Partial tolerance of autoreactive B and T cells to erythrocyte-specific self-antigens in mice

Haematologica. 2012 Dec;97(12):1836-44. doi: 10.3324/haematol.2012.065144. Epub 2012 Jun 24.

Abstract

Background: Breakdown of humoral tolerance to RBC antigens may lead to autoimmune hemolytic anemia, a severe and sometimes fatal disease. The underlying mechanisms behind the breakdown of humoral tolerance to RBC antigens are poorly understood.

Design and methods: In order to study the pathogenesis of autoimmune hemolytic anemia, we developed a murine model with RBC-specific expression of a model antigen carrying epitopes from hen egg lysozyme and ovalbumin.

Results: Humoral tolerance was observed; this was not broken even by strong immunogenic stimulation (lysozyme or ovalbumin with adjuvant). Autoreactive CD4(+) T cells were detected by tetramer enrichment assays, but failed to activate or expand despite repeat stimulation, indicating a nonresponsive population rather than deletion. Adoptive transfer of autoreactive CD4(+) T cells (OT-II mice) led to autoantibody (anti-lysozyme) production by B cells in multiple anatomic compartments, including the bone marrow.

Conclusions: These data demonstrate that B cells autoreactive to RBC antigens survive in healthy mice with normal immune systems. Furthermore, autoreactive B cells are not centrally tolerized and are receptive to T-cell help. As the autoreactive T cells are present but non-responsive, these data indicate that factors that reverse T-cell non-responsiveness may be central to the pathogenesis of autoimmune hemolytic anemia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autoantigens / immunology*
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Erythrocytes / cytology
  • Erythrocytes / immunology*
  • Erythrocytes / metabolism
  • Flow Cytometry
  • Humans
  • Immune Tolerance / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Muramidase / immunology*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology

Substances

  • Autoantigens
  • hen egg lysozyme
  • Muramidase