cyclic-gmp and Lupus-Erythematosus--Systemic

Topics: Animals; Ascorbic Acid; Chediak-Higashi Syndrome; Concanavalin A; Cyclic GMP; Disease Models, Animal; Humans; Immunity, Cellular; Leukocytes; Lupus Erythematosus, Systemic; Mice; Mice, Inbred NZB; Prostaglandins

Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease

Topics: Animals; Autoimmunity; B-Lymphocytes; Cyclic GMP; Gain of Function Mutation; Guanosine; Humans; Lupus Erythematosus, Systemic; Mice; Myeloid Differentiation Factor 88; Toll-Like Receptor 7

Production of high titer of antibodies against nuclear components is a hallmark of systemic lupus erythematosus, an autoimmune disease characterized by the progressive chronic inflammation of multiple joints and organs. Organ damage and dysfunction such as renal failure are typical clinical features in lupus. Cell hypermetabolism and hypertrophy can accelerate organ dysfunction. In this study we focus on a specific murine model of lupus, the MRL/lpr strain, and investigated the role of cyclic guanosine monophosphate (cGMP) catabolism in organ remodeling of main target tissues (kidney, spleen and liver) in comparison with age-matched control mice. In MRL/lpr-prone mice, the cGMP-phosphodiesterase (PDE) activities were significantly increased in the kidney (3-fold, P<0.001), spleen (2-fold, P<0.001) and liver (1.6-fold, P<0.05). These raised activity levels were paralleled by both an increased activity of PDE1 in the kidney (associated with nephromegaly) and in the liver, and PDE2 in the spleen of lupus-prone mice. The up-regulation of PDE1 and PDE2 activities were associated with a decrease in intracellular cGMP levels. This underlines an alteration of cGMP-PDE signaling in the kidney, spleen and liver targeting different PDEs according to organs. In good agreement with these findings, a single intravenous administration to MRL/lpr mice of nimodipine (PDE1 inhibitor) but not of EHNA (PDE2 inhibitor) was able to significantly lower peripheral hypercellularity (P=0.0401), a characteristic feature of this strain of lupus-prone mice. Collectively, our findings are important for generating personalized strategies to prevent certain forms of the lupus disease as well as for understanding the role of PDEs and cGMP in the pathophysiology of lupus.

Topics: Animals; Cyclic GMP; Female; Lupus Erythematosus, Systemic; Mice; Mice, Inbred CBA; Mice, Inbred MRL lpr; Up-Regulation

Isolated congenital heart block may be associated with autoimmune disorder such as Sjögren Syndrome and systemic lupus erythematosus. In this work we demonstrate circulating autoantibodies against neonatal heart M1 muscarinic acetylcholine receptor (mAChR) in the sera of children with congenital heart block. This antibody were able to react with the second extracellular loop of the human M1 mAChR as demonstrated using a synthetic peptide in enzyme immune assay and binding assay. Affinity purified anti-peptide IgG as well as total IgG from children with congenital heart block, interfered with the specific radioligand occupancy from neonatal heart M1 mAChR, interacting irreversibly. The antipeptide antibodies also displayed an 'agonist-like' activity, i.e. decreased contractility, activated nitric oxide synthase activity and increased production of cyclic GMP. All of these effects were selectively blunted by pirenzepine and neutralized by the synthetic M1 peptide. Both binding and biological effects were obtained using neonatal rat heart instead adult heart and were independent of Ro/SS-A and La/SS-B antibodies and were also absent in the sera of normal children. A clinical relevance of these findings is demonstrated by a strong association between the existence of circulating M1 mAChR antipeptide antibodies and the presence of isolated congenital heart block, making these antibodies a proper marker of this disease.

Topics: Amino Acid Sequence; Animals; Autoantibodies; Autoantigens; Child; Child, Preschool; Cyclic GMP; Heart; Heart Block; Heart Defects, Congenital; Humans; Infant; Lupus Erythematosus, Systemic; Molecular Sequence Data; Nitric Oxide Synthase; Peptides; Rats; Receptor, Muscarinic M1; Receptors, Muscarinic

Cyclic-GMP (C-GMP), a normal constituent of the central nervous system, was found to be present in increased amounts in the cerebrospinal fluid (CSF) of systemic lupus erythematosus (SLE) patients with active neurologic disease. Twenty-four CSF samples from 17 patients with SLE were evaluated for C-GMP concentration by radioimmunoassay. This study extends our initial observations and examines three groups of SLE patients based on their clinical status at the time of each lumbar puncture: those with active neurologic and psychologic abnormalities (group I), active neurologic abnormalities (group II), and psychologic abnormalities without active neurologic involvement (group III). Groups I and II had mean CSF C-GMP values of 3.1 nM +/- 0.64 (SE) and 4.1 nM +/- 0.10 respectively, which were both significantly higher than the mean for group III (1.2 nM +/- 0.43) (P less than 0.05). Other CSF findings did not display this close correlation with activity of neurologic disease. In 4 SLE patients, significantly higher levels of CSF C-GMP were found on serial sampling during times when neurologic abnormalities were active. Thus elevated CSF C-GMP concentration may be a marker of active neurologic disease in SLE.

Topics: Adult; Blood Sedimentation; Central Nervous System Diseases; Cerebrospinal Fluid; Complement System Proteins; Cyclic GMP; Female; Hemoglobins; Humans; Leukocyte Count; Leukopenia; Lupus Erythematosus, Systemic; Male; Neurocognitive Disorders; Neurologic Manifestations; Prednisone; Psychotropic Drugs; Radioimmunoassay; Spinal Puncture; Thrombocytopenia

Cerebrospinal fluid samples from patients with systemic lupus erythematosus (SLE) and neurologic involvement were evaluated for guanosine 3',5'-cyclic monophosphate (C-GMP) and cyclic adenosine monophosphate (C-GMP) content by radioimmunoassay and radioassay, respectively. Twenty-five samples from 15 patients with SLE had an average C-GMP level of 2.4 nM +/- 0.44 (average +/- SE) compared with 0.68 nM +/- 0.14 in a control group with lumbosacral pain (p less than 0.0002). No significant difference was noted in C-AMP content between patients with SLE and control subjects. C-GMP levels in cerebrospinal fluid samples from patients with SLE who had changing neurologic disease were higher than in those with stable neurologic disease. Elevated C-GMP levels in cerebrospinal fluid correlated with the leukocyte number in cerebrospinal fluid (r = 0.53 p less than 0.01), but not with the initial pressure, protein concentration or daily prednisone dosage. Experimental results suggested that leukocytes in the cerebrospinal fluid were not the source of elevated C-GMP levels. Thus, elevated C-GMP levels in cerebrospinal fluid of patients with SLE appeared to reflect neurologic involvement. C-GMP levels were alos found to be elevated in five patients with other active neurologic diseases; thus, measurement of C-GMP in cerebrospinal fluid may have more general diagnostic value.

Topics: Adolescent; Adult; Aged; Child; Cyclic AMP; Cyclic GMP; Female; Humans; Leukocyte Count; Lupus Erythematosus, Systemic; Lymphocytes; Male; Methods; Middle Aged; Neurologic Manifestations; Prednisone