Autoantibodies in cord blood of offspring from women with rheumatoid arthritis? A pilot study to investigate placental transfer of autoantibodies in women with RA

Rheumatoid arthritis (RA) is a common autoimmune disease characterized by
persistent synovitis, systemic inflammation and the expression of
autoantibodies. Although RA affects 0.5-1% of the population, knowledge
concerning disease pathogenesis remains relatively limited. (1)
The *oldest* autoantibody in RA is rheumatoid factor (RF). RF targets the
Fc-part of human IgG and is mostly present as IgM-RF although IgG-RF and IgA-RF
have also been described in subgroups of patients.
In the past decade, anti-citrullinated protein antibodies (ACPA) have been
identified as a new class of autoantibodies in RA and are now important
diagnostic and prognostic biomarkers. Patients with ACPA positive RA are prone
to suffer from a severe course of the disease with more joint destruction than
ACPA-negative patients. (2) Intriguingly, ACPA can be detected in serum many
years before disease onset.(3)
In 2011, autoantibodies recognizing carbamylated (homocitrulline-containing)
antigens (anti-CarP antibodies) have first been described as a new serological
marker for patients with ACPA negative RA. In this group of patients, anti-CarP
antibodies associate with more severe joint destruction compared to joint
destruction in anti-CarP negative patients.

In most female patients, symptoms of RA ameliorate during pregnancy.
Postpartum, the disease frequently flares. In contrast, other autoimmune
disorders such as systemic lupus erythematodes and pemphigus vulgaris often
worsen during pregnancy, but can also cause placental insufficiency, growth
retardation and premature birth. In addition, these disorders pose an increased
risk for the child because of placental transfer of autoantibodies, which can
lead to neonatal lupus or pemphigus, respectively.
Interestingly, no cases of neonatal RA have so far been described, and no
detailed analysis has been performed to investigate whether and to what extent
autoantibodies from RA patients cross the placenta and can be found in fetal
cord blood.
In principal, placental transfer of antibodies in the human is mediated by the
neonatal Fc receptor that specifically recognizes IgG. The majority of ACPA and
anti-CarP antibodies are of the IgG isotype and, therefore, should be able to
cross the placenta. Consequently, these antibodies can be expected in neonatal
cord blood. Recent evidence indicates, however, that at least ACPA are
different from *conventional* IgG molecules. For example, the vast majority of
ACPA carries highly sialylated N-glycans in the variable region. In contrast,
such glycans are found in only a minority of non-citrulline specific IgG and
have so far not been detected on other autoantibodies. Also, analysis of
glycans in the Fc region revealed important differences between ACPA and the
rest of circulating serum IgG. These observations are relevant, as glycans are
known to modulate the structure of antibodies and the extent to which a
molecule can interact with its receptor.
Given that offspring of mothers with autoantibody positive RA do not show signs
and symptoms of disease, the question arises whether ACPA and other disease
specific autoantibodies do indeed cross the placenta in the same way as has
been described for non-self reactive IgG and other autoantibodies.

To answer the following questions
Do RA-specific autoantibodies cross the placenta, and can they be found in
fetal cord blood in the offspring of mothers suffering from RA?
Do RA-specific autoantibodies in fetal cord blood display different
characteristics (such as fine-specificity, avidity, glycosylation) than their
maternal counterparts?

pilot study

Minimal risk for patient because of venous puncture