Peptide microarray-based characterization of antibody responses to host proteins after bacille Calmette-Guérin vaccination.
BACKGROUND
Bacille Calmette-Guérin (BCG) is the world's most widely distributed vaccine, used against tuberculosis (TB), in cancer immunotherapy, and in autoimmune diseases due to its immunomodulatory properties. To date, the effect of BCG vaccination on antibody responses to host proteins has not been reported. High-content peptide microarrays (HCPM) offer a unique opportunity to gauge specific humoral immune responses.


METHODS
The sera of BCG-vaccinated healthy adults were tested on a human HCPM platform (4953 randomly selected epitopes of human proteins) to detect specific immunoglobulin gamma (IgG) responses. Samples were obtained at 56, 112, and 252 days after vaccination. Immunohistology was performed on lymph node tissue from patients with TB lymphadenitis. Results were analysed with a combination of existing and novel statistical methods.


RESULTS
IgG recognition of host peptides exhibited a peak at day 56 post BCG vaccination in all study subjects tested, which diminished over time. Primarily, IgG responses exhibited increased reactivity to ion transporters (sodium, calcium channels), cytokine receptors (interleukin 2 receptor β (IL2Rβ), fibroblast growth factor receptor 1 (FGFR1)), other cell surface receptors (inositol, somatostatin, angiopoeitin), ribonucleoprotein, and enzymes (tyrosine kinases, phospholipase) on day 56. There was decreased IgG reactivity to transforming growth factor-beta type 1 receptor (TGFβR1) and, in agreement with the peptide microarray findings, immunohistochemical analysis of TB-infected lymph node samples revealed an overexpression of TGFβR in granulomatous lesions. Moreover, the vesicular monoamine transporter (VMAT2) showed increased reactivity on days 112 and 252, but not on day 56 post-vaccination. IgG to interleukin 4 receptor (IL4R) showed increased reactivity at 112 days post-vaccination, while IgG to IL2Rβ and FGFR1 showed decreased reactivity on days 112 and 252 as compared to day 56 post BCG vaccination.


CONCLUSIONS
BCG vaccination modifies the host's immune landscape after 56 days, but this imprint changes over time. This may influence the establishment of immunological memory in BCG-vaccinated individuals.
Centre for Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden; Division of Therapeutic Immunology (TIM), Department of Laboratory Medicine (LABMED), Karolinska Institutet, Stockholm, Sweden.
Davide
D
Valentini
Division of Therapeutic Immunology (TIM), Department of Laboratory Medicine (LABMED), Karolinska Institutet, Stockholm, Sweden.
Martin
M
Rao
Division of Therapeutic Immunology (TIM), Department of Laboratory Medicine (LABMED), Karolinska Institutet, Stockholm, Sweden.
Lalit
L
Rane
Center for Infectious Medicine (CIM), Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Sayma
S
Rahman
Centre for Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden; Division of Therapeutic Immunology (TIM), Department of Laboratory Medicine (LABMED), Karolinska Institutet, Stockholm, Sweden.
Rebecca
R
Axelsson-Robertson
Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden.
Rainer
R
Heuchel
Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden.
Matthias
M
Löhr
Division of Immunobiology, Departments of Internal Medicine and Molecular Microbiology, Saint Louis University Medical Centre, Saint Louis, Missouri, USA.
Daniel
D
Hoft
Center for Infectious Medicine (CIM), Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Susanna
S
Brighenti
Centre for Clinical Microbiology, Division of Infection and Immunity, University College London, and NIHR Biomedical Research Centre, UCL Hospitals NHS Foundation Trust, London, UK.
Alimuddin
A
Zumla
Centre for Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden; Division of Therapeutic Immunology (TIM), Department of Laboratory Medicine (LABMED), Karolinska Institutet, Stockholm, Sweden. Electronic address: markus.maeurer@ki.se.
Markus
M
Maeurer
D000595:Amino Acid Sequence; D000917:Antibody Formation / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D001500:BCG Vaccine / Q000276:immunology*; D006801:Humans; D056724:Immunity, Humoral; D009163:Mycobacterium bovis / Q000276:immunology; D010455:Peptides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D040081:Protein Array Analysis / Q000379:methods*; D014376:Tuberculosis / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control; D014611:Vaccination
D001323:Autoantibodies; D001500:BCG Vaccine; D010455:Peptides
Bacille Calmette–Guérin; Immuno-editing; Immunoglobulin gamma; Peptide microarray