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The role of fetomaternal MHC class II histoincompatibility in regulating tolerance
of the semi-allogenic fetus
Darren R. Ritsick, Cassidy Bommer, Jeffrey Braverman
Braverman IVF and Reproductive Immunology, PC, NY, USA
Introduction – paternal alloantigen-specific Tregs
regulate fetomaternal tolerance
MHC class II alloantigens mediate
linked suppression
Fetomaternal MHC class II disparity
regulates linked suppression during pregnancy
Viviparous pregnancy represents a physiological state in which the maternal
immune system must tolerate a semi-allogenic fetus expressing ‘nonself’ antigens
derived from the paternal genome. A critical role for regulatory T (Treg) cells in
mediating active suppression of the maternal immune response to the semiallogenic fetus is now widely recognized. Significant evidence now exists that that
the Treg cells that expand in pregnancy are specific for paternal antigens and
function in an antigen-specific fashion. However, roles for specific classes of
paternal antigens in the maternal immune response to the fetus are not well
• Linked suppression is a mechanism whereby one tolerated antigen is able to
confer immune tolerance to a second antigen.14
• The ability to induce linked suppression is a property of MHC class II antigens
that is not shared by class I antigens.15
• MHC class II molecules preferentially display MHC class II peptides (pII) that
cover polymorphic stretches od allelic sequences derived from hypervariable
regions of MHC class II chains.16
• It has been noted that “the propensity of MHC II molecules to present themselves
as peptides suggests that pII/MHC II complexes are associated with a specific
function”, but that “the cause of preferential presentation of allelic MHC II
determinants remains puzzling given that gene allelism has no real meaning
within a given mouse strain or human individual” (emphasis added).17
• Indeed gene allelism is rather useful for self/non-self determination amongst
individuals of a species.
• Remission from autoimmunity in pregnancy originally thought to owe to effects of
hormones and “general” immunosuppression, but now known that fetal antigenspecific mechanisms play an important role in the course of maternal
autoimmunity, for better or worse.
• Extent of remission of RA, IBD, and MS during pregnancy is correlated with the
extent of fetomaternal incompatibility at the HLA class II loci.18,19
• Several autoimmune conditions (gestational dermatosis, systemic sclerosis,
thyroiditis) can be triggered during pregnancy by a lack of fetomaternal HLA class
II histoincompatibility.20,21
MHC class II molecules regulate
reproductive outcome
• Paternal alloantigens include MHC antigens (class I and II) and minor H antigens
(mHAgs), including H-Y antigens.
• MHC diversity is maintained through balancing selection. Pathogen-driven
selection is an important mechanism for maintaining MHC diversity, but a role for
sexual selection is also accepted.
• MHC genes are implicated in both pre- and post-copulatory mate choice in
• Post-copulatory mate choice (cryptic female choice) mechanisms include
selective fertilization, selective implantation, and selective abortion.
• Many studies in animals support a role for MHC class II histoincompatibility in
reproductive success through both pre- and post-copulatory mechanisms.2
• Early studies on the role of HLA histoincompatibility in humans produced
inconsistent results due to highly divergent study methods and low resolution
HLA allele typing.
• Despite the highly divergent results, a meta-analysis in 2005 concluded that
there is a significantly increased risk of spontaneous abortion in couples sharing
at least one allele at the HLA-DR locus.3
• Several recent studies using high resolution HLA typing provide further evidence
for a significant inverse correlation between HLA class II locus
histoincompatibility and the occurrence of recurrent spontaneous abortion and
The maternal immune system is exposed
to paternal class II antigens
• The maternal immune system is initially exposed to paternal antigens through
sperm and seminal fluid which contain MHC class II molecules.8
• MHC class II molecules are not expressed at the surface of trophoblasts, but
HLA-DR molecules are expressed intracellularly.9
• HLA-DR is sequestered into vesicular compartments, likely by HLA-DO which is
expressed by trophoblasts and favors sorting of HLA-DR into exosomes.
• Exosomal delivery of antigens to APCs promotes tolerogenic presentation.
• Normal pregnancy is associated with increasing levels of soluble HLA-DR and
decreased levels are noted in women with preeclampsia.
MHC class II antigens regulate immune tolerance
• MHC class II histoincompatibility can promote either immune rejection or
tolerance depending on context.
• MHC class II allele disparity promotes tolerance of tissue allografts transplanted
at immunologically privileged sites including the anterior chamber of the eye and
the liver.10,11
• Introduction of histoincompatible donor MHC class II molecules into the host in
tolerogenic contexts (ie, expression in liver, administration through mucosal
routes, and intravenous administration in exosomes) promotes graft tolerance at
non-immunologically privileged sites.12,13
Clinical implications
• Lack of significant fetomaternal HLA class II incompatibility may lead to failure to
generate tolerance for other classes of paternal antigens by linked suppression.
• Therapies that promote linked suppression may be useful to treat recurrent
miscarriage in couples significantly lacking HLA class II histoincompatibility.
Model for role of paternal MHC class II antigens in fetomaternal tolerance
Maternal naïve
CD4+ T cells
Maternal iTreg cell with
paternal class II antigen
Paternal class II antigenic peptide
Soluble and sperm-associated
paternal MHC class I,
MHC class II, and mHAgs
Maternal MHC class II
Maternal naïve T cell
with paternal class II
antigen specificity
Placental exosomes and other
placental-derived material
containing paternal HLA-DR
Maternal iTreg cell with
paternal class II antigen
Paternal alloantigen uptake,
processing, and presentation
PGE2, TGF-β, and other
tolerogenic factors
Maternal naïve T cell
with specificity for “new”
paternal antigen not
present at conception
Paternal alloantigen uptake,
processing, and presentation
Maternal tolerogenic
Paternal antigen newly expressed by
fetus during progression of gestation
(1) Paternal class II alloantigens present on sperm and in seminal fluid, in the immune
privileged context conferred by factors in the seminal fluid and female reproductive
mucosa, are taken up by maternal tolerogenic APCs and presented on MHC class II
molecules through the indirect pathway to cause the differentiation of naïve T cells with
cognate TCR specificity to iTregs. Although paternal class I and mHAgs are also variably
present, initial indirect presentation to maternal CD4+ T cells is dominated by allelic MHC
class II peptides by virtue of preferential presentation by MHC class II.
(3) Paternal class II molecules are continually released into maternal circulation by the
release of exosomes and other placental-derived material, including apoptotic debris.
This maintains tolerance to paternal antigens that were present at the time of copulation,
as well as allows for linked suppression to occur for paternal antigens newly expressed by
the fetus during progression of gestation (as the class II antigen needs to be co-presented
with any “new” paternal antigens by singular APCs).
Maternal iTreg cell with
paternal mHAg
Linked suppression
Maternal iTreg cell with
paternal class II antigen
Maternal iTreg cell with
specificity for “new”
paternal antigen
Linked suppression
Linked suppression
Maternal naïve T cell
with paternal mHAg
Maternal Treg cell with
autoantigen specificity
Maternal naïve T cell
with autoantigen
Maternal iTreg cell with
paternal class II antigen
Amelioration of maternal
autoimmune disease
Maternal autoantigen
(2) iTregs with specificity for paternal class II allogenic peptides mediate linked
suppression of paternal class I and minor H antigens, thereby inducing a tolerogenic
response by the maternal immune system to the full complement of paternal antigens
present at that time.
(4) Linked suppression of autoantigens in women with autoimmunity also occurs resulting
in amelioration of disease.
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