A population-based investigation of the autoantibody profile in mothers of children with atrioventricular block.

The objective of the study was to investigate the antigen specificity and occurrence of individual autoantibodies in mothers of children diagnosed with atrioventricular (AV) block in a nation-wide setting. Patients with AV block detected before 15 years of age were identified using national quality registries as well as a network of pediatric and adult cardiologists and rheumatologists at the six university hospitals in Sweden. Patients with gross heart malformations, surgically or infectiously induced blocks were excluded. Blood samples were obtained from the mothers and maternal autoantibody profile, including the occurrence of antibodies against Ro52, Ro60, La, SmB, SmD, RNP-70k, RNP-A, RNP-C, CENP-C, Scl-70, Jo-1, ribosomal RNP and histones was investigated in 193 mothers of children with AV block by immunoblotting and ELISA. Autoantibody reactivity was detected in 48% (93/193) of the mothers of children with AV block. In autoantibody-positive mothers, the vast majority, 95% (88/93), had antibodies against Ro52, while 63% (59/93) had autoantibodies to Ro60 and 58% (54/93) had autoantibodies to La. In addition, 13% (12/93) of the autoantibody-positive mothers had antibodies to other investigated antigens besides Ro52, Ro60 and La, and of these anti-histone antibodies were most commonly represented, detected in 8% (7/93) of the mothers. In conclusion, this Swedish population-based study confirms that maternal autoantibodies may associate with heart block in the child. Further, our data demonstrate a dominant role of Ro52 antibodies in association with AV block.

A novel endoproteolytic processing activity in mitochondria of erythroid cells and the role in heme synthesis.

The erythroid isoform of aminolevulinate synthase (eALAS) protein is a major control point in erythroid heme synthesis and hemoglobin formation. Erythroid cells were extracted from mouse blood and bone marrow and metabolically labeled with (35)S-methionine. This was followed by immunoprecipitation of eALAS protein products. The results show that the N-terminus of the expected full-length 59-kd form of the eALAS protein is truncated in bone marrow erythroid cells by approximately 7 kd. More differentiated erythroid cells in the peripheral blood exhibit very little of this protein truncation. Erythroid cells from the bone marrow were isolated using monoclonal antibody TER-119 and were shown to contain a unique endoprotease activity that could cleave the eALAS protein to the shorter form in vitro. With or without the mitochondrial signal sequence, the eALAS protein could serve as a substrate for the cleavage. This cleavage renders a functional eALAS protein and only removes a domain of unclear function, which has previously been reported to vary in size as a result of alternative RNA splicing. The protease activity was enriched from the membranes of mitochondria from bone marrow cells and was shown to be different from mitochondrial processing peptidase, medullasin, and other known proteases. Apart from the mitochondrial processing peptidase that cleaves the import signal sequence, this is the first description of a mitochondrially located site-specific processing protease activity. (Blood. 2000;96:740-746)