Tick-Borne Encephalitis (TBE) and Hepatitis B Nonresponders Feature Different Immunologic Mechanisms in Response to TBE and Influenza Vaccination with Involvement of Regulatory T and B Cells and IL-10

Abstract

Low responsiveness/nonresponsiveness is characterized by an insufficient immune response upon primary and/or booster vaccination and affects 1–10% of vaccinees. In the current study, we aimed to investigate whether nonresponsiveness is an Ag/vaccine-specific phenomenon and to clarify underlying immunological mechanisms. Nonresponders to tick-borne encephalitis (TBE) or hepatitis B Ag with a history of previous TBE vaccinations were booster vaccinated with TBE and influenza vaccine and compared with TBE high responders in terms of humoral and cellular immune response. Postboosters in TBE high responder existing TBE titers increased, and solid humoral responses to influenza vaccine were induced. In TBE nonresponders, low to undetectable prevaccination TBE titers remained low, whereas sufficient influenza Abs were induced. In both TBE groups, a positive correlation of humoral and cellular immune response was seen as high/low TBE titers were associated with sufficient/lack of Ag-specific T cell proliferation. Furthermore, responses to influenza were robust in terms of Abs and cytokine production. In contrast, in hepatitis B nonresponders, sufficient humoral responses to TBE and influenza Ags were induced despite lacking specific IL-2 and IFN-γ production. Importantly, these patients showed high IL-10 baseline levels in vitro. HLA-DR subtypes associated with hepatitis B nonresponsiveness were overrepresented in this group, and high IL-10 levels were linked to these subtypes. Whereas TBE and hepatitis B nonresponders had increased IL-10–producing FOXP3+ T regulatory cells upon vaccination, only in hepatitis B nonresponders, showing elevated prevaccination IL-10 levels, a prominent population of B regulatory cells was detected. We conclude that immunological pathways of nonresponsiveness follow different patterns depending both on vaccine Ag and genetic predisposition of the vaccinee.

Persistence of antibodies six years after booster vaccination with inactivated vaccine against Japanese encephalitis

“…This suggests that there is a very small proportion of primary "low-responders", in our case 4% of the tested subjects. This is a phenomenon that has also been described after other vaccinations such as TBE vaccination or hepatitis A and hepatitis B vaccination [24][25][26][27][28]. Antibody kinetics in these three individuals followed a one-component decline.…”

Regulatory B cells in infectious disease

“…Generally, the established Breg subsets in humans include CD19 + CD24 + CD38 + Bregs (1,2,20,21) and CD19 + CD24 + CD27 + Bregs (22), although reports have also included the identification of CD19 + CD5 + CD1d + Bregs (23,24) and CD19 + TIM-1 + Bregs (17) in humans. However, certain phenotypes are not supported by evidence in human immunodeficiency virus (HIV)-infected individuals, which suggests human ‘Bregs’ lacking the expression of CD1d may not be Bregs.…”

“…Although IL-10 is produced by various cell types and exhibits several pleiotropic effects, the expression of IL-10 by human and mouse Bregs is central to their negative regulation of adaptive and innate immune responses (1–3,5,15,20,22,25). …”

“…2). Other reports have indicated that increased numbers of Bregs potentially contribute to elevated levels of IL-10 and induce forkhead box P3 (FOXP3) + regulatory T cells (Tregs), which exhibit broader suppressive functions (1,16). …”

“…In previous years, a novel subset of B cells, which exert immunomodulatory effects through the production of interleukin (IL)-10 and transforming growth factor-β (TGF-β) have been identified and classified as regulatory B cells (Bregs). To date, Bregs have been described in a number of reports (1–3), some of which refer to Bregs as IL-10-producing B cells or B10/Br1 cells (4,5). The role of IL-10-producing B cells was first demonstrated in a murine model of chronic intestinal inflammation (6), however, Bregs have also been reported to function in autoimmune diseases (7), allergic diseases (8,9), graft-versus-host disease (10,11) and cancer (12) through antigen-specific and non-specific immunoregulatory mechanisms.…”