Current Projects

Chemokine receptors are GPCRs expressed on the surface of all immune cells, and are essential for appropriate immune responses. Certain chemokine levels are dysregulated in autoimmune skin diseases. However, it is unclear if the same chemokine receptor on different cell types utilize the same signaling pathways and parterns.

One project uses CRISPR/Cas9 gene editing to edit the endogenous loci of chemokine receptors in T and B cells to append a peroxidase tag (APEX), allowing for nearby proteins to be labeled. Combined with RNA-seq and in silico approaches, we are dissecting how chemokine signaling pathways compare between T cells and B cells. This has implications not only for basic understanding of how the adaptative immune system communicates, but also for drug discovery targeting chemokine receptors and CAR-T cell therapies.

Another project dissects the biochemical basis for chemokine signaling at a newly established GPCR signaling pathway (Smith JS et al, Science 2021) and how it differs from established GPCR pathways.

Newly established projects are leveraging Alpha Fold Multimer and other computational tools to rationally design antibodies targeting GPCRs pertinent to dermatology. These efforts aim to create novel therapeutic and diagnostic tools through protein engineering techniques.

These projects encompasses a wide range of methodologies, including traditional biochemical techniques, genetic engineering, immunology and cell based signaling assays, high-resolution mass spectrometry, and protein purification.

Pertinent publications include:

1.Smith JS*, Pack TF *, Inoue A, Lee C, Zheng K, Choi I, Eiger DS, Warman A, Xiong X, Ma Z, Viswanathan G, Levitan I, Rochelle L, Staus DP, Snyder JC, Kahsai AW, Caron MG, Rajagopal S. Noncanonical scaffolding of Gαi and β-arrestin by G protein-coupled receptors. Science. 2021 Mar 12;371(6534):eaay1833. doi: 10.1126/science.aay1833. PMID: 33479120. PMCID: PMC8005335. *Co-first author

2. Zheng K*, Smith JS*, Eiger DS, Warman A, Choi I, Honeycutt CC, Boldizsar N, Gundry JN, Pack TF, Inoue A, Caron MG, Rajagopal S. Biased agonists of the chemokine receptor CXCR3 differentially signal through Gαi: β-arrestin complexes. Sci Signal. 2022 Mar 22;15(726):eabg5203. doi: 10.1126/scisignal.abg5203. PMID: 35316095. PMCID: PMC9890572. *Co-first author

3. Eiger DS*, Smith JS*, Shi T, Stepniewski TM, Tsai CF, Honeycutt C, Boldizsar N, Gardner J, Nicora CD, Moghieb AM, Kawakami K, Choi I, Zheng K, Warman A, Alagesan P, Knape NM, Huang O, Silverman JD, Smith RD, Inoue A, Selent J, Jacobs JM, Rajagopal S. Phosphorylation barcodes direct biased chemokine signaling at CXCR3. Cell Chem Biol. 2023 Apr 20;30(4):362-382.e8. doi: /10.1016/j.chembiol.2023.03.006. PMID: 37030291. PMCID: PMC10147449. *Co-first author

4. Smith JS, Hilibrand AS, Skiba MA, Calvillo-Miranda VG, Kruse AC. The M3 muscarinic acetylcholine receptor can signal through multiple G protein families. Molecular Pharmacology. 2024 Jun 1;105(6):386-94.DOI:  10.1124/molpharm.123.000818. PMID: 38641412

5. Smith JS, Lefkowitz RJ, Rajagopal S. Biased signalling: from simple switches to allosteric microprocessors. Nat Rev Drug Discov. 2018 Apr;17(4):243-260. doi: 10.1038/nrd.2017.229. PMID: 29302067. PMCID: PMC5936084. Recommended on Faculty of 1000.

6. Smith JS*, Nicholson LT, Suwanpradid J, Glenn RA, Knape NM, Alagesan P, Wehrman TS, Gundry JN, Atwater AR, Gunn MD, MacLeod AS, Rajagopal S. Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation. Sci Signal. 2018 Nov 6;11(555):eaaq1075. doi: 10.1126/scisignal.aaq1075. PMID: 30401786. PMCID: PMC6329291.

7. Edward P. Harvey, Jeffrey S. Smith, Joseph D. Hurley, Alyana Granados, Ernst W. Schmid, Jason G. Liang-Lin, Steffanie Paul, Emily M. Meara, Matthew P. Ferguson, Victor G. Calvillo-Miranda, Debora S. Marks, Johannes C. Walter, Andrew C. Kruse, Katherine J. Susa In silico discovery of nanobody binders to a G-protein coupled receptor using AlphaFold-Multimer https://www.biorxiv.org/content/10.1101/2025.03.05.640882v1

8. Claudia Y. Lee, Jeffrey S. Smith, Taylor Kohlmann, Emily M. Meara, Uyen Pham, Frank Kwarcinski, Andrew N. Dates, Issac Choi, Ari S. Hilibrand, Abigail Gillikin, Stephen C. Blacklow, Gregory G. Tall, Andrew C. Kruse, Sudarshan Rajagopal β-arrestin recruitment facilitates a direct association with G proteins  https://doi.org/10.1101/2025.06.24.661366

I specialize in caring for patients with autoimmune skin and connective tissue diseases at Brigham and Women’s Dermatology, focusing on conditions such as cutaneous lupus, dermatomyositis, systemic sclerosis, morphea and undifferentiated autoimmune conditions with a skin phenotype. While these diseases are recognized as autoimmune in nature, their specific pathogenesis remains largely unclear. To address this gap, I have approved IRBs to investigate whether certain diseases are driven by autoantibodies targeting cell surface receptors, similar to the mechanism of autoimmune hypothyroidism. On the clinical research front, I am particularly interested in understanding the side effect profiles of immunomodulators and exploring whether specific characteristics or therapeutic combinations influence outcomes, either positively or negatively. In addition, I contribute to advancing evidence-based medical practices as a primary investigator for the AMETHYST phase II/III. This study evaluates a monoclonal antibody targeting plasmacytoid dendritic cells for the treatment of cutaneous lupus.

Pertinent publications include:

1. Smith JS, Said JT, Elman SA, Smith CEP, Merola JF. Seroconversion of severe acute respiratory syndrome coronavirus 2-infected patients on immunosuppression: A retrospective analysis. J Am Acad Dermatol. 2021 May;84(5):1409-1412. doi: 10.1016/j.jaad.2021.01.100. PMID: 33549649. PMCID: PMC7860940. *Co-first author

2. Elmariah SB, Smith JS, Merola JF. JAK in the [Black] Box: A Dermatology Perspective on Systemic JAK Inhibitor Safety. Am J Clin Dermatol. 2022 Jul;23(4):427-431. doi:10.1007/s40257-022-00701-3. Epub 2022 Jun 9. PMID: 35679017.

3. Smith JS, Aldeeri AA, Elman SA, Krier JB, Merola JF. A novel variant in the GNAS complex locus causes Albright hereditary osteodystrophy with pseudopseudohypoparathyroidism. JAAD Case Rep. 2022 Jan 19;21:103-105. doi: 10.1016/j.jdcr.2021.12.038. PMID: 35198712. PMCID: PMC8850575.

4. DeWane ME, Smith JS, DeSimone MS, Mostaghimi A. A case of refractory verrucous varicella zoster virus in a patient with persistent pancytopenia after CAR-T therapy. Br J Dermatol. 2022 Sep;187(3):e77. doi: 10.1111/bjd.21609. PMID: 35575472.

5. Schunkert EM, Smith JS, Elman SA, Merola JF. Extension-elicited blanching of the dorsal phalanges in systemic sclerosis: A case series. JAAD Case Rep. 2022 Sep 19;30:87-90. doi: 10.1016/j.jdcr.2022.09.005. PMID: 36411842. PMCID: PMC9674863.

6. Smith JS, M Woodbury, JF Merola. Ruxolitinib cream for the treatment of cutaneous sarcoidosis. JAAD Case Rep. 2023 Jun 3;38:111-112. doi: 10.1016/j.jdcr.2023.05.032. PMID: 37521191. PMCID: PMC10372038.

7. Woodbury MJ, Smith KN, Smith JS, Merola JF. Anifrolumab for the treatment of refractory chilblain lupus erythematosus. JAAD Case Reports. DOI: 10.1016/j.jdcr.2023.10.020

8. Kang JB, Smith KN, Meara EM, Cho M, Silverman JD, LaChance AH, Smith JS. Infection risk of rituximab monotherapy versus combination therapy with rituximab and mycophenolic acid in systemic sclerosis: A retrospective cohort study. Journal of the American Academy of Dermatology. 2025 Jan 27.

9. Merola JF, Zhang AJ, Childs BA, Li M, Smith JS, Chong BF, Gottlieb AB, Werth VP, Elman SA, Pérez-Chada LM. INTER-RATER AND INTRA-RATER RELIABILITY OF THE CUTANEOUS LUPUS ACTIVITY-INVESTIGATOR GLOBAL ASSESSMENT-REVISED (CLA-IGA-R) INSTRUMENT. Journal of Investigative Dermatology. 2025 Feb 7.