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

Abstract

The online version of this article has a Supplementary Appendix. BackgroundBreakdown 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 MethodsIn 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. ResultsHumoral 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. ConclusionsThese 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.Key words: tolerance, B cells, T cells, erythrocyte-specific, self-antigen.Citation: Hudson KE, Hendrickson JE, Cadwell CM, Iwakoshi NN, and Zimring JC. Partial tolerance of autoreactive B and T cells to erythrocyte-specific self-antigens in mice. Haematologica 2012;97(12):1836-1844. doi:10.3324/haematol.2012 This is an open-access paper. Partial tolerance of autoreactive B and T cells to erythrocyte-specific self-antigens in mice ABSTRACT© F e r r a t a S t o r t i F o u n d a t i o n

Erythrophagocytosis by plasmacytoid dendritic cells and monocytes is enhanced during inflammation

“…B cells were also investigated for their role in RBC clearance. Autoreactive B cells specific for RBC antigens have been identified in murine models and it is hypothesized that B‐cell receptors specific for RBCs could be generated through random VDJ recombination . As such, we hypothesized that B cells contribute to RBC clearance.…”

“…Autoreactive B cells specific for RBC antigens have been identified in murine models and it is hypothesized that B-cell receptors specific for RBCs could be generated through random VDJ recombination. 30,31 As such, we hypothesized that B cells contribute to RBC clearance. Splenocytes stained to delineate transitional, follicular, and marginal zone B cells (Fig.…”

Erythrocytes as Carriers for Drug Delivery in Blood Transfusion and Beyond

“…Recently developed models[118] have demonstrated some unique aspects of how RBCs interface with the host immune system, including “antigen modulation” by C3 on the RBC surface[119], and resistance of a subset of allogeneic RBCs to antibody mediated clearance[120]. Importantly, erythroid-specific expression of otherwise strongly immunogenic antigens, was able to induce humoral tolerance in mouse models[121]. …”

Drug delivery by erythrocytes: “Primum non nocere”

“…There are reports of reduction of immune reactions, and even induction of tolerance, by loading on or within RBCs [10,37–41]. However, as is evident in allo-immunization after transfusion, the opposite reaction also may occur [42], and is likely to be interdependent on the loading approach and underlying status of the patient.…”