Towards the Unbiased Identification of Antigenic Mimotopes Recognized by Alopecia Areata-Specific Human CD8+ T cells in Situ

Year: 
2016
PI Name: 
Marta Bertolini, PhD
Type:
Research Grant
Status: 
Active

Summary

This project aims to characterize the TCR chains of key alopecia areata (AA) CD8+ T cells by isolating them from lesional skin of AA  patients, to generate antigenic peptides (fragments of protein) that mimic the suspected (auto-)antigens presented to the CD8+ T cells in lesional skin of AA  patients, and to establish a test system in the lab that mimics what happens when a human TCR encounters an (auto-)antigen.

Abstract

The autoimmune hair loss disorder, alopecia areata (AA), results from an autoaggressive attack of certain white blood cells (CD8+ T-cells) directed against hair follicles (HFs) that abnormally present as yet unknown “self”-components ((auto-)antigens). These HF-associated (auto-)antigens are presented to the T-cell receptor (TCR) of CD8+ T-cells. After having previously established all relevant basic techniques to tackle the methodological challenges at hand, we shall, firstly, further characterize the TCR chains of these key AA CD8+ T-cells by isolating them directly from the clinically affected skin of AA patients. Secondly, we shall generate antigenic peptides (fragments of protein) which mimic the suspected (auto-)antigens presented to the CD8+ T-cells in lesional skin of AA patients. Consequently, we shall establish a (very complex) test system in the lab which mimics what happens when a human TCR encounters an (auto-)antigen. This will enable us to visualize, in a follow-up project, for the first time when a particular TCR of a given AA patient recognizes a particular (auto-)antigenic peptide as a crucial basis for identifying the latter. This has never been achieved before in human AA research, yet remains the key challenge for curing AA, rather than just treating it symptomatically. Overall, the proposed project promises not only a much better understanding of how AA develops in a given patient, but also constitutes a crucial first step towards developing effective, causal AA therapy that targets the relevant human (auto-)antigen(s) and/or the selfreactive, autoaggressive CD8+ T-cells so that they can be selectively inhibited or made tolerant.

Impact

If successful, this study may contribute to a much better understanding of how alopecia areata develops in a given patient, and it will also constitute a crucial first step toward developing an effective therapy that addresses the underlying cause.

Publications

  • Bertolini M, Altendorf S, Uchida Y, Zhou Q, Rossi A, Dornmair K, Paus R. Towards the clonotype analysis of alopecia areata-specific, intralesional human CD8+ T-lymphocytes [Abstract 405]. J Investig Dermatol. 2016 Sept;136(9):S229. doi: 10.1016/j.jid.2016.06.425.
  • Bertolini M, Altendorf S, Uchida Y, Below D, Kelsch R, Zhou Q, Rossi A, Dornmair K, Paus R. Analysis of the paired TCR alpha- and beta-chains of single, intralesional CD8+T-cells in alopecia areata patients [Abstract 081]. J Investig Dermatol. 2017 May;137(5):S14. doi: 10.1016/j.jid.2017.02.094.
  • Bertolini M, Altendorf S, Uchida Y, Below DA, Zhou Q, Rossi A, Dornmair K, Paus R. Towards the analysis of the paired TCR alpha‐ and beta‐chains of single alopecia areata‐specific human CD8+ T‐cells [Abstract P159 (OP03/04)]. Exp Dermatol. 2017 Mar;26(3):E68-69. doi: 10.1111/exd.13280.