Infection of C3HeB/FeJ mice with the docile strain of lymphocytic choriomeningitis virus induces autoantibodies specific for erythrocyte Band 3

Abstract

SUMMARYC3HeB/FeJ mice infected with the docile strain of lymphocytic choriomeningitis virus ( LCMV-d) develop a persistent infection with a transient haemolytic anaemia. Immunoglobulin can be eluted from the red blood cells ( RBC ) of these mice but it cannot be detected on the RBC by a conventional antiglobulin test. The present study demonstrates that RBC from such mice bear erythrocyte autoantibodies which are predominantly of the IgG2a subclass, with lower levels of autoantibodies of the IgG1, IgG2b and IgG3 subclasses. To identify the target antigen the autoantibodies were eluted from the RBC of LCMV-infected mice. The eluted autoantibody bound to intact normal RBC and precipitated a 105 000 MW component that corresponds to murine Band 3 protein. A monoclonal antibody derived from mice infected with LCMV-d also precipitated mouse Band 3, and reacted specifically by enzyme-linked immunosorbent assay against a purified preparation of Band 3. This study has shown that in C3H mice infected with LCMV-d which develop autoimmune haemolytic anaemia, the target autoantigen is erythrocyte membrane Band 3.

Controlling autoimmunity—Lessons from the study of red blood cells as model antigens

“…The major canine RBC autoantigens are the glycophorins, with Band 3 targeted by autoantibodies from some cases [11]. In mice, Band 3 is the dominant autoantigen in NZB disease [13,17] and is also recognized by RBC antibodies in the forms of AIHA induced by cross-reactivity with rat red blood cells [12], or by LCMV infection [16].…”

“…This conclusion does not exclude the possibility that factors that predispose to autoimmune conditions [1], such as inheritance of particular MHC types, mediate their influence by shaping the helper repertoire. For example, in AIHA induced by LCMV, which only occurs in C3HeB/FeJ mice [15,16], the fine specificity or avidity of Th cells selected by the class II molecules in the thymus may help to determine a response to infection that provokes autoimmune pathology via molecular mimicry.…”

“…However, this obstacle has been overcome in number of conditions that are antibody-mediated, where techniques such as immunoblotting and immunoprecipitation can be used to determine the antibody specificity [1]. Red blood cells (RBC) have not only been model antigens for basic immunological Human AIHA Rh proteins [9,10] Rh proteins [25] Yes [26] IL-10 response to dominant naturally processed Rh protein epitopes [45] Glycophorin A [9,10] Band 3 [10] Canine AIHA Glycophorins [11,33] Glycophorins [33] Yes [32] Not examined Band 3 [11] Murine AIHA NZB mouse Band 3 [13,17] Band 3 [21][22][23][24] Not applicable Weak IL-10 response to Band 3 [24] Band 4.1 (pr) [17] Phosphatidyl choline (pr) [17] Induced by rat RBC Band 3 (cr) [12] Band 3 [31] Yes [4] Recovery due to suppression by CD25 + cells and IL-10 + cells (auo) of auto, but not anti-rat, response [52,4] Glycophorins (cr) [12] Induced by LCMV Band 3 [16] Not examined Yes [4] Not examined Dominant antigen in bold; pr, polyreactive antibody, also binds nuclear antigens, e.g. histones; cr, cross-reacts with rat RBC antigen; auo, authors' unpublished observations.…”

“…There are also important examples of AIHA in laboratory mice [2,3]. The New Zealand Black (NZB) mouse [2,13] develops AIHA spontaneously, and the disease can also be induced in healthy murine strains by repeated immunization with rat red blood cells [4,12], or by infection of C3HeB/FeJ mice with the docile strain of lymphocytic choriomenigitis virus (LCMV) [15,16]. In all species, the condition is a classic example of type II hypersensitivity, characterized by autoantibodies that bind RBC and reduce their life span through phagocytosis by splenic macrophages and/or complement-mediated lysis [5,6].…”

Public, private and non-specific antibodies induced by non-cytopathic viral infections

“…Conversely, polyclonal B-cell activation might generate a potentially harmful repertoire of IgG specificities that could be potentially auto-reactive, thereby enhancing the risk of auto-immunity or immune complex disease [64,65]. Autoimmune thrombocytopenia is a common complication of HIV infection in humans [66], and antibody-dependent autoimmune haemolytic anemia has been described following LCMV infection of some mouse strains [67]. However, autoantibodies following HIV infection were not found to be associated with clinical autoimmune manifestations [68], indicating that auto-reactive antibodies may often be of a low affinity or avidity.…”