Bottini Lab

Bottini Lab

"We focus on genes that control biochemical signaling inside immune cells and are involved in rheumatoid arthritis, juvenile diabetes, scleroderma and other autoimmune diseases. We try to understand how these genes work in order to identify new ways to treat autoimmune diseases." — Nunzio Bottini, M.D., Ph.D. // Associate Professor
Division of Cellular Biology

Overview

The Bottini laboratory studies the mechanism of action of signaling molecules encoded by human autoimmune disease-predisposing genes and also analyzes signal transduction pathways in pathological specimens from patients. The goal is to dissect relevant intracellular pathways to design new methods for disease activity monitoring and to identify new treatment strategies. The laboratory specializes in the study of a family of signaling enzymes called protein tyrosine phosphatases, which regulates phosphorylation of proteins on tyrosine residues.

The first focus of the laboratory is on phosphatase genes that increase risk of autoimmune disease. Dr. Bottini was the first to report that a mutation in the PTPN22 gene, encoding a phosphatase, increases the risk of autoimmunity in humans. Currently PTPN22 is ranked as a major gene for rheumatoid arthritis, juvenile diabetes, and lupus. Dr. Bottini’s laboratory is focused on understanding the mechanism of action and regulation of PTPN22 with the goal to develop personalized ways to treat disease in carriers of autoimmune-predisposing gene variants.

A second focus of the laboratory is on studying biochemical signaling (focusing in particular on the role of phosphatases) in tissue resident cells in arthritis, scleroderma and other autoimmune diseases. The goal is to develop ways to inhibit the disease promoting action of these cells to help control disease activity without depressing the ability of the immune system to fight against infections and tumors.

From The Lab

Jan 20, 2016 // PR Newswire

Harrington Discovery Institute at University Hospitals announces 2016 grant funding to 10 physician-scientists

Jan 14, 2016 // Crains Cleveland Business

UH Harrington Discovery Institute awards grant funding to 10 physician-scientists

Jan 13, 2016 // Harrington Discovery Institute

Harrington Discovery Institute at University Hospitals announces 2016 grant funding to 10 physician-scientists

May 20, 2015

Potential new drug target for the treatment of rheumatoid arthritis

Mar 20, 2015

La Jolla Institute scientists reveal potential new drug target for the treatment of rheumatoid arthritis

Bottini Lab

Publications

Nanomedicine

Nanodrugs to target articular cartilage: an emerging platform for osteroarthritis therapy

2016-02
Bottini M, Bhattacharya K, Fadeel B, Magrini A, Bottini N, Rosato N
Arthritis Rheumatol

Receptor protein tyrosine phosphatase alpha enhances rheumatoid synovial fibroblast signaling and promotes srthritis in mice

2016-02
Stanford SM, Svensson MN, Sacchetti C, Pilo CA, Wu DJ, Kiosses WB, Hellvard A, Bergum B, Aleman Muench GR, Elly C, Liu…
J Clin Invest

Chondrocyte clocks make cartilage time-sensitive material

2016-01
Doody KM, Bottini N
Ann Rheum Dis

TGF_ responsive tyrosine phosphatase promotes rheumatoid Synovial fibroblast invasiveness

2016-01
Stanford SM, Aleman Muench GR, Bartok B, Sacchetti C, Kiosses WB, Sharma J, Maestre MF, Bottini M, Mustelin T, Boyle…
Nature Reviews Rheumatology

Decade in review-translational rheumatology: ten years after: rheumatology research from bench to bedside

2015-11
Bottini N, Firestein GS
Journal of Immunology

Ptpn22 and Cd2 variations are associated with altered protein expression and susceptibility to type 1 diabetes in nonobese diabetic mice

2015-11
Fraser HI, Howlett S, Clark J, Rainbow DB, Stanford SM, Wu DJ, Hsieh YW, Maine CJ, Christensen M, Kuchroo V, Sherman…
PLoS One

Phosphatase inhibitors function as novel, broad spectrum botulinum neurotoxin antagonists in mouse and human embryonic stem cell-derived motor neuron-based assays

2015-06
Kiris E, Nuss JE, Stanford SM, Wanner LM, Cazares L, Maestre MF, Du HT, Gomba GY, Burnett JC, Fussio R, Bottini N,…
Science Translational Medicine

Targeting phosphatase-dependent proteoglycan switch for rheumatoid arthritis therapy

2015-05
Doody KM, Stanford SM, Sacchetti C, D Svensson MN, Coles CH, Mitakidis N, Kiosses WB, Bartok B, Fos C, Cory E, Sah RL,…
N/A

Allosteric small molecule inhibitors of LMPTP

2015-01
Ardecky RJ, Hedrick MP, Stanford SM, Bliss MR, Zou J, Gosalia P, Yamamoto F, Milewski M, Barron N, Sun Q, Ganji S,…
ACS Nano

Polyethylene-glycol-modified single-walled carbon nanotubes for intra-articular delivery to chondrocytes

2014-12
Sacchetti C, Liu-Bryan R, Magrini A, Rosato N, Bottini N, Bottini M
Clinical and Experimental Immunology

The protein tyrosine phosphatase PTPN22 controls FOXP3 regulatory T cell induction but is dispensable for Th1 cell polarization

2014-10
Fousteri G, Jofra T, Debernardis I, Stanford SM, Laurenzi A, Bottini N, Battaglia M
Nature Reviews Rheumatology

PTPN22: the archetypal non-HLA autoimmunity gene

2014-10
Stanford SM, Bottini N
Journal of Clinical Investigation

Ion channel TRPV1-dependent activation of PTP1B suppresses EGFR-associated intestinal tumorigenesis

2014-09
de Jong PR, Takahashi N, Harris AR, Lee J, Bertin S, Jeffries J, Jung M, Duong J, Triano AI, Lee J, Niv Y, Herdman DS,…
Cell Research

PEST control: regulation of molecular barcodes by tyrosine phosphatases

2014-09
Doody KM, Bottini N
Annual Review of Immunology

Tyrosine phosphatase PTPN22: multifuctional regulator of immune signaling, development, and disease

2014-03
Bottini N, Peterson EJ
Antioxidants & Redox Signaling

Cellular biochemistry methods for investigating protein tyrosine phosphatases

2014-03
Stanford SM, Ahmed V, Barrios AM, Bottini N
ChemMedChem

Covalent inhibition of the lymphoid tyrosine phosphatase

2014-02
Ahmed VF, Bottini N, Barrios AM
PLoS One

Autoimmunity-associated LYP-W620 does not impair thymic negative selection of autoreactive T cells

2014-02
Wu DJ, Zhou W, Enouz S, Orrú V, Stanford SM, Maine CJ, Rapini N, Sawatzke K, Engel I, Fiorillo E, Sherman LA,…
Journal of Nanoscience and Nanotechnology

Targeted nanodrugs for cancer therapy:prospects and challenges

2014-01
Bottini M, Sacchetti C, Pietroiusti A, Bellucci S, Magrini A, Rosato N, Bottini N
Methods

pCAP-based peptide substrates: the new tool in the box of tyrosine phosphatase assays

2014-01
Stanford SM, Krishnamurthy D, Kulkarni RA, Karver CE, Bruenger E, Walker LM, Ma CT, Shung TD, Sergienko E, Bottini N,…
Current Rheumatology Reports

Epigenetics in rheumatoid arthritis: a primer for rheumatologists

2013-11
Bottini N, Firestein GS
ChemMedChem

Thiuram disulfides as pseudo-irreversible inhibitors of lymphoid tyrosine phosphatase

2013-09
Kulkarni RA, Stanford SM, Vellore NA, Krishnamurthy D, Bliss MR, Baron R, Bottini N, Barrios AM
ChemBioChem

Substrate selection influences molecular recognition in a screen for lymphoid tyrosine phosphatase inhibitors

2013-09
Kulkarni RA, Vellore NA, Bliss MR, Stanford SM, Falk MD, Bottini N, Baron R, Barrios AM
Immunity

The autoimmunity-associated gene PTPN22 potentiates toll-like receptor-driven, type 1 interferon-dependent immunigy

2013-07
Wang Y, Stanford SM, Zhou W, Curtsinger JM, Mikulski Z, Shaheen ZR, Cheng G, Sawatzke K, Campbell AM, Auger JL, Bilgic…
Journal of Medicinal Chemistry

A potent and selective small-molecure inhibitor for the lymphoid-specific tyrosine phosphatase (LYP), a target associated with autoimmune diseases

2013-06
He Y, Liu S, Menon A, Stanford S, Oppong E, Gunawan AM, Wu L, Wu DJ, Barrios AM, Bottini N, Cato AC, Zhang ZY
Bioconjugate Chemistry

In vivo targeting on intratumor regulatory T cells using PEG-modified single-walled carbon nanotubes

2013-06
Sacchetti C, Rapini N, Magrini A, Cirelli E, Bellucci S, Mattei M, Rosato N, Bottini N, Bottini M
Arthritis and Rheumatism

Protein tyrosine phosphatase expression profile of rheumatoid arthritis fibroblast-like synoviocytes: a novel role of SH2 domain-containing phosphatase 2 as a modulator of invasion and usrvival

2013-05
Stanford SM, Maestre MF, Campbell AM, Bartok B, Kiosses WB, Boyle DL, Arnett HA, Mustelin T, Firestein GS, Bottini N
ACS Nano

Surface polyethylene glycol conformation influences the protein corona of polyethylene glycol-modified single-walled carbon nanotubes: potential implications on biological performance

2013-03
Sacchetti C, Motamedchaboki K, Magrini A, Palmieri G, Mattel M, Bernardini S, Rosato N, Bottini N, Bottini M
Nature Reviews Rheumatology

Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors

2012-11
Bottini N, Firestein GS
Immunology

Regulation of TCR signalling by tyrosine phosphatases: from immune homeostasis to autoimmunity

2012-09
Stanford SM, Rapini N, Bottini N
Proceedings of the National Academy of Sciences of the United States of America

High-throughput screen using a single-cell tyrosine phosphatase assay reveals biologically active inhibitors of tyrosine phosphatase CD45

2012-08
Stanford SM, Panchal RG, Walker LM, Wu DJ, Falk MD, Mitra S, Damle SS, Ruble D, Kalcheva T, Zhang S, Zhang ZY, Bavari…
Journal of Immunology

PTPN22 alters the development of regulatory T cells in the thymus

2012-06
Maine CJ, Hamilton-Williams EE, Cheung J, Stanford SM, Bottini N, Wicker LS, Sherman LA
Human Immunology

Novel association of acid phosphatase locus1*C allele with systemic lupus erythematosus

2012-01
Teruel M, Martin JE, Ortego-Centeno N, Jimenez-Alonso J, Sanchez-Roman J, de Ramon E, Gonzalez-Escribano MF, Pons-Estel…
Inflammatory Bowel Diseases

Differential association of two PTPN22 coding variants with Crohn's disease and ulcerative colitis

2011-11
Diaz-Gallo LM, Expino-Paisan L, Fransen K, Gomez-Garcia M, van Sommersen S, Cardena C, Rodrigo L, Mendoza JL, Taxonera…
Biomacromolecules

PEG-modified carbon nanatubes in biomedicine: current status and challenges ahead

2011-10
Bottini M, Rosato N, Bottini N
Arthritis Research & Therapy

Association of acid phosphatase locus 1*C allele with the risk of cardiovascular events in rheumatoid arthritis patients

2011-07
Teruel M, Martin JE, Gonzalez-Juanatey C, Lopez-Mejias R, Miranda-Filloy JA, Blanco R, Balsa A, Pascual-Salcedo D,…
Journal of Medicinal Chemistry

Discovery of a novel series of inhibitors of lymphoid tyrosine phosphatase with activity in human T cells

2011-03
Stanford SM, Krishnamurthy D, Falk MN, Messina R, Debnath B, Li S, Liu T, Kazemi R, Dahl R, He YT, Yu XA, Chan AC,…
Arthritis and Rheumatism

The PTPN22 R236Q polymorphism is a risk factor for rheumatoid arthritis in caucasis case-control samples

2011-02
Rodriguez-Rodriguez L, Taib WRW, Topless R, Steer S, Gonzalez-Escribano MF, Balsa A, Pascual-Salcedo D, Gonzalez-Gay…

Principal Investigator

bottini

Nunzio Bottini, M.D., Ph.D.

Associate Professor

Nunzio Bottini, M.D., Ph.D. is a scientist in the La Jolla Institute Division of Cellular Biology and the Type 1 Diabetes Research Center. Dr. Bottini joined the La Jolla Institute from the USC Keck School of Medicine in 2009. Dr. Bottini is interested in the genetics of autoimmune diseases, and in the role of molecules called phosphatases in signal transduction.

Dr. Bottini received his M.D. in 1996 from the University of Rome, where he also obtained his Ph.D. and completed his internship and residency. He received postdoctoral research training in biochemistry and signal transduction at the Sanford-Burnham Medical Research Institute in La Jolla, and completed a clinical fellowship in Rheumatology at the University of California San Diego. Dr. Bottini also holds an appointment as an Associate Professor of Medicine and consulting physician in the Division of Rheumatology, Allergy and Immunology of the University of California San Diego.

Dr. Bottini serves on grant review panels for the NIH, the Rheumatology Research Foundation, the Arthritis Foundation, the JDRF and several other groups and also is a reviewer for various scientific journals. At the USC School of Medicine he was an Assistant Professor in the Institute for Genetic Medicine. Previously, he served as an Assistant Professor of Medicine at the University of Rome in Italy.

Lab Members

Alex Funderburk, B.S

Technician

Biosketch: I graduated with High Honors from the University of California, Davis with a Bachelor’s degree in Biochemistry and Molecular Biology. I joined the Bottini laboratory in 2014 as a Research Technician.

Research Focus: I am currently involved in two research projects focused on the role of protein tyrosine phosphatases in systemic sclerosis and working to develop a cell-based assay to determine the functional effect of disease-associated genetic polymorphisms.

Career Goals: I aim to become a scientific researcher involved in the study of human diseases with a focus on treatment and drug development.

Nathaniel Harder, B.S.

Technician

Biosketch: I graduated from the University of California, Davis in 2015 with a Bachelor’s Degree in Biochemistry and Molecular Biology. I joined the Bottini lab in September 2015 as a Research Technician.

Research Focus: I am currently investigating the ties between protein tyrosine phosphatases and their roles in post-translational amino acid modifications, specifically in respect to how these modifications are involved in the exacerbation of rheumatoid arthritis.

Career Goals: My goal is to pursue a Ph.D. in Chemistry and to pursue a career in research with an emphasis on macromolecular structures.

Christian Maine

Visiting Scientist

An Chi Mei

Postdoctoral Fellow

Caila Pilo, B.S.

Technician

Biosketch: I graduated from the University of California, Davis in 2013 with a Bachelor’s Degree in Biochemistry and Molecular Biology. I joined the Bottini lab in December 2014 as a Research Technician. My research background includes work with double strand break repair in DNA at UC Davis and with the role of T cells in the epidermis at The Scripps Research Institute.

Research Focus: My current project focuses on protein tyrosine phosphatases and their roles in signal cascades within synovial fibroblasts, particularly in rheumatoid arthritis.

Career Goals: My goal is to pursue a Ph.D. in either Biochemistry or Immunology. I then hope to pursue a career in research with an emphasis on the discovery of new targets and treatments for autoimmune diseases.

Michelle Le Roux

Cristiano Sacchetti, Ph.D.

Postdoctoral fellow

Biosketch: I obtained my M.S. degree cum laudae in Medical Biotechnology in 2007 and a Ph.D. in Molecular Medicine in 2011 from the University of Rome Tor Vergata (Rome, Italy). Between 2011 and 2013 I trained as a postdoctoral fellow in the nanomedicine group of Dr. Massimo Bottini at the University of Rome Tor Vergata and the Sanford-Burnham Medical Research Institute (La Jolla, CA). I joined the Bottini laboratory as a post-doctoral fellow in January 2014.

Research Focus: My research is focused on the role of tyrosine phosphorylation and tyrosine phosphatases in the pathogenic action of scleroderma fibroblasts.

Career Goals: My goal is to become an independent research investigator applying my expertise to developing new drugs for the treatment of scleroderma and other autoimmune diseases.

Eugenio Santelli, Ph.D.

Scientific Associate

Biosketch: I obtained an M.S. degree in Industrial Chemistry from the University of Milan in 1993 and a Ph.D. in Structural Biology from the ETH Zurich in 2000. Subsequently, I moved to the Sanford-Burnham Medical Research Institute initially as a postdoc, then as a Staff Scientist, and joined the Bottini lab at La Jolla Institute for Allergy and Immunology as a Scientific Associate in 2015.

Research Focus: I am currently focusing on the biophysical and biochemical side of several multidisciplinary efforts aimed at understanding and/or modulating the function of medically relevant protein tyrosine phosphatases in the immune system and in fibroblast-like synoviocytes.

Career Goals: I plan to further develop my career towards the applied biological sciences.

Christian Secchi, Ph.D.

Postdoctoral fellow

Biosketch: I obtained my M.S. degree cum laude in Molecular Biotechnology in 2009 from the University of Sassari, Italy. I then completed my Ph.D. in Clinical Proteomics with a thesis entitled “Role of Syk in tyrosine phosphorylation changes associated with redox signaling in T cells ” in the laboratory of Dr. Francesco Turrini at the University of Verona in 2014. During my Ph.D. training I worked in Dr. Elizabeth Komives’s Lab at UCSD as a visiting graduate student. I joined the Bottini laboratory in August 2015.

Research Focus: My research projects investigate protein tyrosine phosphatase (PTP) activity in chronic diseases using in vitro and in vivo models. I am particularly interested in the development of PTP-based drugs for the treatment of common autoimmune diseases such as rheumatoid arthritis.

Career Goals: My goal is to become an independent researcher focused on the development of innovative autoimmune disease treatments.

stanford

Stephanie Stanford, Ph.D.

Instructor

Biosketch: I graduated from Azusa Pacific University in 2005 with a B.S. degree in Chemistry. I then obtained my Ph.D. in Genetic, Molecular and Cellular Biology from the University of Southern California in 2010. I began working as a postdoc in the Bottini laboratory at the La Jolla Institute for Allergy and Immunology in April 2010 and was promoted to the Instructor position in July 2014.

Research Focus: My research projects are focused on the roles of protein tyrosine phosphatases (PTPs) in diabetes and rheumatoid arthritis. I am interested in understanding how genetic polymorphisms in genes encoding PTPs can mediate disease pathogenesis, and in defining new drug targets for immune-mediated diseases among the PTPome.

Career Goals: I plan to pursue a career in scientific research focused on signaling molecules involved in human disease.

Mattias Svensson, Ph.D.

Postdoctoral fellow

Biosketch: In 2009 I obtained my M.Sc. in pharmacy from the University of Gothenburg in Sweden. Later in February 2014 I completed my PhD in the group of Dr. Maria Bokarewa at the University of Gothenburg (Gothenburg, Sweden) with a thesis entitled “Tyrosine kinase Flt3/Flt3-ligand signaling in the modulation of immune responses in experimental arthritis”. I joined the Bottini laboratory as a post-doctoral fellow in March 2014.

Research Focus: My research focuses on the involvement of protein tyrosine phosphatases (PTPs) in rheumatoid arthritis. With the use of animal models my focus is to better understand how PTPs influence susceptibility and development of rheumatoid arthritis.

Career Goals: My goal is to become an independent researcher focusing on mechanisms that underlie autoimmune diseases and through my research help to better understand what makes some people susceptible to autoimmunity.

Kuninobu Wakabayashi, M.D., Ph.D.

Visiting Scientist

Biosketch: I graduated from Showa University School of Medicine (Tokyo, Japan) in 2004. I then obtained my Ph.D. in Medical Science in 2012. I practiced as a rheumatologist in Showa University Hospital. I joined the Bottini laboratory as a Visiting Scientist in February 2015.

Research Focus: My research project focuses on protein tyrosine phosphatases (PTPs) in synoviocytes of patients with rheumatoid arthritis.

Career Goals: My goal is to investigate the mechanisms of rheumatic diseases as an independent research investigator, and through my research contribute to connect basic understandings to clinical findings and improve therapies for patients.

Vida Zhang, B.S.

Technician

Biosketch: I graduated from the University of California, Berkeley with a Bachelor’s Degree in Molecular and Cell Biology and a minor in Classics. I joined the Bottini laboratory in 2014 as a Research Technician.

Research Focus: I am researching the role of protein tyrosine phosphatases in diabetes and metabolic syndrome in order to identify potential new therapeutic targets for these disorders.

Career Goals: My goal is to attend medical school and pursue a career studying human diseases and treatments.

Bottini Lab

Research Projects

The Bottini laboratory at LJI studies intracellular signaling pathways in cell types involved in human autoimmune connective tissue diseases, with particular emphasis on rheumatoid arthritis and systemic sclerosis. The laboratory studies the mechanism of action of signaling molecules encoded by human disease-predisposing genes and also analyzes signal transduction pathways in pathological specimens from patients. The goal is to dissect relevant intracellular pathways to design new methods for disease activity monitoring and to identify new treatment strategies.

The laboratory specializes in the study of a family of signaling enzymes called protein tyrosine phosphatases, which regulates phosphorylation of proteins on tyrosine residues.

The laboratory strongly emphasizes translational "bed to bench to bedside" research and collaborations with pharmaceutical companies are routinely sought to accelerate translation of laboratory findings into the clinic.

GENETICS OF AUTOIMMUNE DISEASES

WHY we work in this area

Autoimmune diseases are caused by a complex combination of genetic and environmental factors. For example, genetic studies in the past 15 years have identified almost 100 different relevant genes for rheumatoid arthritis (see this recent review http://www.ncbi.nlm.nih.gov/pubmed/24276088). A major problem is that the mechanism of action of most of these genes in human autoimmunity is currently unknown. Understanding the effect of disease-associated genetic variations on gene function is important because it might pave the way to targeting these genes or other components of the pathways to which the genes belong for novel therapies. In addition, genes are partially responsible for the fact that not all therapies work in all patients. Thus studying the function of such genes will enable development of more efficient personalized therapies that are tailored on the specific mechanism that causes disease in each patient.

WHAT we are doing in this area

Two major autoimmunity genes, PTPN22 and PTPN2 encode for enzymes with tyrosine phosphatase activity. Dr. Bottini reported the initial discovery that a single nucleotide substitution in PTPN22 significantly increases the risk of autoimmunity in human carriers (see http://www.ncbi.nlm.nih.gov/pubmed/15004560). Part of the Bottini laboratory is dedicated to understanding the mechanism of action of PTPN22 in autoimmunity. PTPN22 currently ranks as the second most important gene in rheumatoid arthritis, and the third in type 1 diabetes. It also increases the risk of other connective tissues diseases including systemic lupus erythematosus and systemic sclerosis. The laboratory uses a range of approaches from manipulation of PTPN22 expression in human cell lines and cells from human subjects, to modeling of the gene function in mice affected by autoimmune disease. Since PTPN22 plays a major role in autoimmune diabetes, this is an area of major interaction with the LJI Type 1 Diabetes Center.

HOW we support our work in this area

Work on the genetics of autoimmune diseases in the laboratory is currently supported by donations to the LJI Type 1 Diabetes Center, the JDRF, the Rheumatology Research Foundation, and the NIAID.

EXAMPLES of PUBLICATIONS from our laboratory in this area

http://www.annualreviews.org/doi/abs/10.1146/annurev-immunol-032713-120249 A recent review on the immunology of PTPN22 in autoimmunity.

http://www.ncbi.nlm.nih.gov/pubmed/23871208 In collaboration with Drs. Erik Peterson at University of Minnesota and Klaus Ley at LJI, the Bottini laboratory discovered that PTPN22 –which was believed to operate mainly if not exclusively at the level of B and T cells- also plays an important role in signaling in myeloid cells.

http://www.ncbi.nlm.nih.gov/pubmed/20538612 Biochemical work on PTPN22 showed that the phosphatase can be regulated by phosphorylation in a portion of the molecule that affects the activity of the enzyme. The common and autoimmune predisposing variants of the phosphatase are differentially regulated.

http://www.ncbi.nlm.nih.gov/pubmed/18981062 The Bottini laboratory discovered a second mutation in PTPN22, which leads to reduced function and protects humans from systemic lupus erythematosus and rheumatoid arthritis.

http://www.ncbi.nlm.nih.gov/pubmed/16273109 Biochemical work in cell lines and cells from human carriers of the autoimmune-predisposing mutation shows that the common and autoimmune predisposing variants of the phosphatase differentially regulate intracellular signaling in T cells.

KEY COLLABORATORS OUTSIDE LJI
Michel Tremblay, PhD, McGill University, Montreal, Canada
Tony Tiganis, PhD, Monash University, Victoria, Australia

RHEUMATOID ARTHRITIS

WHY we work in this area

Rheumatoid arthritis (RA) is a common rheumatologic disease where the immune system mistakenly attacks joint tissues causing inflammation (arthritis). If the inflammation is not controlled, with time it leads to damage of the cartilage and bone, resulting in deformities of the joints, chronic pain and functional limitation. Immunological research in the past 15 years has led to the development of several medications able to suppress the hyperactivation of the immune system (so called immunosuppressants), which are now available for patients affected by RA. Although immunosuppressants are in general very effective, a consistent proportion of patients (up to 1/3) do not experience a complete remission of their symptoms, despite trying several of these medications. We cannot combine two immunosuppressant medications to improve control of inflammation because higher suppression of the immune system would increase the risk of infections to unacceptable levels. Therefore our goal is to explore other therapies that can be used in combination with immunosuppressants in hope to benefit patients who do not respond well to immunosuppressants alone.

WHAT we are doing in this area

We turned our attention to a cell type that is present locally in the joint lining, called the synoviocyte. The synoviocyte is sensitive to the activation of cells of the immune system in the joints and in rheumatoid arthritis plays a disease-promoting role by boosting inflammation, directly damaging the cartilage, and indirectly stimulating the cells that damage the bone. Inhibition of synoviocyte activity is believed to result in decreased inflammation and joint damage but it does not result in general suppression of the immune system. Thus anti-synoviocyte therapies could be combined with currently available immunosuppressive therapies to improve control of disease activity in subjects who do not respond well to the immunosuppressant alone. We study biochemical signaling pathways inside synoviocytes trying to identify pathways that are abnormal in RA and/or can be targeted to reduce the activation of synoviocytes in RA. We found that synoviocytes express several molecules with tyrosine phosphatase activity and we are now focused on studying these molecules and assessing whether they can be targeted for therapies of RA.

HOW we support our work in this area

The work on synoviocytes in the Bottini laboratory is currently supported by a grant from the NIAMS and a contract from industry.

EXAMPLES of PUBLICATIONS from our laboratory in this area

http://www.ncbi.nlm.nih.gov/pubmed/23335101 Our first survey of tyrosine phosphatase expression in synoviocytes from RA patients led to the identification of a phosphatase that could be targeted for reducing the aggressiveness of these cells in RA.

http://www.ncbi.nlm.nih.gov/pubmed/23147896 A recent review that summarizes the features of synoviocytes and why they are important in RA.

KEY COLLABORATORS OUTSIDE LJI
Gary Firestein, MD, University of California San Diego, San Diego, CA
Costantino Pitzalis, MD, William Harvey Research Institute, London, UK

SYSTEMIC SCLEROSIS

WHY we work in this area

Systemic sclerosis (SSc) is an autoimmune disease that leads to scarring of the skin and internal organs, resulting in significant limitations in quality of life and often reduced life expectancy in patients. SSc is an orphan disease, and a major problem is that -with the possible exception of heavy immunosuppression- no medication so far has been able to arrest the progression of skin or internal organ scarring. Although the disease is caused by immune system hyperactivation, progression of disease is associated with dysfunction of small blood vessels which ultimately triggers activation of local cells in the skin or internal organs –called fibroblasts. Fibroblasts are normally responsible for wound healing however in systemic sclerosis they become abnormally hyperactive and produce increased amounts of tissue matrix which leads to inappropriate scarring. Most patients are diagnosed at a stage of disease when activation of fibroblasts is prominent and there are scarred (called “fibrotic”) areas of the skin. In that stage steroids and conventional immunosuppression or approaches targeted to the blood vessels are ineffective at slowing down the scarring. Thus several groups have turned their attention to the fibroblast as the key cell whose anomalies need to be normalized by pharmacological intervention if we want to modify disease course in SSc.

WHAT we are doing in this area

We study biochemical signaling pathways inside skin fibroblasts trying to identify pathways that are abnormal in SSc and/or can be targeted to reduce the abnormal tendency of SSc fibroblast that causes scarring. In preliminary experiments we found that synoviocytes express several molecules with tyrosine phosphatase activity and we are now focused on studying these molecules and assessing whether they can be targeted for therapies of SSc. The laboratory recently partnered with UCSD CIT to recruit a new groups of patients with SSc and healthy control subjects and study their skin fibroblasts. Details of the study can be found in the ongoing clinical studies page.

HOW we support our work in this area

The work on dermal fibroblasts in the Bottini laboratory is currently supported by a grant from the pharmaceutical industry.

KEY COLLABORATORS OUTSIDE LJI

Sergio Jimenez, MD, Thomas Jefferson University, Philadephia, PA
Shervin Assassi, MD, University of Texas at Houston, Houston, TX
Francesco Boin, MD, University of California San Francisco, San Francisco, CA
Zhong-Yin Zhang, PhD, Indiana University, Indianapolis, IN