Goetz Ehrhardt

My laboratory focuses on two research areas. The first project centers on the regulation of human memory B cells by FCRL proteins. A separate project aims at harnessing the adaptive immune system of the evolutionary distant sea lamprey for biomarker discovery.

Regulation of memory B cells by FCRL proteins.

FCRL molecules are a recently identified family of immunoregulatory receptors with preferential expression on B lineage cells. Their extracellular domains consist of 3-9 immunoglobulin domains and their intracellular domains contain immunoreceptor tyrosin-based activation (ITAM) and or inhibitory (ITIM) motifs. Biochemical analyses demonstrated a strong regulatory activity on B cell receptor (BCR) signaling. Among B lineage cells, the FCRL receptors display a memory B cell centric pattern of expression. Our work focuses mostly on FCRL4. Expression of this family member is restricted to a unique population of memory B cells located in mucosa-associated lymphoid tissues (MALT). These memory B cells are morphologically and functionally distinct from their FCRL4-negative counterparts. They respond readily to simulated T cell dependent stimulation and not to T cell independent stimulation. This is in contrast to FCRL4-negative memory B cells, which respond readily to both stimuli. Interestingly, FCRL4-postive memory B cells are dysregulated in the infectious diseases HIV and malaria and encode the majority of antibodies to the HIV gp120 envelope protein.

Very little is known about B cell regulation by FCRL proteins, including the identity of the ligands for most FCRL-family members. We are interested determining the function of FCRL proteins in the regulation of memory B cells. What are the ligand(s) for FCRL molecules and which cells express them? Why is FCRL4 expressed only on a subpopulation of memory B cells? Do genetic lesions of FCRL-family members contribute to B cell disorders? Answers to these questions will help our understanding of human memory B cells responses.

Biomarker discovery using the unique lamprey VLR antibodies.

Mammalian monoclonal antibodies are widely used tools in various research disciplines and important reagents for clinical applications. However, structural constraints and the need of the host to maintain tolerance restrict the antibody repertoire. Only recently, the adaptive immune system of the evolutionary distant jawless sea lamprey was identified. Unlike mammalian antibodies, the variable lymphocyte receptor (VLR) antibodies of the sea lamprey are based on beta-sheet forming leucine-rich repeat (LRR) units. They are secreted as decameric complexes assembled by iteration of the same gene product. VLR antibodies are extremely stable and recognize their antigens in a highly specific manner. The solved structures of monoclonal VLR antibodies complexed to their antigens indicate a mode of antibody/antigen interaction that is distinct from conventional antibody/antigen interactions. Because of the large evolutionary distance of lampreys and the radically different protein architecture, we hypothesize that VLR antibodies may recognize antigens that conventional antibodies cannot detect for structural or tolerogenic reasons.

We are interested in generating monoclonal VLR antibodies to healthy human lymphocyte populations and lymphocytes from malignant disorders. These monoclonal VLR antibodies will be characterized for their binding specificities, for correlation of VLR binding with clinical diagnostic and/or prognostic factors and for the identification of the antigen recognized by the VLR antibodies. Ultimately, we aim to establish VLR antibodies as a new class of research reagents complementing the existing panels of conventional monoclonal antibodies.

Recent Publications

• Liu Y, Budylowski P, Dong S, Li Z, Goroshko S, Leung LYT, Grunebaum E, Campisi P, Propst EJ, Wolter NE, Rini JM, Zia A, Ostrowski M, Ehrhardt GR. SARS-CoV-2-reactive mucosal B cells in the upper respiratory tract of uninfected individuals. J Immunol. 2021 Nov 15;207(10):2581-2588

• Leung LYT, Khan S, Budylowski P, Li Z, Goroshko S, Liu Y, Dong S, Carlyle JR, Rini JM, Ostrowski M, Ehrhardt GR. Detection and neutralization of SARS-CoV-2 using non-conventional variable lymphocyte receptor antibodies of the evolutionarily distant sea lamprey. Front Immunol. 2021 Jun 21;12:659071.

• Liu Y, Goroshko S, Leung LYT, Dong S, Khan S, Campisi P, Propst EJ, Wolter NE, Grunebaum E, Ehrhardt GR. FCRL4 is an Fc receptor for systemic IgA, but not mucosal secretory IgA. J Immunol. 2020 Jul 15;205(2):533-538. doi: 10.4049/jimmunol.2000293

• Khan S, Liu Y, Ernst LM, Leung LYT, Budylowski P, Dong S, Campisi P, Propst EJ, Wolter NE, Grunebaum E, Ostrowski M, Ehrhardt GR. Detection of human CD38 using variable lymphocyte receptor (VLR) tetramers. Cells 2020 Apr 12;9(4):950. doi: 10.3390/cells9040950.

• Chan JTH, Liu Y, Khan S, St-Germain JR, Zou C, Leung LYT, Yang J, Shi M, Grunebaum E, Campisi P, Propst EJ, Holler T, Bar-Or A, Wither JE, Cairo CW, Moran MF, Palazzo AF, Cooper MD, Ehrhardt GR. A tryrosine sulfation-dependent HLA-I modification identifies memory B cells and plasma cells. Science Advances 2018 Nov 7;4(11):eaar7653

• Liu Y, McDaniel JR, Khan S, Campisi P, Propst EJ, Holler T, Grunebaum E, Georgiou G, Ippolito GC and Ehrhardt GR. Antibodies encoded by FCRL4-bearing memory B cells preferentially recognize commensal microbiota. J Immunol. 2018 Jun 15;200(12):3962-3969.

• Identification of Human Plasma Cells with a Lamprey Monoclonal Antibody. Yu C, Liu Y, Chan J, Tong J, Li Z, Shi M, Davani D, Parsons M, Khan S, Zhan W, Kyu S, Grunebaum E, Campisi P, Propst EJ, Jaye DL, Trudel S, Moran MF, Ostrowski M, Herrin BR, Lee FE, Sanz I, Cooper MD and Ehrhardt GR. JCI – Insight 2016;1(3):e84738.

• Involvement of the HCK and FGR src-family kinases in FCRL4-mediated immune regulation. Liu Y, Bezverbnaya K, Zhao T, Parsons MJ, Shi M, Treanor B and Ehrhardt GR. J Immunol. 2015;194(12):5851-60.

• Regulation of VH replacement by B cell receptor-mediated signaling in human immature B cells. Liu J, Lange MD, Hong SY, Xie W, Xu K, Huang L, Yu Y, Ehrhardt GR, Zemlin M, Burrows PD, Su K, Carter RH and Zhang Z. J Immunol. 2013;190(11):5559-66.

• Purification and identification of cell surface antigens using lamprey monoclonal antibodies. Yu C, Ali S, St-Germain J, Liu Y, Yu X, Jaye DL, Moran MF, Cooper MD and Ehrhardt GR. J Immunol Methods 2012;386(1-2):43-9.

• FcR-like 2 Inhibition of B cell receptor-mediated activation of B cells. Jackson TA, Haga CL, Ehrhardt GR, Davis RS, Cooper MD. J Immunol. 2010 Dec 15;185(12):7405-12.

• Immunoregulatory Roles for Fc Receptor-Like Molecules. Ehrhardt GR, Cooper MD. Curr Top Microbiol Immunol. 2010 Aug 3.

• Inhibitory signaling potential of a TCR-like molecule in lamprey. Yu C, Ehrhardt GR, Alder MN, Cooper MD, Xu A. Eur J Immunol. 2009 Feb;39(2):571-9.

• Discriminating gene expression profiles of memory B cell subpopulations. Ehrhardt GR, Hijikata A, Kitamura H, Ohara O, Wang JY, Cooper MD. J Exp Med. 2008 Aug 4;205(8):1807-17.

• Structure and specificity of lamprey monoclonal antibodies. Herrin BR, Alder MN, Roux KH, Sina C, Ehrhardt GR, Boydston JA, Turnbough CL Jr, Cooper MD. Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2040-5.

• Fc receptor-like 5 inhibits B cell activation via SHP-1 tyrosine phosphatase recruitment. Haga CL, Ehrhardt GR, Boohaker RJ, Davis RS, Cooper MD. Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9770-5.

• Expression of the immunoregulatory molecule FcRH4 defines a distinctive tissue-based population of memory B cells. Ehrhardt GR, Hsu JT, Gartland L, Leu CM, Zhang S, Davis RS, Cooper MD. J Exp Med. 2005 Sep 19;202(6):783-91.

• An extended family of Fc receptor relatives. Davis RS, Ehrhardt GR, Leu CM, Hirano M, Cooper MD. Eur J Immunol. 2005 Mar;35(3):674-80.
   
• Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey. Pancer Z, Amemiya CT, Ehrhardt GR, Ceitlin J, Gartland GL, Cooper MD. Nature. 2004 Jul 8;430(6996):174-80.