6, IL-8, interferon-γ, monocyte chemoattractant protein 1, macrophage inflammatory protein 1ß, and tumor necrosis factor α compared with nondepressed group. The nondepressed group had greater probability of elevated IL-17 (p < .001) and IL-1ß (p < .01). CONCLUSIONS: MDD in patients with CHF was associated with altered inflammation marker levels compared with patients with CHF who had no depression. Whether effective depression treatment will normalize the altered inflammation marker levels requires further study. TRIAL REGISTRATION: ClinicalTrials.gov NCT00078286.


Subject(s)
Depressive Disorder, Major/blood , Heart Failure/blood , Inflammation/blood , Aged , Biomarkers/blood , Chronic Disease , Comorbidity , Depressive Disorder, Major/drug therapy , Depressive Disorder, Major/epidemiology , Female , Heart Failure/epidemiology , Humans , Inflammation/epidemiology , Male , Middle Aged , Randomized Controlled Trials as Topic , Selective Serotonin Reuptake Inhibitors/therapeutic use , Sertraline/therapeutic use
5.
J Invest Dermatol ; 135(4): 1016-1024, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25501661

ABSTRACT

Mice with epidermal deletion of JunB transcription factor displayed a psoriasis-like inflammation. The relevance of these findings to humans and the mechanisms mediating JunB function are not fully understood. Here we demonstrate that impaired JunB function via gene silencing or overexpression of a dominant negative mutant increased human keratinocyte cell proliferation but decreased cell barrier function. RNA-seq revealed over 500 genes affected by JunB loss of function, which included the upregulation of an array of proinflammatory molecules relevant to psoriasis. Among these were tumor necrosis factor α (TNFα), CCL2, CXCL10, IL6R, and SQSTM1, an adaptor protein involved in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. Chromatin immunoprecipitation (ChIP)-Seq and gene reporter analyses showed that JunB directly suppressed SQSTM1 by binding to a consensus AP-1 cis element located around 2 kb upstream of SQSTM1-transcription start site. Similar to JunB loss of function, SQSTM1-overexpression induced TNFα, CCL2, and CXCL10. Conversely, NF-κB inhibition genetically with a mutant IκBα or pharmacologically with pyrrolidine dithiocarbamate (PDTC) prevented cytokine, but not IL6R, induction by JunB deficiency. Taken together, our findings indicate that JunB controls epidermal growth, barrier formation, and proinflammatory responses through direct and indirect mechanisms, pinpointing SQSTM1 as a key mediator of JunB suppression of NF-κB-dependent inflammation.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Heat-Shock Proteins/genetics , Inflammation/metabolism , NF-kappa B/metabolism , Transcription Factors/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Animals , Cell Adhesion , Cell Proliferation , Chemokine CCL2/metabolism , Chemokine CXCL10/metabolism , Chromatin Immunoprecipitation , Cytokines/metabolism , Epidermis/metabolism , Gene Deletion , Genes, Reporter , HEK293 Cells , Heat-Shock Proteins/metabolism , Humans , Keratinocytes/cytology , Mice , Mutation , Oligonucleotide Array Sequence Analysis , Pyrrolidines/chemistry , Regeneration , Sequence Analysis, RNA , Sequestosome-1 Protein , Skin Physiological Phenomena , Thiocarbamates/chemistry , Transcription Factors/genetics
8.
J Am Acad Dermatol ; 59(3): 418-25, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18603326

ABSTRACT

BACKGROUND: Skin cancer and photoaging changes result from ultraviolet (UV)-induced oxidative stress. Topical antioxidants may protect skin from these effects. OBJECTIVE: We sought to determine whether a stable topical formulation of 15% L-ascorbic acid, 1% alpha-tocopherol, and 0.5% ferulic acid (CEFer) could protect human skin in vivo from substantial amounts of solar-simulated UV radiation. METHODS: CEFer and its vehicle were applied to separate patches of normal-appearing human skin for 4 days. Each patch was irradiated with solar-simulated UV, 2 to 10 minimal erythema doses, at 2-minimal erythema dose intervals. One day later, skin was evaluated for erythema and sunburn cells, and immunohistochemically for thymine dimers and p53. UV-induced cytokine formation, including interleukin (IL)-1alpha, IL-6, IL-8, and IL-10, and tumor necrosis factor-alpha, were evaluated by real-time polymerase chain reaction. RESULTS: CEFer provided significant and meaningful photoprotection for skin by all methods of evaluation. LIMITATIONS: The number of patients evaluated was relatively small. CONCLUSION: CEFer provided substantial UV photoprotection for skin. It is particularly effective for reducing thymine dimer mutations known to be associated with skin cancer. Its mechanism of action is different from sunscreens and would be expected to supplement the sun protection provided by sunscreens.


Subject(s)
Antioxidants/therapeutic use , Ascorbic Acid/therapeutic use , Coumaric Acids/therapeutic use , DNA Damage/drug effects , Skin/radiation effects , Sunburn/prevention & control , alpha-Tocopherol/therapeutic use , Administration, Cutaneous , Adult , Cytokines/genetics , Cytokines/metabolism , DNA Primers , Drug Combinations , Erythema/etiology , Erythema/prevention & control , Humans , Immunohistochemistry , Polymerase Chain Reaction , Pyrimidine Dimers/analysis , RNA, Messenger/analysis , Radiation Dosage , Skin/metabolism , Skin/pathology , Skin Neoplasms/genetics , Skin Neoplasms/prevention & control , Statistics, Nonparametric , Sunburn/genetics , Tumor Suppressor Protein p53/analysis , Ultraviolet Rays/adverse effects
9.
J Infect Dis ; 196(9): 1425-30, 2007 Nov 01.
Article in English | MEDLINE | ID: mdl-17922409

ABSTRACT

BACKGROUND: Endogenous antimicrobial peptides participate in the innate defense of skin against a variety of pathogens. The systemic expression of these peptides in normal-appearing skin of patients with infective cellulitis is unknown. METHODS: Study patients were adults with infective cellulitis and signs of systemic inflammation. Skin biopsy and serum specimens were obtained from patients and from control subjects with no active infection. Cathelicidin and human beta-defensin 2 mRNA expression were determined by real-time polymerase chain reaction. RESULTS: Skin biopsy specimens from 11 patients and 4 uninfected control subjects were analyzed. The relative expression level for cathelicidin mRNA was elevated in both the involved and the distal normal-appearing skin of patients with cellulitis, compared with expression in the skin of control subjects (mean ratios, 39.46 vs. 1.32, P=.0059; and 21.41 vs. 1.32, P=.0059). Similarly, the relative expression level of human beta -defensin 2 mRNA was elevated in both the involved skin (mean ratios, 20,844 vs. 11.65; P=.0015) and in distal normal-appearing skin of patients with cellulitis (mean ratios, 201.1 vs. 11.65; P=.0103). DISCUSSION: In response to cutaneous infection there is a local and distal increase in endogenous antimicrobial peptide mRNA in both involved and normal-appearing skin. These observations show, for the first time to our knowledge, that after infection the human body responds by increasing systemic innate immunity.


Subject(s)
Antimicrobial Cationic Peptides/genetics , Cellulitis/metabolism , beta-Defensins/genetics , Adult , Antimicrobial Cationic Peptides/metabolism , Cellulitis/microbiology , Female , Gene Expression Regulation , Humans , Interleukin-6/blood , Male , Middle Aged , RNA, Messenger/genetics , RNA, Messenger/metabolism , Skin/metabolism , beta-Defensins/metabolism , Cathelicidins
10.
J Invest Dermatol ; 127(9): 2158-65, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17597819

ABSTRACT

Patients with dermatitis herpetiformis (DH) have a gluten-sensitive enteropathy and while on gluten-containing diets have elevated levels of serum IL-8. We hypothesized that the mucosal immune response to gluten is responsible for the elevated serum IL-8. Six DH patients were studied while on a gluten-free diet (GFD), whereas four continued on a normal diet. Patients were followed for a mean 2.2 years and serum IL-8 was analyzed. Small bowel biopsies from five DH patients on normal diets, two DH patients on GFD, and six subjects with no small bowel abnormalities were analyzed for IL-8 mRNA. Serum IL-8 levels normalized in five of six patients on GFD and decreased in one, whereas serum IL-8 levels showed no statistically significant change in DH patients on normal diets. Small bowel biopsies from DH patients on normal diets had increased expression of IL-8 mRNA compared to normal subjects, whereas patients on a GFD showed no significant increase in small bowel mRNA. No significant IL-8 mRNA was detected in normal skin biopsies from patients with DH. These observations suggest that the IL-8 in the serum of patients with DH originates from the small bowel as a mucosal immune response to gluten ingestion.


Subject(s)
Dermatitis Herpetiformis/blood , Glutens/metabolism , Interleukin-8/blood , Adult , Aged , Biopsy , Celiac Disease/diet therapy , Diet , Female , Humans , Immunoglobulin A/chemistry , Interleukin-8/metabolism , Intestine, Small/metabolism , Male , Middle Aged , RNA, Messenger/metabolism
11.
J Invest Dermatol ; 126(6): 1331-7, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16575390

ABSTRACT

The mechanisms that lead to the development of skin lesions in patients with dermatitis herpetiformis (DH) are not known. We hypothesized that an ongoing immune response in the gut of patients with DH would result in an increase in circulating cytokines and be associated with endothelial cell activation, creating a proinflammatory environment in the skin. Skin biopsies from the normal-appearing inner arm of 11 DH patients, with no active skin lesions, and 12 normal subjects were analyzed for E-selectin (E-sel) and ICAM-1 mRNA. DH patients' skin expressed markedly increased levels of E-sel mRNA. Mean E-sel mRNA expression in DH skin was 1,271 (range 63.78-5861) times greater than that of a control, normal skin (P<0.001) with no significant increased expression of ICAM-1 mRNA. Serum levels of soluble E-selectin (sE-sel), IgA anti-tissue transglutaminase antibodies, and serum IL-8 levels were significantly increased in patients with DH. These studies demonstrate that patients with DH have evidence of endothelial cell activation in the skin and systemic manifestations of the ongoing inflammation associated with the mucosal immune response. Endothelial cell activation may play a critical role in the development of skin lesions in patients with DH and may represent a common mechanism for cutaneous manifestations of inflammatory gastrointestinal diseases.


Subject(s)
Dermatitis Herpetiformis/immunology , E-Selectin/blood , Endothelial Cells/immunology , Interleukin-8/blood , Skin/immunology , Tumor Necrosis Factor-alpha/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Child , Dermatitis Herpetiformis/pathology , E-Selectin/genetics , Endothelial Cells/chemistry , Endothelial Cells/pathology , Female , GTP-Binding Proteins/immunology , Gastroenteritis/complications , Gastroenteritis/immunology , Humans , Immunoglobulin A/blood , Intercellular Adhesion Molecule-1/genetics , Intercellular Adhesion Molecule-1/metabolism , Interleukin-8/genetics , L-Selectin/blood , Male , Middle Aged , Protein Glutamine gamma Glutamyltransferase 2 , RNA, Messenger/analysis , RNA, Messenger/metabolism , Skin/chemistry , Skin/pathology , Transglutaminases/immunology , Tumor Necrosis Factor-alpha/genetics
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