Our knowledge about the etiology of AIHA is still limited. Factors that may play a role are antigen mimicry; immune deficiency; and, to a lesser extent, probably genetic factors. AIHA, similar to other autoimmune diseases, is a consequence of the loss of immunologic (self-) tolerance against antigens expressed on the erythrocyte surface. Production of RBC antibodies is a result of the interaction of T and B cells, as well as regulatory factors (e.g., T-regulatory cells, cytokines). Disturbances of the Th1/2 T-cell subset balance with IL-10/IL-12 imbalance toward Th2 cells as well as the occurrence of clonal regulatory T cells specific for a RBC autoantigen have been described. Moreover, BAFF-dependent B-cell and plasma-cell activation plays a role with the possible emergence of long-lived autoreactive plasma cells.
This may be linked to the fact that AIHA does not only occur in immunocompetent individuals but frequently occurs in patients with acquired B or T-cell defects such as CLL, common variable immunodeficiency (CVID), HIV infection, or immunosuppressive therapy, particularly after stem-cell or solid-organ transplantation. Polymorphisms or altered expression of negative regulators of T-cell responses such as cytotoxic T lymphocyte antigen 4 (CTLA4) or interleukin-10 may also play a role. Mouse models (New Zealand black mice) have revealed an association of genetic loci with antierythrocyte antibody production or cold agglutinin escape tolerance after Mycoplasma infection.
Various target antigens have been described, with Rhesus polypeptides, glycophorin A, and erythrocyte band 3 being the most prominent in wAIHA. Cold reactive antibodies frequently target the I or i blood group-specific antigens. Events linked to the development of secondary AIHA by induction of cross-tolerance (molecular mimicry) are infections (M. pneumoniae [I antigen target], parvovirus B19, herpes viruses), neoplastic diseases (paraneoplasia), and drugs by various mechanisms. Important differences exist in the pathogenesis of wAIHA and cAIHA. The pathogenesis of primary wAIHA is largely unknown. Secondary wAIHA is a complication of several congenital or acquired immune deficiencies. Both moderate (e.g., in CLL) and severe (HIV, post-trans plant, congenital severe T-cell deficiencies) T-cell and humoral immune deficiency predispose to wAIHA, but no correlation has been established between the type and severity of immune deficiency and the risk of AIHA. One poorly understood phenomenon is the lack of a clear relationship between the presence of RBC antibodies and anemia. In many instances, no anemia is present despite a strongly positive DAT or high titers of cAIHAs. There is also only a poor correlation between antibody titers and severity of anemia. Another unexplained finding in secondary AIHA is the occurrence of both wAIHAs and cAIHAs in the same condition, for example, in lymphomas or infections.
Antibodies in primary AIHA are frequently polyreactive and polyclonal (no clonal B cells detected by polymerase chain reaction [PCR]). Antibodies in CAD are mostly produced by PCR-detectable, oligoclonal, or monoclonal B-cell populations. The nature of these antibodies has been extensively studied in CAD. However, in only a few cases has it been established that the RBC antibody is clonal. In most reports, clonality of RBC antibodies was assumed if the patient had a paraproteinemia.
B-cell neoplasms, expressing IgMκ antibodies, directed against RBC antigens have few somatic mutations, which seem to be fairly restricted to certain Igheavy and light-chain families (VH4–34, VκIV). Moreover, a VH4–34 CLL confounding subclone was shown to arise from a pre-existing CAD-producing, B-cell population. The restricted clonality of CAD-producing B cells is further corroborated by the detection of clonal Ig rearrangements and recurrent chromosomal aberrations (trisomy 3). CLL cells may also drive AIHA by presenting the autoantigen (e.g., erythrocyte protein band 3) to T cells.
