The Immune and Pathogenic Mechanisms of Autoimmune Neonatal Heart Block

Autoimmune neonatal heart block (NHB) is the dysfunction and damaging of a fetal heart
caused by passively acquired maternal autoantibodies, in which autoantibodies are transferred
from the placenta to the developing fetus. More specifically, the autoantibodies responsible
are the Ro/SSA and La/SSB autoantibodies which affect the corresponding
ribonucleoproteins (Ambrosi et al 2012)1. The effects of the autoantibodies include
inflammation, fibrosis, calcification and leading to blockage of signal conduction at the
atrioventricular (AV) node or even to the sino-atrial (SA) node, which may develop to an
irreversible complete AV block, with a mortality rate of 30% and require affected infants
with permanent pacemaker implantation (Buyon et al. 2008)2.
Currently, the exact pathogenic mechanisms of the development of NHB is yet unknown,
however, the direct correlation of NHB and maternal Ro/SSA and La/SSB autoantibodies
have already been established since the early 1980s1. Furthermore, extensive researches have
identified that two unrelated proteins of the Ro/SSA autoantigen called Ro52 and Ro60 also
contribute greatly to the development of NHB, as evidence has shown a significantly high
percentage of mothers of children with NHB containing Ro52 and Ro60 autoantibodies. This
is shown by the experiments done by Salomonsson et al. (2005)3 where a specific epitope
amino acid sequence p200 of the Ro52 protein was immunized to rats, and the results showed
that all rats developed NHB.
Based on the above knowledge and experimental studies of heart block, two possible
pathogenic mechanisms have been developed to answer how maternal antibodies induce a
pathogenic response on their fetal target autoantigens, and they include the apoptosis and
calcium channel hypothesis. The apoptosis hypothesis proposes that Ro/La antigens become
accessible to the maternal autoantibodies through the process of apoptosis, which is a process
of cell elimination in the form of cell death that is closely controlled and is crucial in cell
development2. It is suggested that the process of apoptosis leads to the translocation of
intracellular Ro/La antigens to the surface, which then becomes the target of the maternal
Ro/La autoantibodies that is circulating in the fetal through the placental of the mother2.
Under healthy physiological conditions, the apoptotic cells are removed without causing any
inflammation response. This is done so by adjacent cardiocytes acting as phagocytes and
removing the apoptotic cells, which is shown in figure 1 (upper panel) below

Figure 1: Illustration of the removal of apoptotic cells in healthy cardiocytes (upper panel)
and the inflammation response triggered by opsonization of apoptotic cells (bottom panel)4

with the phosphatidylserine (PS) receptors acting as the surface receptor that initiates the
removal process. In comparison, the opsonized apoptotic cells bound by the autoantibodies
triggers an inflammation response as the autoantibodies inhibits the uptake of apoptotic
cardiocytes by the healthy cardiocytes, and instead directs to macrophages engulfment of the
apoptotic cell2. This results in accumulation of apoptotic cardiocytes, thus can lead to further
inflammation in the area, and production of inflammatory and fibrosing cytokines and
eventually resulting in damage to the targeted cell, as shown in figure 1 bottom panel. This
hypothesis is supported by the significantly large amount of apoptosis cells observed in
autopsy from foetuses that have suffered from NHB2, however one major flaw of the
hypothesis is that it fails the findings fail to explain the dysfunction in conduction system
myocytes such as the AV node myocytes as the experiment is performed in ventricular
myocytes, which is the major cause of the NHB.
The calcium channel hypothesis was formulated based on that AV node is controlled by Ltype and T-type calcium channel, which its role is the conduction of signal between the atria
and ventricle myocytes (Karnabi et al. 2010)5. The maternal autoantibodies circulating the
fetus are able to bind to the calcium channels by identifying protein subunits of the channel,
which have been observed to have the effect of degradation and internalisation of the
channel, which results in low numbers of signal conduction and also insufficient strength in
excitation of the calcium channels caused by inhibition of inward calcium fluxes through the

channels4. This ultimately leads to dysfunction of the calcium channel, thus affecting the AV
node and contractile function of the heart. Furthermore, the research done by Salomonsson et
al. (2005)3 also have shown that prolonged disturbance in calcium ions levels may induce an
apoptotic process, as intracellular calcium levels increase due to the inhibition, subsequently
leading to loss of function and eventually apoptosis. This increased apoptosis occurring in the
fetal heart leads to further Ro/La maternal autoantibodies to bind to the apoptotic cells, which
further amplifies the inflammatory response as discussed in the apoptosis hypothesis,
resulting in irreversible damage to cardiomyocytes and finally complete NHB1.
Despite hypothesis have been developed to explain the possible pathogenic mechanisms of
the development of NHB, and strong links between maternal autoantibodies have long been
discovered, statistically only 1-2% of the pregnancies in which the mother is tested with antiRo-positive develop NHB1. This suggests that the proposed hypothesis currently developed
still fails to explain all aspects of the cause of NHB, and studies have suggested that other
autoantibodies may also be responsible. For example, a protein responsible for calcium
storage called calreticulin have been found more frequently in mothers of children with NHB
in comparison to a mother of a healthy children (Orth et al. 1996)6. Thus, future research
should focus on identifying unknown autoantibodies that contribute to NHB. In addition, at
the same time more studies should be conducted on calcium channels as current evidence
proves conclusively that calcium ion channels play a significant role in development of NHB
regardless of the autoantibodies, and that a suitable calcium channel agonist will be crucial in
finding, in order to reverse the effects of the calcium channel inhibition caused by the
maternal autoantibodies.

References
1. Ambrosi A, Herlenius MW. Congenital heart block: evidence for a pathogenic role of
maternal autoantibodies. Arthritis Res Ther. 2012; 14(2): 208
2. Buyon B, Clancy RM. Dying right to live longer: positing apoptosis as a link between
maternal autoantibodies and congenital heart block. New York University School of
Medicine. 2008; 17: 86-90.
3. Salomonsson S, et al. Ro/SSA autoantibodies directly bind cardiomyocytes, disturb
calcium homeostasis, and mediate congenital heart block. J Exp Med. 2005; 201(1):
11-17.
4. Buyon B, Clancy RM. Figure 1, Illustration of apoptosis of healthy cardiocytes and
inflammatory response caused by autoantibodies, viewed 17 October 2016.
5. Karnabi E, Boutjdir M. Role of calcium channels in congenital heart block.
Scandinavian journal of immunology. 2010; DOI: 10.1111/j.1365-3083.2010.02439.x
6. Orth T, et al. Complete congenital heart block is associated with increased
autoantibody titers against calreticulin. Eur J Clin Invest. 1996; 26: 205-215