Pamela V. Taylor

Connective-Tissue Disease, Antibodies to Ribonucleoprotein, and Congenital Heart Block

The relation between congenital heart block and maternal connective-tissue disease was studied by antibody screening of serum samples obtained in connection with 45 cases of isolated congenital complete heart block. Serum was available from 41 mothers (17 who had connective-tissue disease and 24 who were healthy) and 21 children. Thirty-four mothers had antibody to a soluble tissue ribonucleoprotein antigen called Ro(SS-A), which was identified by immunodiffusion. Anti-Ro(SS-A) was found in seven of eight serum samples collected from affected children when they were less than three months old but in none of 13 samples obtained when these children were older. It appears that maternal anti-Ro(SS-A) antibody crosses the placenta and is a marker for risk of congenital complete heart block; its absence from maternal serum suggests that a child is unlikely to be affected. Anti-Ro(SS-A) or a related antibody is probably involved in the pathogenesis of congenital complete heart block.

Maternal Antibodies against Fetal Cardiac Antigens in Congenital Complete Heart Block

An immunologic basis for congenital heart block has been proposed previously. To investigate the association between congenital heart block and maternal antibodies capable of crossing the placenta, we used immunofluorescence to examine serum samples from 41 mothers and 8 affected children, together with serum from controls, for antibodies to fetal cardiac tissue. Twenty-one mothers (51 percent) had IgG antibody reactive with fetal heart tissue, as compared with only 9 of 94 controls (10 percent; P less than 0.001). Three of 8 affected babies, but none of 50 healthy babies, had similar antibodies. The antibodies reacted with all myocardial tissue and were not directed specifically to the conduction system. They also reacted with other fetal tissues and could be distinguished from nuclear and smooth-muscle autoantibodies. We also observed a higher occurrence of antibodies to cytomegalovirus, but not to Epstein-Barr virus, in these mothers. Autopsy specimens from babies with congenital heart block examined by immunoperoxidase staining showed deposition of immunoglobulin and complement components in all cardiac tissues. These findings strengthen the case implicating immune reactivity related to maternal antibody in the development of some but not all cases of congenital heart block.

Ro and La antigens and maternal anti-La idiotype on the surface of myocardial fibres in congenital heart block☆

Congenital complete heart block (CCHB) is a rare but potentially fatal disease of infants born to mothers with autoimmune disease where maternal autoantibodies to Ro (SS-A) are thought to cross the placenta and damage fetal cardiac tissue. We have adopted a novel approach to demonstrate the localization and specificity of maternal autoantibodies deposited in fetal heart. We raised an anti-idiotype against maternal anti-La antibodies, which reacted strongly with the surface immunoglobulin on the myocardial fibres from a CCHB heart but not a control fetal heart of the same age. Maternal immunoglobulin eluted from the CCHB heart reacted with La (SS-B) by ELISA. Using monoclonal and affinity-purified antibodies to La and affinity-purified anti-Ro antibodies, both antigens were identified on the surface of the fibres of the affected heart. Surface co-expression of immunoglobulin, complement and Class II antigen, consistent with a local immune response, was also found. This is the first definitive demonstration of Ro and La antigens and specific maternal anti-La antibody and idiotype on the surface of myocardial fibres in CCHB. It suggests that induction of Ro and La antigens on the surface of myocardial fibres during fetal development may be critical in the localization of the specific autoantibodies and subsequent evolution of congenital complete heart block.

Presence of autoantibodies in women with unexplained infertility

Serum samples from 41 patients suffering from unexplained infertility and 351 normal pregnant women were assayed for a range of autoantibodies by means of immunofluorescence, counterimmunoelectrophoresis, double immunodiffusion, Western blots, and enzyme-linked immunosorbent assays. The prevalence of autoantibodies to smooth muscle, phospholipid, and nuclear antigens, the latter when detected by immunofluorescence, was elevated in women with infertility compared with normal pregnant women (p less than 0.001, less than 0.001, and less than 0.05, respectively). Antiviral antibodies were not detected. The reason for the high level of autoreactivity in infertile women is unclear, but smooth muscle and antiphospholipid antibodies may actively interfere with the reproductive process.

Maternal and fetal immune responses to human trophoblast antigens

Maternal and fetal cord leukocytes were tested in cytotoxicity assays against cultured autochthonous trophoblast cells. Significant lysis occurred with both categories of leukocyte, but the degree of cytotoxicity was less with fetal cells. These results suggest reduced fetal immunocompetence, the presence of fetal suppressor cells, or the presence of histocompatibility factors in trophoblast. Both fetal and maternal sera exhibited blocking activity in these tests and the source of this activity is discussed. The presence of particulate placental antigen inhibited trophoblast lysis by maternal leukocytes and no difference was observed between the effects of autochthonous and heterologous antigens.

Congenital AV-block: Role of Anti-Ro and Anti-La Antibodies

ConclusionsIt seems fairly definite that the development of congenital AV block depends upon the transplacental passage of maternal autoantibody to the fetus. There is compelling evidence for the involvement of anti-Ro (SS-A)/La (SS-B) antibodies in this process, although the definitive pathogenic antibody may be a different, closely related, one. Anti-Ro (SS-A)/La (SS-B) antibodies are certainly markers for risk of occurrence of CCHB, since all mothers of babies born with such heart block possess these antibodies.There is at present no way of predicting which mothers with anti-Ro (SS-A)/La (SS-B) antibodies will have babies with CCHB. The risk of recurrence of heart block in a subsequent child of a women with one child with CCHB has been estimated as about one in four.Demonstration of anti-Ro (SS-A)/La (SS-B) antibodies in maternal serum should alert the clinician to both the likelihood of the later development of CTD in the woman, and the possibility of CCHB in the fetus/neonate. Echocardiography will help to confirm the diagnosis and facilitate the early institution of pacemaker therapy, if required.Increasing evidence that pathogenic events leading to AV block are related to autoantibody mechanisms opens up the possibility that it could be prevented by removal of the antibody from the maternal circulation or blocking its effect with an appropriate monoclonal or anti-idiotypic antibody.

Autoantibodies to soluble cellular antigens in unexplained recurrent abortion and infertility

In 36 women with unexplained primary recurrent abortion, 13 with secondary unexpained recurrent abortion, 25 with primary unexplained infertility, 7 with secondary unexplained infertility and two groups of control women, autoantibodies to soluble cellular antigens were measured by Western blotting to a disaggregated HeLa cell antigen preparation, by counter immunoelectrophoresis and by indirect immunofluorescence. Using Western blotting the women with primary infertility and those with secondary recurrent abortion had a significantly higher prevalence of autoantibodies (P less than 0.01 in each case). This was not shown using the other methods. It is possible that these antibodies could be causally related to the pathology of the conditions studied.