ABSTRACT
X-linked autoimmunity-allergic disregulation syndrome (XLAAD) is an X-linked recessive immunological disorder characterized by multisystem autoimmunity, particularly early-onset type 1 diabetes mellitus, associated with manifestations of severe atopy including eczema, food allergy, and eosinophilic inflammation. Consistent with the allergic phenotype, analysis of two kindreds with XLAAD revealed marked skewing of patient T lymphocytes toward the Th2 phenotype. Using a positional-candidate approach, we have identified in both kindreds mutations in JM2, a gene on Xp11.23 that encodes a fork head domain-containing protein. One point mutation at a splice junction site results in transcripts that encode a truncated protein lacking the fork head homology domain. The other mutation involves an in-frame, 3-bp deletion that is predicted to impair the function of a leucine zipper dimerization domain. Our results point to a critical role for JM2 in self tolerance and Th cell differentiation.
Subject(s)
Autoimmune Diseases/genetics , Diabetes Mellitus, Type 1/genetics , Food Hypersensitivity/genetics , Genetic Linkage/genetics , Nuclear Proteins/genetics , Transcription Factors/genetics , X Chromosome/genetics , Amino Acid Sequence , Autoimmune Diseases/immunology , Base Sequence , Cell Differentiation , DNA Mutational Analysis , Diabetes Mellitus, Type 1/immunology , Female , Food Hypersensitivity/immunology , Forkhead Transcription Factors , Haplotypes , Humans , Leucine Zippers , Male , Molecular Sequence Data , Mutation/genetics , Nuclear Proteins/chemistry , Nuclear Proteins/immunology , Pedigree , Protein Structure, Tertiary , RNA Splice Sites/genetics , Sequence Alignment , Sequence Homology, Amino Acid , Syndrome , Th2 Cells/cytology , Th2 Cells/immunology , Transcription Factors/chemistry , Transcription Factors/immunology , X Chromosome/immunologyABSTRACT
Felodipine is a Calcium blocker and nitroglycerin, a nitrate vasodilating agent, were compared. Two parameters were studied in vitro on bovine aortic media. Calcium uptake and vascular tone. The Calcium uptake measurement was performed by incubating in Krebs solution small slices of the preparation in the presence of 45Ca. Studies on vascular tone were performed on deendothelialized bovine aortic rings suspended in Krebs solution. Felodipine (1nM-100microM) decreases Ca2+ uptake and relaxes the preparation while nitroglycerin's 1nM-100microM) action is also inhibiting but very weak. When the preparation is stimulated by alpha 1-adrenergic against phenylephrine 1microM, then nitroglycerin 100microM has a much stronger inhibiting effect on Call uptake and vascular tone than felodipine 100microM. These results are reversed when the preparation is stimulated by KC165.4mM. Then felodipine 100nM exerts a strong inhibiting effect on Ca2+ uptake and vascular tone while nitroglycerin's 100nM inhibiting action is very weak. It is well known that in cases of endothelium disfunction the adrenergic stimulation provokes vasoconstriction and ischemia. This ischemia induces a second phase of vasoconstriction that is due to a depolarization provoked by the increased levels of extracellular K+. Felodipine is able to antagonize the consequences of such a depolarization. Thus, felodipine may be useful as an additional agent to nitroglycerin's treatment and that is the clinical message of our findings.
ABSTRACT
It is known that clonidine exerts a hyperpolarizing action and alpha 2-adrenergic activity. The experimental work investigates the conditions under which each action of clonidine is developed on vascular smooth muscle. Two parameters were studied in vitro on bovine aortic media, Ca2+ uptake and vascular tone. The Ca2+ uptake measurement was performed by incubating in Krebs' solution small slices of the preparation in the presence of 45Ca. Studies on vascular tone were performed on deendothelialized bovine aortic rings suspended in Krebs' solution. Low concentrations of clonidine (1 nM-1 microM) decrease Ca2+ uptake and relax the preparation, indicating dominance of the inhibiting action of clonidine may be due to an hyperpolarization. Clonidine 10 microM results in equalization of the opposing actions of Ca2+ uptake and vascular tone. When the preparation is stimulated by alpha 1-adrenergic against phenylephrine 1 microM, clonidine 1 nM-10 microM potentates the Ca2+ uptake and vascular contraction in a monophasic way, indicating that the depolarizing mechanisms connected with the alpha 1-adrenergic stimulation totally inhibit the relaxing action of clonidine possibly due to hyperpolarization. This action is restricted in the presence of yohimbine (alpha 2-adrenergic blocker).
