Wesemann Lab

60 Fenwood Road Building for Transformative Medicine, 5002O Boston, MA 02115
Lab Phone: 617-525-1285 - Office Phone: 617-525-1295
dwesemann@bwh.harvard.edu

The Wesemann laboratory uses mouse genetics, human studies, cellular biology, single cell transcriptomics, and computation to elucidate the underlying features and elasticity of antibody recognition capacity. We study the dynamic regulation, functional significance, and evolutionary implications/origins of the anticipatory naïve antibody repertoire and its somatically evolving counterpart in germinal centers. Findings from these projects have paradigm-shifting potential for fundamental immunology and are relevant to infectious disease, vaccinology, allergy, and autoimmunity.


Understanding Immunity to COVID-19

The nature and longevity of the immune response to SARS-CoV-2 is not fully understood. We have ongoing human research protocols to collect samples over time after natural infection as well as before and after vaccination to better understand anti-virus immunity. Initial findings from our laboratory show that individuals differ in the immune effectiveness and abilities to sustain antibody responses after COVID-19. Our current work is focused on identifying the key features that regulate long-lived antibody production and antibody evolution over time. We are collecting samples from volunteers in the Boston area who have recovered from COVID-19 (volunteer here ). We are also recruiting volunteers to donate blood samples before and after vaccination to determine the nature and longevity of antibody responses from different vaccine platforms as they role out (volunteer here ).

Principles Shaping Antibody Repertoires

B cell antibody (i.e. immunoglobulin (Ig)) repertoire composition shapes immune responses. The generation of Ig diversity begins with Ig variable (V) region exon assembly from gene segments, random inter-segment junction sequence diversity, and combinations of Ig heavy and light chain. This generates vast preemptive sequence freedom in early developing B lineage cell Ig genes that can anticipate a great diversity of threats. This freedom is met with large restrictions that ultimately define the initial naïve Ig repertoire. Activation-induced somatic hypermutation (SHM), which further diversifies Ig V regions, is also met with strong selection that shapes Ig affinity maturation. While individual repertoire features, such as affinity for self and competition for foreign antigen, are known to drive selection, the selection filters themselves may be subject to regulation. We are carrying out investigations testing the hypothesis that tolerance filter stringency is flexible, to enable demand-driven regulation to dynamically balance antigen recognition capacities and associated autoimmune risks according to host needs for both primary naïve and activation-dependent Ig repertoires.

Germinal Center B Cell Clonal Selection and Somatic Antibody Evolution

Two Ig diversification mechanisms collaborate to provide protective humoral immunity. Combinatorial assembly of IgH and IgL V region exons from gene segments generates preimmune Ig repertoires, expressed as B cell receptors (BCRs). Secondary diversification occurs when Ig V regions undergo SHM and affinity-based selection toward antigen in activated germinal center (GC) B cells. Secondary diversification is thought to only ripen the antigen-binding affinity of Igs that already exist (i.e., cognate Igs) because of chance generation during preimmune Ig diversification. However, some high affinity antibodies may have evolved from BCRs that may have had no initial recognition of antigen. We recently discovered that intrinsic GC B cell flexibility allows for somatic, noncognate B cell evolution, permitting de novo antigen recognition and subsequent antibody affinity maturation without initial preimmune BCR engagement. We are currently developing models to understand this process in physiologically competitive environments as well as its relevance to the initial activation of unmutated germline ancestors of protective antibodies.

Origins of Somatic Hypermutation

Jawless vertebrate (agnathan) immune systems are supported by lymphocyte subsets that express variable receptors (VLRs) analogous to jawed vertebrate (gnathostome) BCRs. In contrast to BCRs, which are made of Ig domains, VLRs are made of leucine rich repeat (LRR) domain-containing gene segments. Three types of VLRs have been identified, termed VLRA, VLRB, and VLRC—and they are expressed on agnathan lymphocytes that share gene expression modules with abT cells, B cells, and gdT cells, respectively. Despite sharing genes capable of somatic gene mutation, agnathans do not appear to have developed a somatic mutation and affinity maturation system as gnathostome B cell-expressed Igs have. We are carrying out computational and wet lab investigations to compare the gnathostome and agnathan systems to identify fundamental features that enable somatic receptor evolution.

Lymphocyte Antigen Receptor and Cell Fate

IgH isotypes (e.g., IgM, IgG, and IgE) are generated as secreted/soluble antibodies (sIg) or as membrane-bound (mIg) B cell receptors (BCRs) through alternative RNA splicing. IgH isotype dictates soluble antibody function, but how mIg isotype influences B cell behavior is not well defined. We recently found that the IgH locus produces transcripts that generate IgM, IgG1, and IgE in an alternative splice form bias hierarchy, regardless of cell stage. We are carrying out additional work to understand how BCR expression and IgH isotype influence B lineage cell fate function.

Human Immunology

We have ongoing human studies recruiting human participants to elucidate the role of antibodies and lymphocyte dynamics in human health and disease, including autoimmunity, immune deficiency, and allergy.


Publications

For complete listing click here

Memory B cell repertoire for recognition of evolving SARS-CoV-2 spike. Pei Tong, Avneesh Gautam, Ian Windsor, Meghan Travers, Yuezhou Chen, Nicholas Garcia, Noah B. Whiteman, Lindsay G.A. McKay, Felipe J.N. Lelis, Shaghayegh Habibi, Yongfei Cai, Linda J. Rennick, W. Paul Duprex, Kevin R. McCarthy, Christy L. Lavine, Teng Zuo, Junrui Lin, Adam Zuiani, Jared Feldman, Elizabeth A. MacDonald, Blake M. Hauser, Anthony Griffths, Michael S. Seaman, Aaron G. Schmidt, Bing Chen, Donna Neuberg, Goran Bajic, Stephen C. Harrison, Duane R. Wesemann bioRxiv 2021.03.10.434840; doi: https://doi.org/10.1101/2021.03.10.434840. Online ahead of print. Link

Quick COVID-19 Healers Sustain Anti-SARS-CoV-2 Antibody Production. Chen Y, Zuiani A, Fischinger S, Mullur J, Atyeo C, Travers M, Lelis FJN, Pullen KM, Martin H, Tong P, Gautam A, Habibi S, Bensko J, Gakpo D, Feldman J, Hauser BM, Caradonna TM, Cai Y, Burke JS, Lin J, Lederer JA, Lam EC, Lavine CL, Seaman MS, Chen B, Schmidt AG, Balazs AB, Lauffenburger DA, Alter G, Wesemann DR. Cell. 2020 Nov 3:S0092-8674(20)31458-6. doi: 10.1016/j.cell.2020.10.051. Online ahead of print. PMID: 33171099 Link

Treatment of Chronic Granulomatous Disease-Related Pulmonary Aspergillus Infection in Late Pregnancy. Johnson JA, Pearson JC, Kubiak DW, Dionne B, Little SE, Wesemann DR. Open Forum Infect Dis. 2020 Sep 26;7(10):ofaa447. doi: 10.1093/ofid/ofaa447. eCollection 2020 Oct. PMID: 33134418 Free PMC article. Link

Viral epitope profiling of COVID-19 patients reveals cross-reactivity and correlates of severity. Shrock E, Fujimura E, Kula T, Timms RT, Lee IH, Leng Y, Robinson ML, Sie BM, Li MZ, Chen Y, Logue J, Zuiani A, McCulloch D, Lelis FJN, Henson S, Monaco DR, Travers M, Habibi S, Clarke WA, Caturegli P, Laeyendecker O, Piechocka-Trocha A, Li J, Khatri A, Chu HY; MGH COVID-19 Collection & Processing Team, Villani AC, Kays K, Goldberg MB, Hacohen N, Filbin MR, Yu XG, Walker BD, Wesemann DR, Larman HB, Lederer JA, Elledge SJ. Science. 2020 Sep 29:eabd4250. doi: 10.1126/science.abd4250. Online ahead of print. PMID: 32994364 Link

DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Yu J, Tostanoski LH, Peter L, Mercado NB, McMahan K, Mahrokhian SH, Nkolola JP, Liu J, Li Z, Chandrashekar A, Martinez DR, Loos C, Atyeo C, Fischinger S, Burke JS, Slein MD, Chen Y, Zuiani A, Lelis FJN, Travers M, Habibi S, Pessaint L, Van Ry A, Blade K, Brown R, Cook A, Finneyfrock B, Dodson A, Teow E, Velasco J, Zahn R, Wegmann F, Bondzie EA, Dagotto G, Gebre MS, He X, Jacob-Dolan C, Kirilova M, Kordana N, Lin Z, Maxfield LF, Nampanya F, Nityanandam R, Ventura JD, Wan H, Cai Y, Chen B, Schmidt AG, Wesemann DR, Baric RS, Alter G, Andersen H, Lewis MG, Barouch DH. Science. 2020 Aug 14;369(6505):806-811. doi: 10.1126/science.abc6284. Epub 2020 May 20. PMID: 32434945 Link

Origins of peanut allergy-causing antibodies. Wesemann, Duane R. and Nagler, Cathryn R. Science. 2020; 367:1072-1073 PDF

Game of clones: How measles remodels the B cell landscape. Wesemann DR. Sci. Immunol. 2019 Nov 1;4:41. PDF

Affinity War:forging immunoglobulin repertoires. Zuo T, Gautam A, Wesemann DR. Curr Opin Immunol. 2019 Jan 25;57:32-39. PDF

Microbial symbionts regulate the primary Ig repertoire. Chen Y, Chaudhary N, Yang N, Granato A, Turner JA, Howard SL, Devereaux C, Zuo T, Shrestha A, Goel RR, Neuberg D, Wesemann DR. J Exp Med. 2018 May 7; 215(5):1397-1415. PDF

Analyzing Immunoglobulin Repertoires. Chaudhary N, Wesemann DR. Front. Immunol. 2018 March 14;9:462. PDF

Deployment of Transchromosomal Bovine for Personalized Antimicrobial Therapy. Silver JS, Ashbaugh CD, Miles JJ, Wu H, Marecki GT, Hwang JK, Jiao JA, Abrams M, Sullivan EJ, Wesemann DR. Clin Infect Dis. 2017 Dec 20. PDF

The neonatal window of opportunity – early priming for life. Renz H, Adkins BD, Bartfeld S, Blumberg RS, Farber DL, Garssen J, Ghazal P, Hackam DJ, Marsland BJ, McCoy KD, Penders J, Prinz I, Verhasselt V, von Mutius E, Weiser JN, Wesemann DR, Hornef MW. J Allergy Clin Immunol. 2017 Dec 13. PDF

Stochasticity enables BCR-independent germinal center initiation and antibody affinity maturation. Silver J, Zuo T, Chaudhary N, Kumari R, Tong P, Giguere S, Granato A, Donthula R, Devereaux C, Wesemann DR. J Exp Med. 2018 Jan 2;215(1):77-90. PDF

IgH isotype-specific B cell receptor expression influences B cell fate. Tong P, Granato A, Zou T, Chaudhary N, Zuiani A, Han SS, Donthula R, Shrestha A, Sen D, Magee JM, Gallagher MP, van der Poel CE, Carroll MC, Wesemann DR. PNAS. 2017 Sep 18;114(40):E8411-E8420. PDF

Lactobacillus-Deficient Cervicovaginal Bacterial Communities Are Associated with Increased HIV Acquisition in Young South African Women. Gosmann C, Anahtar MN, Handley SA, Farcasanu M, Abu-Ali G, Bowman BA, Padavattan N, Desai C, Droit L, Moodley A, Dong M, Chen Y, Ismail N, Ndung’u T, Ghebremichael MS, Wesemann DR, Mitchell C, Dong KL, Huttenhower C, Walker BD, Virgin HW, Kwon DS. Immunity. 2017 Jan 17;46:29-37. PDF

The Microbiome, Timing, and Barrier Function in the Context of Allergic Disease. Wesemann DR, Nagler CR. Immunity. 2016 Apr 19;44(4):728-38. PDF

Primary immunoglobulin repertoire development: time and space matter. Granato A, Chen Y, Wesemann DR. Curr Opin Immunol. 2015 Apr;33:126-31. PDF

Microbes and B cell development. Wesemann DR. Adv Immunol. 2015;125:155-78. PDF

Molecular Mechanisms of IgE Class Switch Recombination. Tong P, Wesemann DR. Curr Top Microbiol Immunol. 2015;388:21-37 PDF

Detection of true IgE-expressing mouse B lineage cells. Gallagher MP, Shrestha A, Magee JM, Wesemann DR. J Vis Exp. 2014 Dec 1;(94) PDF

Early B lineage development occurs in the gut lamina propria and is influenced by commensal microbes. Wesemann DR, Portuguese A, Meyers RM, Gallagher MP, Cluff-Jones K, Magee J, Panchakshari R, Rodig S, Kepler TB, Alt FW. Nature. 2013 Sep 5;501(7465):112-5. PDF

Reprogramming IgH isotype-switched B cells to functional-grade induced pluripotent stem cells. Wesemann DR, Portuguese AJ, Magee JM, Gallagher MP, Zhou X, Panchakshari RA, Alt FW. Proc Natl Acad Sci U S A.2012 Aug 21;109(34):13745-50. PDF

Immature B cells preferentially switch to IgE with increased direct Sμ to Sε recombination. Wesemann DR, Magee JM, Boboila C, Calado DP, Gallagher MP, Portuguese AJ, Manis JP, Zhou X, Recher M, Rajewsky K, Notarangelo LD, Alt FW. J Exp Med. 2011 Dec 19;208(13):2733-46. PDF


Members

Duane Wesemann

Duane Wesemann, MD, PhD

Principal Investigator

Associate Professor of Medicine, Harvard Medical School

Associate Physician, Brigham and Women's Hospital

Founder
yuezhou

Yuezhou Chen, MD, PhD

Postdoctoral Fellow

M.D. China Academy of Chinese Medical Sciences, 2014

Ph.D. Cell Biology, Peking University, 2009

Joined 2014
Duane Wesemann

Pei Tong, PhD

Postdoctoral Fellow

Associate Professor of Medicine, Harvard Medical School Associate Physician, Brigham and Women's Hospital

Joined 2014
Duane Wesemann

Avneesh Kumar Gautam, PhD

Postdoctoral Fellow

Ph. D. Biotechnology, National Center for Cell Sciences, 2017

M. Sc. Biotechnology, IIT Bombay, 2009

Joined 2018
Noah Whiteman

Noah Whiteman

Researcher, Lab Manager

B.A. Lawrence University 2019

Joined 2019
Ali Sanjari Moghaddam

Ali Sanjari Moghaddam, MD

Postdoctoral Fellow

M.D. Shahid Beheshti University of Medical Sciences

Joined 2021
Duane Wesemann

Mehrdad Zarghami, MD

Postdoctoral Fellow

_____

Joined 2021

Former Lab Members

Duane Wesemann

Adam Zuiani, PhD

postdoctoral fellow

Ph.D. Washington University, 2016

2017 - 2021
Armin Jayaswal

Armin Jayaswal

Research Trainee

B.S. Biology, Brandeis University, 2021

Joined 2020
Felipe Lelis

Felipe Lelis, PhD

Postdoctoral Fellow

Associate Professor of Medicine, Harvard Medical School Associate Physician, Brigham and Women's Hospital

2018-2021
Teng Zuo

Teng Zuo, phd

Postdoctoral Fellow

Ph.D. Biological and Biomedical Sciences, Tsinghua University, 2015

B.S. Biology, University of Science and Technology of China, 2010

2015-2021
Shaghayegh Habibi

Shaghayegh Habibi, MD

Postdoctoral Fellow

M.D. Fasa University of Medical Sciences, 2015

2018-2021
Meghan Travers

Meghan Travers, PhD

Postdoctoral Fellow

Ph.D. in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, 2019

B.S. in Biological Engineering, Cornell University, 2009

2019-2021

Lab news

Pei Tong's paper published pre-print

in bioRxiv


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