Borrelia burgdorferi-Induced Changes in the Class II Self-Immunopeptidome Displayed on HLA-DR Molecules Expressed by Dendritic Cells

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.

An Unusual Case of Lyme Carditis With Persistent Third-Degree Heart Block

“…Instead, immune cells cross-react and affect neighboring healthy host cells. 2 Borrelia is also observed to form a biofilm or biofilm-like material responsible for antibiotic resistance, evading immune response, and chronic persisting symptoms. 3 More invasive forms of borreliosis express multiple plasminogen-binding surface proteins that degrade fibronectin (a component of the extracellular matrix) and induce the release of metalloproteases, causing basement membrane degradation, all of which assist in dissemination.…”

Case Report: PANDAS and Persistent Lyme Disease With Neuropsychiatric Symptoms: Treatment, Resolution, and Recovery

“…A basic metabolic panel, CBC, urinalysis, ESR, and ANA were completely within normal limits. Genetic testing indicated that the patient was a carrier of the HLA-DRB1, 2 , and 4 genes which are reported to occur more frequently in patients with Lyme disease and rheumatoid arthritis ( 17 – 19 ). It is also been observed that B. burgdorferi can alter the repertoire of self-peptides bound to MHC class II molecules and influence the likelihood of autoreactive T-cells which could lead to infection-induced autoimmune illnesses ( 20 ).…”

Unconventional Approaches to Direct Detection of Borreliosis and Other Tick Borne Illnesses: A Path Forward

“…Explanations range from 1) “hit and run” by the pathogen followed by persistent autoimmunity, or residual tissue damage, after the resolution of active infection [ 12 ], 2) persistent latent or smoldering infection [ 13 ] in systemic tissues and organs distant from the tick bite skin site, to, 3) immune cloaking and immune dysregulation. A novel mechanism for dysregulated immunity, beyond peptide mimicry [ 14 ], has been recently proposed [ 15 ]. New experimental data suggest that Borrelia alters the repertoire of self-peptides bound to MHC II class molecules in professional antigen presenting cells, and induces overexpression of self-antigen presenting MHC II molecules [ 15 ].…”

“…A novel mechanism for dysregulated immunity, beyond peptide mimicry [ 14 ], has been recently proposed [ 15 ]. New experimental data suggest that Borrelia alters the repertoire of self-peptides bound to MHC II class molecules in professional antigen presenting cells, and induces overexpression of self-antigen presenting MHC II molecules [ 15 ]. Authors propose that high levels of MHC II molecule expression above the threshold of established tolerance mechanisms, can induce lymphocyte activation and stimulate an immune response against self-antigens [ 15 ].…”

“…New experimental data suggest that Borrelia alters the repertoire of self-peptides bound to MHC II class molecules in professional antigen presenting cells, and induces overexpression of self-antigen presenting MHC II molecules [ 15 ]. Authors propose that high levels of MHC II molecule expression above the threshold of established tolerance mechanisms, can induce lymphocyte activation and stimulate an immune response against self-antigens [ 15 ]. In parallel, there is also evidence that Borrelia can persist in affected tissues in humans for months or years [ 16 ].…”