The focus of the University of Chicago ACE (UCACE) is in situ human autoimmunity. During the last funding cycle, we successfully developed techniques to fully characterize the transcriptional state of single B cells and plasmablasts sorted from tissue samples and to pair this with analyses of functional immunoglobulin repertoire. Application of this approach to lupus tubulointerstitial inflammation (TII) and renal acute mixed allograft rejection (AMR) suggest that the activation state, antigenic repertoire and mechanisms of antigenic-driven B cell selection in human inflammation is fundamentally different than that typically observed in secondary lymphoid organs (Collaborative Project). In Celiac disease, B cells expressing transglutaminase 2 (TG2) specific antibodies are massively expanded in the duodenal mucosa. A highly-restricted repertoire of VH genes encode these antibodies, most notably VH5-51. Remarkably, this VH gene is also over-represented in the recirculating IgA+ B cell pool which is rich in anti-microbial activity. These findings suggest a model in which microbial antigens select for pathogenic TG2 reactive antibodies in susceptible hosts (Principle Project). Our second technical innovation is unique to the UCACE (Collaborative Project). Previous work has demonstrated that by quantifying the distance between T and B cells in multicolor confocal images (Cell Distance Mapping, CDM) we could identify competent TFH cells and functional relationships with B cells. We have now implemented a deep convolutional neural network (DCNN) that accurately identifies both cell position and shape in multicolor confocal images. In mice, analysis of the DCNN output (CDM3) indicates that T cell shape as a function of distance from dendritic cells (DCs) discriminates between cognate and non- cognate T cell:DC interactions with a sensitivity and specificity approaching that of two-photon emission microscopy (TPEM). In lupus TII, CDM3 both confirmed that myeloid DCs present antigen to CD4+ T cells in situ and identified plasmacytoid DCs as an important antigen presenting cell (APC) in severe TII. Finally, in the Pilot Project, we are applying microfluidics to develop in vitro culture systems capable of studying cognate interactions between single cells. These projects demonstrate a novel pipeline of methodologies to identify in situ cell populations, characterize their function and quantify the adaptive cell networks through which they cooperate to drive local adaptive immunity and inflammation.

Public Health Relevance

The focus of the University of Chicago Autoimmunity Center of Excellence is in situ adaptive autoimmunity. Across autoimmune diseases such as lupus nephritis, rheumatoid arthritis and Celiac disease, local immune responses in affected tissues drive tissue damage leading to overall morbidity and mortality. The purpose of the UCACE is to better understand these in situ adaptive mechanisms, which will enable the development of more effective and less toxic therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI082724-12
Application #
9920098
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Johnson, David R
Project Start
2009-06-10
Project End
2024-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
12
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Kinloch, Andrew J; Kaiser, Ylva; Wolfgeher, Don et al. (2018) In Situ Humoral Immunity to Vimentin in HLA-DRB1*03+ Patients With Pulmonary Sarcoidosis. Front Immunol 9:1516
Chen, Yao-Qing; Wohlbold, Teddy John; Zheng, Nai-Ying et al. (2018) Influenza Infection in Humans Induces Broadly Cross-Reactive and Protective Neuraminidase-Reactive Antibodies. Cell 173:417-429.e10
Henry, Carole; Palm, Anna-Karin E; Krammer, Florian et al. (2018) From Original Antigenic Sin to the Universal Influenza Virus Vaccine. Trends Immunol 39:70-79
Wilson, Patrick C; Cobey, Sarah (2018) Characterization of the immunologic repertoire: A quick start guide. Immunol Rev 284:5-8
Stamper, Christopher T; Wilson, Patrick C (2018) What Are the Primary Limitations in B-Cell Affinity Maturation, and How Much Affinity Maturation Can We Drive with Vaccination? Is Affinity Maturation a Self-Defeating Process for Eliciting Broad Protection? Cold Spring Harb Perspect Biol 10:
Leon, Paul E; Wohlbold, Teddy John; He, Wenqian et al. (2017) Generation of Escape Variants of Neutralizing Influenza Virus Monoclonal Antibodies. J Vis Exp :
He, Wenqian; Chen, Chi-Jene; Mullarkey, Caitlin E et al. (2017) Alveolar macrophages are critical for broadly-reactive antibody-mediated protection against influenza A virus in mice. Nat Commun 8:846
DiPiazza, Anthony; Nogales, Aitor; Poulton, Nicholas et al. (2017) Pandemic 2009 H1N1 Influenza Venus reporter virus reveals broad diversity of MHC class II-positive antigen-bearing cells following infection in vivo. Sci Rep 7:10857
Lau, Denise; Lan, Linda Yu-Ling; Andrews, Sarah F et al. (2017) Low CD21 expression defines a population of recent germinal center graduates primed for plasma cell differentiation. Sci Immunol 2:
Bunker, Jeffrey J; Erickson, Steven A; Flynn, Theodore M et al. (2017) Natural polyreactive IgA antibodies coat the intestinal microbiota. Science 358:

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