Hsu, Hui-Chen, PhD
Associate Professor of Medicine
Shelby Building, Room 311
1825 University Boulevard
Dr. Hsu's webpage in the School of Medicine
BS, Chinese Culture University, Taipei, Taiwan, 1986
MS, Rutgers University, New Brunswick, NJ, 1990
PhD, Rutgers University, New Brunswick, NJ, 1995
Postdoctoral Fellow, University of Alabama at Birmingham, 1999
We have identified that autoimmune BXD2 mice exhibit unique features, including spontaneous formation of germinal centers, increased expression of activation-induced cytidine deaminase (AID), increased production of pathogenic autoantibodies that are polyreactive, significantly increased percentage of IL-17high CD4 TH cells (TH-17) and IL-17Rhigh B cells, and significantly increased numbers of type I interferon producing plasmacytoid dendritic cells in the spleens of these mice. We are currently studying the interconnection of high IL-17, high type I IFN and the development of spontaneous germinal centers in these mice. We have identified that a small population of B cells, known as marginal zone precursor B cells (MZ-P) that can be located in either the marginal zone or inside the follicle, express high levels of interferon alpha receptor (IFNaR). We showed that, in BXD2 mice, type I IFNs strongly signaled through IFNaR on these MZ-P B cells more than any other mature B cell subpopulations, which up-regulated the co-stimulatory molecule CD86 and the activation molecular CD69, but interestingly, down-modulated the effects of another localization molecule known as sphingosine-1-phosphate (S1P). S1P has been described as playing a key role in anchoring B cells in the marginal zone. However, under the influence of IFNaR signaling, down-regulation of the effects of S1P enables displacement of the MZ-P B cell from the marginal zone to the germinal center. In addition, these MZ-P B cells can carry antigens that they acquire in the marginal zone, and deliver them to the germinal center. At the same time, the MZ-P B cells serve as excellent antigen-presenting B cells to CD4 T cells in the germinal center light zone, and can intensify a germinal center response. These mechanisms were verified using BXD2 mice that lacked either the IFNaR or lacked the CD86 co-stimulatory molecule. Further understanding of the novel mechanisms of up-regulation of type I IFN by pDCs around autoantibody-producing germinal centers, and the development and delivery of autoantigens by MZ-P B cells is being analyzed to develop novel therapies for treatment of systemic lupus erythematosus.
We are developing new lupus mouse models to study the safety and efficacy of using an anti-human DR5 antibody (TRA-8) as novel therapy of lupus and other autoimmune diseases. Death receptor 5 (DR5) is a cell surface receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Investigators at UAB have generated a unique anti-human DR5 antibody (TRA-8) that triggers the death of DR5+ cells. TRA-8 was selected due to its signaling of apoptosis (differing from TRAIL, which can induce proliferation). We have recently identified that TRA-8 exhibits a unique function to kill CD4 T cells and inflammatory macrophages. We have developed a transgenic mouse model that expresses a Floxed-STOP humanized DR5 mouse transgene (hu/mo DR5 Tg) and have expressed this hu/mo DR5 Tg in macrophages in autoimmune mice that develop lupus-like disease. The ongoing project is to test the method of action and effectiveness of TRA-8 in depleting inflammatory cells to determine its potential utility as a therapy for patients with autoimmune and inflammatory diseases.
Li H, Wu Q, Li J, Yang P, Zhu Z, Luo B, Hsu H-C, and Mountz JD. 2013. Cutting Edge: Defective follicular exclusion of apoptotic antigens due to marginal zone macrophage defects in autoimmune BXD2 mice. J Immunol 190(9):4465-9. PMC3656168.
Hwang Y, Hsu H-C, Lim F, Wu Q, Yang P, Fisher G, Hunter GR and Mountz JD. 2013. Increased vitamin D is associated with decline of naïve, but accumulation of effector, CD8 T cells during early aging. Advances in Aging Research 2(2), 72-80.
Wang JH, New JS, Xie S, Yang PA, Wu Q, Li J, Luo B, Ding Y, Druey KM, Hsu H-C
, and Mountz JD. 2013. Extension of the germinal center stage of B-cell development promotes autoantibodies in BXD2 mice. Arthritis & Rheum
65(10), 2703-2712. (Supplementary Table
Li J, Yang PA, Wu Q, Li, H, Ding Y, Hsu H-C,
Spalding DM, and Mountz JD. 2013. Death receptor 5-targeted depletion of interleukin 23 producing macrophages, Th1, and Th1/17 associated with defective tyrosine phosphatase in mice and patients with rheumatoid arthritis. Arthritis & Rheum 65(10), 2594-2605. (Supplementary Table
Ding Y, Li J, Wu Q, Yang P, Luo B, Xie S, Druey KM, Zajac AJ, Hsu H-C, and Mountz JD. 2013. IL-17RA is essential for optimal localization of follicular T helper cells in the germinal center light zone to promote autoantibody-producing B cells. J Immunol 191:1614-1624.
Li J, Hsu HC,
Yang P, Wu Q, Li H, Edgington LE, Bogyo M, Kimberly RP, Mountz JD. 2011. Treatment of arthritis by macrophage depletion and immunomodulation: Testing an apoptosis-mediated therapy in a humanized death receptor mouse model. Arthritis Rheum
. doi: 10.1002/art.33423 PMID: 22006294
[Epub ahead of print]. Supplementary Table 1
Mountz JD, Li J, Hsu HC.
Systemic autoimmunity caused by Fas deficiency in macrophages - a new perspective of the first identified autoimmune gene. Arthritis Rheum.
2011 Dec 2. doi: 10.1002/art.34321. [Epub ahead of print] No abstract available. PMID: 22139895
, Zhou T, Kim H, Barnes S, Yang P-A, Wu Q, Zhou J, Freeman BA, Luo M and Mountz, JD. 2006. Production of a novel class of polyreactive pathogenic autoantibodies in BXD2 mice causes glomerulonephritis and arthritis. Arthritis Rheum
54:343-355. PMID: 16385526
, Scott DK, Zhang P, Yang P, Wu Q, Shroeder HW Jr, Gerald LB, Ravssin E, Jazwinski M and Mountz JD. 2006. CD8 T-cell immune phenotype of successful aging. Mech Ageing Dev
, 127:231-239. PMID: 16313945
Chen J, Wu Q, Yang P, Hsu H-C
and Mountz JD. 2006. In vivo
analysis of adenovirus-specific cytotoxic T lymphocyte response in mice deficient in CD28, fas ligand, and perforin. Hum Gene Ther
17:669-682. PMID: 16776575
Chen J, Wu Q, Yang P, Hsu H-C
and Mountz JD. 2006. Determination of specific CD4 and CD8 T cell epitopes after AAV2- and AAV8-hF.IX gene therapy. Mol Ther
13:260-269. PMID: 16324888
, Wu Y, Yang P, Wu Q, Fitzgerald A, Chen J, Job G, Wang J, Accatitti-Loper MA, Grizzle WE, Carter RH and Mountz JD. 2007. Over-expression of AID in B cells is associated with production of highly pathogenic autoantibodies. J Immunol
178:5357-5365. PMID: 17404321
, Yang PA, Wu Q, Riley M, Wang J, Chen J, Tousson A, Stanus AA, Le TV, Xu H, Lorenz RG,
Kolls J, Carter RH, Chaplin D, Lu L, Williams RW and Mountz JD. 2008. Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nature Immunol
9:166-175. PMID: 18157131
Wang, J, Li J, Wu Q, Yang PA, Pawar RD, Xie S, Timares L, Raman C, Chaplin DD, Lu L, Mountz JD, and Hsu H-C.
2010. Marginal Zone Precursor B Cells as Cellular Agents for Type I IFN Promoted Antigen Transport in Autoimmunity. Journal Immunol, 184:
442-451. PMID: 19949066
Xie S, Hsu H-C,
Wang J, Wu Q, Li H, Li J, and Mountz JD. 2010 IL-17 activates the classical NF-kB signaling pathway to upregulate chemokine signal inhibitor molecules RGS16 and RGS13 in autoimmune B cells of BXD2 mice. J. Immunol.,
184: 2289-2296. PMID: 20139273
Chen J, Li J, Lim FC, Wu Q, Douek DC, Scott DK, Ravussin E, Hsu H-C
, Jazwinski SM, Mountz JD 2010; for The Louisiana Healthy Aging Study. Maintenance of naïve CD8 T cells in nonagenarians by leptin, IGFBP3 and T3. Mech Ageing Dev,
131:29-37 PMID: 19941883
Mountz JD. 2010 Metabolic syndrome, hormones, and maintenance of T cells during aging. Curr Opin Immunol.
22(4): 541-548 PMID: 20591642
Jazwinski SM, Kim S, Dai J, Li L, Bi X, Jiang JC, Arnold J, Batzer MA, Walker JA, Welsh DA, Lefante CM, Volaufova J, Myers L, Su LJ, Hausman DB, Miceli MV, Ravussin E, Poon LW, Cherry KE, Welsch MA; Georgia Centenarian Study and the Louisiana Healthy Aging Study. HRAS1 and LASS1 with APOE are associated with human longevity and healthy aging. Aging Cell.
9(5):698-708. doi: 10.1111/j.1474-9726.2010.00600.x. PMID: 20569235
, Yang PA, Wu Q, Wang J, Godwin J, Guentert T, Li J, Stockard CR, Le T, Chaplin DD, Grizzle WE, and Mountz, JD. Inhibition of the catalytic function of activation-induced cytidine deaminase (AICDA) promotes apoptosis of germinal center B cells. Arthritis Rheum
, 2011 Jan 21. doi: 10.1002/art.30257. PMID: 21305519
Wang JH, Wu Q, Yang PA, Li H, Li J, Mountz JD and Hsu H-C.
Type I IFN-dependent CD86high
marginal zone-precursor B cells are potent T-cell costimulators. Arthritis Rheum
, 2011 Jan 10. [Epub ahead of print]; PMID: 21225691
Mountz, JD, Wang JH, Xie S and Hsu H-C.
Cytokine regulation of B-cell migratory behavior favors formation of germinal centers in autoimmune disease. Discovery Medicine
11(56):76-85, 2011. PMID: 21276413
, Yang P, Wu Q, Wang J, Job G, Guentert T, Li J, Stockard CR, Le TV, Chaplin DD, Grizzle WE, Mountz JD. 2011. Inhibition of the catalytic function of activation-induced cytidine deaminase (AICDA) promotes apoptosis of germinal center B cells. Arthritis Rheum.
doi: 10.1002/art.30257. [Epub ahead of print] PMID:21305519
Last Updated on September 11, 2013