The pathogenesis of """"""""explained"""""""" pulmonary hypertension (PHT) is unknown, bu PHT occurs as a clinical component of autoimmune diseases. HLA-Class II genes (HLA-DR,DQ,DP) of the human major histocompatibility complex (MHC) ar permissive for autoimmune diseases, subject to additional genetic and environmental modifying influences. This proposal will examine the clinica parameters, HLA predisposition, autoantibodies, alteration in immunocompetent cells, and role of smooth muscle mitogen in certain categories of PHT. The PHT study groups include: adult and juvenile primar pulmonary hypertension (PPH), PPH in human immunodeficiency virus(HIV) seropositive individuals, unexplained PHT in children with specific categories of congenital heart disease (anatomically large congenital pulmonary to systemic communications (PHT+Shunt) and in children with these same congenital shunts without PHT (PHT-Shunt), and in familial PHT. These diverse categories of PHT are all characterized pathologically by obliteration of the small vascular pulmonary arteries. The methodologies include: serological HLA-A,B,C,DR and DQ typing and sequence specific oligonucleotide typing for DR, DQ and DP using polymerase chain amplified DNA to determine the relevant hypervariable gene segments; phenotypic and functional analysis of immunocompetent cells; and measurements of smooth muscle mitogen, such as transforming growth factor-B, platelet derived growth factor and fibroblast growth factors capable of inducing the vascula lesions. Severe combined immunodeficiency (SCID) mice will be reconstitute with immunocompetent cells from the PHT study groups to see which, if any, can serve with or without further manipulation, as a murine model(s) for studies of plexogenic arteriopathy. The results of these experiments shoul define: (i) which PHT study groups have an HLA association and whether ther are shared sequences which presumably can combine with antigens and T cell receptors (TCRs); (2) which PHT study groups have a restricted section of TCR VB gene products, (3) whether alterations in the percentages of NK, T o B cells play a causal role in inducing the vascular lesions; and (4) whethe these PHT groups have the same or different smooth muscle mitogen(s) capabl of causing the smooth muscle hypertrophy. Since autoimmune diseases often respond to anti-inflammatory and or/immunosuppressive therapy the knowledge gained here may have both therapeutic and mechanistic implications.
| Morse, J H; Jones, A C; Barst, R J et al. (1997) Mapping of familial primary pulmonary hypertension locus (PPH1) to chromosome 2q31-q32. Circulation 95:2603-6 |
| Morse, J H; Barst, R J; Fotino, M et al. (1997) Primary pulmonary hypertension, tissue plasminogen activator antibodies, and HLA-DQ7. Am J Respir Crit Care Med 155:274-8 |
| Morse, J H; Barst, R J; Fotino, M et al. (1996) Primary pulmonary hypertension: immunogenetic response to high-mobility group (HMG) proteins and histone. Clin Exp Immunol 106:389-95 |
| Morse, J H; Barst, R J; Itescu, S et al. (1996) Primary pulmonary hypertension in HIV infection: an outcome determined by particular HLA class II alleles. Am J Respir Crit Care Med 153:1299-301 |
