PATHOPHYSIOLOGY OF PULMONARY HYPERTENSION

The pathogenesis of "explained" pulmonary hypertension (PHT) is unknown, but PHT occurs as a clinical component of autoimmune diseases. HLA-Class II genes (HLA-DR,DQ,DP) of the human major histocompatibility complex (MHC) are permissive for autoimmune diseases, subject to additional genetic and environmental modifying influences. This proposal will examine the clinical 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 primary 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 vascular lesions. Severe combined immunodeficiency (SCID) mice will be reconstituted 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 should define: (i) which PHT study groups have an HLA association and whether there 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 or B cells play a causal role in inducing the vascular lesions; and (4) whether these PHT groups have the same or different smooth muscle mitogen(s) capable 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.