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## Overview

#### NIH Distinguished Investigator

Mariana J. Kaplan, M.D.

mariana.kaplan@nih.gov

#### Research Areas (IRP Lab Groups)

Autoimmunity

Cell Biology

Clinical Research

Immunology

Molecular Biology and Biochemistry

Systems Biology

The broad and long-term objectives of the Systemic Autoimmunity Branch are to further the understanding of the pathophysiology and clinical spectrum of systemic autoimmune diseases and to translate this knowledge into better therapies that improve outcomes for patients with these conditions. A major goal of the branch is to combine natural history or treatment studies with basic investigations into the etiology and/or pathophysiology of rheumatic diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).

Additionally, the branch works to train the next generation of scientists and physician-scientists focused on the understanding of the pathogenesis and advancement in the treatments of patients afflicted by systemic autoimmune diseases.

Our research focuses on unraveling fundamental mechanisms underlying immunologic tolerance and understanding innate and adaptive immune pathways crucial to these autoimmune responses in SLE and other autoimmune diseases.

As treatments to suppress aberrant immune responses improve, patients with systemic autoimmunity are able to survive for longer periods of time. As a result, the prevalence of end-stage complications, including the development of accelerated atherosclerosis and myocardial infarction, has increased. We are interested in identifying the immune pathways that promote premature vascular damage in systemic autoimmunity to identify potential preventive strategies.

### Current areas of interest

                          - The role of neutrophils and neutrophil extracellular traps (NETs) in the induction of loss of immunologic tolerance and acceleration of organ and vascular damage in autoimmune diseases.
                          - How type I Interferons (IFNs) contribute to the development of premature atherogenesis and vasculopathy in SLE and other connective tissue diseases.
                          - Alterations of immunometabolism in autoimmunity.
                          - The identification of novel biomarkers and therapeutic targets to mitigate cardiovascular damage and induce immunomodulation in SLE and other systemic rheumatic diseases.

#### Contact Us

Jazmon McNair

                    Bethesda                                MD                                20892            

jazmon.mcnair@nih.gov

#### Related NIAMS Labs

                                    - Functional Immunogenomics Section
                                    - Lupus Clinical Trials Unit
                                    - Lupus Genomics and Global Health Disparities Unit
                                    - Vasculitis Translational Research Program

#### Scientific Advances

September 23, 2023

Neutrophil Extracellular Traps (NETs) Trigger Pathogenic Inflammation and Bone Loss in Periodontitis

February 3, 2023

Role of Neutrophil Extracellular Traps (NETs) in Accelerated Bone Erosion and Osteoclast Formation in Rheumatoid Arthritis

January 4, 2023

Spleen Tyrosine Kinase Inhibition Improves Disease Outcome in Severe COVID-19 Patients

August 22, 2022

Multicenter Analysis of Neutrophil Extracellular Trap Dysregulation in Adult and Pediatric COVID-19

July 6, 2022

Itaconic Acid Derivative Is Effective in Keeping Established Murine Lupus Under Control

March 1, 2022

Boosting NAD Metabolism Is Involved in Monocytes IFN Type I Proinflammatory Responses

July 14, 2020

Sex differences in neutrophil biology affect response to type I interferons and cellular metabolism

#### Core Research Facilities

Labs at the NIAMS are supported by the following state-of-the-art facilities and services:
                                        - Biodata Mining and Discovery
                                        - Flow Cytometry
                                        - Genomic Technology
                                        - Laboratory Animal Care and Use
                                        - Light Imaging
                                        - Translational Immunology

## Staff

**Mariana J. Kaplan, M.D.**

mariana.kaplan@nih.gov

**Luz P. Blanco, Ph.D.**

luz.blanco@nih.gov

**Carmelo Carmona-Rivera, Ph.D.**

carmelo.carmona-rivera@nih.gov

**William Ambler, M.D.**

amblerwg@nih.gov

**Norio Hanata, M.D., Ph.D.**

norio.hanata@nih.gov

**Jazmon McNair**

jazmon.mcnair@nih.gov

**Michael Muchow, Ph.D.**

michael.muchow@nih.gov

**Shuichiro Nakabo, M.D., Ph.D.**

shuichiro.nakabo@nih.gov

**Eduardo Patino-Martinez, Ph.D.**

eduardo.patinomartinez@nih.gov

**Jorge Romo-Tena, M.D., Ph.D.**

jorge.romotena2@nih.gov

**Alexandra Woo, B.S.**

wooall@nih.gov

**‌ **

Our lab is always seeking to recruit the best talent in the scientific community. If you are interested in joining our team, please contact us.

## Former Lab Members

### Postdoctoral Students and Scholars

                            - Hege Lynum Pedersen, Ph.D., 2018-2019 (Research Scientist, UiT The Artic University of Norway, Tromso, Norway)
                            - Jose Jiram Torres-Ruiz, M.D., 2018 (Ph.D. student, UNAM, Mexico City)
                            - Liam O’Neill, M.D., 2017-2019 (Rheumatologist and Clinician-Scientist, University of Manitoba, Canada)
                            - Yaima Lightfoot, Ph.D., 2015-2017 (Research Scientist, MD Anderson Cancer Center)
                            - Yudong Liu, M.D., Ph.D., 2015-2018 (Attending Physician, Peking University, China)
                            - Pragnesh Mistry, Ph.D., 2015-2018 (Technology Transfer and Patent Specialist, NHLBI, NIH)
                            - John Reynolds, MRCP, Ph.D., 2014 (Clinical Senior Lecturer in Rheumatology, University of Birmingham, UK)
                            - Ana Barrera, M.D., 2014-2016 (Attending Physician, Hospital ABC, Mexico City)

### Postbaccalaureate Students

                            - Donavon Sandoval-Heglund, B.S., 2019-2020
                            - Xinghao Wang, B.S., 2018-2021 (M.D., Ph.D. student, University of Michigan)
                            - Rishi Goel, Sc.M., since 2018 (M.D. student, University of Pennsylvania)
                            - Phillip Carlucci, B.S., 2016-2018 (M.D. student, NYU)
                            - Diana Chan, B.S., 2016-2018 (D.D.S. student, University of Washington)
                            - Nickie Seto, B.S., 2015-2018
                            - Erica Moore, B.S., 2014-2016 (M.D., Ph.D. student, Albert Einstein College of Medicine)
                            - Jorge Irizarry Caro, 2014-2016 (Internal Medicine Resident, UT Houston)
                            - Monica Purmalek, B.A., 2014-2016 (Resident in Obstetrics and Gynecology, USUHS)

### Graduate Students

                            - Kathleen Bashant, Ph.D., Cambridge/NIH partnership, 2016-2020 (Research Scientist, Vow, Sydney, Australia)
                            - Carolyne Smith, Ph.D., University of Michigan GPP program, 2010-2015 (Scientist, SQZ Biotechnologies)

### Clinical Fellows

                            - Kathleen Vazzana, M.D., 2019-2021 (Practicing Pediatric Rheumatology at Orlando Health Arnold Palmer Hospital for Children)

## Image & Media Gallery

##### In the Lab with NIAMS: Mariana Kaplan, M.D., Senior Investigator

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Dr. Mariana Kaplan, M.D., describes her motivation to study lupus, and the role of neutrophils in this disease. Dr. Kaplan is chief of the Systemic Autoimmunity Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, on the National Institutes of Health campus in Bethesda, MD.

##### Systemic Autoimmunity Branch and Lupus Clinical Trials Unit

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Download High Res(8.09 MB)

##### Systemic Autoimmunity Branch group photo 

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Download High Res(12.38 MB)

##### Granulocytes

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NET formation in low density granulocytes detectedï¿1⁄2by laser confocal microscopy immunofluorescence using human anti neutrophil elastase antibody and Hoechst. A color-coded depth analysis of the immunofluorescence of netting LDGs is displayed.

##### Neutrophil Extracellular Traps

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Neutrophil extracellular traps (NETs) in neutrophils isolated from a patient with rheumatoid arthritis, following stimulation with recombinant IL-17A in vitro. Exuberant NET formation is observed, characterized by long strands of DNA (blue) decorated with the granular protein, neutrophil elastase (red).

## Clinical Trials

Recruiting

### The Natural History of Coronavirus Disease (COVID-19) in Systemic Autoimmune Diseases; An Observational Prospective Study

ClinicalTrials.gov Identifier: NCT04690816 

This is an observational study to characterize how COVID-19 modulates systemic inflammation, autoimmune features and vasculopathy in adult and pediatric patients with a prior diagnosis of systemic autoimmunity, and their overall outcomes including response to potential antiviral treatments or vaccines.

Recruiting

### The Role of Anifrolumab in Improving Markers of Vascular Risk in Patients With Systemic Lupus Erythematosus

ClinicalTrials.gov Identifier: NCT05440422 

This is a double blind placebo-controlled study to characterize whether blocking type I IFN receptor signaling with anifrolumab will lead to improvements in vascular function, decreases in vascular inflammation and modulation of biomarkers of vascular risk in patients with systemic lupus erythematosus (SLE).

Active, not recruiting

### The Role of PPAR-Gamma Agonists in Immunomodulation and Vascular Prevention in SLE (PPAR-SLE)

ClinicalTrials.gov Identifier: NCT02338999

Lupus causes a person's immune system to attack the body. It can cause blood vessel problems, heart attack, or stroke. Researchers want to see if the drug pioglitazone may help and to see how well pioglitazone improves blood vessel function and decreases blood vessel inflammation. To study its effect on lupus symptoms.

## Scientific Publications

## Selected Recent Publications

###             Neutrophil extracellular traps and extracellular histones potentiate IL-17 inflammation in periodontitis.        

220(9).

###             Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome.        

14(1).

###             Apoptosis-induced nuclear expulsion in tumor cells drives S100a4-mediated metastatic outgrowth through the RAGE pathway.        

4(3).

###             Neutrophil extracellular trap-associated carbamylation and histones trigger osteoclast formation in rheumatoid arthritis.        

82(5).

###             Distinct pathogenic roles for resident and monocyte-derived macrophages in lupus nephritis.        

7(21).

###             Low-density granulocytes in systemic autoimmunity and autoinflammation.        

314(1).

###             Neutrophil extracellular traps in systemic autoimmune and autoinflammatory diseases.        

23(5).

###             Casting a Wide NET.        

209(5).

###             Peroxisome proliferator activated receptor-γ agonist pioglitazone improves vascular and metabolic dysfunction in systemic lupus erythematosus.        

81(11).

###             Single-Cell Analysis Reveals the Range of Transcriptional States of Circulating Human Neutrophils.        

209(4).

###             Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19.        

7(16).

###             Modulation of the Itaconate Pathway Attenuates Murine Lupus.        

74(12).

###             Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19.        

7(16).

###             Boosting NAD+ blunts TLR4-induced type I IFN in control and systemic lupus erythematosus monocytes.        

132(5).

###             Mitochondria shape neutrophils during hypoxia.        

139(2).

###             Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus.        

12(1).

###             Patients with COVID-19: in the dark-NETs of neutrophils.        

28(11).

###             Cholesterol-Induced M4-Like Macrophages Recruit Neutrophils and Induce NETosis.        

12().

###             RNA Externalized by Neutrophil Extracellular Traps Promotes Inflammatory Pathways in Endothelial Cells.        

73(12).

###             Linking clotting and autoimmunity.        

371(6534).

###             Bite of the wolf: innate immune responses propagate autoimmunity in lupus.        

131(3).

###             Proteomic, biomechanical and functional analyses define neutrophil heterogeneity in systemic lupus erythematosus.        

80(2).

###             Effects of Gasdermin D in Modulating Murine Lupus and its Associated Organ Damage.        

72(12).

###             Interferon lambda promotes immune dysregulation and tissue inflammation in TLR7-induced lupus.        

117(10).

## Key Publications

###             Modulation of cardiometabolic disease markers by type I interferon inhibition in systemic lupus erythematosus.        

###             Sex differences in neutrophil biology modulate response to type I interferons and immunometabolism.        

117(28).

###             VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease.        

366(6472).

###             Transcriptomic, epigenetic, and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus.        

116(50).

###             Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis.        

2(10).

###             Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease.        

22(2).

###             Deficiency of adenosine deaminase 2 triggers adenosine-mediated NETosis and TNF production in patients with DADA2.        

134(4).

###             Peptidylarginine deiminases 2 and 4 modulate innate and adaptive immune responses in TLR-7-dependent lupus.        

3(23).

###             Revealing the cellular degradome by mass spectrometry analysis of proteasome-cleaved peptides.        

###             Dysregulated neutrophil responses and neutrophil extracellular trap formation and degradation in PAPA syndrome.        

77(12).

###             Neutrophil subsets and their gene signature associate with vascular inflammation and coronary atherosclerosis in lupus.        

3(8).

###             Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis.        

2(10).

###             A role for muscarinic receptors in neutrophil extracellular trap formation and levamisole-induced autoimmunity.        

2(3).

###             Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease.        

22(2).

###             NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis.        

5(178).

###             CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus.        

127(4).

See all Publications on PubMed

## News & Highlights

Announcement | December 7, 2023

### NIAMS’ Mariana Kaplan Named NIH Distinguished Investigator

Read More

Announcement | April 12, 2023

### NIH and NIAMS Host Visit From White House COVID-19 Response Coordinator 

Read More

NIAMS-Related Article | July 18, 2022

### A Biological Betrayal

Read More

NIH News in Health | June 6, 2022

### Understanding Autoimmune Diseases

Read More

Spotlight on Research | November 23, 2021

### New treatment shows promise in reducing the risk of cardiovascular disease in people with lupus

Read More

Featured | March 17, 2021

### Dr. Kaplan Receives GPP Outstanding Mentor Award

Read More

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