In lupus nephritis (LuN) renal biopsies are used to assess the extent of renal involvement, assign prognosis and to aid in making therapeutic decisions. We and other groups have demonstrated that the degree of tubulointerstitial inflammation (TH) and scarring, independent of co-variance with glomerular pathological features, predict progression to renal failure. As demonstrated in Preliminary Results, within the inflamed tubulointerstitium there was selection for repertoires of antibodies that were specific for molecules associated with inflammation including vimentin which coated the surfaces of infiltrating T cells and macrophages. These results suggest a model in which in situ adaptive immunity amplifies inflammation. While these findings identified the antigens driving in situ selection, it was not clear what co-stimulatory signals were also contributing to in situ B cell activation. With the development of novel quantitative imaging methods (Cell Distance Mapping and Analysis, CDMA, Preliminary Results), we were able to demonstrate that T follicular helper cells (TFH) cells were in tight cognate pairs with B cells. TFH-like cells and B cells were observed in the Til associated with both renal allograft T cell mediated rejection (TCMR) and mixed rejection (MR). However, in MR there were TFH-dependent and independent B cell populations while in TCMR the TFH cells appeared incompetent to form conjugates with B cells. These and other data indicate that we can identify functionally different populations of both TFH and B cells in situ. We hypothesize those T cells able to form cognate pairs with B cells in situ will have the molecular features of mature TFH cells. Furthermore, we hypothesize that the molecular signatures of competent TFH cells will be characteristic of each disease. Finally, we hypothesize that for each disease, and for each TFH cell population, different B cell functional repertoires will be selected. These hypotheses will be tested in the following Specific Aims:
Aim 1. Determine the B cell repertoire selected in situ by TFH cells in lupus nephritis.
Aim 2. To characterize the repertoire of B cells that are, and are not, selected by TFH in situ.
Aim 3. Understanding the role of T cell help in in situ autoimmunity.

Public Health Relevance

In human lupus nephritis, inflammation of the tubulointerstitium of the kidney is a strong predictor of who progresses to renal failure. In this grant proposal, we are developing and applying novel analytical tools to understand how immune responses are propagated within the tubulointerstitium of human lupus nephritis. Such studies may reveal new therapeutic targets or biomarkers of severe disease.

Agency
National Institute of Health (NIH)
Type
Research Program--Cooperative Agreements (U19)
Project #
2U19AI082724-06
Application #
8732778
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Chicago
Department
Type
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60637
Liarski, Vladimir M; Kaverina, Natalya; Chang, Anthony et al. (2014) Cell distance mapping identifies functional T follicular helper cells in inflamed human renal tissue. Sci Transl Med 6:230ra46
Steinsbø, Øyvind; Henry Dunand, Carole J; Huang, Min et al. (2014) Restricted VH/VL usage and limited mutations in gluten-specific IgA of coeliac disease lesion plasma cells. Nat Commun 5:4041
Chang, Anthony; Ko, Kichul; Clark, Marcus R (2014) The emerging role of the inflammasome in kidney diseases. Curr Opin Nephrol Hypertens 23:204-10
Kinloch, Andrew J; Chang, Anthony; Ko, Kichul et al. (2014) Vimentin is a dominant target of in situ humoral immunity in human lupus tubulointerstitial nephritis. Arthritis Rheumatol 66:3359-70
Iversen, Rasmus; Di Niro, Roberto; Stamnaes, Jorunn et al. (2013) Transglutaminase 2-specific autoantibodies in celiac disease target clustered, N-terminal epitopes not displayed on the surface of cells. J Immunol 190:5981-91
Andrews, Sarah F; Zhang, Qingzhao; Lim, Samuel et al. (2013) Global analysis of B cell selection using an immunoglobulin light chain-mediated model of autoreactivity. J Exp Med 210:125-42
Di Niro, Roberto; Mesin, Luka; Zheng, Nai-Ying et al. (2012) High abundance of plasma cells secreting transglutaminase 2-specific IgA autoantibodies with limited somatic hypermutation in celiac disease intestinal lesions. Nat Med 18:441-5
Hsieh, Christine; Chang, Anthony; Brandt, Daniel et al. (2011) Predicting outcomes of lupus nephritis with tubulointerstitial inflammation and scarring. Arthritis Care Res (Hoboken) 63:865-74
Chang, Anthony; Henderson, Scott G; Brandt, Daniel et al. (2011) In situ B cell-mediated immune responses and tubulointerstitial inflammation in human lupus nephritis. J Immunol 186:1849-60
Kaur, Kaval; Sullivan, Meghan; Wilson, Patrick C (2011) Targeting B cell responses in universal influenza vaccine design. Trends Immunol 32:524-31

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