The majority of research on the etiology of autoimmune diseases is focused on dysregulation of T-cell and B-cell tolerance mechanisms as the primary causes of these diseases. However, there is a growing realization that innate immune cells can be major contributors to autoimmunity. Mice lacking the Src-family kinase Lyn, which is expressed in B-lympocytes and innate immune cells, develop a profound autoimmune syndrome that resembles human systemic lupus erythematosus. These mice produce a number of autoreactive Abs, including anti-dsDNA, anti-RNA and anti-nuclear Abs that lead to immune complex deposition in the kidneys and progressive glomerulonephritis. A number of studies have focused on alteration in B-cell signaling thresholds, leading to abnormal B-cell selection, as the mechanism of autoimmunity in /yn""""""""x"""""""" mice. Lyn deficiency causes severe dysregulation in the myeloid cell compartment as well, characterized by hyperproliferative responses and increased cytokine secretion following stimulation with a number of agonists. By generating a series of mixed chimeric mice containing only yri''myeloid cells, but WT B-cells and T-cells, we have found that the hyperreactive Lyn-deificient myeloid cells alone are sufficient to drive selection of WT autoreactive B-cells, leading to production of anti-dsDNA, anti-RNA and ANA autoAbs resulting in immune complex deposition in the kidneys. Interestingly, both regular /yn""""""""A mice and the lyn''myeloid cell chimeras have very high levels of serum BAFF, a cytokine produced by innate immune cells that has been implicated in autoimmunity in both mouse and man. The central hypothesis of this application is that overproduction of BAFF by Lyn deficient innate immune cells, in response to endogenous TLR ligands or interferons, plays a major role in the autoimmune process in this model. We will test this hypothesis in three specific aims: 1) analysis of macrophage, dendritic cell and neutrophil lineage specific mutations of Lyn kinase, using a newly generated lyn conditional knockout mouse, to define which innate immune cell lineage is responsible for driving autoimmunity;2) use of lentiviral or mAb mediated means to reduce serum BAFF levels and ask whether this will amerliorate autoimmunity in yri'~ or yri'~ myeloid chimeric mice;3) determine whether chronic TLR stimulation, leading to elevated production of IFNy may be responsible for driving hyperactive Lyn-deficient myeloid cells to produce BAFF, thus exacerbating autoimmunity. Our project will depend on collaborations with other projects in this PO1, both to provide us reagents and insight to investigate autoimmune mechanisms in lyn mice as well as to investigate potential aspects of autoimmunity in other models within the group. (LAY): Autoimmune diseases such as rheumatoid arthritis and lupus are caused by multiple immune system defects. This project will focus on the idea that genetic mutations that affect immune cells adapated to fight infectious pathogens, referred to as the innate immune system, can also lead to autoimmune disease in a mouse model. If this hypothesis is validated, it will significantly alter our understanding of autoimmunity in human patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI078869-05
Application #
8381253
Study Section
Special Emphasis Panel (ZAI1-MP-I)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$374,609
Indirect Cost
$130,911
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Molofsky, Ari B; Van Gool, Frédéric; Liang, Hong-Erh et al. (2015) Interleukin-33 and Interferon-γ Counter-Regulate Group 2 Innate Lymphoid Cell Activation during Immune Perturbation. Immunity 43:161-74
Abram, Clare L; Roberge, Gray L; Hu, Yongmei et al. (2014) Comparative analysis of the efficiency and specificity of myeloid-Cre deleting strains using ROSA-EYFP reporter mice. J Immunol Methods 408:89-100
Hua, Zhaolin; Gross, Andrew J; Lamagna, Chrystelle et al. (2014) Requirement for MyD88 signaling in B cells and dendritic cells for germinal center anti-nuclear antibody production in Lyn-deficient mice. J Immunol 192:875-85
Mayadas, Tanya N; Cullere, Xavier; Lowell, Clifford A (2014) The multifaceted functions of neutrophils. Annu Rev Pathol 9:181-218
Van Gool, Frédéric; Molofsky, Ari B; Morar, Malika M et al. (2014) Interleukin-5-producing group 2 innate lymphoid cells control eosinophilia induced by interleukin-2 therapy. Blood 124:3572-6
Lamagna, Chrystelle; Hu, Yongmei; DeFranco, Anthony L et al. (2014) B cell-specific loss of Lyn kinase leads to autoimmunity. J Immunol 192:919-28
Hammer, Gianna Elena; Ma, Averil (2013) Molecular control of steady-state dendritic cell maturation and immune homeostasis. Annu Rev Immunol 31:743-91
Molofsky, Ari B; Nussbaum, Jesse C; Liang, Hong-Erh et al. (2013) Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J Exp Med 210:535-49
Lamagna, Chrystelle; Scapini, Patrizia; van Ziffle, Jessica A et al. (2013) Hyperactivated MyD88 signaling in dendritic cells, through specific deletion of Lyn kinase, causes severe autoimmunity and inflammation. Proc Natl Acad Sci U S A 110:E3311-20
Graham, Michelle T; Abram, Clare L; Hu, Yongmei et al. (2013) Expression of the TEL-Syk fusion protein in hematopoietic stem cells leads to rapidly fatal myelofibrosis in mice. PLoS One 8:e77542

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