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Open Access Publications from the University of California

Scholarly Works (26 results)

  • Article
  • Peer Reviewed
UCLA Previously Published Works (2018)
OBJECTIVE: Mortality statistics from the Centers for Disease Control and Prevention (CDC) are used for planning health care policy and allocating resources. The CDC uses these data to compile its annual ranking of leading causes of death based on a selected list of 113 causes. Systemic lupus erythematosus (SLE) is not included on this list. Since the ranking is a useful tool for assessing the relative burden of cause-specific mortality, this study was undertaken to rank SLE deaths among the CDCs leading causes of death to see whether SLE is a significant cause of death among females. METHODS: Death counts for the female population of the US were obtained from the CDCs Wide-ranging Online Data for Epidemiologic Research database and then grouped by age and race/ethnicity. Data on the leading causes of death were obtained from the Web-based Injury Statistics Query and Reporting System database. RESULTS: During 2000-2015, there were 28,411 deaths of females with SLE recorded as an underlying or contributing cause of death. SLE ranked among the top 20 leading causes of death in females between 5 and 64 years of age. SLE ranked tenth among those ages 15-24 years, fourteenth among those ages 25-34 years and 35-44 years, and fifteenth among those ages 10-14 years. For African American and Hispanic females, SLE ranked fifth among those ages 15-24 years, sixth among those ages 25-34 years, and eighth or ninth among those ages 35-44 years, after the 3 common external injury causes of death were excluded from the analysis. CONCLUSION: SLE is among the leading causes of death in young females, underscoring its impact as an important public health issue.
    Cover page: Brief Report: Lupus-An Unrecognized Leading Cause of Death in Young Females: A Population-Based Study Using Nationwide Death Certificates, 2000-2015.
    • Thesis
    • Peer Reviewed
    UCLA Electronic Theses and Dissertations (2017)

    Hydrocarbon oils, such as 2,6,10,14-tetramethylpentadecane (TMPD) and Hexadecane, are alkanes present in crude oil, food and in mineral oils used in cosmetics, laxatives, and food-coatings. Individuals exposed to TMPD have increased inflammatory diseases.� To understand the pathogenesis of TMPD-induced inflammation, investigators have administered TMPD intraperitoneally (ip) to animals that develop autoantibodies, nephritis, arthritis, pneumonitis, and diffuse pulmonary hemorrhage (DPH) depending on animals’ genetic background. We established disease assessment methods, dose response, routes of exposure, and evaluated immune cells’ role in pathogenesis of TMPD-induced inflammation. Compared to none of controls, 73% of C57Bl/6 mice given TMPD (500 μl, ip) exhibited weight-loss, and pneumonitis, vasculitis and/or DPH. We established clinical (20% weight-loss), semi-quantitative, and quantitative assessments of TMPD-DPH. DPH/pneumonitis rates were much decreased at lower doses (250-125 μl, ip) of TMPD. However, oropharyngeal aspiration of as low as 6 μl TMPD caused rapid morbidity/mortality, with increased serum creatinine kinase, aspartate aminotransferase, and pneumonitis; 75% animals survived 4 μl-dose and exhibited pneumonitis/DPH. All immune cells tested were abnormal in diseased lungs at 2-weeks post-TMPD (500 μl, ip). At Day 7, prior to histopathological changes, while both Hexadecane and TMPD caused myeloid cell abnormalities, only TMPD caused lung-infiltration with B-cells that expressed B1 subset markers: CD19+CD11b+/CD19+CD5+. Such B1-cells were simultaneously reduced in their usual location (peritoneal cavity). CD19-/- mice that have less B1-cells have less DPH with ip TMPD than wildtype mice. Adoptive transfer of CD45.1+�wildtype peritoneal-fluid cells into the peritoneum of CD45.2+CD19-/- recipients led to lung-infiltration with CD45.1+ B-cells and more DPH/pneumonitis than CD19-/- recipients reconstituted with CD19-/- B-cells. Furthermore, ip TMPD induced in the lungs a differential expression of a set of immune/inflammatory genes including chemokine Cxcl13 that is known to drive B1 B- cells’ migration. However, pneumonitis/DPH development was independent of B-cells, when the lungs were directly exposed to TMPD via oropharyngeal aspiration. Thus, a systemic (ip) exposure to TMPD induces B1 B-cells to traffic from the peritoneum to the lungs and cause pneumonitis/DPH. Our observations have implications for chemically-induced inflammation, and DPH that is often a fatal complication in humans with inflammatory diseases and upon exposure to pesticides/cocaine.

      Cover page: Mechanisms of Chemically-Induced Diffuse Pulmonary Hemorrhage
      • Thesis
      • Peer Reviewed
      UCLA Electronic Theses and Dissertations (2018)

      Langerhans cells (LC) are the premier antigen presenting cells on epithelial surfaces. The key to LCs’ functions is their residence in peripheral tissues as well as their capacity to migrate to local draining lymphoid organs. The present dissertation’s goal is to elucidate the specific roles LCs play in the context of autoimmunity, by employing a mouse model genetically prone to develop multi-organ autoimmune disease, in which LCs can be traced and selectively depleted in vivo.

      Previous studies have elucidated LCs’ ability to induce tolerance against skin-specific self-antigen and as well as to protect against the development of autoimmune skin inflammation. However, LCs’ role in other, non-skin, organs where they are present, such as in cornea on eye surface and in gastric and genital mucosa, remains largely unknown. We found that LCs were altered in distribution and density in the cornea of autoimmune-prone mice. Importantly, aselective depletion of LCs led to acceleration of corneal inflammation, along with increased T cell activation and proliferation in eye-draining lymph nodes. These data allowed us to show for the first time that LCs play a protective role against corneal autoimmune disease, potentially through inhibition of T cell activation in a tissue-specific manner.

      Homeostatic migration of LCs from their tissue of residence to local draining lymph nodes is a hallmark of LC biology, however, the underlying mechanisms are largely unclear. We studied mechanism of LCs migration using models of autoimmune dermatitis, where LC migration was previously shown to be defective prior to the onset of clinical disease. We demonstrate that skin-resident dendritic epidermal T cells are reduced in the epidermis of these autoimmune-prone mice, and that a glycolipid that ameliorates skin inflammation restores DETCs and LC migration. This rescue of LC migration in autoimmune mice by skin-resident dendritic epidermal T cells is mediated, at least in part, via CD40–CD40L signaling. Such ‘local’ control of migratory behavior of tissue-resident dendritic cells can regulate systemic immune response in a tissue-specific manner, which has important implications for protection against inflammation, autoimmune diseases and graft rejection, and vaccination against cancers and infections.

        Cover page: Langerhans Cells in Autoimmunity: New Perspectives in Function and Homeostasis
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2008)
        Tissue-resident dendritic cells, such as Langerhans cells (LC), normally carry Ags from tissues to lymph nodes to induce immunity to tissue Ags. In this study, we report that LC are reduced in the skin-draining lymph nodes of MRL-Fas(lpr/lpr) and MRL-Fas(+/+) mice that develop T cell-mediated autoimmune skin inflammation as compared with MHC-matched healthy strains. This deficiency of LC in skin-draining lymph nodes is due to a profound impairment of LC migration, resulting in the accumulation of activated LC in the skin. Such a defect in LC migration develops before the onset of skin lesions and correlates with the onset and severity of dermatitis. The reduced, rather than increased, migration of LC from skin to skin-draining lymph nodes represents a novel functional abnormality of LC in autoimmune dermatitis.
          Cover page: Cutting Edge: Migration of Langerhans Dendritic Cells Is Impaired in Autoimmune Dermatitis
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2016)
          Invariant natural killer T (iNKT) cells are unique subset of innate-like T cells recognizing glycolipids. iNKT cells can rapidly produce copious amounts of cytokines upon antigen stimulation and exert potent immunomodulatory activities for a wide variety of immune responses and diseases. We have revealed the regulatory effect of iNKT cells on autoimmunity with a serial of publications. On the other hand, the role of iNKT cells in parasitic infections, especially in recently attractive topic hygiene hypothesis, has not been clearly defined yet. Bacterial and parasitic cell wall is a cellular structure highly enriched in a variety of glycolipids and lipoproteins, some of which may serve as natural ligands of iNKT cells. In this review, we mainly summarized the recent findings on the roles and underlying mechanisms of iNKT cells in parasite infections and their cross-talk with Th1, Th2, Th17, Treg, and innate lymphoid cells. In most cases, iNKT cells exert regulatory or direct cytotoxic roles to protect hosts against parasite infections. We put particular emphasis as well on the identification of the natural ligands from parasites and the involvement of iNKT cells in the hygiene hypothesis.
            Cover page: Effects of Invariant NKT Cells on Parasite Infections and Hygiene Hypothesis.
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2021)
            OBJECTIVE: To identify secular trends associated with systemic sclerosis (SSc) mortality over a 48-year period. METHODS: Using national mortality data compiled by the Centers for Disease Control and Preventions Wide-Ranging Online Data for Epidemiologic Research, and population data from the US Census Bureau, we calculated an age-standardized mortality rate (ASMR) for SSc and non-SSc (all other causes), and we also calculated the ratio of the SSc ASMR to the non-SSc ASMR for each year from 1968 to 2015. We then used a joinpoint regression model to evaluate mortality trends overall and by sex and race. RESULTS: From 1968 to 2015, there were 46,798 deaths with SSc recorded as the underlying cause of death and 106,058,839 non-SSc deaths. There were an additional 9,063 deaths with SSc recorded as a contributing cause of death from 1999 to 2015. Whereas the non-SSc ASMR decreased throughout the 48-year time period, the SSc ASMR increased from 1968 to 2000, followed by decreases each year from 2001 to 2015. The SSc ASMR also decreased for deaths where SSc was a contributing cause from 1999 to 2015. Women and Black persons had higher SSc ASMRs and SSc ASMR to non-SSc ASMR ratios than men and White persons, respectively. Additionally, SSc ASMRs and SSc ASMR to non-SSc ASMR ratios increased at higher rates in women and White persons than in men and Black persons, respectively, during the initial three decades. CONCLUSION: Mortality attributable to SSc increased from 1968 to 2000, followed by a steady decline from 2001 to 2015. However, SSc mortality relative to non-SSc mortality remains high. SSc mortality has disproportionately changed by sex and race over the 48-year period assessed in the present study.
              Cover page: Trends in Systemic Sclerosis Mortality Over Forty-Eight Years, 1968-2015: A US Population-Based Study.
              • Article
              • Peer Reviewed
              UCLA Previously Published Works (2023)

              Objective

              We aimed to assess systemic sclerosis (SSc) mortality by age in the general population over the past five decades.

              Methods

              This is a population-based study using a national mortality database and census data of all United States residents. We calculated the proportions of deaths for SSc and for all other causes (non-SSc) by age, and calculated age-standardized mortality rate (ASMR) for SSc and non-SSc, and the ratio of SSc-ASMR to non-SSc-ASMR by age groups for each year from 1968 through 2015. We performed joinpoint regression to estimate average annual percent change (AAPC) for each of these parameters.

              Results

              SSc was recorded as the underlying cause of death in 5,457 decedents aged ≤44 years, 18 395 aged 45-64, and 22 946 aged ≥65 from 1968 through 2015. At ages ≤44, the proportion of annual deaths decreased more for SSc than for non-SSc: AAPC, -2.2% (95% CI, -2.4% to -2.0%) for SSc vs -1.5% (-1.9% to -1.1%) for non-SSc. Consistently, SSc-ASMR decreased from 1.0 (95% CI, 0.8-1.2) in 1968-0.4 (0.3-0.5) per million persons in 2015, a cumulative decrease of 60% at an AAPC of -1.9% (95% CI, -2.5% to -1.2%) at ages ≤44. The ratio of SSc-ASMR to non-SSc-ASMR ratio also decreased (cumulative -20%; AAPC -0.3%) in ≤ 44-year group. In contrast, those aged ≥65 experienced a steep increases in SSc-ASMRs (cumulative 187.0%; AAPC 2.0% [95% CI, 1.8-2.2]) and SSc-ASMR: non-SSc-ASMR ratio (cumulative 395.4%; AAPC 3.3% [95% CI, 2.9-3.7]).

              Conclusion

              Mortality for SSc has steadily decreased at younger ages over the past five-decades.
                Cover page: Steady decrease in systemic sclerosis mortality rates at younger ages over the past five decades.Creative Commons 'BY' version 4.0 license
                • Article
                • Peer Reviewed
                UCLA Previously Published Works (2011)
                Systemic lupus erythematosus is a chronic autoimmune disease characterized by loss of tolerance to self-Ags and activation of autoreactive T cells. Regulatory T (Treg) cells play a critical role in controlling the activation of autoreactive T cells. In this study, we investigated mechanisms of potential Treg cell defects in systemic lupus erythematosus using MRL-Fas(lpr/lpr) (MRL/lpr) and MRL-Fas(+/+) mouse models. We found a significant increase in CD4(+)CD25(+)Foxp3(+) Treg cells, albeit with an altered phenotype (CD62L(-)CD69(+)) and with a reduced suppressive capacity, in the lymphoid organs of MRL strains compared with non-autoimmune C3H/HeOuj mice. A search for mechanisms underlying the altered Treg cell phenotype in MRL/lpr mice led us to find a profound reduction in Dicer expression and an altered microRNA (miRNA, miR) profile in MRL/lpr Treg cells. Despite having a reduced level of Dicer, MRL/lpr Treg cells exhibited a significant overexpression of several miRNAs, including let-7a, let-7f, miR-16, miR-23a, miR-23b, miR-27a, and miR-155. Using computational approaches, we identified one of the upregulated miRNAs, miR-155, that can target CD62L and may thus confer the altered Treg cell phenotype in MRL/lpr mice. In fact, the induced overexpression of miR-155 in otherwise normal (C3H/HeOuj) Treg cells reduced their CD62L expression, which mimics the altered Treg cell phenotype in MRL/lpr mice. These data suggest a role of Dicer and miR-155 in regulating Treg cell phenotype. Furthermore, simultaneous appearance of Dicer insufficiency and miR-155 overexpression in diseased mice suggests a Dicer-independent alternative mechanism of miRNA regulation under inflammatory conditions.
                  Cover page: Dicer Insufficiency and MicroRNA-155 Overexpression in Lupus Regulatory T Cells: An Apparent Paradox in the Setting of an Inflammatory Milieu
                  • Article
                  • Peer Reviewed
                  UCLA Previously Published Works (2023)

                  Objective

                  Male sex and black race incur poor prognosis in systemic sclerosis (SSc). There is no nationwide population-based assessment of premature SSc death burden by sex and race.

                  Methods

                  This is a population-based study comprising all recorded SSc deaths across the United States. We constructed histograms depicting the number of SSc deaths for each age by sex and race, and calculated the cumulative percent death at each age and the median age of death. We determined the odds ratios for the risk of premature death from SSc by sex and race. We then calculated the percent of total SSc deaths for different age groups by sex and race from 1970 to 2015. We performed chi-square test with Yates's correction and quantified the odds ratio (OR) with 95% confidence interval (CI).

                  Results

                  The median age of SSc death was 63 years in males versus 68 years in females, and 57 years in blacks versus 70 years in whites. The odds for SSc death before 65 years age was 1.8 (95% CI, 1.6-2.0) for males compared with females and 5.1 (95% CI, 4.4-6.0) for blacks compared with whites. The higher odds for premature death in males than in females was similar for both races. Differences in the proportions of premature deaths from 1970 to 2015 increased between males and females (-5% to 17%) and between blacks and whites (14% to 36%).

                  Conclusion

                  Males and black persons die of SSc at younger ages. The worsening premature death burden gap between the two sexes and races over the last five decades is troublesome.
                    Cover page: Worsening premature death burden gap from systemic sclerosis in men and black persons: A US nationwide population-based studyCreative Commons 'BY' version 4.0 license
                    • Article
                    • Peer Reviewed
                    UCLA Previously Published Works (2013)
                    Abstract Introduction β2-microglobulin (β2m) is required for the surface expression of MHC class I and class I-like proteins such as CD1d, Qa1 and neonatal Fc receptor (FcRn), all of which may impact the development of autoimmunity. Since CD1d is known to bind and present phospholipid antigens to T cells, we asked if the deficiency of β2m or CD1d will impact the development of anti-phospholipid antibodies as compared to other aspects of lupus autoimmunity. Methods We introgressed the β2m-null genotype onto the NZB and NZW backgrounds for 12 to 14 generations to generate genetically lupus-susceptible (NZB/NZW)F1 (BWF1) mice that are β2m-deficient (β2m°). Circulating immunoglobulins (Ig), rheumatoid factor (RF), anti-DNA and anti-cardiolipin (anti-CL) antibodies, and renal disease were analyzed in these and CD1d-deficient (CD1d°) BWF1 mice that we had previously generated. Results Whereas β2m° BWF1 mice had reduced serum IgG, they had increased mortality, nephritis, serum IgG anti-DNA antibody and RF as compared to heterozygous and wild-type littermates. These effects were recapitulated in CD1d° BWF1 mice, except that they also had increased serum IgG as compared to control littermates. Intriguingly, both β2m° and CD1d° mice had lower serum anti-CL antibody levels than in control littermates. Such CD1d dependence of anti-CL antibody production is not mediated by CD1d/glycolipid-reactive iNKT cells, as these cells reduced the production of RF and anti-DNA antibodies but had no effect on anti-CL antibodies. Conclusions We report a novel dichotomous role of β2m and CD1d, whereby these molecules differently regulate autoimmunity against phospholipid versus non-phospholipid autoantigens.
                      Cover page: Germline deletion of beta2 microglobulin or CD1d reduces anti-phospholipid antibody, but increases autoantibodies against non-phospholipid antigens, in NZB/W F1 model of lupus
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