A postulated association between primary pulmonary hypertension (PPH) and autoimmune diseases prompted this study. To see if autoantibodies and an association with the major histocompatibility locus (MHC) accompany the familial form of pulmonary hypertension (PHT), we determined human leukocyte antigen (HLA)-class I (A,B,C) and HLA-class II (DR,DQ) typing serologically, serum immunoglobulin (Ig) isotypes, and antinuclear (ANA)-autoantibodies in three families in which more than one member had PPH (FPPH) and in a fourth family with PPH and PHT associated with congenital heart disease. The three FPPH families had 15 PPH+ members, eight (in whom the alleles were determined or could be inferred) typed for HLA-DRw52 and seven for HLA-DR3,DRw52,DQw2. These three families each had one PPH+, DR3+ member, with an immunoglobulin isotype deficiency, one with IgA and two with mild IgG. The fourth family differed in that both the patient and asymptomatic relatives had varying autoantibodies and different HLA associations. This family had an anti-centromere+ child with PHT and a congenital heart lesion, a mother who died of PPH, and asymptomatic ANA+ relatives (father anti-Sm+/anti-RNP+; autoantibodies unknown in fraternal twin sister and in maternal grandmother). HLA typing showed that the proband and her fraternal twin sister received DR5,DRw52,DQw3 from their father whereas the proband received DR4,DRw53,DQw3 from the mother and her sister received DR2,DQw1. In summary, three FPPH families had multiple PPH+ members who lacked autoantibodies and typed for HLA-DR3,DRw52,DQw2, whereas a fourth family with familial PHT had PHT+ and PHT- members with autoantibodies and different HLA associations. These data support the hypothesis that Ig isotype deficiencies and autoimmunity occur in distinct immunogenetically defined subsets of familial PHT, susceptibility to which is determined in part by gene(s) within or near the HLA region on chromosome 6.
