Bacterial protease for the treatment of IgA nephropathy*
Nephrol Dial Transplant
Bacterial protease for the treatment of IgA nephropathy∗
Frank Eitner 0
J u¨rgen Floege 0
0 Division of Nephrology and Immunology, Rheinisch-Westfa ̈lische Technische Hochschule Aachen , Aachen , Germany
glomerulonephritis; Haemophilus influenzae; IgA nephropathy; IgA protease
-
Mesangial IgA1 deposition accompanied by a
mesangioproliferative glomerulonephritis is the key pathological finding
in IgA nephropathy (IgAN) patients [
1–3
]. Although the
pathogenesis of IgAN is still not completely understood, it
is generally accepted that mesangial IgA1 deposits trigger
local inflammatory mechanisms and thereby initiate and/or
maintain the glomerulonephritis [
2,3
]. Consequently, the
specific removal of mesangial IgA1 deposits might be a
promising therapeutic approach for IgAN. Lamm et al.
studied a bacterial IgA protease, isolated from Haemophilus
influenzae, which exhibits substrate specificity for the hinge
region of human IgA1. This protease cleaved human IgA1
and IgA1-containing immune complexes in vitro. They next
studied the effects of this protease in mice with
experimental glomerular IgA deposition. For this, healthy BALB/c
mice first received an intravenous injection of immune
complexes, consisting of human IgA1 and goat-anti-F(ab )2,
which resulted in mesangial positivity for human IgA.
Administration of the IgA protease 1 h after the injection of
the immune complexes significantly reduced the degree
of mesangial IgA immunofluorescence intensity within the
next hour as compared to mice not treated with a protease.
The authors conclude that IgA protease may have potential
as a therapeutic agent for human IgAN.
The treatment of IgAN patients is a dilemma. We still
do not have any specific therapeutic approach, which is
largely due to our incomplete understanding of the
pathogenesis of IgAN. Over the past years, we have made
significant progress in identifying specific characteristics of
the mesangial IgA deposits in IgAN patients, i.e. the
dior polymeric nature of IgA, the predominance of the IgA1
isoform and the relative undergalactosylation of the
IgA1hinge region [
1–3,4–7
]. However, precise mechanisms that
lead to the mesangial deposition of IgA1 are unknown,
as are mechanisms underlying the initiation of overt
inflammatory glomerular injury. Today’s IgAN therapy is
directed against very late stages in the development of the
disease (Figure 1). Both antihypertensive and
immunosuppressive therapies have proven beneficial in IgAN patients
with a risk for progressive disease [
2,8–10
]. However,
because of the lack of large clinical trials and the lack of
direct comparisons of different strategies, the best IgAN
therapy for progressive IgAN is still a matter of debate
[
9,11
].
The study by Lamm et al. introduces a completely novel
and more upstream treatment strategy by targeting the
mesangial IgA1 deposits (Figure 1). The rationale behind
aiming for this stage of the IgAN disease is quite
convincing. The disappearance of IgA deposits is typically
associated with a clinical and pathological resolution of the
glomerulonephritis and vice versa [
12
]. It is therefore
justified to hypothesize that specific removal of glomerular
IgA deposits by a bacterial protease cleaving human IgA1
might benefit patients with IgAN.
There are a number of open issues that might prevent the
immediate translation of this innovative therapeutic
strategy to human IgAN patients. One of the most
challenging problems in experimental IgAN research is the general
lack of relevant IgAN animal models, which is largely
explained by our incomplete knowledge of the pathogenesis
of human IgAN [
13–15
]. The development of IgAN
models is further complicated by the fact that there are
major differences in the IgA systems of humans and rodents.
Only humans and some non-human primate species have
an IgA1 isoform with a characteristic O-galactosylation
pattern within the hinge region [
6,7,10
]. A pure mouse
model can therefore not reproduce the characteristics of
the mesangial IgA1 deposits of the human disease as listed
above. To at least partially address these problems, mouse
models of IgAN have been created, in which human IgA1
was introduced into the mice. This typically results in
relatively artificial model systems that leave open questions
regarding their true relevance for the human IgAN disease,
but such models offer clear advantages compared to na¨ıve
mice.
What are the potential obstacles that one may encounter
when translating the experimental approach of Lamm et al.
to patients with IgAN? First, the duration of treatment
has to be considered: mice were treated for 1 h following
a 1-h-long disease induction period. In contrast, human
IgAN is a slowly progressive disease. In IgAN patients
presenting with microhaematuria and no or minimal
proteinuria, it took 2 years for the first cases of proteinuria
to exceed 1 g/day and 8 years for the first cases of
increasing serum creatini (...truncated)