Abstract

TJ6 is a novel protein which has immunosuppressive activity and may have a
functional role in fetal allograft survival during pregnancy. Initial studies indicated
that when mice were treated with an anti-TJ6 binding mAb early in pregnancy, the
pregnancies were completely ablated and that TJ6 expression is enhanced
dramatically during pregnancy. In addition we have cloned the cDNA for TJ6 which
encodes a possible transmembrane domain that may include six to seven
transmembrane regions. Therefore, we examined TJ6 expression on PBL of pregnant
and nonpregnant women and found that TJ6 is expressed primarily on CD19
+
B cells
from pregnant but not nonpregnant women. TJ6 was not expressed on CD3
+

lymphocytes from either group but was expressed on CD56
+
cells from a small
population of pregnant women which preliminary data indicate may correlate with the
occurrence of spontaneous abortion in these women. Here we also show that TJ6
transcripts are highly expressed in the developing fetoplacental unit as well as in the
developing thymus. We also begin to characterize the expression of TJ6 isoforms in
an acute lymphocytic leukemia cell line (SB), murine thymus, and the developing
murine fetoplacental unit, as well as the expression of a membrane form of TJ6
present on human lymphocytes during pregnancy. All of these cells and tissues
expressed TJ6 proteins which were smaller than predicted based on either the cDNA
sequence or the in vitro translation even though they all expressed mRNA similar in
size. The TJ6 isoforms varied in size from the 45-kDa isoform in SB cells to the 52-
kDa isoform of the fetoplacental unit to a 70-kDa isoform in murine thymus. Flow
cytometric analysis also demonstrated that similar to the CD19
+
B cells from pregnant
women, TJ6 is expressed on the surface of SB cells.

Am J Reprod Immunol. 1995 Oct;34(4):219-24.






Reciprocal alteration in circulating TJ6+ CD19+ and TJ6+ CD56+ leukocytes in
early pregnancy predicts success or miscarriage.
Coulam CB1, Beaman KD.
Author information


Abstract
PROBLEM:
TJ6 is a cytokine whose membrane form is regularly expressed on the B lymphocytes
of women during pregnancy. In a previous study we have shown that pregnancies that
end in a spontaneous abortion are characterized by an increase in natural killer (NK)
cells and that NK cells in these pregnancies also expressed TJ6, whereas NK cells
from pregnancies that terminate normally neither increase in number nor do they
express significant amounts of the cytokine.
METHODS:
To evaluate the ability of TJ6 to predict pregnancy outcome, 61 blood samples from
pregnant women were studied. Blood samples were drawn between 5 and 12 weeks of
gestation and analyzed for lymphocyte expression of TJ6 using Cytoron Absolute
flow cytometry and two-color fluorescence. The percentage of CD19+ (B) cells and
CD56+ (NK) cells that expressed TJ6 was calculated, and this percentage was
correlated with subsequent pregnancy outcome classified as successful (viable birth)
or unsuccessful (abortion, stillbirth). TJ6 CD19 and TJ6 CD56 was determined in 32
blood samples from women with successful pregnancy outcomes and 29 samples
from women with unsuccessful pregnancy outcome.
RESULTS:
The mean TJ6 CD19 expression for successful pregnancies was 10.6% and for
unsuccessful pregnancies was 5.1% (P < 0.03). The mean TJ6 CD56+ percentage of
circulating cells that express TJ6 expression for successful pregnancies was 3.3% and
for unsuccessful pregnancies was 10.4% (P = 0.02). All unsuccessful pregnancies had
less than 90% of circulating CD19 cells express TJ6 and/or greater than 50% of
circulating CD56 cells express TJ6. Use of the expression of TJ6 on CD19 and CD56
cells during the first trimester predicts viable pregnancy with a sensitivity of 100%,
specificity of 100%, positive predictive value of 100%, and negative predictive value
of 100%.
CONCLUSIONS:
The work now being reported validates the hypothesis that expression of TJ6 on NK
cells obtained from pregnant women predicts the outcome of pregnancy. In addition
we show that this prognosticator can be reliably demonstrated early in the first
trimester.
PMID: 8579758 [PubMed - indexed for MEDLINE]

Infertility Fertility-Related Medical Conditions Current - Page: 1, 2, 3, 4
Recurrent Miscarriage: A Form of Infertility, pg 4
Dr. Alan Beer, a pioneer in reproductive immunology, recommends inquiring about
testing for immunological loss issues in the following cases:
two or more miscarriages or IVF failures
low ovulatory response to drug stimulation
a blighted ovum pregnancy
unexplained infertility
previous known immunity issues, such as rheumatoid arthritis or lupus
previous pregnancies in which fetal growth was inhibited
secondary infertility with repeat miscarriage as the primary issue
Some testing (DQ Alpha, specifically) in the realm of reproductive immunology is
DNA-related (see "Genetics/Chromosomal" issues above.) In short, if a woman and
man are too closely related in genetic terms, the woman's body will likely treat a
resulting embryo as a foreign invader and reject the pregnancy. In some cases, a
normal first pregnancy may result, but with the interesting feature of creating a
maternal cellular response that is negative to subsequent pregnancies.
Antibody issues involve the response of a woman's body to any pregnancy and testing
should include:
Natural killer cells
Antinuclear antibody (ANA)
Anti-DNA/Histone antibodies
Antiphospholipid antibodies (APA)
TJ6 protein
Lupus anticoagulant antibody
Hormone antibody assay
APTT (a blood clotting test)
Antithyroid antibodies
It should be stated that diagnosis and treatment of immunological causes is relatively
new. Some physicians are skeptical about requiring of patients the amount of testing
involved in reproductive immunology, and some plainly disagree with theories on its
incidence and treatment. Consumers would be wise to just be aware of this common
skepticism when they ask their own providers about immunological causes of
recurrent miscarriage.
Headlines
As referenced earlier, news headlines about causes of recurrent miscarriage are
attention-getting among those who struggle with the ongoing devastation and future
fears. One of the most recent findings by Austrian researchers has linked a gene
variation to repeat loss.
Specifically, they saw more losses in women with two copies of a particular variation
(allele 2) of a gene that is involved in creating a cytokine. Cytokines work to regulate
a body's inflammation response, and earlier research has linked high cytokine levels
to women with more than one miscarriage.
In effect, this finding at a genetic level is a step toward greater understanding of the
immunological causes of miscarriage.
For the vast number of individuals and couples who are experiencing recurrent loss
without explanation, there is hope through advancing science. It would bode them
well to try and stay on top of published research. It is also crucial to work with a
medical team that is as interested as you are in finding the causes of your previous
losses, in order to hopefully treat and prevent any more in the future.
H. TJ6 Protein
There is another cell in the lining of the uterus that produces a protein called TJ6. This
protein production is stimulated by Progesterone that helps in controlling NK cells by
attaching to their DNA and breaking up the NK cell's development. This TJ6, which
is a small protein, has the main task of controlling the NK cells.


J Reprod Immunol. 1996 Feb;30(1):17-27.
Expression of membrane form of the pregnancy associated protein TJ6 on
decidual lymphocytes in the first trimester of pregnancy.
Rubesa G1, Beaman KD, Beer AE, Haller H, Rukavina D.
Author information
Abstract
TJ6, a newly described protein produced locally in the uterine decidua during
pregnancy, may be involved in maintaining a unique immunological environment at
the maternal-fetal interface. The aim of this study was to determine whether TJ6 is
expressed as membrane form on decidual lymphocytes (DL), to define the phenotypes
of TJ6m (membrane form TJ6) expressing cells and to analyze the fluorescence
intensity of TJ6m expression. Peripheral blood lymphocytes (PBL) and DL were
obtained from first trimester pregnancies undergoing elective termination and
immunophenotyped for TJ6m and other cell surface antigens (CD3, CD8, CD19,
CD56, CD16) by flow cytometry. This is the first study showing that TJ6 molecules
are present on decidual lymphocytes in human pregnancy. TJ6m expression on PBL
was not different from that of DL. However, a significantly higher percentage of
double positive (TJ6m+CD3+, TJ6m+,CD8+,TJ6m+CD19+) cells were found in PBL
when compared to DL. The average fluorescence intensity (AFI) for the TJ6m marker
among cells with CD8+, CD19+ and CD56+ double positive was significantly higher
in DL as compared with those of PBL. The AFI for granularity of double positive DL
was significantly higher than observed in PBL.
PMID: 8920165 [PubMed - indexed for MEDLINE]






Publication Types, MeSH Terms, Substances, Grant Support

TJ6
TJ6 is a pregnancy-associated protein isolated originally from murine placenta and
identified independently as RTF [Regeneration and tolerance factor]. TJ6 exists in
soluble (TJ6s) and membrane-bound (TJ6m) forms (Mandal and Beaman, 1995;
Nichols et al, 1994). Several isoforms have been described. TJ6 has been identified as
a regulatory subunit of the vacuolar ATPase proton pump (see: ATP6V0A2).
In mice and humans TJ6 protein is expressed on most of the placenta-associated
mononuclear cells at all stages of pregnancy. The protein is expressed in murine
thymus and also by an acute lymphocytic leukemia cell line (SB).
Expression of TJ is enhanced dramatically during pregnancy in mice and humans.
Treatment of mice early in pregnancy with a monoclonal antibody raised against TJ6
completely ablates pregnancy.
TJ6 is an anti-proliferative protein for cells activated directly through the T-cell
receptor complex (Mandal and Beaman, 1995).
TJ6 has immunosuppressive activity and may have a functional role in fetal allograft
survival during pregnancy. TJ6 expression on both NK-cells and B-cells appears to
correlate with an unsuccessful outcome of pregnancy (Beaman et al, 1996).
Copyright 2012 by H IBELGAUFTS. All rights reserved.

Science. Author manuscript; available in PMC Feb 27, 2009.

Published in final edited form as:
Science. Dec 5, 2008; 322(5907): 15621565.
doi: 10.1126/science.1164511
Am J Reprod Immunol. 1997 Sep;38(3):183-8.
Expression of TJ6 during pregnancy.
Kang JA1, McBey BA, Angkachatchai V, Croy BA, Beaman KD.
Author information


Abstract
PROBLEM:
TJ6 will be one of the molecules involved in fetal-specific immune
suppression during pregnancy. In the mouse and human decidua, the
regulation of uterine natural killer (uNK) cells is important during
pregnancy.
METHOD OF STUDY:
To further understand the possible functions of TJ6 during pregnancy,
syngeneic, allogeneic, and mutant mice were examined for TJ6
expression.
RESULTS:
Immunoblotting showed that TJ6 protein was expressed on most of the
placenta-associated mononuclear cells, and the size was 70-72 kDa at
all stages of pregnancy. The expression of TJ6 mRNA was studied by a
ribonuclease protection assay in syngeneic and allogeneic matings, and
in immune-deficient mice of genotypes scid/scid and scid/scid.bg/bg.
CONCLUSIONS:
Genetic disparity, lack of T and B lymphocytes, and loss of NK lytic
function had no significant effect on the expression of TJ6 mRNA.
PMID: 9325490 [PubMed - indexed for MEDLINE]

Publication Types, MeSH Terms, Substances, Grant Support


LinkOut - more resources


PubMed Commons home

Am J Reprod Immunol. 1996 Apr;35(4):342-7.
Transforming growth factor-beta 2-related-decidual
suppressor factor is not related to TJ6 protein.
Merali FS1, Arck PC, Beaman K, Clark DA.
Author information


Abstract
Transforming growth factor (TGF)-beta 2-related-decidual suppressor
factor (DSF) and TJ6 protein are both immunosuppressive molecules
present in murine and human pregnancy. Treatment of mice with either
anti-TJ6 or anti-TGF-beta 2 neutralizing antibodies results in increased
fetal loss. Western blots of supernatants from pregnant mouse decidua
probed with anti-TJ6 (soluble form) showed a doublet at a similar
molecular size as when the blot was probed with anti-TGF-beta 2
antibody. The problem is to determine whether TJ6 and DSF are the
same protein. In order to determine if TJ6 and DSF are the same or
different proteins, we used affinity column purified TGF-beta 2-DSF and
stained Western blots with anti-TJ6. The TGF-beta 2-monoclonal
antibody affinity column-purified DSF that stained with anti TGF-beta 2
was not reactive with anti-TJ6 antibody. TJ6 has only a 30% gene
sequence homology and a 13% amino acid homology to TGF-beta 2.
TJ6 and TGF-beta 2-related DSF appear to be different
immunosuppressive proteins in decidua.
PMID: 8739451 [PubMed - indexed for MEDLINE]

Publication Types, MeSH Terms, Substances


LinkOut - more resources


PubMed Commons home
PubMed Commonss




Biol Reprod. 1997 May;56(5):1351-60.
Decidua-associated suppressor cells in abortion-
prone DBA/2-mated CBA/J mice that release bioactive
transforming growth factor beta2-related
immunosuppressive molecules express a bone
marrow-derived natural suppressor cell marker and
gamma delta T-cell receptor.
Clark DA1, Merali FS, Hoskin DW, Steel-Norwood D, Arck PC, Croitoru K,
Murgita RA, Hirte H.
Author information


Abstract
The decidua of allopregnant mice contains a novel population of Thy1
Lyt1 CD4 CD8 asialoGM1- non-B small lymphocytic suppressor cells
that release transforming growth factor (TGF) SS2-related suppressor
molecules. The "null" phenotype of this cell population is similar to some
bone marrow-derived natural suppressor cell (NSC) populations, and
the latter may release TGF(beta)s. We now report that the TGF beta2-
producing suppressor cells in the uterine decidua of DBA/2-mated
CBA/J female mice-linked to prevention of abortions-are inactivated
effectively by 1E5/B5.1 but not by 2C1.1 rat monoclonal antibodies to
murine pregnancy-associated splenic NSC in the presence of
complement. Immunostaining of a subpopulation of cells in decidua with
1E5/B5.1 but not with 2C1.1 was shown by flow cytometry. Release of
suppressor factor was also abrogated by 1E5/B5.1 + complement but
not by 2C1.1 + complement, and the suppressor factor was specifically
neutralized by anti-TGF beta2 and not by anti-TGF beta3. Splenic
pregnancy NSC are susceptible to 2C1.1, produce TGF beta1, and
express CD3 and alpha beta T-cell receptor (TcR) chains. Release of
suppressor factor by the decidual NSC was abrogated by treatment with
anti-CD3 (145 2C11) and anti-TcR gamma delta (GL4) monoclonal
antibodies + complement, but not by anti-TcR alpha beta (H57) +
complement; and cells sorted using anti-TcR gamma delta (GL3)
released suppressive activity in vitro. Slightly more suppressive activity
was released by implantation-site decidua where there was no
epithelium than from epithelialized inter-implantation-site decidua; no
significant activity was released from placental tissue, but combining
implantation-site tissue with placental tissue led to release of enhanced
levels of immunosuppressive activity. There appear to be subtypes of
bone marrow-derived TcR+ NSC with different phenotypes and tissue
localization patterns in pregnancy. The previously reported dependence
of decidual NSC activity on the presence of soluble signals from fetal
trophoblast may be explainable by the ability of cells bearing TcR
gamma delta to recognize and react to placental trophoblast cell
antigen.
PMID: 9160738 [PubMed - indexed for MEDLINE] Free full text

Publication Types, MeSH Terms, Substances


Am J Reprod Immunol. 1999 Jul;42(1):44-8.
The role of gamma/delta T cells in progesterone-
mediated immunomodulation during pregnancy: a
review.
Szekeres-Bartho J1, Barakonyi A, Polgar B, Par G, Faust Z, Palkovics T,
Szereday L.
Author information


Abstract
PROBLEM:
To determine if pregnancy is recognized by the immune system and if
inadequate recognition of fetal antigens might result in failed pregnancy.
METHOD OF STUDY:
Review of literature and current data.
RESULTS:
In the decidua gamma/delta TCR positive cells significantly increase in
number. A subset of gamma/delta T cells reacts with nonpolymorphic
Class I or Class I like molecules. Trophoblast recognition is mediated by
the V gamma 1 subset which recognize a conserved mammalian
sequence on the trophoblast. Almost all gamma/delta T cells in the
decidua are activated and use the V delta 1 chain, whereas the majority
of human peripheral gamma/delta lymphocytes expresses V gamma
9/V delta 2 TCR. Peripheral gamma/delta T cells of healthy pregnant
women preferentially use V gamma V delta 1 chains, on the other hand,
those of recurrent aborters use the V gamma 9V delta 2 combination.
Signaling via the V gamma 1.4V delta 1 receptor induces a Th2 type
response, whereas activation of the lymphocytes via the V gamma 9V
delta 2 receptor results in increased IL-12 production and natural killer
(NK) activity. In the presence of progesterone, activated lymphocytes
synthesize the progesterone induced blocking factor (PIBF), which
inhibits NK activity and exerts an anti abortive effect in vivo. Decidual
CD56+ and gamma delta+ cells are to a high extent the same
population.
CONCLUSION:
All decidual CD56+ cells express PIBF, thus it cannot be excluded that
local production of this substance contributes to low decidual NK activity
and thus to the success of the pregnancy.
PMID: 10429766 [PubMed - indexed for MEDLINE]

Publication Types, MeSH Terms, Substances



J Reprod Immunol. 1996 Feb;30(1):17-27.
Expression of membrane form of the pregnancy
associated protein TJ6 on decidual lymphocytes in
the first trimester of pregnancy.
Rubesa G1, Beaman KD, Beer AE, Haller H, Rukavina D.
Author information


Abstract
TJ6, a newly described protein produced locally in the uterine decidua
during pregnancy, may be involved in maintaining a unique
immunological environment at the maternal-fetal interface. The aim of
this study was to determine whether TJ6 is expressed as membrane
form on decidual lymphocytes (DL), to define the phenotypes of TJ6m
(membrane form TJ6) expressing cells and to analyze the fluorescence
intensity of TJ6m expression. Peripheral blood lymphocytes (PBL) and
DL were obtained from first trimester pregnancies undergoing elective
termination and immunophenotyped for TJ6m and other cell surface
antigens (CD3, CD8, CD19, CD56, CD16) by flow cytometry. This is the
first study showing that TJ6 molecules are present on decidual
lymphocytes in human pregnancy. TJ6m expression on PBL was not
different from that of DL. However, a significantly higher percentage of
double positive (TJ6m+CD3+, TJ6m+,CD8+,TJ6m+CD19+) cells were
found in PBL when compared to DL. The average fluorescence intensity
(AFI) for the TJ6m marker among cells with CD8+, CD19+ and CD56+
double positive was significantly higher in DL as compared with those of
PBL. The AFI for granularity of double positive DL was significantly
higher than observed in PBL.
PMID: 8920165 [PubMed - indexed for MEDLINE]

Publication Types, MeSH Terms, Substances, Grant Support


LinkOut - more resources


PubMed Commons home