This proposal will examine the immunopathogenesis of inflammatory disease (IVD) in human Sjogren's Syndrome (SS), a common autoimmune connective tissue disorder (CTD), and in a strain of autoimmune mice (MRL/MP), which shares many features with SS. Two main histopathologic tgypes of IVD have been described in SS: neutrophilic (NIVD), histopathologically indistinguishable from leukocytoclastic vasculitis, and mononuclear (MIVD) in which mononuclear cells (lymphocytes, monocytes, and plasma cells) comprise the vascular inflammatory infiltrates. A new model of IVD is proposed in which the infiltration of vessel walls by mononuclear cells (principally lymphocytes) is the primary initiating event, followed by an influx of neutrophils. The following specific aims will be examined by immunocytochemical techniques and in vitro culture systems permitting the dissection of cellular and antibody interactions with vascular endothelium: 1) To determine by phenotypic characterization of inflammatory vascular infiltrates whether vascular inflammation is initiated by early migration of T lymphocytes through vascular endothelium. 2) To assess the effects of T lymphocytes on vascular endothelial cell survival, proliferation, and mediator release (arachidonic acid metabolism). 3) To determine whether pre-B cells within inflamed vessel walls are induced by interleukin 3 (IL-3) synthesizing T-helper cells to proliferate and differentiate into RF synthesizing B and plasma cells. 4) To determine whether the local production of RF and in situ deposition of immune complexes activate the complement pathway(s) and induce neutrophil chemotaxis or whether lymphocytes in IVD infiltrates synthesize a lymphokine chemoattractant for neutrophils. Either of these mechanisms could be responsible for mediating the transition from MIVD to NIVD. 5) To determine whether autoantibodies to endothelial cell surface antigens are present in SS patients and MRL/MP mice and to clarify the effects of such antibodies on endothelial cell survival and function. 6) To determine whether the development of IVD can be modulated in vivo by infusion of antibodies to subsets of lymphocytes involved in the vascular inflammation anti-idiotypic antibodies against RF, or antibodies to Class II (I-A) determinants. These studies have relevance to understanding the immunopathogenesis of IVD in CTD, but also in other clinical settings.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL034723-01
Application #
3347937
Study Section
Pathology A Study Section (PTHA)
Project Start
1985-07-01
Project End
1990-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Alexander, E L; Ranzenbach, M R; Kumar, A J et al. (1994) Anti-Ro(SS-A) autoantibodies in central nervous system disease associated with Sjogren's syndrome (CNS-SS): clinical, neuroimaging, and angiographic correlates. Neurology 44:899-908
Spezialetti, R; Bluestein, H G; Peter, J B et al. (1993) Neuropsychiatric disease in Sjogren's syndrome: anti-ribosomal P and anti-neuronal antibodies. Am J Med 95:153-60
Alexander, E; Buyon, J P; Provost, T T et al. (1992) Anti-Ro/SS-A antibodies in the pathophysiology of congenital heart block in neonatal lupus syndrome, an experimental model. In vitro electrophysiologic and immunocytochemical studies. Arthritis Rheum 35:176-89
Alexander, E L; McNicholl, J; Watson, R M et al. (1989) The immunogenetic relationship between anti-Ro(SS-A)/La(SS-B) antibody positive Sjogren's/lupus erythematosus overlap syndrome and the neonatal lupus syndrome. J Invest Dermatol 93:751-6
Alexander, E L; Beall, S S; Gordon, B et al. (1988) Magnetic resonance imaging of cerebral lesions in patients with the Sjogren syndrome. Ann Intern Med 108:815-23
Alexander, E; Provost, T T (1987) Sjogren's syndrome. Association of cutaneous vasculitis with central nervous system disease. Arch Dermatol 123:801-10
Provost, T T; Vasily, D; Alexander, E (1987) Sjogren's syndrome. Cutaneous, immunologic, and nervous system manifestations. Neurol Clin 5:405-26
Alexander, E L; Firestein, G S; Weiss, J L et al. (1986) Reversible cold-induced abnormalities in myocardial perfusion and function in systemic sclerosis. Ann Intern Med 105:661-8
Malinow, K; Yannakakis, G D; Glusman, S M et al. (1986) Subacute sensory neuronopathy secondary to dorsal root ganglionitis in primary Sjogren's syndrome. Ann Neurol 20:535-7