Alice Gilman-Sachs

Down-regulation of maternal antiphospholipid antibodies during early pregnancy and pregnancy outcome

OBJECTIVE We investigated the hypothesis that maternal autoimmune responses to phospholipid antigens measured before and during pregnancy are not related to successful pregnancy outcome. STUDY DESIGN One hundred twenty-three women with recurrent spontaneous abortions were serially tested for antiphospholipid antibodies during their pregnancies. RESULTS In 72 women with recurrent spontaneous abortions and without antiphospholipid antibodies before the pregnancy, the incidence of antiphospholipid antibody production at the time of pregnancy termination was significantly higher in those who miscarried the index pregnancy than those who were delivered of a live-born infant. In 51 antiphospholipid antibody-positive women with recurrent spontaneous abortions there were dramatic increases in titers of anticardiolipin antibody and antiphosphatidylserine antibody in those who miscarried the index pregnancy (p < 0.005). In women who were delivered of a live-born infant, the titers remained stable or decreased during pregnancy. CONCLUSIONS Down-regulation of antiphospholipid antibody production during early pregnancy is associated with favorable pregnancy outcome.

Antibodies to phospholipids and nuclear antigens in non-pregnant women with unexplained spontaneous recurrent abortions

In a collaborative study of 73 non-pregnant Kuwaiti women with unexplained spontaneous recurrent abortion (RSA), 30 control healthy non-pregnant multiparous Kuwaiti women and 20 North American women who received elective abortion(s), autoantibodies to 6 phospholipids and 9 nuclear antigens were measured. Women with recurrent spontaneous abortions demonstrated 3 times higher incidence of antibodies to phospholipids (30.1%) than controls (10% each) (P = 0.029). The incidence of both IgM and IgA class antiphospholipid antibodies were significantly higher than those of controls. The incidence of antibodies to cardiolipin in women with recurrent spontaneous abortions (12.3%) was significantly higher than those of controls (P = 0.035) and incidence of IgM but not IgG anticardiolipin antibody was significantly higher in women with RSAs than in controls (P = 0.053). The incidences of anti-polyinosinic acid (P = 0.035) and anti-histone 1 antibody (P = 0.052) were significantly higher in women with recurrent spontaneous abortions than controls. There was no significant difference in the incidence of autoantibodies between primary and secondary aborters. However, women with a history of second trimester abortions showed a higher incidence of antiphospholipid antibodies than women with first trimester abortions only. Recurrent spontaneous abortion is associated with autoantibodies to phospholipid epitopes including IgA antiphospholipid antibodies.

Intravenous immunoglobulin infusion therapy in women with recurrent spontaneous abortions of immune etiologies

We have investigated clinical effectiveness of intravenous immunoglobulin G infusion (IVIg) on antiphospholipid antibody titers in five women with evidence of antiphospholipid antibody-associated recurrent spontaneous abortions and one with antinuclear antibody who became refractory to conventional autoimmune treatment during pregnancy and experienced pregnancy complications. Three women developed intrauterine growth retardation and three had complicated twin pregnancies with rising autoantibody titers. Antiphospholipid antibody and antinuclear antibody titers were tested pre and 2 weeks after each IVIg infusion. We report that: (i) IgG antiphospholipid antibody titers were significantly suppressed after each IVIg infusion (P < 0.05); (ii) IgM antiphospholipid antibody titers were also significantly suppressed after each IVIg infusion (P < 0.0001); (iii) decreased titers of autoantibodies paralleled increased levels of maternal IgG which lasted for at least 30 days; the autoantibodies showed a definite rise again prior to the next infusion; (iv) antinuclear antibody titers were effectively suppressed; and (v) rising autoantibody titers combined clinical manifestation of intrauterine growth retardation and women with complicated twin pregnancies. We conclude that IVIg infusion effectively suppresses IgM and IgG autoantibodies to phospholipids and antinuclear antibody in autoimmune women with a history of recurrent spontaneous abortions and refractory to conventional anticoagulation or immunosuppressive treatment.

Flow Cytometric Analysis of Lymphocyte Subsets in Peripheral Blood of Chronic Headache Patients

SYNOPSIS

Characterization of antibodies induced by paternal lymphocyte immunization in couples with recurrent spontaneous abortion

This study was designed to identify and characterize the allo- and autoantibodies induced following successful paternal lymphocyte immunization to prevent recurrent spontaneous abortion. Firstly the titers of maternal anti-paternal antibodies in women with successful pregnancies as determined by the flow cytometry crossmatch (FCXM) were highly variable; however, in all cases, the initial pre-immunization titers were negative and the post-immunization titers were positive by the FCXM in successfully treated women. Secondly, the specificities of maternal alloantibodies to paternal HLA antigens (immunogen) were evaluated. No all predicted antibodies to mismatched paternal HLA antigens were found by microlymphocytotoxicity (MCX) assays and the specificities varied. Thirdly, antibodies in post- but not preimmunization sera reacted with two lymphoid cell lines, SupT1 and SB; in addition, the rise and fall of the titers of these sera with paternal cells seemed to be reflected with the cell lines by the FCXM. Fourthly, autoantibodies to activated lymphocytes were detected and seemed to correlate with successful immunization since women who had another abortion following immunotherapy lacked these autoantibodies. These findings suggest that the antibody response following successful immunotherapy is complex and needs to be studied further to understand the mechanism of this treatment.

Inhibition of binding of anti-CD3 antibodies to paternal lymphocytes correlates with failure of immunotherapy for treatment of recurrent spontaneous abortions

A two color flow cytometry crossmatch (FCXM) was used to evaluate the induction of anti-lymphocyte antibodies in 34 women undergoing immunotherapy for recurrent spontaneous abortions. All women had anti-lymphocyte antibodies that reacted with T-cells when analyzed by FCXM. However, inhibition of the binding of anti-CD3 to paternal CD3 lymphocytes in the presence of maternal antipaternal lymphocyte antiserum was found for some couples following lymphocyte immunotherapy for spontaneous recurrent abortions. Ten couples who had another spontaneous abortion following immunotherapy showed inhibition. In contrast, eight couples who did not show inhibition of the binding of anti-CD3 T lymphocytes to paternal lymphocytes by maternal anti-lymphocyte antiserum had live births. Women of the remaining 16 couples were either pregnant and awaiting birth or not pregnant. Thus, by FCXM it may be possible to predict those couples who will have successful pregnancies following this treatment.

Comparison of the immune response to Ars-BGG in germfree or conventional piglets.

Neonatal germfree (GF) colostrum-deprived and conventional (CV) colostrum-fed piglets were immunized IP with p-azo-phenyl-arsonate-bovine gamma globulin (Ars-BGG) in Freunds adjuvant to study the development of the immune response in the absence or presence of maternal antibodies and environmental antigens. Overall, the immune response varied greatly within each group but did not differ in GF from CV piglets statistically. Affinity immunoblot analysis suggested that anti-Ars antibody was more restricted in GF than CV piglets and clonotype shifts occurred more in GF than CV piglets after each antigenic stimulation. In contrast, the clonotype pattern of the anti-BGG antibody was similarly heterogeneous in the two groups. Based on the affinity immunoblot data the antibodies generated to the Ars-haptenic group in CV piglets are more heterogeneous than GF piglets and suggest that clonotype generation is influenced by maternal antibodies and environmental antigens.