Bio


Lisa Zaba M.D. Ph.D., is Clinical Associate Professor of Dermatology, and Director of the Merkel cell carcinoma (MCC) multi-disciplinary clinic. She also has a special interest in managing skin side effects from various cancer treatments, including side effects from immune checkpoint inhibitors, targeted therapies, and chemotherapeutic agents. Dr. Zaba completed medical school at Cornell University, PhD in immunology at Rockefeller University, Residency and Post-Doc at Stanford University in 2013.

Clinical Focus


  • Dermatology

Academic Appointments


Administrative Appointments


  • Director of MCC Multi-Disciplinary Clinic, Stanford (2021 - Present)
  • Director of Cutaneous Oncology at CCSB, Stanford (2018 - Present)

Honors & Awards


  • Research Scholar, New York Academy of Science (2002)
  • Member, Alpha Omega Alpha, Weill Cornell Medical College (2003)
  • Recipient, World Congress scholarship for Psoriasis research (2008)
  • Recipient, Clinical Translational Science grant for Psoriasis research (2008)
  • Intern of the Year, Memorial Sloan Kettering Cancer Center (2010)
  • Recipient, National Dermatology Foundation Award for Scleroderma research (2013)

Professional Education


  • Board Certification: American Board of Dermatology, Dermatology (2013)
  • Residency: Stanford School of Medicine (2013) CA
  • Internship: Memorial Sloan Kettering Cancer Center Transitional Year Training (2010) NY
  • Medical Education: Weill Cornell Medical College (2009) NY

All Publications


  • Health Care Utilization and Costs in Systemic Therapies for Metastatic Melanoma from 2016 to 2020. The oncologist Qian, M. F., Betancourt, N. J., Pineda, A., Maloney, N. J., Nguyen, K. A., Reddy, S. A., Hall, E. T., Swetter, S. M., Zaba, L. C. 2022

    Abstract

    BACKGROUND: Widespread implementation of immune checkpoint inhibitors (ICI) and targeted therapies for metastatic melanoma has led to a decline in melanoma-related mortality but increased healthcare costs. We aimed to determine how healthcare utilization varied by systemic, non-adjuvant melanoma treatment from 2016 to 2020.PATIENTS AND METHODS: Adults with presumed stage IV metastatic melanoma receiving systemic therapy from 2016 to 2020 were identified in Optum, a nationwide commercial claims database. Treatment groups were nivolumab, pembrolizumab, ipilimumab+nivolumab (combination-ICI), or BRAF+MEK inhibitor (BRAFi+MEKi) therapy. Outcomes included hospitalizations, days hospitalized, emergency room (ER) visits, outpatient visits, and healthcare costs per patient per month (pppm). Multivariable regression models were used to analyze whether cost and utilization outcomes varied by treatment group, with nivolumab as reference.RESULTS: Among 2018 adult patients with metastatic melanoma identified, mean (SD) age was 67 (15) years. From 2016 to 2020, nivolumab surpassed pembrolizumab as the most prescribed systemic melanoma therapy while combination-ICI and BRAFi+MEKi therapies remained stable. Relative to nivolumab, all other therapies were associated with increased total healthcare costs (combination-ICI: beta = $47 600 pppm, 95%CI $42 200-$53 100; BRAFi+MEKi: beta = $3810, 95%CI $365-$7260; pembrolizumab: beta = $6450, 95%CI $4420-$8480). Combination-ICI and BRAFi+MEKi therapies were associated with more inpatient hospital days.CONCLUSIONS: Amid the evolving landscape of systemic therapy for advanced melanoma, nivolumab monotherapy emerged as the most used and least costly systemic treatment from 2016 to 2020. Its sharp increase in use in 2018 and lower costs relative to pembrolizumab may in part be due to earlier adoption of less frequent dosing intervals.

    View details for DOI 10.1093/oncolo/oyac219

    View details for PubMedID 36302223

  • Risk factors for and prognostic impact of positive surgical margins after excision of Merkel cell carcinoma JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Maloney, N. J., Nguyen, K. A., So, N. A., Aasi, S. Z., Zaba, L. C. 2022; 87 (2): 444-446
  • Yield of sentinel lymph node biopsy in sebaceous carcinoma and predictors of advanced disease: a retrospective analysis of the National Cancer Database. Journal of the American Academy of Dermatology Maloney, N. J., Nguyen, K. A., So, N. A., Zaba, L. C. 2022

    View details for DOI 10.1016/j.jaad.2022.07.015

    View details for PubMedID 35843481

  • Histologic subtype of cutaneous immune-related adverse events predicts overall survival in patients receiving immune checkpoint inhibitors. Journal of the American Academy of Dermatology Hirotsu, K. E., Scott, M. K., Marquez, C., Tran, A. T., Rieger, K. E., Novoa, R. A., Robinson, W. H., Kwong, B. Y., Zaba, L. C. 2021

    View details for DOI 10.1016/j.jaad.2021.11.050

    View details for PubMedID 34875301

  • Dermatologic toxicities of targeted antineoplastic agents and immune checkpoint inhibitor therapy in pediatric patients: A systematic review. Pediatric blood & cancer Liu, L. Y., Teng, J. M., Spunt, S. L., Strelo, J. L., Kwong, B. Y., Zaba, L. C. 2021: e29346

    Abstract

    Cutaneous adverse events (cAEs) from targeted antineoplastic agents and immune checkpoint inhibitors are common in children with cancer and may lead to dose reduction or cessation of critical oncologic treatment. Timely diagnosis and proper management of cAEs in pediatric oncology patients is essential to optimize ongoing cancer-directed therapy and improve quality of life. This systematic review of published studies summarizes dermatologic toxicities to targeted anticancer treatments and immune checkpoint inhibitors.

    View details for DOI 10.1002/pbc.29346

    View details for PubMedID 34569142

  • Clinical features of drug-induced hypersensitivity syndrome to BRAF inhibitors with and without previous immune checkpoint inhibition: a review. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer Maloney, N. J., Rana, J., Yang, J. J., Zaba, L. C., Kwong, B. Y. 2021

    Abstract

    PURPOSE: Cutaneous reactions to BRAF inhibitors are common, but severe reactions resembling or consistent with drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) are relatively rare. Several reports suggest that cutaneous reactions including DRESS/DIHS to BRAF inhibitors are more frequent and severe in the setting of previous immune checkpoint inhibition (ICI).METHODS: To characterize existing literature on these reports, we queried the PubMed/MEDLINE database for cases of DIHS/DRESS to BRAF inhibitors.RESULTS: We identified 23 cases of DIHS to BRAF inhibitors following checkpoint inhibition and 14 cases without prior checkpoint inhibitor therapy. In both cohorts, DIHS occurred relatively early, with median time to onset from drug exposure of 8-10days. Patients who received prior ICI were less likely to have peripheral eosinophilia (26% vs 71%), atypical lymphocytes (9% vs 50%), renal involvement (61% vs 79%), hepatic involvement (52% vs 86%), and lymphadenopathy (9% vs 43%) compared to patients who did not receive prior ICI. Thrombocytopenia was more common with prior ICI (17% vs 7%). Only patients who received prior ICI experienced hypotension (26%) during the course of their DIHS. All cases of BRAF-induced DIHS generally improved on systemic steroids/supportive care, and no cases of death were identified.CONCLUSION: Dermatologists should consider a diagnosis of DIHS following BRAF inhibitor initiation, particularly in the setting of past checkpoint inhibition, with atypical features including relatively rapid onset and steroid responsiveness, lack of peripheral eosinophilia, lymphocytosis, or lymphadenopathy, and increased risk of thrombocytopenia and hypotension.

    View details for DOI 10.1007/s00520-021-06543-9

    View details for PubMedID 34546454

  • Risk factors for and prognostic impact of positive surgical margins after excision of Merkel cell carcinoma. Journal of the American Academy of Dermatology Maloney, N. J., Nguyen, K. A., So, N. A., Aasi, S. Z., Zaba, L. C. 2021

    View details for DOI 10.1016/j.jaad.2021.09.014

    View details for PubMedID 34537251

  • Synergistic effect of lymphovascular invasion and nodal involvement on prognosis in Merkel cell carcinoma: a retrospective analysis in the National Cancer Database. Journal of the American Academy of Dermatology Nguyen, K. A., Maloney, N. J., Yang, J. J., Zaba, L. C. 2021

    View details for DOI 10.1016/j.jaad.2021.08.055

    View details for PubMedID 34499993

  • NUTRITIONAL DEFICIENCY CONTRIBUTING TO REFRACTORY ERYTHRODERMA IN HEMATOPOETIC CELL TRANSPLANT PATIENTS: DISTINCTIVE CLINICAL AND HISTOPATHOLOGICAL FINDINGS. Journal of the American Academy of Dermatology Winge, M. C., Rieger, K. E., Kim, J., Weng, W., Johnston, L. J., Miklos, D. B., Strelo, J., Zaba, L. C., Pugliese, S. B., Novoa, R. A., Kwong, B. Y. 2021

    View details for DOI 10.1016/j.jaad.2021.07.077

    View details for PubMedID 34450206

  • Competing risks analysis of Merkel cell carcinoma with concurrent chronic lymphocytic leukemia and non-Hodgkin lymphoma. Dermatology online journal Nguyen, K. A., Maloney, N. J., Yang, J. J., Bach, D. Q., Zaba, L. C. 2021; 27 (8)

    Abstract

    BACKGROUND: Although hematogenous malignancy is a risk factor for poorer prognosis in Merkel cell carcinoma (MCC), current guidelines make no specific recommendations for surveillance.OBJECTIVE: We aim to characterize MCC-specific mortality compared to other causes of death for patients with hematologic malignancy in MCC, which will guide workup and surveillance strategies.METHODS: The Surveillance, Epidemiology, and End Results-18 registry was queried for MCC patients with chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma (NHL).RESULTS: Of 8519 patients with MCC, 146 (1.7%) had CLL and 234 (2.8%) had NHL. Chronic lymphocytic leukemia patients had 5-year cumulative incidence of MCC-specific mortality of 38.4% versus 28.4% in patients without CLL/NHL. For both cohorts, oncologic risk was highest within the first three years of diagnosis with competing risks favored thereafter. On competing risk regression, a history of CLL trended toward statistical significance with poorer MCC-specific mortality (subdistribution hazard ratio: 1.33, 95% CI: 0.963-1.834, P=0.084), while NHL was not prognostic.CONCLUSIONS: Merkel cell carcinoma patients with CLL may benefit from more aggressive initial management. Surveillance for similar length in CLL patients with MCC may be appropriate; this co-morbidity did not affect the timeframe by which the risk of competing causes of death exceeded oncologic risks.

    View details for DOI 10.5070/D327854684

    View details for PubMedID 34755954

  • Histopathologic correlation of skin manifestations of multisystemic inflammatory syndrome in adults (MIS-A) associated with SARS-CoV-2 infection. JAAD case reports So, N. A., So, J., Centkowski, S., Rana, J., Aleshin, M., Kwong, B. Y., Rieger, K., Zaba, L. C., Chiou, A. S. 2021

    View details for DOI 10.1016/j.jdcr.2021.06.031

    View details for PubMedID 34405113

  • Complete remission from intralesional talimogene laherparepvec for regionally advanced Merkel cell carcinoma in an immunocompromised solid organ transplant patient. JAAD case reports Hirotsu, K. E., Hua, V., Tran, A. T., Morris, L., Reddy, S. A., Kwong, B. Y., Zaba, L. C. 2021; 13: 144-146

    View details for DOI 10.1016/j.jdcr.2021.05.005

    View details for PubMedID 34195326

  • Drug-induced hypersensitivity syndrome like reaction with angioedema and hypotension associated with BRAF inhibitor use and antecedent immune checkpoint therapy. JAAD case reports Rana, J., Maloney, N. J., Rieger, K. E., Pugliese, S. B., Strelo, J. L., Liu, A., Zaba, L. C., Kwong, B. Y. 2021; 13: 147-151

    View details for DOI 10.1016/j.jdcr.2021.04.033

    View details for PubMedID 34195327

  • Response to "Mohs surgery for early-stage Merkel cell carcinoma (MCC) achieves local control better than wide local excision +/- radiation therapy with no increase in MCC-specific death". International journal of dermatology Nguyen, K. A., Maloney, N. J., Fonseca, A., Nghiem, P., Zaba, L. C. 2021

    View details for DOI 10.1111/ijd.15723

    View details for PubMedID 34143433

  • Merkel cell carcinoma patients with solid organ transplant or hematologic malignancy: demographics, survival, and prognosticators. Journal of the American Academy of Dermatology Maloney, N. J., Yang, J. J., Zaba, L. C. 2021

    View details for DOI 10.1016/j.jaad.2021.05.042

    View details for PubMedID 34082038

  • Prognostic value of bone marrow metabolism on pretreatment 18F-FDG PET/CT in patients with metastatic melanoma treated with anti-PD-1 therapy. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Nakamoto, R., Zaba, L. C., Liang, T., Reddy, S. A., Davidzon, G., Aparici, C. M., Nguyen, J., Moradi, F., Iagaru, A., Franc, B. L. 2021

    Abstract

    Purpose: To investigate the prognostic value of 18F-FDG PET/CT parameters in melanoma patients before beginning anti-PD-1 therapy. Methods: Imaging parameters including SUVmax, metabolic tumor volume (MTV), and bone marrow to liver SUVmean ratio (BLR) were measured from baseline PET/CT in 92 patients before the start of anti-PD-1 therapy. Association with survival and imaging parameters combined with clinical factors was evaluated. Clinical and laboratory data between high (> median) and low (≤ median) BLR groups were compared. Results: Multivariate analyses demonstrated that BLR was an independent prognostic factor for PFS and OS (P = 0.017, P = 0.011, respectively). The high BLR group had higher levels of white blood cell count/neutrophil count and C-Reactive Protein than the low BLR group (P < 0.05). Conclusion: Patients with high BLR were associated with poor PFS and OS, potentially explained by evidence of systemic inflammation known to be associated with immunosuppression.

    View details for DOI 10.2967/jnumed.120.254482

    View details for PubMedID 33547210

  • How we treat Merkel cell carcinoma: within and beyond current guidelines. Future oncology (London, England) Park, S. Y., Doolittle-Amieva, C., Moshiri, Y., Akaike, T., Parvathaneni, U., Bhatia, S., Zaba, L. C., Nghiem, P. 2021

    Abstract

    Merkel cell carcinoma (MCC) is an aggressive skin cancer associated with a high risk of local recurrence and distant metastasis. Optimal care of this potentially life-threatening cancer is critical but challenging because: physicians are often unfamiliar with its management due to rarity, and MCC management remains controversial, in part because it is rapidly evolving across multiple specialties. While guidelines offer a broad overview of management, they are often not sufficient when making decisions for individual patients. Herein, we present a literature review as well as practical approaches adopted at our institutions for staging, surveillance and therapy of MCC. Each of these areas are discussed in light of how they can be appropriately customized for prevalent but challenging situations. We also provide representative examples of MCC patient scenarios and how they were managed by a multidisciplinary team to identify suitable evidence-based, individualized treatment plans.

    View details for DOI 10.2217/fon-2020-1036

    View details for PubMedID 33511866

  • Prognostic value of lymphovascular invasion in early-stage Merkel cell carcinoma: a retrospective analysis in the National Cancer Database. Journal of the American Academy of Dermatology Maloney, N. J., Nguyen, K. A., Yang, J. J., Zaba, L. C. 2021

    View details for DOI 10.1016/j.jaad.2021.07.018

    View details for PubMedID 34293387

  • Imaging Characteristics and Diagnostic Performance of 2-deoxy-2-[18F]fluoro-D-Glucose PET/CT for Melanoma Patients Who Demonstrate Hyperprogressive Disease When Treated with Immunotherapy. Molecular imaging and biology Nakamoto, R., C Zaba, L., Rosenberg, J., Arani Reddy, S., W Nobashi, T., Ferri, V., Davidzon, G., Mari Aparici, C., Nguyen, J., Moradi, F., Iagaru, A., Lewis Franc, B. 2020

    Abstract

    PURPOSE: We investigated the ability of baseline 2-deoxy-2-[18F]fluoro-D-glucose PET/CT parameters, acquired before the start of immunotherapy, to predict development of hyperprogressive disease (HPD) in melanoma patients. We also evaluated the diagnostic performances of ratios of baseline and first restaging PET/CT parameters to diagnose HPD without information of the tumor growth kinetic ratio (TGKR) that requires pre-baseline imaging before baseline imaging (3 timepoint imaging).PROCEDURES: Seventy-six patients who underwent PET/CT before and approximately 3months following initiation of immunotherapy were included. PET/CT parameters, including metabolic tumor volume (MTV) for all melanoma lesions and total measured tumor burden (TMTB) based on irRECIST, were measured from baseline PET/CT (MTVbase and TMTBbase) and first restaging PET/CT (MTVpost and TMTBpost). The ratios of MTV (MTVpost/MTVbase, MTVr) and TMTB (TMTBpost/TMTBbase, TMTBr) were calculated.RESULTS: MTVbase of HPD patients (n=9, TGKR ≥2) was larger than that of non-HPD (n=67, TGKR <2) patients (P<0.05), and HPD patients demonstrated shorter median overall survival (7 vs. more than 60months, P<0.05). The area under the curve (AUC) of MTVbase (≥155.5ml) to predict the risk of HPD was 0.703, with a sensitivity of 66.7% and specificity of 81.2%. The AUCs of MTVr (≥1.25) and TMTBr (≥1.27) to diagnose HPD without information of TGKR were 0.875 and 0.977 with both sensitivities of 100%, and specificities of 79% and 83.9%, respectively.CONCLUSIONS: Patients at high risk of developing HPD could not be accurately identified based on baseline PET/CT parameters. The ratios of baseline and first restaging PET/CT parameters may be helpful to diagnose HPD, when patients do not undergo pre-baseline imaging.

    View details for DOI 10.1007/s11307-020-01526-4

    View details for PubMedID 32789649

  • Increased Mortality in Asians With Systemic Sclerosis in Northern California. ACR open rheumatology Chung, M. P., Dontsi, M., Postlethwaite, D., Kesh, S., Simard, J. F., Fiorentino, D., Zaba, L. C., Chung, L. 2020

    Abstract

    OBJECTIVE: The objective of this study is to evaluate racial/ethnic differences in disease manifestations and survival in a US cohort of patients with systemic sclerosis (SSc), with a focus on Asian patients.METHODS: A retrospective cohort study was conducted among Kaiser Permanente Northern California adults with an incident SSc diagnosis by a rheumatologist from 2007 to 2016, confirmed by a chart review to fulfill 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria. Self-reported race/ethnicity was categorized as non-Hispanic white, Asian, Hispanic, and black. Disease manifestations and survival were compared, using white patients as the reference.RESULTS: A total of 609 patients with incident SSc were identified: 89% were women, and 81% had limited cutaneous SSc, with a mean age at diagnosis of 55.4 ± 14.8 years. The racial/ethnic distribution was 51% non-Hispanic white (n = 310), 25% Hispanic (n = 154), 16% Asian (n = 96), and 8% black (n = 49). Compared with white patients, black patients had a greater prevalence of diffuse disease (14.5% vs. 44.9%; P < 0.001), and Asians had higher rates of anti-U1-RNP antibodies (32.1% vs. 11.9%; P = 0.005). Nine-year overall survival rates following SSc diagnosis were lower in Asian (52.3%), black (52.2%), and Hispanic patients (68.2%) compared with white patients (75.8%). Pulmonary hypertension and infections were the leading causes of death in Asian patients. Asian race was associated with higher mortality on univariable (hazard ratio [HR] 1.83 [95% confidence interval (CI) 1.08-2.99]; P = 0.020) and multivariable analyses (HR 1.80 [95% CI 0.99-3.16]; P = 0.047) when adjusting for age, sex, body mass index, cutaneous subtype, smoking status, interstitial lung disease, pulmonary hypertension, renal crisis, and malabsorption syndrome.CONCLUSION: Asian patients with SSc in this US cohort had increased mortality compared with white patients. These patients warrant close monitoring for disease progression.

    View details for DOI 10.1002/acr2.11126

    View details for PubMedID 32198914

  • Chromatin accessibility landscapes of skin cells in systemic sclerosis nominate dendritic cells in disease pathogenesis. Nature communications Liu, Q., Zaba, L., Satpathy, A. T., Longmire, M., Zhang, W., Li, K., Granja, J., Guo, C., Lin, J., Li, R., Tolentino, K., Kania, G., Distler, O., Fiorentino, D., Chung, L., Qu, K., Chang, H. Y. 2020; 11 (1): 5843

    Abstract

    Systemic sclerosis (SSc) is a disease at the intersection of autoimmunity and fibrosis. However, the epigenetic regulation and the contributions of diverse cell types to SSc remain unclear. Here we survey, using ATAC-seq, the active DNA regulatory elements of eight types of primary cells in normal skin from healthy controls, as well as clinically affected and unaffected skin from SSc patients. We find that accessible DNA elements in skin-resident dendritic cells (DCs) exhibit the highest enrichment of SSc-associated single-nucleotide polymorphisms (SNPs) and predict the degrees of skin fibrosis in patients. DCs also have the greatest disease-associated changes in chromatin accessibility and the strongest alteration of cell-cell interactions in SSc lesions. Lastly, data from an independent cohort of patients with SSc confirm a significant increase of DCs in lesioned skin. Thus, the DCs epigenome links inherited susceptibility and clinically apparent fibrosis in SSc skin, and can be an important driver of SSc pathogenesis.

    View details for DOI 10.1038/s41467-020-19702-z

    View details for PubMedID 33203843

  • Sites of distant metastasis in Merkel cell carcinoma differ by primary tumor site and are of prognostic significance: a population-based study in the Surveillance, Epidemiology, and End Results database from 2010-2016. Journal of the American Academy of Dermatology Maloney, N. J., Nguyen, K. A., Bach, D. Q., Zaba, L. C. 2020

    View details for DOI 10.1016/j.jaad.2020.08.023

    View details for PubMedID 32781190

  • Prognostic value of volumetric PET parameters at early response evaluation in melanoma patients treated with immunotherapy. European journal of nuclear medicine and molecular imaging Nakamoto, R. n., Zaba, L. C., Rosenberg, J. n., Reddy, S. A., Nobashi, T. W., Davidzon, G. n., Aparici, C. M., Nguyen, J. n., Moradi, F. n., Iagaru, A. n., Franc, B. L. 2020

    Abstract

    The purpose of this study was to investigate the prognostic value of whole-body metabolic tumor volume (MTV) and other metabolic tumor parameters, obtained from baseline and first restaging 18F-FDG PET/CT scans in melanoma patients treated with immune checkpoint inhibitors (ICIs).Eighty-five consecutive melanoma patients (M, 57; F, 28) treated with ICIs who underwent PET/CT scans before and approximately 3 months after the start of immunotherapy were retrospectively enrolled. Metabolic tumor parameters including MTV for all melanoma lesions were measured on each scan. A Cox proportional hazards model was used for univariate and multivariate analyses of metabolic parameters combined with known clinical prognostic factors associated with overall survival (OS). Kaplan-Meier curves for patients dichotomized based on median values of imaging parameters were generated.The median OS time in all patients was 45 months (95% CI 24-45 months). Univariate analysis demonstrated that MTV obtained from first restaging PET/CT scans (MTVpost) was the strongest prognostic factor for OS among PET/CT parameters (P < 0.0001). The median OS in patients with high MTVpost (≥ 23.44) was 16 months (95% CI 12-32 months) as compared with more than 60 months in patients with low MTVpost (< 23.44) (P = 0.0003). A multivariate model including PET/CT parameters and known clinical prognostic factors revealed that MTVpost and the presence of central nervous system lesions were independent prognostic factors for OS (P = 0.0004, 0.0167, respectively). One pseudoprogression case (1.2%) was seen in this population and classified into the high MTVpost group.Whole-body metabolic tumor volume from PET scan acquired approximately 3 months following initiation of immunotherapy (MTVpost) is a strong prognostic indicator of OS in melanoma patients. Although the possibility of pseudoprogression must be considered whenever evaluating first restaging PET imaging, it only occurred in 1 patient in our cohort.

    View details for DOI 10.1007/s00259-020-04792-0

    View details for PubMedID 32296882

  • Successful treatment of HIV-negative Kaposi sarcoma with ipilimumab and nivolumab and concurrent management of baseline psoriasis and bullous pemphigoid. JAAD case reports Tabata, M. M., Novoa, R. A., Bui, N. Q., Zaba, L. C. 2020; 6 (5): 447–49

    View details for DOI 10.1016/j.jdcr.2020.03.001

    View details for PubMedID 32382643

    View details for PubMedCentralID PMC7200441

  • Clinicopathologic characterization of enfortumab vedotin-associated cutaneous toxicity in patients with urothelial carcinoma. Journal of the American Academy of Dermatology Hirotsu, K. E., Rana, J. n., Wang, J. Y., Raghavan, S. S., Rieger, K. E., Srinivas, S. n., Fan, A. C., Kwong, B. Y., Novoa, R. A., Zaba, L. n. 2020

    View details for DOI 10.1016/j.jaad.2020.11.067

    View details for PubMedID 33301805

  • Chromatin Accessibility Landscape of Cutaneous T Cell Lymphoma and Dynamic Response to HDAC Inhibitors. Cancer cell Qu, K. n., Zaba, L. C., Satpathy, A. T., Giresi, P. G., Li, R. n., Jin, Y. n., Armstrong, R. n., Jin, C. n., Schmitt, N. n., Rahbar, Z. n., Ueno, H. n., Greenleaf, W. J., Kim, Y. H., Chang, H. Y. 2017

    Abstract

    Here, we define the landscape and dynamics of active regulatory DNA in cutaneous T cell lymphoma (CTCL) by ATAC-seq. Analysis of 111 human CTCL and control samples revealed extensive chromatin signatures that distinguished leukemic, host, and normal CD4(+) T cells. We identify three dominant patterns of transcription factor (TF) activation that drive leukemia regulomes, as well as TF deactivations that alter host T cells in CTCL patients. Clinical response to histone deacetylase inhibitors (HDACi) is strongly associated with a concurrent gain in chromatin accessibility. HDACi causes distinct chromatin responses in leukemic and host CD4(+) T cells, reprogramming host T cells toward normalcy. These results provide a foundational framework to study personal regulomes in human cancer and epigenetic therapy.

    View details for PubMedID 28625481

  • Individuality and Variation of Personal Regulomes in Primary Human T Cells CELL SYSTEMS Qu, K., Zaba, L. C., Giresi, P. G., Li, R., Longmire, M., Kim, Y. H., Greenleaf, W. J., Chang, H. Y. 2015; 1 (1): 51-61

    Abstract

    Here we survey variation and dynamics of active regulatory elements genome-wide using longitudinal samples from human individuals. We applied Assay of Transposase Accessible Chromatin with sequencing (ATAC-seq) to map chromatin accessibility in primary CD4+ T cells isolated from standard blood draws of 12 healthy volunteers over time, from cancer patients, and during T cell activation. Over 4,000 predicted regulatory elements (7.2%) showed reproducible variation in accessibility between individuals. Gender was the most significant attributable source of variation. ATAC-seq revealed previously undescribed elements that escape X chromosome inactivation and predicted gender-specific gene regulatory networks across autosomes, which coordinately affect genes with immune function. Noisy regulatory elements with personal variation in accessibility are significantly enriched for autoimmune disease loci. Over one third of regulome variation lacked genetic variation in cis, suggesting contributions from environmental or epigenetic factors. These results refine concepts of human individuality and provide a foundational reference for comparing disease-associated regulomes.

    View details for DOI 10.1016/j.cels.2015.06.003

    View details for Web of Science ID 000209925400012

    View details for PubMedCentralID PMC4522940

  • Individuality and variation of personal regulomes in primary human T cells. Cell systems Qu, K., Zaba, L. C., Giresi, P. G., Li, R., Longmire, M., Kim, Y. H., Greenleaf, W. J., Chang, H. Y. 2015; 1 (1): 51-61

    Abstract

    Here we survey variation and dynamics of active regulatory elements genome-wide using longitudinal samples from human individuals. We applied Assay of Transposase Accessible Chromatin with sequencing (ATAC-seq) to map chromatin accessibility in primary CD4+ T cells isolated from standard blood draws of 12 healthy volunteers over time, from cancer patients, and during T cell activation. Over 4,000 predicted regulatory elements (7.2%) showed reproducible variation in accessibility between individuals. Gender was the most significant attributable source of variation. ATAC-seq revealed previously undescribed elements that escape X chromosome inactivation and predicted gender-specific gene regulatory networks across autosomes, which coordinately affect genes with immune function. Noisy regulatory elements with personal variation in accessibility are significantly enriched for autoimmune disease loci. Over one third of regulome variation lacked genetic variation in cis, suggesting contributions from environmental or epigenetic factors. These results refine concepts of human individuality and provide a foundational reference for comparing disease-associated regulomes.

    View details for PubMedID 26251845

  • Distinctive cutaneous and systemic features associated with antitranscriptional intermediary factor-1? antibodies in adults with dermatomyositis. Journal of the American Academy of Dermatology Fiorentino, D. F., Kuo, K., Chung, L., Zaba, L., Li, S., Casciola-Rosen, L. 2015; 72 (3): 449-455

    Abstract

    Antibodies against transcriptional intermediary factor (TIF)-1γ are associated with malignancy in dermatomyositis (DM). Identification of clinical findings associated with anti-TIF-1γ antibodies in DM is a high priority for both patient diagnosis and risk assessment.We sought to define the clinical phenotype of patients with anti-TIF-1γ DM.Using a novel, sensitive, and specific assay for anti-TIF-1γ antibodies, we retrospectively tested plasma from 134 adult patients with DM and examined associations between anti-TIF-1γ antibodies and particular clinical and laboratory features.In all, 55 (41%) patients had autoantibodies to TIF-1γ. Anti-TIF-1γ positive patients were less likely to have systemic features including interstitial lung disease, Raynaud phenomenon, and arthritis/arthralgia. Patients with TIF-1γ autoantibodies had more extensive skin involvement, and some patients manifested characteristic findings including palmar hyperkeratotic papules, psoriasis-like lesions and a novel finding of hypopigmented and telangiectatic ("red on white") patches.This was a retrospective study from a single tertiary referral center.TIF-1γ is the most commonly targeted DM-specific autoantigen in adults in a large US cohort. Although these patients tend to have less systemic involvement, their skin disease is often extensive and characteristic. Recognition of cutaneous findings in anti-TIF-1γ positive patients may allow more accurate and timely diagnosis and effective treatment of patients with DM.

    View details for DOI 10.1016/j.jaad.2014.12.009

    View details for PubMedID 25595720

  • Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position NATURE METHODS Buenrostro, J. D., Giresi, P. G., Zaba, L. C., Chang, H. Y., Greenleaf, W. J. 2013; 10 (12): 1213-?

    Abstract

    We describe an assay for transposase-accessible chromatin using sequencing (ATAC-seq), based on direct in vitro transposition of sequencing adaptors into native chromatin, as a rapid and sensitive method for integrative epigenomic analysis. ATAC-seq captures open chromatin sites using a simple two-step protocol with 500-50,000 cells and reveals the interplay between genomic locations of open chromatin, DNA-binding proteins, individual nucleosomes and chromatin compaction at nucleotide resolution. We discovered classes of DNA-binding factors that strictly avoided, could tolerate or tended to overlap with nucleosomes. Using ATAC-seq maps of human CD4(+) T cells from a proband obtained on consecutive days, we demonstrated the feasibility of analyzing an individual's epigenome on a timescale compatible with clinical decision-making.

    View details for DOI 10.1038/NMETH.2688

    View details for Web of Science ID 000327698100025

    View details for PubMedID 24097267

  • Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nature methods Buenrostro, J. D., Giresi, P. G., Zaba, L. C., Chang, H. Y., Greenleaf, W. J. 2013; 10 (12): 1213-1218

    Abstract

    We describe an assay for transposase-accessible chromatin using sequencing (ATAC-seq), based on direct in vitro transposition of sequencing adaptors into native chromatin, as a rapid and sensitive method for integrative epigenomic analysis. ATAC-seq captures open chromatin sites using a simple two-step protocol with 500-50,000 cells and reveals the interplay between genomic locations of open chromatin, DNA-binding proteins, individual nucleosomes and chromatin compaction at nucleotide resolution. We discovered classes of DNA-binding factors that strictly avoided, could tolerate or tended to overlap with nucleosomes. Using ATAC-seq maps of human CD4(+) T cells from a proband obtained on consecutive days, we demonstrated the feasibility of analyzing an individual's epigenome on a timescale compatible with clinical decision-making.

    View details for DOI 10.1038/nmeth.2688

    View details for PubMedID 24097267

  • Most Patients With Cancer-Associated Dermatomyositis Have Antibodies to Nuclear Matrix Protein NXP-2 or Transcription Intermediary Factor 1?. Arthritis and rheumatism Fiorentino, D. F., Chung, L. S., Christopher-Stine, L., Zaba, L., Li, S., Mammen, A. L., Rosen, A., Casciola-Rosen, L. 2013; 65 (11): 2954-2962

    Abstract

    Since dermatomyositis (DM) is associated with an increased risk of malignancy, accurate identification of patients likely to harbor cancers is important. Using immunoprecipitations from radiolabeled cell lysates, several groups recently showed that anti-transcription intermediary factor 1γ (anti-TIF-1γ) antibodies are associated with malignancy in DM. We undertook this study to develop sensitive, specific assays to detect antibodies against TIF-1γ and nuclear matrix protein NXP-2 and to evaluate their association with malignancy in DM.To detect anti-TIF-1γ antibodies, immunoprecipitations were performed using lysates made from HeLa cells overexpressing TIF-1γ, with detection by immunoblotting. Anti-NXP-2 antibodies were assayed by immunoprecipitation using (35) S-methionine-labeled NXP-2 generated by in vitro transcription/translation. We analyzed patient sera from DM cohorts seen at the Stanford University Dermatology Clinic (n = 111) and the Johns Hopkins Myositis Center (n = 102).A total of 17% and 38% of patients had antibodies against NXP-2 and TIF-1γ, respectively. Reactivity against either NXP-2 or TIF-1γ identified 83% of patients with cancer-associated DM. In addition to older age and male sex, cancer was associated with antibodies to NXP-2 or TIF-1γ on multivariate analysis (odds ratio 3.78 [95% confidence interval 1.33-10.8]). Stratification by sex revealed that anti-NXP-2 was specifically associated with cancer in males (odds ratio 5.78 [95% confidence interval 1.35-24.7]).These studies demonstrate that anti-NXP-2 and anti-TIF-1γ antibodies are frequent DM specificities (found in 55% of patients) and are present in most patients with cancer-associated DM.

    View details for DOI 10.1002/art.38093

    View details for PubMedID 24037894

  • A Subpopulation of CD163-Positive Macrophages Is Classically Activated in Psoriasis JOURNAL OF INVESTIGATIVE DERMATOLOGY Fuentes-Duculan, J., Suarez-Farinas, M., Zaba, L. C., Nograles, K. E., Pierson, K. C., Mitsui, H., Pensabene, C. A., Kzhyshkowska, J., Krueger, J. G., Lowes, M. A. 2010; 130 (10): 2412-2422

    Abstract

    Macrophages are important cells of the innate immune system, and their study is essential to gain greater understanding of the inflammatory nature of psoriasis. We used immunohistochemistry and double-label immunofluorescence to characterize CD163(+) macrophages in psoriasis. Dermal macrophages were increased in psoriasis compared with normal skin and were identified by CD163, RFD7, CD68, lysosomal-associated membrane protein 2 (LAMP2), stabilin-1, and macrophage receptor with collagenous structure (MARCO). CD163(+) macrophages expressed C-lectins CD206/macrophage mannose receptor and CD209/DC-SIGN, as well as costimulatory molecules CD86 and CD40. They did not express mature dendritic cell (DC) markers CD208/DC-lysosomal-associated membrane glycoprotein, CD205/DEC205, or CD83. Microarray analysis of in vitro-derived macrophages treated with IFN-γ showed that many of the genes upregulated in macrophages were found in psoriasis, including STAT1, CXCL9, Mx1, and HLA-DR. CD163(+) macrophages produced inflammatory molecules IL-23p19 and IL-12/23p40 as well as tumor necrosis factor (TNF) and inducible nitric oxide synthase (iNOS). These data show that CD163 is a superior marker of macrophages, and identifies a subpopulation of "classically activated" macrophages in psoriasis. We conclude that macrophages are likely to contribute to the pathogenic inflammation in psoriasis, a prototypical T helper 1 (Th1) and Th17 disease, by releasing key inflammatory products.

    View details for DOI 10.1038/jid.2010.165

    View details for Web of Science ID 000281868400013

    View details for PubMedID 20555352

    View details for PubMedCentralID PMC2939947

  • Identification of TNF-related apoptosis-inducing ligand and other molecules that distinguish inflammatory from resident dendritic cells in patients with psoriasis JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Zaba, L. C., Fuentes-Duculan, J., Eungdamrong, N., Johnson-Huang, L. M., Nograles, K. E., White, T. R., Pierson, K. C., Lentini, T., Suarez-Farinas, M., Lowes, M. A., Krueger, J. G. 2010; 125 (6): 1261-1268

    Abstract

    Previous work has identified CD11c(+)CD1c(-) dendritic cells (DCs) as the major "inflammatory" dermal DC population in patients with psoriasis vulgaris and CD1c(+) DCs as the "resident" cutaneous DC population.We sought to further define molecular differences between these 2 myeloid dermal DC populations.Inflammatory and resident DCs were single-cell sorted from lesional skin biopsy specimens of patients with psoriasis, and the transcriptome of CD11c(+)CD1c(-) versus CD1c(+) DCs was determined. Results were confirmed with RT-PCR, flow cytometry, immunohistochemistry, and double-labeled immunofluorescence. Human keratinocytes were cultured for functional studies.TNF-related apoptosis-inducing ligand (TRAIL), Toll-like receptors 1 and 2, S100A12/ENRAGE, CD32, and many other inflammatory products were differentially expressed in inflammatory DCs compared with resident DCs. Flow cytometry and immunofluorescence confirmed higher protein expression on CD1c(-) versus CD1c(+) DCs. TRAIL receptors, death receptor 4, and decoy receptor 2 were expressed in keratinocytes and dermal cells. In vitro culture of keratinocytes with TRAIL induced CCL20 chemokine.CD11c(+)CD1c(-) inflammatory DCs in psoriatic lesional skin express a wide range of inflammatory molecules compared with skin-resident CD1c(+) DCs. Some molecules made by inflammatory DCs, including TRAIL, could have direct effects on keratinocytes or other skin cell types to promote disease pathogenesis.

    View details for DOI 10.1016/j.jaci.2010.03.018

    View details for Web of Science ID 000278831000013

    View details for PubMedID 20471070

    View details for PubMedCentralID PMC2910451

  • Evaluation of the Psoriasis Transcriptome across Different Studies by Gene Set Enrichment Analysis (GSEA) PLOS ONE Suarez-Farinas, M., Lowes, M. A., Zaba, L. C., Krueger, J. G. 2010; 5 (4): e10247

    Abstract

    Our objective was to develop a consistent molecular definition of psoriasis. There have been several published microarray studies of psoriasis, and we compared disease-related genes identified across these different studies of psoriasis with our own in order to establish a consensus.We present a psoriasis transcriptome from a group of 15 patients enrolled in a clinical study, and assessed its biological validity using a set of important pathways known to be involved in psoriasis. We also identified a key set of cytokines that are now strongly implicated in driving disease-related pathology, but which are not detected well on gene array platforms and require more sensitive methods to measure mRNA levels in skin tissues. Comparison of our transcriptome with three other published lists of psoriasis genes showed apparent inconsistencies based on the number of overlapping genes. We extended the well-established approach of Gene Set Enrichment Analysis (GSEA) to compare a new study with these other published list of differentially expressed genes (DEG) in a more comprehensive manner. We applied our method to these three published psoriasis transcriptomes and found them to be in good agreement with our study.Due to wide variability in clinical protocols, platform and sample handling, and subtle disease-related signals, intersection of published DEG lists was unable to establish consensus between studies. In order to leverage the power of multiple transcriptomes reported by several laboratories using different patients and protocols, more sophisticated methods like the extension of GSEA presented here, should be used in order to overcome the shortcomings of overlapping individual DEG approach.

    View details for DOI 10.1371/journal.pone.0010247

    View details for Web of Science ID 000276854300011

    View details for PubMedID 20422035

    View details for PubMedCentralID PMC2857878

  • Atopic dermatitis keratinocytes exhibit normal T(H)17 cytokine responses JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Nograles, K. E., Suarez-Farinas, M., Shemer, A., Fuentes-Duculan, J., Chiricozzi, A., Cardinale, I., Zaba, L. C., Kikuchi, T., Ramon, M., Bergman, R., Krueger, J. G., Guttman-Yassky, E. 2010; 125 (3): 744-746

    View details for DOI 10.1016/j.jaci.2009.12.934

    View details for Web of Science ID 000275883200035

    View details for PubMedID 20226306

    View details for PubMedCentralID PMC4059394

  • Dendritic Cells in the Pathogenesis of Sarcoidosis AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY Zaba, L. C., Smith, G. P., Sanchez, M., Prystowsky, S. D. 2010; 42 (1): 32-39

    Abstract

    Sarcoidosis is a noncaseating granulomatous disease, likely of autoimmune etiology, that causes inflammation and tissue damage in multiple organs, most commonly the lung, but also skin, and lymph nodes. Reduced dendritic cell (DC) function in sarcoidosis peripheral blood compared with peripheral blood from control subjects suggests that blunted end organ cellular immunity may contribute to sarcoidosis pathogenesis. Successful treatment of sarcoidosis with tumor necrosis factor (TNF) inhibitors, which modulate DC maturation and migration, has also been reported. Together, these observations suggest that DCs may be important mediators of sarcoidosis immunology. This review focuses on the phenotype and function of DCs in the lung, skin, blood, and lymph node of patients with sarcoidosis. We conclude that DCs in end organs are phenotypically and functionally immature (anergic), while DCs in the lymph node are mature and polarize pathogenic Th1 T cells. The success of TNF inhibitors is thus likely secondary to inhibition of DC-mediated Th1 polarization in the lymph node.

    View details for DOI 10.1165/rcmb.2009-0033TR

    View details for Web of Science ID 000273204500006

    View details for PubMedID 19372243

    View details for PubMedCentralID PMC2809219

  • Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signaling, not immediate response TNF genes JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Zaba, L. C., Suarez-Farinas, M., Fuentes-Duculan, J., Nograles, K. E., Guttman-Yassky, E., Cardinale, I., Lowes, M. A., Krueger, J. G. 2009; 124 (5): 1022-1030

    Abstract

    TNF inhibitors have revolutionized the treatment of psoriasis vulgaris as well as psoriatic and rheumatoid arthritis and Crohn disease. Despite our understanding that these agents block TNF, their complex mechanism of action in disease resolution is still unclear.To analyze globally the genomic effects of TNF inhibition in patients with psoriasis, and to compare genomic profiles of patients who responded or did not respond to treatment.In a clinical trial using etanercept TNF inhibitor to treat psoriasis vulgaris (n = 15), Affymetrix gene arrays were used to analyze gene profiles in lesional skin at multiple time points during drug treatment (baseline and weeks 1, 2, 4, and 12) compared with nonlesional skin. Patients were stratified as responders (n = 11) or nonresponders (n = 4) on the basis of histologic disease resolution. Cluster analysis was used to define gene sets that were modulated with similar magnitude and velocity over time.In responders, 4 clusters of downregulated genes and 3 clusters of upregulated genes were identified. Genes downmodulated most rapidly reflected direct inhibition of myeloid lineage immune genes. Upregulated genes included the stable dendritic cell population genes CD1c and CD207 (langerin). Comparison of responders and nonresponders revealed rapid downmodulation of innate IL-1beta and IL-8 sepsis cascade cytokines in both groups, but only responders downregulated IL-17 pathway genes to baseline levels.Although both responders and nonresponders to etanercept inactivated sepsis cascade cytokines, response to etanercept is dependent on inactivation of myeloid dendritic cell genes and inactivation of the T(H)17 immune response.

    View details for DOI 10.1016/j.jaci.2009.08.046

    View details for Web of Science ID 000272108000023

    View details for PubMedID 19895991

    View details for PubMedCentralID PMC2852188

  • IL-22-producing "T22" T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing T(H)17 T cells JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Nograles, K. E., Zaba, L. C., Shemer, A., Fuentes-Duculan, J., Cardinale, I., Kikuchi, T., Ramon, M., Bergman, R., Krueger, J. G., Guttman-Yassky, E. 2009; 123 (6): 1244-1252

    Abstract

    Psoriasis and atopic dermatitis (AD) are common inflammatory skin diseases. An upregulated TH17/IL-23 pathway was demonstrated in psoriasis. Although potential involvement of TH17 T cells in AD was suggested during acute disease, the role of these cells in chronic AD remains unclear.To examine differences in IL-23/TH17 signal between these diseases and establish relative frequencies of T-cell subsets in AD.Skin biopsies and peripheral blood were collected from patients with chronic AD (n = 12) and psoriasis (n = 13). Relative frequencies of CD4+ and CD8+ T-cell subsets within these 2 compartments were examined by intracellular cytokine staining and flow cytometry.In peripheral blood, no significant difference was found in percentages of different T-cell subsets between these diseases. In contrast, psoriatic skin had significantly increased frequencies of TH1 and TH17 T cells compared with AD, whereas TH2 T cells were significantly elevated in AD. Distinct IL-22-producing CD4+ and CD8+ T-cell populations were significantly increased in AD skin compared with psoriasis. IL-22+CD8+ T-cell frequency correlated with AD disease severity.Our data established that T cells could independently express IL-22 even with low expression levels of IL-17. This argues for a functional specialization of T cells such that "T17" and "T22" T-cells may drive different features of epidermal pathology in inflammatory skin diseases, including induction of antimicrobial peptides for "T17" T cells and epidermal hyperplasia for "T22" T-cells. Given the clinical correlation with disease severity, further characterization of "T22" T cells is warranted, and may have future therapeutic implications.

    View details for DOI 10.1016/j.jaci.2009.03.041

    View details for Web of Science ID 000266799100013

    View details for PubMedID 19439349

    View details for PubMedCentralID PMC2874584

  • Resident and "Inflammatory'' Dendritic Cells in Human Skin JOURNAL OF INVESTIGATIVE DERMATOLOGY Zaba, L. C., Krueger, J. G., Lowes, M. A. 2009; 129 (2): 302-308

    Abstract

    Dendritic cells (DCs) are a heterogeneous group of antigen-presenting leukocytes that are important in activation of both the innate and adaptive arms of the immune system. Although there are several different DC populations in the body, DCs are globally defined by their capacity for potent antigen presentation and naive T-cell activation. In noninflamed human skin during steady state, there are three main cutaneous DC populations: epidermal Langerhans cells, dermal myeloid DCs, and dermal plasmacytoid DCs. In psoriasis, a model for cutaneous inflammation, there is an additional population of myeloid dermal DCs--"inflammatory DCs"--which appears to be critical for disease pathogenesis.

    View details for DOI 10.1038/jid.2008.225

    View details for Web of Science ID 000262655600007

    View details for PubMedID 18685620

    View details for PubMedCentralID PMC2746703

  • Psoriasis Is Characterized by Accumulation of Immunostimulatory and Th1/Th17 Cell-Polarizing Myeloid Dendritic Cells JOURNAL OF INVESTIGATIVE DERMATOLOGY Zaba, L. C., Fuentes-Duculan, J., Eungdamrong, N., Abello, M., Novitskaya, I., Pierson, K. C., Gonzalez, J., Krueger, J. G., Lowes, M. A. 2009; 129 (1): 79-88

    Abstract

    Myeloid dermal dendritic cells (DCs) accumulate in chronically inflamed tissues such as psoriasis. The importance of these cells for psoriasis pathogenesis is suggested by comparative T-cell and DC-cell counts, where DCs outnumber T cells. We have previously identified CD11c(+)-blood dendritic cell antigen (BDCA)-1(+) cells as the main resident dermal DC population found in normal skin. We now show that psoriatic lesional skin has two populations of dermal DCs: (1) CD11c(+)BDCA-1(+) cells, which are phenotypically similar to those contained in normal skin and (2) CD11c(+)BDCA-1(-) cells, which are phenotypically immature and produce inflammatory cytokines. Although BDCA-1(+) DCs are not increased in number in psoriatic lesional skin compared with normal skin, BDCA-1(-) DCs are increased 30-fold. For functional studies, we FACS-sorted psoriatic dermal single-cell suspensions to isolate these two cutaneous DC populations, and cultured them as stimulators in an allogeneic mixed leukocyte reaction. Both BDCA-1(+) and BDCA-1(-) myeloid dermal DC populations induced T-cell proliferation, and polarized T cells to become T helper 1 (Th1) and T helper 17 (Th17) cells. In addition, psoriatic dermal DCs induced a population of activated T cells that simultaneously produced IL-17 and IFN-gamma, which was not induced by normal skin dermal DCs. As psoriasis is believed to be a mixed Th17/Th1 disease, it is possible that induction of these IL-17(+)IFN-gamma(+) cells is pathogenic. These cytokines, the T cells that produce them, and the inducing inflammatory DCs may all be important new therapeutic targets in psoriasis.

    View details for DOI 10.1038/jid.2008.194

    View details for Web of Science ID 000261829100011

    View details for PubMedID 18633443

    View details for PubMedCentralID PMC2701224

  • Low Expression of the IL-23/Th17 Pathway in Atopic Dermatitis Compared to Psoriasis JOURNAL OF IMMUNOLOGY Guttman-Yassky, E., Lowes, M. A., Fuentes-Duculan, J., Zaba, L. C., Cardinale, I., Nograles, K. E., Khatcherian, A., Novitskaya, I., Carucci, J. A., Bergman, R., Krueger, J. G. 2008; 181 (10): 7420-7427

    Abstract

    The classical Th1/Th2 paradigm previously defining atopic dermatitis (AD) and psoriasis has recently been challenged with the discovery of Th17 T cells that synthesize IL-17 and IL-22. Although it is becoming evident that many Th1 diseases including psoriasis have a strong IL-17 signal, the importance of Th17 T cells in AD is still unclear. We examined and compared skin biopsies from AD and psoriasis patients by gene microarray, RT-PCR, immunohistochemistry, and immunofluorescence. We found a reduced genomic expression of IL-23, IL-17, and IFN-gamma in AD compared with psoriasis. To define the effects of IL-17 and IL-22 on keratinocytes, we performed gene array studies with cytokine-treated keratinocytes. We found lipocalin 2 and numerous other innate defense genes to be selectively induced in keratinocytes by IL-17. IFN-gamma had no effect on antimicrobial gene-expression in keratinocytes. In AD skin lesions, protein and mRNA expression of lipocalin 2 and other innate defense genes (hBD2, elafin, LL37) were reduced compared with psoriasis. Although AD has been framed by the Th1/Th2 paradigm as a Th2 polar disease, we present evidence that the IL-23/Th17 axis is largely absent, perhaps accounting for recurrent skin infections in this disease.

    View details for DOI 10.4049/jimmunol.181.10.7420

    View details for Web of Science ID 000260913900084

    View details for PubMedID 18981165

    View details for PubMedCentralID PMC3470474

  • Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways BRITISH JOURNAL OF DERMATOLOGY Nograles, K. E., Zaba, L. C., Guttman-Yassky, E., Fuentes-Duculan, J., Suarez-Farinas, M., Cardinale, I., Khatcherian, A., Gonzalez, J., Pierson, K. C., White, T. R., Pensabene, C., Coats, I., Novitskaya, I., Lowes, M. A., Krueger, J. G. 2008; 159 (5): 1092-1102

    Abstract

    Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines, yet the relative contribution of interferon (IFN)-gamma, interleukin (IL)-17 and IL-22 on disease pathogenesis is still unknown.In this study, we sought to identify the cytokines produced by skin-resident T cells in normal skin, localize the receptors for these cytokines, and examine how these cytokines alter gene expression profiles of the cells bearing cognate receptors.We used intracellular cytokine staining and flow cytometry to evaluate T cell cytokine production, and immunohistochemistry and double-label immunofluorescence to localize cytokine receptors in skin. Gene array analysis of cytokine-treated keratinocytes was performed using moderated paired t-test controlling for false discovery rate using the Benjamini-Hochberg procedure.We demonstrate that T-helper cells producing IL-17, IL-22 and/or IFN-gamma, as well as the cells bearing cognate cytokine receptors, are present in normal human skin. Keratinocytes stimulated with IL-17 expressed chemokines that were different from those induced by IFN-gamma, probably contributing to the influx of neutrophils, dendritic cells and memory T cells into the psoriatic lesion. In contrast, IL-22 downregulated genes associated with keratinocyte differentiation and caused epidermal alterations in an organotypic skin model.Our results suggest that the Th17 cytokines IL-17 and IL-22 mediate distinct downstream pathways that contribute to the psoriatic phenotype: IL-17 is more proinflammatory, while IL-22 retards keratinocyte differentiation.

    View details for DOI 10.1111/j.1365-2133.2008.08769.x

    View details for Web of Science ID 000260184200006

    View details for PubMedID 18684158

    View details for PubMedCentralID PMC2724264

  • Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells JOURNAL OF INVESTIGATIVE DERMATOLOGY Lowes, M. A., Kikuchi, T., Fuentes-Duculan, J., Cardinale, I., Zaba, L. C., Haider, A. S., Bowman, E. P., Krueger, J. G. 2008; 128 (5): 1207-1211

    Abstract

    The importance of T helper 17 (Th17) cells in inflammation and autoimmunity is now being appreciated. We analyzed psoriasis skin lesions and peripheral blood for the presence of IL-17-producing T cells. We localized Th17 cells predominantly to the dermis of psoriasis skin lesions, confirmed that IL-17 mRNA increased with disease activity, and demonstrated that IL-17 mRNA expression normalized with cyclosporine therapy. IL-22 mRNA expression mirrored IL-17 and both were downregulated in parallel with keratin 16. Th17 cells are a discrete population, separate from Th1 cells (which are also in psoriasis lesions), and Th2 cells. Our findings suggest that psoriasis is a mixed Th1 and Th17 inflammatory environment. Th17 cells may be proximal regulators of psoriatic skin inflammation, and warrant further attention as therapeutic targets.

    View details for DOI 10.1038/sj.jid.5701213

    View details for Web of Science ID 000255250400020

    View details for PubMedID 18200064

  • Identification of cellular pathways of "Type 1," Th17 T cells, and TNF- and inducible nitric oxide synthase-producing dendritic cells in autoimmune inflammation through pharmacogenomic study of cyclosporine a in psoriasis JOURNAL OF IMMUNOLOGY Haider, A. S., Lowes, M. A., Suarez-Farinas, M., Zaba, L. C., Cardinale, I., Khatcherian, A., Novitskaya, I., Wittkowski, K. M., Krueger, J. G. 2008; 180 (3): 1913-1920

    Abstract

    Therapeutic modulation of psoriasis with targeted immunosuppressive agents defines inflammatory genes associated with disease activity and may be extrapolated to a wide range of autoimmune diseases. Cyclosporine A (CSA) is considered a "gold standard" therapy for moderate-to-severe psoriasis. We conducted a clinical trial with CSA and analyzed the treatment outcome in blood and skin of 11 responding patients. In the skin, as expected, CSA modulated genes from activated T cells and the "type 1" pathway (p40, IFN-gamma, and STAT-1-regulated genes). However, CSA also modulated genes from the newly described Th17 pathway (IL-17, IL-22, and downstream genes S100A12, DEFB-2, IL-1beta, SEPRINB3, LCN2, and CCL20). CSA also affected dendritic cells, reducing TNF and inducible NO synthase (products of inflammatory TNF- and inducible NO synthase-producing dendritic cells), CD83, and IL-23p19. We detected 220 early response genes (day 14 posttreatment) that were down-regulated by CSA. We classified >95% into proinflammatory or skin resident cells. More myeloid-derived than activated T cell genes were modulated by CSA (54 myeloid genes compared with 11 lymphocyte genes), supporting the hypothesis that myeloid derived genes contribute to pathogenic inflammation in psoriasis. In circulating mononuclear leukocytes, in stark contrast, no inflammatory gene activity was detected. Thus, we have constructed a genomic signature of successful treatment of psoriasis which may serve as a reference to guide development of other new therapies. In addition, these data also identify new gene targets for therapeutic modulation and may be applied to wide range of autoimmune diseases.

    View details for DOI 10.4049/jimmunol.180.3.1913

    View details for Web of Science ID 000252632900068

    View details for PubMedID 18209089

  • Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses JOURNAL OF EXPERIMENTAL MEDICINE Zaba, L. C., Cardinale, I., Gilleaudeau, P., Sulhvan-Whalen, M., Suarez-Farinas, M., Fuentes-Duculan, J., Novitskaya, I., Khatcherian, A., Bluth, M. J., Lowes, M. A., Krueger, J. G. 2007; 204 (13): 3183-3194

    Abstract

    Biological agents have dramatically improved treatment options for patients with severe psoriasis. Etanercept (tumor necrosis factor [TNF] receptor-immunoglobulin fusion protein) is an effective treatment for many psoriasis patients, and blockade of TNF is considered to be its primary action. However, in this clinical trial, we show that etanercept has early inhibitory effects on a newly appreciated type of T cells: T helper type 17 (Th17) cells. Etanercept reduced the inflammatory dendritic cell products that drive Th17 cell proliferation (interleukin [IL] 23), as well as Th17 cell products and downstream effector molecules (IL-17, IL-22, CC chemokine ligand 20, and beta-defensin 4). In contrast, Th1 cellular products and effector molecules (interferon gamma, lymphotoxin alpha, and myxovirus resistance 1) were reduced late in disease resolution. This study suggests a role for Th17 in addition to Th1 cells in the pathogenesis of psoriasis. Th17 cells may be particularly important in driving epidermal activation in psoriatic plaques, whereas Th1 cells must also be eliminated for final disease resolution.

    View details for DOI 10.1084/jem.20071094

    View details for Web of Science ID 000252153100015

    View details for PubMedID 18039949

    View details for PubMedCentralID PMC2150965

  • Normal human dermis contains distinct populations of CD11c(+)BDCA-1(+) dendritic cells and CD163(+)FXIIIA(+) macrophages JOURNAL OF CLINICAL INVESTIGATION Zaba, L. C., Fuentes-Duculan, J., Steinman, R. M., Krueger, J. G., Lowes, M. A. 2007; 117 (9): 2517-2525

    Abstract

    We used a panel of monoclonal antibodies to characterize DCs in the dermis of normal human skin. Staining for the CD11c integrin, which is abundant on many kinds of DCs, revealed cells in the upper dermis. These cells were positive for blood DC antigen-1 (BDCA-1; also known as CD1c), HLA-DR, and CD45, markers that are also expressed by circulating myeloid DCs. A small subset of CD11c+ dermal cells expressed DEC-205/CD205 and DC-lysosomal-associated membrane glycoprotein/CD208 (DC-LAMP/CD208), suggesting some differentiation or maturation. When BDCA-1+ cells were selected from collagenase digests of normal dermis, they proved to be strong stimulators for T cells in a mixed leukocyte reaction. A second major population of cells located throughout the dermis was positive for factor XIIIA (FXIIIA), but lacked CD11c and BDCA-1. They expressed the macrophage scavenger receptor CD163 and stained weakly for HLA-DR and CD45. Isolated CD163+ dermal cells were inactive in stimulating T cell proliferation, but in biopsies of tattoos, these cells were selectively laden with granular pigments. Plasmacytoid DCs were also present in the dermis, marked by CD123 and BDCA-2. In summary, the normal dermis contains typical immunostimulatory myeloid DCs identified by CD11c and BDCA-1, as well as an additional population of poorly stimulatory macrophages marked by CD163 and FXIIIA.

    View details for DOI 10.1172/JCI32282

    View details for Web of Science ID 000249384600023

    View details for PubMedID 17786242

    View details for PubMedCentralID PMC1957542