Pathogenesis of IgA Nephropathy

Harabuchi Y (ed): Recent Advances in Tonsils and Mucosal Barriers of the Upper Airways.
Adv Otorhinolaryngol. Basel, Karger, 2011, vol 72, pp 60–63

Aberrant Glycosylation of IgA1 and Anti-

Glycan Antibodies in IgA Nephropathy:
Role of Mucosal Immune System
Jan Novaka ⭈ Zina Moldoveanua ⭈ Bruce A. Juliana,b ⭈ Milan Raskaa,e ⭈
Robert J. Wyattc ⭈ Yusuke Suzukif ⭈ Yasuhiko Tominof ⭈ Ali G. Gharavid ⭈
Jiri Mesteckya,b ⭈ Hitoshi Suzukia,f
Departments of aMicrobiology and bMedicine, University of Alabama at Birmingham, Birmingham, Ala., cChildren’s Foundation
Research Center at Le Bonheur Children’s Medical Center, Memphis, Tenn., and dDepartment of Medicine, Division of Nephrology,
College of Physicians and Surgeons, Columbia University, New York, N.Y., USA; eDepartment of Immunology, Palacky University in
Olomouc, Olomouc, Czech Republic; fDepartment of Medicine, Division of Nephrology, Juntendo University Faculty of Medicine,
Tokyo, Japan

Abstract is supported by several observations: the aberrant

IgA nephropathy (IgAN), the most common glomerulo-
nephritis, is characterized by mesangial IgA1-containing
immunodeposits, proliferation of mesangial cells, and
matrix expansion. Clinical onset is frequently heralded
by synpharyngitic hematuria, macroscopic hematuria
during an upper-respiratory tract infection. Clinical and
laboratory data support a postulated extrarenal origin
of the glomerular IgA1, likely derived from circulating
immune complexes containing polymeric IgA1, deficient
in galactose in the hinge-region O-glycans, bound by
antiglycan antibodies. This aberrant IgA1 is produced by
IgA1-secreting cells with abnormal activities of specific
glycosyltransferases. The galactose deficiency affects
IgA1 induced by mucosal antigens and elevated circu-
lating levels of this abnormal IgA1 are hereditable, sug-
gesting interactions of genetic and environmental fac-
tors. An abnormal mucosal immune response resulting
in production of galactose-deficient IgA1 in IgAN patients
glycosylation affects mostly polymeric IgA1 produced by
mucosal-associated IgA1-secreting cells (including those
from tonsils), the synpharyngitic nature of the macro-
scopic hematuria, and the association of disease sever-
ity with polymorphisms of a pattern-recognition receptor,
TLR9. Thus, IgAN is an auto-immune disease, induced by
mesangial deposition of circulating complexes contain-
ing galactose-deficient IgA1. The aberrant glycosylation
of IgA1 may reflect abnormal mucosal immune responses
to infections of the upper respiratory tract in genetically
predisposed individuals.
Copyright © 2011 S. Karger AG, Basel
IgA nephropathy (IgAN), the most common type
of glomerulonephritis in the world, is character-
ized by mesangial immunodeposits of IgA1, fre-
quently accompanied by complement component
3, and IgG or IgM or both. Hematuria is typical
and often includes episodes of macroscopic bleed-
ing that coincide with mucosal infections, includ-
ing those of the upper respiratory tract or digestive
system. Proliferation of mesangial cells and expan-
sion of extracellular matrix are found in patients
with mild clinical disease, but progressive glom-
erular and interstitial sclerosis lead to end-stage
renal failure within 20 years after diagnosis in 20–
40% of patients. IgAN recurs in 50–60% of renal
allografts; however, immune deposits in a kidney
transplanted from a donor with subclinical IgAN
into a patient with non-IgAN renal disease clear
within several weeks. Moreover, idiotypic deter-
minants are shared between the circulating com-
plexes and the mesangial deposits, but a disease-
specific idiotype has not been identified. These
findings suggest that the cause of IgAN is extrare-
nal and is most likely due to deposition of circulat-
ing immune complexes containing IgA1 [1].
The apparent association between the immune
complexes and upper-respiratory tract infections
prompted an early search for antigens of environ-
mental or microbial origin in the renal deposits.
Although a variety of findings have been pub-
lished, there is a current consensus that there is
generally no IgAN-specific environmental or mi-
crobial antigen in renal immunodeposits.
Analysis of the glycosylation of IgA1 in pa-
tients with IgAN has provided new insights into
the mechanisms underlying the formation of im-
mune complexes and their deposition in the me-
sangium. Specifically, an aberrant glycosylation
of IgA1 O-glycans, galactose deficiency, is a key
pathogenetic factor contributing to the develop-
ment of IgAN, as aberrantly glycosylated IgA1 is
recognized by antiglycan antibodies (IgG and/
or IgA1) [2, 3] and, consequently, immune com-
plexes form. Circulating complexes in patients
with IgAN contain IgA1 with galactose-deficient
hinge-region O-glycans and this IgA1 is the pre-
dominant glycosylation variant of IgA1 in the me-
sangium. Collectively, these observations indicate
that aberrant glycosylation of IgA1 plays a pivotal
role in the pathogenesis of IgAN.
IgA Nephropathy and Mucosal Immune System
In humans, IgA1 represents one of the two
structurally and functionally distinct subclasses
of IgA. Unlike IgA2, IgM and IgG, IgA1 contains
a structurally unique hinge-region segment be-
tween the first and second constant region do-
mains of its heavy chains with up to six O-glycans
consisting of N-acetylgalactosamine (GalNAc)
with a β1,3-linked galactose; both residues may be
sialylated. The carbohydrate composition of the
O-glycans on normal human serum IgA1 is vari-
able, with galactose-GalNAc disaccharide, and its
mono- and di-sialylated variants as the prevailing
forms. Galactose-deficient variants with terminal
GalNAc or sialylated GalNAc are rarely found in
the O-glycans of serum IgA1 of normal individu-
als, but are much more common in that of IgAN
patients. The aberrant IgA1 predominates in the
glomerular immunodeposits and in the circulat-
ing complexes and is produced though biosyn-
thetic processes in IgA1-secreting cells [4].
O-glycans of IgA1 are synthesized in a step-
wise manner, beginning with attachment of
GalNAc to Ser or Thr catalyzed by a member of
the UDP-GalNAc-transferase enzyme family. The
O-glycan can be then extended by sequential at-
tachment of galactose and/or sialic acid residues
to the GalNAc. Addition of galactose is mediated
by core 1 β1,3-galactosyltransferase (C1GalT1)
that transfers galactose from UDP-galactose to
the GalNAc. The stability of this enzyme dur-
ing proteosynthesis depends on its interaction
with the C1GalT1-specific molecular chaperone,
Cosmc, that assists in the folding of the enzyme.
In the absence of Cosmc, the C1GalT1 protein
is degraded rapidly and the hinge region fails to
receive its normal complement of galactose resi-
dues. The O-glycan structure is completed by a
sialyltransferase that attaches sialic acid to the ga-
lactose. If sialic acid is linked to GalNAc prior to
the attachment of galactose, this ‘premature’ sia-
lylation by e.g., ST6GalNAcII precludes the sub-
sequent attachment of galactose. Therefore, the
relative activities of ST6GalNAcII and C1GalT1
directly influence the glycosylation of IgA1.
61

Fig. 1. Potential processes lead- Epithelial cells
ing to the increased production of
nephritogenic, aberrantly glycosy-
lated, IgA1. We postulate that some
of the events during an infection
of the upper-respiratory tract, by
viruses or bacteria, in a genetically
predisposed individual send signals
indirectly via cells in the mucosa
(epithelial cells, T cells, dendritic
B cells
cells) or directly to the B cells re-
sulting in differentiation of IgA1-
secreting plasma cells with altered
expression and activity of the key
glycosyltransferases and secretion
of galactose-deficient IgA1.
Aberrant glycosylation in IgAN affects only
IgA1, not other glycoproteins with O-glycans.
This aberrancy of IgA1 is not due to variation in
the coding sequence of the IgA1 hinge region,
but rather to the abnormal regulation of particu-
lar enzymes in IgA1-producing cells. Specifically,
the activity of C1GalT1 is reduced and that of
ST6GalNAcII is elevated [4]. Consequently, these
cells secrete IgA1 that contains terminal as well as
sialylated GalNAc [4, 5]. The result is an increased
fraction of IgA1 molecules in IgAN patients with
O-glycans that are galactose-deficient and contain
GalNAc that is frequently sialylated [4, 6].
It is of interest that the aberrant glycosyla-
tion affects the dimeric and polymeric but not
the monomeric forms of the IgA1 secreted by
the cells from patients with IgAN [4]. Similarly,
it has been shown that a substantial portion of
IgA1 in the mesangial deposits is polymeric [7].
These observations seem to imply mucosal ori-
gin of the pathogenic IgA1, as the polymeric J-
chain-containing forms of IgA1 are mostly pro-
duced at mucosal sites. Moreover, it was shown
that IgA1 synthesized in response to mucosally
62
Upper-respiratory tract infection
(viruses, bacteria, their products)
T cells, dendritic cells
? Gene polymorphisms ?
(TLRs?)
Cytokines, chemokines, …
Plasma cells
differentiation
C1GalT1
ST6GalNAcII
Aberrantly glycosylated IgA1
acquired antigens is galactose-deficient in the O-
glycans [8]. However, the levels of aberrantly gly-
cosylated IgA1 in the circulation of patients with
IgAN are elevated and this phenotype is heredit-
able. It is therefore possible that a combination of
genetic and environmental factors is required for
the overproduction of galactose-deficient IgA1 to
cause IgAN. This conclusion is further supported
by the observation that polymorphisms of one of
the pattern-recognition receptors, TLR9, are as-
sociated with the clinical severity of IgAN [9].
One can thus envision a process wherein events
during an infection of the upper-respiratory tract,
by viruses or bacteria, in a genetically predisposed
individual send signals indirectly via cells in the
mucosa (epithelial cells, T cells, dendritic cells) or
directly to the B cells resulting in differentiation
of IgA1-secreting plasma cells with altered ex-
pression/activity of the key glycosyltransferases.
The consequence would be increased production
of nephritogenic, aberrantly glycosylated, IgA1
(fig. 1).
As outlined above, these issues of the interac-
tions of IgA1-producing cells with microbiota of
Novak et al.
the upper-respiratory tract in IgAN patients are
not well understood. Similarly, it is not clear where
the cells secreting polymeric galactose-deficient
IgA1 reside. Are tonsils an inductive site for these
cells? To which tissues are then these cells directed
and by what mechanisms? Do the cells that pro-
duce the polymeric galactose-deficient IgA1 home
to peripheral lymphoid tissues, mucosal tissues or
both [10]? Are the cells that synthesize the anti-
glycan antibodies also primed in tonsils, or in oth-
er sites of the upper-respiratory or digestive tract?
These questions illustrate the important challeng-
es that researchers and clinicians must answer to
unravel the pathogenesis of IgAN. It can be hoped
that new relevant information may be forthcom-
ing from clinical trials involving tonsillectomy.
In summary, developments during the past
decade have defined IgAN as an auto-immune
disease, in which aberrantly glycosylated IgA1 is
bound by antiglycan antibodies and the resultant
immune complexes deposit in the renal mesan-
gium and induce injury. Future studies are need-
ed to define involvement of the mucosal immune
system in the pathogenetic processes leading
to the formation of the nephritogenetic IgA1-
containing immune complexes.
Acknowledgements
The authors acknowledge grants from NIDDK supporting
their research of IgAN, DK082753, DK078244, DK080301,
DK075868, DK083663, DK071802, and DK077279, and by
GAP302/10/1055 Czech Science Foundation and NT11081
Ministry of Health of the Czech Republic, and express their
gratitude to the patients and their families for participation
in various IgAN studies.

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Jan Novak
University of Alabama at Birmingham, Department of Microbiology
845 19th Street South, Room 734
Birmingham, AL 35294 (USA)
Tel. +1 205 934 4480, E-Mail jannovak@uab.edu

IgA Nephropathy and Mucosal Immune System 63