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2.
Oral Dis ; 21(7): 858-65, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26096224

ABSTRACT

OBJECTIVE: Activation of the cholinergic anti-inflammatory pathway (CAP) has been shown to reduce inflammation in animal models, while abrogation of the pathway increases inflammation. We investigated whether modulation of CAP influences inflammation in the non-obese diabetic (NOD) mouse model for Sjögren's syndrome and type 1 diabetes. METHODS: The alpha-7 nicotinic acetylcholine receptor (α7nAChR) was stimulated with AR-R17779 or nicotine in NOD mice. In a second study, unilateral cervical vagotomy was performed. α7nAChR expression, focus scores, and salivary flow were evaluated in salivary glands (SG) and insulitis score in the pancreas. Cytokines were measured in serum and SG. RESULTS: α7nAChR was expressed on myoepithelial cells in SG. Monocyte chemotactic protein-1 levels were reduced in SG after AR-R17779 treatment and tumor necrosis factor production was increased in the SG of the vagotomy group compared to controls. Focus score and salivary flow were unaffected. NOD mice developed diabetes more rapidly after vagotomy, but at completion of the study there were no statistically significant differences in number of mice that developed diabetes or in insulitis scores. CONCLUSION: Intervention of the CAP in NOD mice leads to minimal changes in inflammatory cytokines, but did not affect overall inflammation and function of SG or development of diabetes.


Subject(s)
Diabetes Mellitus, Type 1/metabolism , Pancreatitis/metabolism , Salivary Glands/metabolism , Sjogren's Syndrome/metabolism , alpha7 Nicotinic Acetylcholine Receptor/metabolism , Animals , Bridged-Ring Compounds/pharmacology , Chemokine CCL2/metabolism , Disease Models, Animal , Female , Inflammation , Islets of Langerhans/pathology , Mice , Mice, Inbred NOD , Nicotine/pharmacology , Pancreatitis/pathology , Saliva/metabolism , Salivary Glands/drug effects , Salivation/drug effects , Spiro Compounds/pharmacology , Tumor Necrosis Factor-alpha/biosynthesis , Vagotomy , alpha7 Nicotinic Acetylcholine Receptor/drug effects
3.
Mol Ther ; 22(4): 821-7, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24304965

ABSTRACT

BAFF (B-cell-activating factor of the tumor necrosis factor family), a pivotal cytokine for B-cell activation, is overexpressed by salivary gland (SG) epithelial cells in primary Sjogren's syndrome (pSS). ΔBAFF, a physiological inhibitor of BAFF, is a minor alternative splice variant of BAFF. A U7 RNA was reengineered to deliver antisense sequences targeting BAFF splice regions. A major decrease of BAFF messenger RNA (mRNA) and protein secretion, concomitantly with the increase of ΔBAFF mRNA, was observed in vitro. In vivo, SG retrograd instillation of nonobese diabetic mice by the modified U7 cloned into an adeno-associated virus vector significantly decreased BAFF protein expression and lymphocytic infiltrates and improved salivary flow. This study offers a rationale for localized therapeutic BAFF inhibition in pSS and represents a proof of concept of the interest of exon skipping in autoimmune diseases.


Subject(s)
B-Cell Activating Factor/biosynthesis , RNA, Messenger/genetics , Sjogren's Syndrome/genetics , Sjogren's Syndrome/therapy , Animals , B-Cell Activating Factor/antagonists & inhibitors , B-Cell Activating Factor/genetics , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , Dependovirus , Exons/genetics , Humans , Lymphocyte Activation/genetics , Mice , Mice, Inbred NOD/genetics , Mice, Inbred NOD/metabolism , RNA Splicing/genetics , RNA, Messenger/antagonists & inhibitors , RNA, Small Nuclear/genetics , Sjogren's Syndrome/pathology
4.
Neth J Med ; 70(4): 190-2, 2012 May.
Article in English | MEDLINE | ID: mdl-22641627

ABSTRACT

This case report describes a female HIV-positive patient diagnosed with pelvic actinomycosis using 16S rRNA gene sequence analysis. Actinomycosis is notoriously difficult to diagnose by microbiological culture. 16S rRNA gene sequence analysis allows rapid definitive diagnosis of actinomycosis and is potentially of great value in a clinical setting. This is the first report of pelvic actinomycosis in an HIV-1 infected patient.


Subject(s)
Abdominal Abscess/microbiology , Actinomycosis/diagnosis , HIV Infections/diagnosis , HIV-1 , Pelvis/microbiology , Abdominal Abscess/etiology , Abdominal Abscess/pathology , Actinomycosis/complications , Actinomycosis/drug therapy , Adult , Anti-Bacterial Agents/therapeutic use , Female , HIV Infections/complications , HIV Infections/pathology , Humans , Tomography, X-Ray Computed
5.
Oral Dis ; 18(4): 365-74, 2012 May.
Article in English | MEDLINE | ID: mdl-22212434

ABSTRACT

OBJECTIVE: Patients with Sjögren's syndrome (SS) show aberrant expression of the B cell-related mediators, B cell-activating factor (BAFF), and a proliferation-inducing ligand (APRIL) in serum and salivary glands (SGs). We studied the biological effect of neutralizing these cytokines by local gene transfer of the common receptor transmembrane activator and CAML interactor (TACI) in an animal model of SS. MATERIAL AND METHODS: A recombinant serotype 2 adeno-associated virus (rAAV2) encoding TACI-Fc was constructed, and its efficacy was tested in the SGs of non-obese diabetic mice. Ten weeks later, SG inflammation was evaluated and serum and SG tissue were analyzed for inflammatory markers including immunoglobulins (Ig) and cytokines. RESULTS: AAV2-TACI-Fc gene therapy significantly reduced the number of inflammatory foci in the SG, owing to a decrease in IgD(+) cells and CD138(+) cells. Moreover, IgG and IgM levels, but not IgA levels, were reduced in the SG. Overall expression of mainly proinflammatory cytokines tended to be lower in AAV2-TACI-Fc-treated mice. Salivary flow was unaffected. CONCLUSION: Although local expression of soluble TACI-Fc reduced inflammation and immunoglobulin levels in the SG, further research will have to prove whether dual blockade of APRIL and BAFF by TACI-Fc can provide a satisfying treatment for the clinical symptoms of patients.


Subject(s)
Genetic Therapy/methods , Recombinant Fusion Proteins/therapeutic use , Sjogren's Syndrome/therapy , Transmembrane Activator and CAML Interactor Protein/therapeutic use , Animals , B-Cell Activating Factor/antagonists & inhibitors , B-Lymphocytes/pathology , Cytokines/analysis , Dependovirus/genetics , Disease Models, Animal , Female , Genetic Vectors/genetics , Immunoglobulin A/analysis , Immunoglobulin D/analysis , Immunoglobulin G/analysis , Immunoglobulin M/analysis , Inflammation Mediators/analysis , Ligands , Mice , Mice, Inbred NOD , Plasma Cells/pathology , Recombinant Fusion Proteins/genetics , Saliva/chemistry , Saliva/metabolism , Secretory Rate/physiology , Sialadenitis/immunology , Sialadenitis/pathology , Sjogren's Syndrome/blood , Sjogren's Syndrome/pathology , Submandibular Gland/immunology , Submandibular Gland/metabolism , Submandibular Gland/pathology , Syndecan-1/analysis , Transduction, Genetic , Transmembrane Activator and CAML Interactor Protein/genetics , Tumor Necrosis Factor Ligand Superfamily Member 13/antagonists & inhibitors
6.
Oral Dis ; 18(1): 96-106, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21914088

ABSTRACT

OBJECTIVE: Non-obese diabetic (NOD) mice develop an autoimmune exocrinopathy that shows similarities with Sjögren's syndrome. They provide an experimental model to study the pathoetiogenesis of this disease. MATERIALS AND METHODS: Salivary gland (SG) function and salivary sodium content were measured in 8-, 12-, 16- and 20-week-old NOD and age-matched CB6 mice. In NOD mice, SG expression of phenotypic cell markers, B cell-stimulating and costimulatory molecules were evaluated. Cytokine levels were measured in serum and SG homogenates. RESULTS: Microscopically evident SG inflammation in NOD mice was preceded by expression of intercellular adhesion molecule 1 on epithelial cells in the presence of macrophages and relatively high levels of cytokines. Next, an influx consisting of mainly T, B, natural killer, plasma and dendritic cells was seen. Most cytokines, except for interleukin (IL)12/IL23p40 and B cell-activating factor, decreased or remained stable over time, while glandular function deteriorated from 16 weeks of age onward compared with CB6 mice. CONCLUSION: Sjögren's syndrome-like disease in NOD mice occurs in multiple stages; immunological and physiological abnormalities can be detected before focal inflammation appears and salivary output declines. Extrapolating this knowledge to human subjects could help in understanding the pathogenesis and aid the identification of potential therapeutic targets.


Subject(s)
Disease Models, Animal , Salivary Glands/physiopathology , Sialadenitis/physiopathology , Sjogren's Syndrome/etiology , Sjogren's Syndrome/immunology , Animals , B-Cell Activating Factor/biosynthesis , CD40 Antigens/biosynthesis , Cytokines/biosynthesis , Cytokines/blood , Female , Intercellular Adhesion Molecule-1/biosynthesis , Intercellular Adhesion Molecule-1/blood , Interleukins/biosynthesis , Interleukins/blood , Lymphocytes/immunology , Macrophages/immunology , Mice , Mice, Inbred NOD , Mice, Inbred Strains , Saliva/chemistry , Saliva/metabolism , Salivary Glands/chemistry , Salivary Glands/pathology , Secretory Rate , Sialadenitis/pathology , Sodium/analysis , Th1 Cells/immunology , Th2 Cells/immunology , Time Factors
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