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Scholarly Works (8 results)

  • Thesis
  • Peer Reviewed
UC Berkeley Electronic Theses and Dissertations (2016)

Autoimmune disease disproportionately affects more women than men. Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are two prototypic female-predominant autoimmune diseases. Despite different clinical manifestations, similarities exist. Both are characterized by a dysregulated immune response to self-tissues. For both diseases, the strongest genetic risk factors are linked to human leukocyte antigen (HLA) alleles. Pregnancy affects their course and may also contribute to risk. This dissertation investigates mother-child HLA relationships and risk of developing RA or SLE.

Chapter 1 provides background on RA and SLE and a literature review outlining the rationale for the dissertation. The chapter states the hypotheses of the project and the specific aims addressed in each chapter.

Chapter 2 addresses the question of mother-child histocompatibility and risk of RA or SLE. The study tests the hypothesis that having any children who are compatible from the perspective of the mother increases the risk of developing RA or SLE. Results show that having any histocompatible children at HLA-B and DPB1 increase risk of RA in the mother. Increased structural similarity as quantified by a sequence similarity matching score at DPB1 was associated with decreased risk of SLE. Mother-child compatibility at minor histocompatibility antigen ZAPHIR was likewise associated with decreased risk of SLE but compatibility at LB-WNK1 increased risk for mothers who were also HLA-compatible at HLA-A with their children. This is the first study investigating the relationship between minor histocompatibility antigen compatibility and risk of SLE. This study supports the hypothesis that mother-child HLA relationships are associated with risk of RA and SLE.

Chapter 3 addresses the question of whether having children who carry HLA alleles associated with increased risk of SLE contributes to its development among mothers. The alleles investigated include DRB1*03:01, *15:01, *08:01. In addition, the study tests the hypothesis that molecular mimicry by means of exposure to DRB1*04:01 that codes for a similar amino acid sequence to the Epstein-Barr virus, a known SLE risk factor, increases risk among mothers. There was no association between SLE risk-associated alleles. However, increased risk of SLE was associated with having at least one child who carried the DRB1*04:01 allele among women negative for the allele but with at least one of the predisposing alleles. This study supports the hypothesis that a child’s alleles inherited from the father influence a mother’s subsequent risk of SLE.

Chapter 4 investigates the association between having children who carry alleles encoding amino acids (AA) associated with RA including the “shared epitope”, the sequence DERAA at AA positions 70-74, AA valine, lysine, alanine at positions 11, 71, 74 of the HLA-DRB1 molecule, aspartic acid at position 9 of HLA-B and phenylalanine at position 8 of DPB1. The study finds increased risk of RA among mothers who had any child with SE, DERAA, valine, lysine and alanine encoding alleles, independent of maternal carrier status. Among non-carrier mothers, increased risk of RA was associated with having children who carried DERAA.

Chapter 5 summarizes the key findings and results from each study and the conclusions of this work. Future directions are also addressed.

    Cover page: Fetal-Maternal HLA Relationships and Autoimmune Disease
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2022)

    Objective

    To assess concordance and acceptability of a modified menstrual pad compared with a clinician-collected high-risk human papillomavirus (HPV) sample.

    Methods

    This was a prospective observational study. Women presenting for either cervical cancer screening or with a history of high-risk HPV positivity were eligible. Three samples were requested from participants: 1) clinician-collected cervical specimens; 2) self-collected vaginal swabs; and 3) a modified menstrual pad, which was taken home for use during the next menstruation. All samples were processed using the Cobas HPV test. Menstrual pad dried blood spots were eluted, then similarly processed.

    Results

    Of 153 women enrolled in the study, 106 provided menstrual pad samples and clinician-collected cervical specimens for high-risk HPV analysis. For samples in which the interval between the clinician-collected specimen and the menstrual pad sample was less than 2 months, the concordance was 94% (95% CI 83-98). For women who tested positive for high-risk HPV who presented for general screening and those with more than cervical intraepithelial neoplasia 2, menstrual pad and clinician-collected specimen agreement was 100% (95% CI 32.5-100). Among participants, 22.9% expressed discomfort with the self-collected vaginal swabs and opted out of collection. Overall, 94.0% of participants preferred the menstrual pad over clinician-collected sampling. Twelve patients were found to be positive for HPV on the menstrual pad sample but negative on the clinician-collected specimen.

    Conclusion

    Among women who tested positive for HPV, the menstrual pad showed highly concordant results compared with clinician-collected sampling. This collection approach shows promise for integration into cervical cancer prevention programs.
      Cover page: Screening for High-Risk Human Papillomavirus Using Passive, Self-Collected Menstrual Blood
      • Article
      Obstetrics and Gynecology (2022)
      In 2017, the Maternal Fetal Medicine Units (MFMU) Network disseminated a Trial of Labor after Cesarean (TOLAC) calculator. An updated (2021) version of the calculator does not include race and ethnicity, but instead focuses on prior medical and OB history, in addition to age and BMI. The objective of this study was to compare the actual vs predicted VBAC rates between the old and new MFMU calculators.
        Cover page: Comparison between the old and new MFMU TOLAC Calculator – Which is more accurate?
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2018)

        Objectives

        Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) disproportionately affect women during and following childbearing years. Antihuman leucocyte antigen (HLA) alloantibody responses are common in healthy parous women, and as these diseases are both linked with HLA and immune dysregulation, we sought to evaluate anti-HLA antibodies in RA and SLE.

        Methods

        Anti-HLA antibodies were measured among parous SLE cases (n=224), parous RA cases (n=202) and healthy parous controls (n=239) and compared with each other as well as with nulliparous female and male controls. Antibody specificities were identified and compared against subject HLA types to determine autoreactivity versus alloreactivity. The association of anti-HLA antibodies with clinical outcomes was evaluated.

        Results

        Levels and frequencies of anti-HLA antibodies were significantly higher among parous females with SLE (52%) or RA (46%) compared with controls (26%), and anti-HLA antibodies were also found among nulliparous females and males with SLE and RA. Autoreactive anti-HLA antibodies were observed among SLE and RA antibody-positive subjects, but not healthy controls, with the highest frequency of autoreactive anti-HLA antibodies found in the SLE subjects. Higher levels of anti-HLA antibodies were associated with nephritis among the nulliparous SLE cases (p<0.01). The presence of anti-class I HLA antibodies was associated with younger age at diagnosis among both the RA and SLE nulliparous cases.

        Conclusions

        Both autoreactive and alloreactive anti-HLA antibodies were found at high levels in RA and SLE subjects. These occurred even in the absence of alloexposure, particularly among SLE subjects and may be linked with disease severity.
          Cover page: Increased alloreactive and autoreactive antihuman leucocyte antigen antibodies associated with systemic lupus erythematosus and rheumatoid arthritis
          • Article
          • Peer Reviewed
          UC Berkeley Previously Published Works (2016)
          Systemic lupus erythematosus (SLE) disproportionately affects women of reproductive age. During pregnancy, women are exposed to various sources of fetal material possibly constituting a significant immunologic exposure relevant to the development of SLE. The objective of this study was to investigate whether having any children who carry DRB1 alleles associated with SLE increase the risk of maternal SLE. This case-control study is based on the University of California, San Francisco Mother-Child Immunogenetic Study and from studies at the Inova Translational Medicine Institute. Analyses were conducted using data for 1304 mothers (219 cases/1085 controls) and their respective 1664 children. We selected alleles based on their known association with risk of SLE (DRB1*03:01, *15:01, or *08:01) or Epstein-Barr virus (EBV) glycoproteins (*04:01) due to the established EBV association with SLE risk. We used logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI) for each allele of interest, taking into account maternal genotype and number of live births. We found an increase in risk of maternal SLE associated with exposure to children who inherited DRB1*04:01 from their father (OR 1.9; 95% CI, 1.1-3.2), among *04:01 allele-negative mothers. Increased risk was only present among mothers who were positive for one or more SLE risk-associated alleles (*03:01, *15:01 and/or *08:01). We did not find increased risk of maternal SLE associated with any other tested allele. These findings support the hypothesis that a child's alleles inherited from the father influence a mother's subsequent risk of SLE.
            Cover page: A Child’s HLA-DRB1 genotype increases maternal risk of systemic lupus erythematosus
            • Article
            • Peer Reviewed
            UC San Francisco Previously Published Works (2018)
            Healthy pregnancy is the most successful form of graft tolerance, whereas preterm labor (PTL) may represent a breakdown in maternal-fetal tolerance. Although maternal immune responses have been implicated in pregnancy complications, fetal immune responses against maternal antigens are often not considered. To examine the fetal immune system in the relevant clinical setting, we analyzed maternal and cord blood in patients with PTL and healthy term controls. We report here that the cord blood of preterm infants has higher amounts of inflammatory cytokines and a greater activation of dendritic cells. Moreover, preterm cord blood is characterized by the presence of a population of central memory cells with a type 1 T helper phenotype, which is absent in term infants, and an increase in maternal microchimerism. T cells from preterm infants mount a robust proliferative, proinflammatory response to maternal antigens compared to term infants yet fail to respond to third-party antigens. Furthermore, we show that T cells from preterm infants stimulate uterine myometrial contractility through interferon-γ and tumor necrosis factor-α. In parallel, we found that adoptive transfer of activated T cells directly into mouse fetuses resulted in pregnancy loss. Our findings indicate that fetal inflammation and rejection of maternal antigens can contribute to the signaling cascade that promotes uterine contractility and that aberrant fetal immune responses should be considered in the pathogenesis of PTL.
              Cover page: Alloreactive fetal T cells promote uterine contractility in preterm labor via IFN-γ and TNF-α.
              • Article
              • Peer Reviewed
              UC Berkeley Previously Published Works (2017)

              Objective

              To investigate whether a child's genotype affects a mother's risk of rheumatoid arthritis (RA) beyond the risk associated with her genotype and to test whether exposure to fetal alleles inherited from the father increases risk of RA among mothers without risk alleles.

              Methods

              A case-control study was conducted among 1165 mothers (170 cases/995 controls) and their respective 1482 children. We tested the association between having any child with alleles encoding amino acids (AAs) associated with RA including the 'shared epitope' (SE) and DERAA AA sequences at positions 70-74; AA valine, lysine and alanine at positions 11, 71 and 74 of HLA-DRB1; aspartic acid at position 9 of HLA-B and phenylalanine at position 9 of DPB1. We used logistic regression models to estimate OR and 95% CI for each group of alleles, adjusting for maternal genotype and number of live births.

              Results

              We found increased risk of RA among mothers who had any child with SE (OR 3.0; 95% CI 2.0 to 4.6); DERAA (OR 1.7; 95% CI 1.1 to 2.6); or valine (OR 2.3; 95% CI 1.6 to 3.5), lysine (OR 2.3; 95% CI 1.5 to 3.4) and alanine (OR 2.8; 95% CI 1.2 to 6.4) at DRB1 positions 11, 71 and 74, respectively. Among non-carrier mothers, increased risk of RA was associated with having children who carried DERAA (OR 1.7; 95% CI 1.0 to 2.7) and alleles encoding lysine at DRB1 position 71 (OR 2.3; 95% CI 1.5 to 4.8).

              Conclusion

              Findings support the hypothesis that a child's genotype can contribute independently to risk of RA among mothers.
                Cover page: Increased risk of rheumatoid arthritis among mothers with children who carry DRB1 risk-associated alleles
                • Article
                • Peer Reviewed
                UC Berkeley Previously Published Works (2020)
                The study objective was to test the hypothesis that having histocompatible children increases the risk of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), possibly by contributing to the persistence of fetal cells acquired during pregnancy. We conducted a case control study using data from the UC San Francisco Mother Child Immunogenetic Study and studies at the Inova Translational Medicine Institute. We imputed human leukocyte antigen (HLA) alleles and minor histocompatibility antigens (mHags). We created a variable of exposure to histocompatible children. We estimated an average sequence similarity matching (SSM) score for each mother based on discordant mother-child alleles as a measure of histocompatibility. We used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals. A total of 138 RA, 117 SLE, and 913 control mothers were analyzed. Increased risk of RA was associated with having any child compatible at HLA-B (OR 1.9; 1.2-3.1), DPB1 (OR 1.8; 1.2-2.6) or DQB1 (OR 1.8; 1.2-2.7). Compatibility at mHag ZAPHIR was associated with reduced risk of SLE among mothers carrying the HLA-restriction allele B*07:02 (n = 262; OR 0.4; 0.2-0.8). Our findings support the hypothesis that mother-child histocompatibility is associated with risk of RA and SLE.
                  Cover page: Mother−child histocompatibility and risk of rheumatoid arthritis and systemic lupus erythematosus among mothers
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