Abstract
The MHC class II antigen processing and presentation pathway has evolved to derive short amino acid peptides from proteins that enter the endocytic pathway, load them onto MHC class II molecules and display them on the surface of antigen presenting cells for recognition by CD4+ T cells. Under normal circumstances, peptides bound to MHC class II molecules are derived from host (self) proteins and not recognized by T cells due to tolerance mechanisms. Pathogens induce significant changes in the biology of antigen presenting cells, including upregulation of MHC processing and presentation. We therefore hypothesized that exposure to pathogens may alter the repertoire of self-peptides bound to MHC class II molecules. To test this hypothesis, we isolated monocyte-derived dendritic cells from healthy subjects, exposed them to the TLR-2 agonist lipoteichoic acid or live Borrelia burgdorferi, the causative agent of Lyme disease, and isolated and characterized HLA-DR associated peptides using mass spectrometry. Our results show that lipoteichoic acid-stimulated, B. burgdorferi-stimulated and unstimulated monocyte-derived dendritic cells largely derive their self-peptides from similar overlapping sets of host proteins. However, lipoteichoic acid and B. burgdorferi stimulation promote the processing and presentation of new sets of HLA-DR associated self-peptides derived from unique protein sources. Examination of processes and compartments these proteins reside in, indicate that activation of monocyte-derived dendritic cells changes the range of host self-proteins available for processing and presentation on MHC class II molecules. These findings reveal that the HLA-DR-bound self-immunopeptidome presented by mo-DCs is dynamic in nature and changes with activation state reflective of cellular function. In addition, among the repertoire of self-peptides bound to HLA-DR are several epitopes known to be recognized by autoreactive T cells. These studies are relevant to our basic understanding of pathogen-induced changes in monocyte-derived dendritic cell function, and the mechanisms involved in infection-induced autoimmune illnesses such as Lyme arthritis.
Highlights
Lyme disease is an inflammatory illness initiated by infection with the Borrelia burgdorferi spirochete following a bite from an infected Ixodes tick [1]
Given the importance of DCs in the initiation of T cell-dependent responses and the key role for CD4+effector T cells in human Lyme disease pathogenesis, we investigated the consequences of B. burgdorferi interaction with human monocyte-derived dendritic cells in vitro
Our results showed that B. burgdorferi strains A3 and B31 at multiplicities of infection of 1 or 10, induce upregulation of HLADR on the surface of monocyte-derived dendritic cells (mo-DCs) in a time and dose dependent manner when compared to unstimulated mo-DCs and those stimulated with lipoteichoic acid (LTA) (Figure 1)
Summary
Lyme disease is an inflammatory illness initiated by infection with the Borrelia burgdorferi spirochete following a bite from an infected Ixodes tick [1]. A number of patients with undetected and untreated early Lyme disease will develop lateonset musculoskeletal (Lyme arthritis) or neurological symptoms (Neuroborreliosis) [3]. While the acute infection and lateonset disease can be controlled by antibiotic therapy, in a subset of patients, arthritis with inflammation can be antibioticrefractory [4]. This outcome has been termed post-infectious Lyme arthritis, with autoimmune processes presumed to play a major role and controversial, bacterial persistence cannot be excluded from contributing to the development of the illness [5]. Infection with B. burgdorferi triggers poorly understood immune processes, and considering the rising incidence of Lyme disease as well as the complexity of disease outcomes, a deeper understanding of the immune-mediated process triggered by Borrelia is needed
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