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| Dr. William Matzner, Simi Valley, California |
Excerpt: Correlation Between Beta 2-Glycoprotein Antibodies
and Antiphospholipid Antibodies In Patients With Reproductive Failure
This is an excerpt of an article originally published
in American Journal of Reproductive Immunology and was co-authored by Dr.
William Matzner. The full article is available here.
INTRODUCTION
Antibodies
to negatively charged phospholipids in sera of women with immune mediated
reproductive failure are believed important etiologic factors. Initial studies focused on the presence of
antibodies to cardiolipin which had been shown to cause clotting abnormalities
in some patients with Systemic Lupus Erythematosus (SLE), and in subset of women who suffer recurrent
miscarriage. Miscarriage is believed due to thrombotic event; anticardiolipin
antibodies (aCL) can cause platelet membrane and endothelial wall damage,
interfere with protein C (natural anticoagulant) activation, and inhibit
prostacyclins. Cardiolipin is found
primarily within the inner mitochondrial membrane, unlike the other phospholipids
which are found on the cell surface.
Among patients with recurrent miscarriages or failed IVF, the majority
of APA is directed to epitopes other that cardiolipin (approximately 90%).
Antibodies
to various phospholipid epitopes have been best characterized by solid phase
enzyme linked immunosorbent assay (ELISA); phospholipid is coated onto a
polystyrene plate, and the antibody detected by binding to phospholipid forming
a “sandwich” with a color marker which is quantified. Binding proteins are necessary for APA
detection as evidenced by the perceived absence of APA when newborn or fetal
calf serum are withheld from the assay.
Beta 2 glycoprotein (beta 2 GP) is the specific protein involved in the
binding of aCL to solid phase cardiolipin.
Hypothetical mechanisms include; a) the aCL recognizes a cardiolipin
beta 2 GP complex, b) the beta 2 GP is
the target for aCL (not the phospholipid) and
c) the actual epitope is part of the native structure of beta 2 GP. The
dependence of antibodies to beta 2 GP may be disease specific. One study has
shown that patients with SLE who manufacture aCL actually had antibodies
against the beta 2 GP component. In
another study a positive correlation between aCL and anti beta 2 GP in SLE was
identified, but not between aCL and beta 2 GP in patients with end stage renal
disease.
To
further complicate diagnosis, false positive aCL to epitopes such as syphilis,
dsDNA and others are not uncommon.
Corroborating evidence for confusion include studies which show a
correlation between lupus anticoagulant activity of aCL and the presence of
beta 2 GP versus the absence of correlation between beta 2 GP and aCL levels in
SLE. Another recent study claims a
significant correlation between previous thrombosis and beta 2 GP, but not
between fetal losses and a beta 2 GP.
Patients with APA likely represent a heterogeneous group with antibodies
directed to either the phospholipid and/or phospholipid binding proteins.
We
examine the potential correlation of antibodies to beta 2 GP with that of
several negatively charged phospholipids in patients who have been unsuccessful
with in vitro fertilization.
STUDY
GROUP
One
hundred twenty three (123) consecutive patients, all under 40 years of
age, with a history of reproductive
failure as demonstrated by one or more failed IVFs. None of the patients had male factor as an
etiology for their infertility, nor an overt history of thromboembolic
disorders. These women did not have a
history of recurrent pregnancy loss.
APA
ELISA
Patient
sera were tested for antibodies to two isotypes (IgG, IgM) of six different
phospholipids (cardiolipin, phosphatidylethanolamine, phosphatidylserine,
phosphatidylinositol, phosphatidylglycerol, and phosphatidic acid) by solid
phase ELISA as previously described in detail.
BETA 2
GLYCOPROTEIN ELISA
All
patient sera were tested for beta 2 GP by a solid phase ELISA to IgG and IgM
isotypes, as supplied by INOVA DIAGNOSITICS (San Diego , CA).
RESULTS
Of the
123 women that were tested, 33/123 had
one or more positive IgG antibodies to phospholipids, of which 9/ 33 were to
cardiolipin. However, only 1/123 had IgG
antibodies to beta 2 GP and she was APA negative. Thirty eight of one hundred twenty three
(38/123) women had one or more IgM antibodies to phospholipids, with 0/123
directed to cardiolipin IgM. In
contrast, only 8/123 had IgM antibodies to beta 2 GP. Five of the eight (5/8) patients had IgM APA;
4/5 had IgM antibodies to PE and one to PI.
DISCUSSION
Our
study revealed no correlation between APA and Beta 2 GP antibodies. The Beta 2 GP antibody prevalence was about
7% (9/123) with 4 associated with PE IgM and 1 with PI IgM, and 4 Beta 2 GP
antibodies (1-IgG, 3 IgM) without any APA.
Unlike
some of our predecessors, we were unable
to identify a correlation between aCL and Beta 2 GP antibodies. Teixido, et. al., observed something similar.
It is possible that in the population we studied, there maybe a relationship
with oxidized low density lipoproteins as other have reported.
This study
shows once again, that women unsuccessful with IVF have significant APA
positivity, and that the incidence of
aCL is low. There is no correlation
between beta 2 GP antibody and APA status in this population. Therefore, beta 2 GP antibody in not clinically
beneficial to detect phospholipid related autoimmune abnormalities in IVF
failure patients.
About William L.
Matzner, M.D., PhD, FACP
Dr.
William Matzner works in the area of healthcare economics consulting at
Healthcare Analytics, LLC, in California. He graduated Phi Beta Kappa from
Stanford University. He received his M.D. with Honors from Baylor College of
Medicine. In 1988, he was the Solomon Scholar for Resident Research at Cedar
Sinai Medical Center. Dr. Matzner subsequently was awarded a PhD in Neuro
Economics from Claremont Graduate University. He is board certified in Internal
Medicine and Palliative Medicine. He has researched and published extensively
on the issue of reproduction and immunology in medical literature. He has been
in private practice since 1989, specializing in Reproductive Immunology and
Internal medicine.
Website: https://drwilliammatzner.com
Consulting Website: https://healthcareanalytics.biz
William Matzner, MD (Simi Valley, California), has been practicing medicine since 1989, Internal Medicine and Reproductive Immunology. M.D. with Honors from Baylor College of Medicine.
