The goal of this proposal is to determine the mechanisms for loss of B cell tolerance to phospholipids and mechanisms for tissue damage by anti-phospholipid antibodies in NZW/BXSB F1 (W/B) mice that develop both proliferative glomerulonephritis and anti-phospholipid syndrome. Disease is accelerated in male W/B mice that carry the Yaa locus containing a reduplication of the TLR7 gene. We have shown that T cell help is required for initial activation of anti-phospholipid B cells and induction of high affinity IgG autoantibodies. Our proposal is based on the following hypotheses: 1) Over-expression of TLR7 alters either B cell selection or B cell activation threshold, thus rendering naove B cells more prone to the T cell activation that is required for disease initiation and production of clas switched autoantibodies. 2) Immune complex formation and opsonization of apoptotic particles by IgG anti-phospholipid antibodies results in delivery of nucleic acids to TLR containing endosomes. Engagement of TLRs induces both IFN1 that fosters plasma cell maturation and BAFF that enhances B cell survival and class switching;disease can then be propagated by T cell independent mechanisms that are prominent in males bearing excess TLR7. Because excess IFN1 production is a feature of SLE and IFN1 induces upregulation of TLR7, particularly in females, similar mechanisms may pertain in individuals with the IFN signature even though genetic TLR7 overexpression has not been found in humans with SLE. To address these hypotheses, we will use mice with an autoreactive transgenic heavy chain and examine B cell selection at sequential stages of the B cell developmental pathway. This strategy will allow us to examine the role of intrinsic alterations in B cell signaling, exogenous signals from the innate immune system and T cell help in the initial loss of tolerance to autoantigens and in the perpetuation of the anti- phospholipid response. Our data will also help determine why anti-phospholipid syndrome fails to respond to conventional immunosuppressive therapies and help suggest new strategies for treating this devastating syndrome. Our third hypothesis is that pathogenic autoantibodies alone can cause the manifestations of the anti- phospholipid syndrome that are mediated by Fc receptor or complement dependent mechanisms but that the formation of thromboses requires other inflammatory mediators to activate the endothelium. We will test the hypothesis that one mechanism for this """"""""second hit"""""""" is endothelial cell death mediated via the ceramide pathway. Our long term goal is to define the interactions of the crucial pathways that contribute to induction and propagation of the anti-phospholipid syndrome so as to best devise individualized therapies for patients with SLE.

Public Health Relevance

Antiphospholipid syndrome (APS) is a devastating autoimmune condition that causes recurrent blood clots and has no effective treatment apart from lifelong anticoagulation. In patients with lupus anti-phospholipid antibodies are found more commonly and are associated clinical thromboses more often than in the general population. There is very little currently known about how the antibodies that cause APS are regulated. We use a mouse model of APS that has many similarities to the human disease. We will study the role of major components of the immune response in regulating the initiation and perpetuation of the autoimmune antibody response to phospholipids and will determine how inflammation in SLE patients triggers clotting events. Because there is a dearth of clinical trials for APS, an increased understanding of the role of the immune system in causing APS may form the basis for a rational clinical trial in this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI083901-04S1
Application #
8666335
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Johnson, David R
Project Start
2010-02-01
Project End
2015-01-31
Budget Start
2013-07-03
Budget End
2014-01-31
Support Year
4
Fiscal Year
2013
Total Cost
$44,491
Indirect Cost
$18,087
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Liu, Zheng; Davidson, Anne (2012) Taming lupus-a new understanding of pathogenesis is leading to clinical advances. Nat Med 18:871-82
Bethunaickan, Ramalingam; Sahu, Ranjit; Liu, Zheng et al. (2012) Anti-tumor necrosis factor * treatment of interferon-*-induced murine lupus nephritis reduces the renal macrophage response but does not alter glomerular immune complex formation. Arthritis Rheum 64:3399-408
Davidson, Anne (2012) The rationale for BAFF inhibition in systemic lupus erythematosus. Curr Rheumatol Rep 14:295-302
Moisini, Ioana; Huang, Weiqing; Bethunaickan, Ramalingam et al. (2012) The Yaa locus and IFN-ýý fine-tune germinal center B cell selection in murine systemic lupus erythematosus. J Immunol 189:4305-12
Huang, Weiqing; Moisini, Ioana; Bethunaickan, Ramalingam et al. (2011) BAFF/APRIL inhibition decreases selection of naive but not antigen-induced autoreactive B cells in murine systemic lupus erythematosus. J Immunol 187:6571-80
Liu, Zheng; Bethunaickan, Ramalingam; Huang, Weiqing et al. (2011) Interferon-? accelerates murine systemic lupus erythematosus in a T cell-dependent manner. Arthritis Rheum 63:219-29
Liu, Zheng; Zou, Yongrui; Davidson, Anne (2011) Plasma cells in systemic lupus erythematosus: the long and short of it all. Eur J Immunol 41:588-91
Liu, Zheng; Davidson, Anne (2011) BAFF and selection of autoreactive B cells. Trends Immunol 32:388-94
Liu, Zheng; Bethunaickan, Ramalingam; Huang, Weiqing et al. (2011) IFN-? confers resistance of systemic lupus erythematosus nephritis to therapy in NZB/W F1 mice. J Immunol 187:1506-13
Liu, Zheng; Davidson, Anne (2011) BAFF inhibition: a new class of drugs for the treatment of autoimmunity. Exp Cell Res 317:1270-7

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