PATHOMECANISME AUTOIMMUNE HEMOLYTIC ANEMIA

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,
cyto-kines). Disturbances of the Th1/2 T-cell subset balance as well as the
occurrence of clonal regulatory T cells specific for a RBC auto-antigen have been
described. This may be linked to the fact that AIHA does not only occur in
immunocompetent individuals but frequently occurs in patients with acquired T-
cell defects such as HIV infection or immunosuppressive therapy, particularly after
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 polypep-tides,

glycophorin, 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 second-ary AIHA by induction of cross-tolerance
(molecular mimicry) are infections (Mycoplasma pneumoniae [I antigen target],
parvovirus, herpes viruses), neoplastic diseases (paraneoplasia), and drugs by
various mechanisms. There are important differences in the patho-genesis 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, posttransplant,
congenital severe T-cell deficiencies) T-cell and humoral immune deficiency
predispose to WAIHA, but no correlation between the type and severity of immune
deficiency and the risk of AIHA has been established. One phenomenon that is
poorly understood is the lack of a clear relation-ship between the presence of RBC
antibodies and anemia. In many instances, there is no anemia 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 some
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 Ig heavy
and light chain families (VH4-34, VκIV). More-over, a VH4-34 CLL confounding
subclone was shown to arise from a preexisting CAD-producing B-cell population.
The restricted clonal-ity 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.

Source:

Liebman, H. A., & Weitz, I. C. (2017). Autoimmune Hemolytic Anemia. In

Medical Clinics of North America (Seventh Edition, Vol. 101).
https://doi.org/10.1016/j.mcna.2016.09.007