Human primary Sjögren's syndrome autoantibodies as mediators of nitric oxide release coupled to lacrimal gland muscarinic acetylcholine receptors.
IgG obtained from sera of primary Sjögren's syndrome (pSS-IgG) patients and its interaction with M3 muscarinic cholinoceptors of rat exorbital lacrimal glands were studied by indirect immunofluorescence (IFI) and binding assay. Primary Sjögren's syndrome IgG stained epithelial cells with a continuous fluorescence pattern. The IFI imagen was attenuated by incubating the pSS-IgG with a synthetic peptide corresponding to the second extracellular loop of M3 muscarinic cholinoceptor. Primary SS-IgG was also able to bound irreversibly to muscarinic acetylcholine receptors (mAChRs) displacing the specific cholinergic antagonist QNB. Moreover, these antibodies triggered intracellular signals coupled to M3 muscaric cholinoceptors such as nitric oxide synthase (NOS) activation and cGMP production. Both primary Sjögren's syndrome IgG effects mimicked carbachol action and were abrogated by specific muscarinic antagonist 4-DAMP. The nitric oxide pathway through muscarinic cholinoceptors activation by pSS-IgG on rat exorbital lacrimal gland is also described. We proposed that chronic interaction of these autoantibodies on lacrimal gland muscarinic acetylcholine receptors could lead to tissue damage through nitric oxide release after immunological stimulation.
Bacman
S R
SR
CEFYBO (CONICET), Pharmacology Department, School of Dentistry, Buenos Aires University, Argentina.
Berra
A
A
Sterin-Borda
L
L
Borda
E S
ES
D000328:Adult; D000818:Animals; D001323:Autoantibodies / Q000302:isolation & purification / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007074:Immunoglobulin G / Q000302:isolation & purification / Q000494:pharmacology; D007765:Lacrimal Apparatus / Q000187:drug effects* / Q000378:metabolism; D008875:Middle Aged; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012859:Sjogren's Syndrome / Q000276:immunology*
D001323:Autoantibodies; D007074:Immunoglobulin G; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D010446:Peptide Fragments; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP