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Clinical and Experimental Nephrology (2019) 23:291–303
https://doi.org/10.1007/s10157-018-1665-0
REVIEW ARTICLE
T cells in IgA nephropathy: role in pathogenesis, clinical significance
and potential therapeutic target
Jakub Ruszkowski1 · Katarzyna A. Lisowska1 · Małgorzata Pindel1 · Zbigniew Heleniak2 · Alicja Dębska‑Ślizień2 ·
Jacek M. Witkowski1
Received: 2 August 2018 / Accepted: 25 October 2018 / Published online: 7 November 2018
© The Author(s) 2018
Abstract
Background Immunoglobulin A nephropathy (IgAN), the most frequent cause of primary glomerulonephritis worldwide,
is an autoimmune disease with complex pathogenesis. In this review, we focus on T cells and summarize knowledge about
their involvement in pathophysiology and treatment of IgAN
Methods We reviewed the literature for (1) alterations of T cell subpopulations in IgAN, (2) experimental and clinical proofs
for T cells’ participation in IgAN pathogenesis, (3) clinical correlations with T cell-associated alterations, and (4) influence
of drugs used in IgAN therapy on T cell subpopulations.
Results We found that IgAN is characterized by higher proportions of circulatory Th2, Tfh, Th17, Th22 and γδ T cells, but
lower Th1 and Treg cells. We discuss genetic and epigenetic makeup that may contribute to this immunological phenotype.
We found that Th2, Th17 and Tfh-type interleukins contribute to elevated synthesis of galactose-deficient IgA1 (Gd-IgA1)
and that the production of anti-Gd-IgA1 autoantibodies may be stimulated by Tfh cells. We described the roles of Th2,
Th17, Th22 and Treg cells in the renal injury and summarized correlations between T cell-associated alterations and clinical features of IgAN (proteinuria, reduced GFR, hematuria). We detailed the impact of immunosuppressive drugs on T cell
subpopulations and found that the majority of drugs have nonoptimal influence on T cells in IgAN patients.
Conclusions T cells play an important role in IgAN pathogenesis and are correlated with its clinical severity. Clinical trials
with the drugs targeting the reported alterations of the T-cell compartment are highly desirable.
Keywords Glomerulonephritis · IgA nephropathy · T lymphocytes
Introduction
Immunoglobulin A nephropathy (IgAN) is characterized by
the presence of immune complexes, predominantly containing polymeric IgA1, in the glomerular mesangium, which
leads to glomerular injury [1]. It is the most common cause
of primary glomerulonephritis in the world [1, 2]. However, the distribution of IgAN varies in different geographic
regions; it is observed in up to 60% of all biopsies performed
* Jakub Ruszkowski
jakub.ruszkowski@gumed.edu.pl
1
Department of Pathophysiology, Faculty of Medicine,
Medical University of Gdańsk, Dębinki 7, 80‑211 Gdańsk,
Poland
2
Department of Nephrology, Transplantology and Internal
Medicine, Faculty of Medicine, Medical University
of Gdańsk, Gdańsk, Poland
for glomerular disease in Asia compared with 30% in Europe
and 10% in North America [3]. Geographical variability of
detected IgAN prevalence can be explained by ethnic-based
differences in the number of risk alleles as well as bias factors such as the presence of screening urinalysis and the
differences in policies for performing renal biopsies [1].
IgAN can affect all ages, but is more common in children
and young adults (20–30 years of age) [1]. Even though the
disease usually follows a benign clinical course, it eventually results in end-stage renal disease (ESRD) in 15–20%
of patients within 10 years and 30–40% of patients within
20–30 years after the first clinical presentation [1].
According to the well-accepted definition proposed by
Suzuki et al., IgAN is an autoimmune disease with a multihit pathogenetic process. At least four processes (called
“hits”) are necessary for the development of IgAN: (1)
increased synthesis of circulating galactose-deficient-IgA1
(Gd-IgA1), (2) production of autoantibodies binding to
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Gd-IgA1, (3) formation of pathogenic Gd-IgA1-containing
immune complexes, and then (4) mesangial deposition of
these immune complexes resulting in mesangial cells activation and initiation of glomerular injury [4]. There are several
factors involved in the etiology of IgAN. Recent reviews
highlight the role of B cells and complement in the IgAN
pathogenesis [5]. However, in this review, we focus on T
cells and summarize knowledge about their involvement in
IgAN pathogenesis, their clinical significance, and we also
consider their role as a potential therapeutic target in the
treatment.
T cell subpopulations
T lymphocytes are a heterogeneous population of cells,
characterized by the presence of a T-cell receptor (TCR)/
CD3 complex on the cell surface, that participate in the
adaptive immune response. The majority of human T cells
have TCR composed of one α-chain and one β-chain, and
so are called αβ T cells; while a relatively minor group of
human T cells expresses a unique TCR composed of γ and
δ chains (the γδ T cells). The αβ T cells are functionally
subdivided into helper (Th), cytotoxic (Tc) and regulatory T (Treg) populations [6]. In contrast, γδ T cells are
composed of two subsets that express either Vδ1 or Vδ2
gene; Vγ9Vδ2 T cells are the predominant subpopulation
in human peripheral blood and will be called γδ T cells
in this article.
Mature Th cells express the surface protein CD4 and
can be differentiated into specific subtypes (Th1, Th2,
Th9, Th17, Th22, Tfh). Each of the abovementioned subpopulations produces a specific set of cytokines essential
for a successful response to infection [7].
Th1 and Th2 lymphocytes are the two main and bestknown subpopulations of T helper cells. Th1 primarily
participate in cell-mediated immunity and play an important role in the elimination of intracellular pathogens. They
enhance cellular cytotoxicity and activate macrophages
predominantly through production of interferon gamma
(IFN-γ) [8]. In contrast, Th2 lymphocytes control humoral
immunity, which is meditated by the immunoglobulins,
and play an important role in the removal of multicellular
parasites through production of interleukin (IL) 4, IL-5
and IL-13 [7]. Similarly to Th2, the Tfh are specialized
in cooperation with B cells; they promote via IL-21 the
survival and maturation of B cells, and such processes
as immunoglobulin class switching and antibody affinity
maturation [9, 10].
Th17 and Th22 lymphocytes are subpopulations defined
by their ability to produce high concentrations of IL-17
and IL-22, respectively. Both subpopulations have a similar role: they take part in the immune response against
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Clinical and Experimental Nephrology (2019) 23:291–303
extracellular bacteria, e.g., both stimulate epithelial cells
to produce antibacterial peptides [11]. Additionally, Th17
lymphocytes secrete pro-inflammatory cytokines such as
IL-17A and IL-17F, which act on a variety of cells upregulating the expression of pro-inflammatory cytokines,
chemokines, and metalloproteases [11]. Hence, Th17 cells
are considered to be involved in autoimmune processes. In
contrast, IL-22 made by Th22 cells affects only epithelial
cells of skin, digestive and respiratory tracts, and kidney
[11, 12].
Tregs are the main population of lymphocytes characterized by high expression of FoxP3 transcription factor
that counteract the excessive immune response, and protect the body from autoimmune responses. Treg can be
divided into natural Treg (nTreg) arising in the thymus
and inducible Treg (iTreg), which differentiate outside the
thymus during the immune response. Another subdivision
of the Tregs involves their functional state; thus resting
and activated Tregs are described. Treg cells exert their
suppressor effect on almost all cells in the immune system
through secreted cytokines (mainly IL-10) and intercellular contact (through membrane-bound proteins such as
CTLA-4) [7].
Alterations of T cell subpopulations in IgA
nephropathy
In Table 1, we summarized the findings concerning changes
in frequency and function of Th1, Th2, Th17, Th22, Tfh,
Tc, Treg and γδ T cells in patients suffering from IgAN. In
short, IgAN is characterized by higher proportions of circulatory Th2, Tfh, Th17, Th22 and γδ T cells, but lower Th1
and Tregs (especially these induced and activated) [13–20].
Additionally, He et al. reported lower Th1/Th2 ratio among
tonsillar lymphocytes of IgAN patients who suffered from
tonsillitis compared to those with chronic tonsillitis without
kidney disease [21], and Huang et al. observed a decreased
frequency of tonsillar Tregs in IgAN patients [22].
Changes observed in the T cell subpopulations may be
associated with the different genetic and epigenetic makeup
of IgAN patients. Genetic studies confirm that there is Th1/
Th2 imbalance in IgAN. Family-based study showed an
association between IFN-γ polymorphism and higher susceptibility to the development of IgAN [23]. The + 874T/A
polymorphism occurs in the binding site for transcription
factor NF-κB (nuclear factor kappa-light-chain-enhancer of
activated B cells), and the risk variant (+ 874A) is associated with decreased NF-κB binding affinity and decreased
IFN-γ production in response to stimulation in vitro [23].
Thus IFN-γ, Th1-type cytokine, might have a protective role
against the development of IgAN. Furthermore, genomewide association studies (GWASs) have reported significant
Clinical and Experimental Nephrology (2019) 23:291–303
Table 1 Changes in T cell
subpopulations and serum
cytokine concentrations in the
peripheral blood of patients
with IgA nephropathy
T cell subpopulation
Th1
% in PBL
IFN-γ
IL-2
Th2
% in PBL
IL-4
IL-5
IL-6
Th17
% in PBL
IL-17A
Th22
% in PBL
IL-22
Tfh
% in PBL
IL-21
Tc
% in PBL
Treg
Treg % in PBL
Activated Treg % in PBL
Resting Treg % in PBL
iTreg % in PBL
nTreg % in PBL
IL-10
TGF-β1
γδ T cells
% in PBL
293
Alterations compared with
References
Healthy control
Other CKD as
a control
↓/N
↓/↑
↑
n.d.
n.d.
n.d.
[15, 16]
[15, 29, 78]
[29, 78]
↑
↑
↑
↑
n.d.
n.d.
n.d.
n.d
[15]
[29, 78]
[15]
[13]
↑
↑
↑
n.d.
[13–16]
[13, 15, 18, 29, 78]
↑
↑
↑
↑
[14, 16]
[14]
↑
↑
n.d.
n.d.
[17]
[13, 17, 78]
N
n.d
[62]
↓
↓
N
↓
N
↓/↑
↑/N/↓
n.d
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
[15, 19]
[13]
[13]
[18]
[18]
[13, 15, 18, 29, 78]
[13, 18, 32]
↑
n.d.
[20]
Disagreement in literature was shown using slash
CKD chronic kidney disease, PBL peripheral blood lymphocytes, ↑ increased versus control, ↓ decreased
versus control, N unchanged versus control
associations of IgAN development with polymorphisms of
several genes involved in Th17 cells development and function [24]. One of the IgAN risk alleles is known for higher
expression of CARD9 gene. Protein encoded by this gene
integrates signals stimulating Th17 differentiation following
microbial exposition (mainly, but not limited to, fungal and
mycobacterial) [24, 25]. Function of Th17 cells is strictly
depended on their key transcription factor which can be
degraded by the product of the UBR5 gene. The expression
of UBR5 may be modified by another genetic polymorphism
linked to increased risk of IgAN development [24]. Additionally, Th2- and Th17-polarization was associated with
a deficiency of microRNA miR-155 in peripheral blood
mononuclear cells (PBMC) of IgAN patients [15], which
physiologically inhibits Th2 differentiation by suppression
of IL-4 promoter transactivators: c-Maf and GATA3—the
key transcription factors for Th2 cells [26].
Some studies suggest Th1 polarization but they are based
on in vitro post-stimulation observations or animal models
of IgAN [27, 28]. Meanwhile, human studies revealed either
low [15] or only slightly elevated [29] IFN-γ serum concentrations in IgAN patients in contrast to clear significant
elevation of Th2-type cytokines. It should be emphasized
that IL-2, sometimes reported as a marker of Th1 polarization [27], is not restricted to Th1 subset; high amounts of
IL-2 are also secreted by other Th subpopulations, activated
Tc cells, NK T cells, and dendritic cells [30]. Furthermore,
IL-2 is not secreted in all phases of Th1 development [8].
13
294
Strikingly, studies have shown that neither IL-2 production
by PBMC nor serum IL-2 levels correlates with serum IgA
levels, the severity of histologic changes in the kidneys of
IgAN patients, or other clinical parameters [29, 31]. There
are also a lot of controversies about the level of transforming
growth factor β1 (TGF-β1) in patients with IgAN. A cohort
study demonstrated elevated serum concentration of TGF-β1
in 100 Chinese patients, especially higher in advanced stages
of IgAN [32]. It is supported by an observed deficiency of
the miR-886 precursor that led to the overexpression of
TGF-β [27]. However, another study, which included 63
Chinese patients, showed no significant difference in serum
TGF-β1 level compared to the healthy control [13], and the
smallest study had showed even a lowered serum level of
TGF-β1 [18].
Studies agree on numerical deficiency and suggest a
decreased immunosuppressive function of Tregs in IgAN
[33]. Above-mentioned miR-155 deficiency might inhibit
the maturation and differentiation of Treg cells of IgAN
[15]. Ling-Wei et al. also reported elevated expression of
miR-133a and miR-133b in PBMC of IgAN patients, and
confirmed that these molecules inhibit Treg differentiation
in IgAN through binding to FOXP3 mRNA with subsequent limitation of FOXP3 translation [19]. Next factor that
might contribute to numerical deficiency of Tregs in IgAN
is chronic tonsillitis; tonsillectomy for IgAN patients leads
to some increase in the frequency of blood Treg cells, but
still the observed numbers are lower than in healthy subjects
[34]. On the other hand, the functional defect may be the
result of IL-10 promoter polymorphisms associated with a
reduced IL-10 production. These polymorphisms predispose
to the development of IgAN in Korean and Chinese populations [35, 36], to faster progression in Caucasians [37],
and even to recurrence of IgAN after transplantation [38].
However, some studies reported the contrary results [39].
Another factor affecting the function of Tregs in IgAN is
an expression of CTLA-4; Jacob et al. reported that polymorphisms attributed to decreased CTLA-4 gene expression
were associated with higher proteinuria in IgAN patients
[40]. However, the actual Treg’s CTLA-4 protein level was
not investigated.
Finally, an excessive activity of immunoproteasomes may
contribute to Th17/Treg disequilibrium in IgAN. It has been
evidenced that immunoproteasome subunit coded by PSMB8
gene is necessary for Th17 differentiation and inhibits Treg
differentiation [41, 42]. It was demonstrated that PBMC of
IgAN patients had higher expression of PSMB8 gene [43,
44], especially those individuals with high proteinuria [43]
or those experiencing greater annual loss of eGFR [45].
GWAS reported lower risk of developing IgAN by patients
with polymorphism that lowers PSMB8 gene expression
[46].
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Clinical and Experimental Nephrology (2019) 23:291–303
Elevated synthesis of Gd‑IgA1—the role
of Th2, Th17 and Tfh‑type interleukins
The first hit in the multi-hit pathogenesis of IgAN is the
appearance in the circulation of aberrantly glycosylated
IgA1 with some hinge-region O-glycans deficient in galactose (Gd-IgA1) [4]. The origin of such autoantigens is
still unclear; the most common hypothesis claims that it
is a consequence of reduced galactosylation during posttranslational modification of IgA1, but there are arguments
that it might be the IgA1 produced by mucosally primed
plasma cells [4, 5]. There are two possible mechanisms of
reduced rate of galactosylation: (1) premature sialylation by
ST6 N-acetylgalactosaminide alpha-2,6-sialyltransferase 2
(ST6GALNAC2), which prevents addition of galactose to
N-acetylgalactosamine (GalNAc), and (2) lower activity
of core 1 β1,3-galactosyltransferase (C1GALT1) due to its
decreased expression or stability, the latter depends on the
C1GALT1 specific chaperone 1 (C1GALT1C1), previously
called COSMC [47]. In fact, Gd-IgA1-producing cells from
IgAN patients have elevated expression of ST6GALNAC2,
and decreased expression of C1GALT1 and C1GALT1C1
[47, 48].
Because mucosal infections coincide with IgAN exacerbation, it is believed that inflammation might impede IgA1
galactosylation in IgAN. Indeed, T cells might also participate in an aberrant IgA1 galactosylation process (Fig. 1).
Already in 2008, Chintalacharuvu et al. confirmed that
Th2-polarization promotes hypogalactosylation of IgA in a
mouse model of IgAN [49]. Further studies on human B cell
line and IgA1-secreting cells from IgAN patients revealed
that IL-4 (but not IL-5) is responsible for this effect; it has
been shown that IL-4 enhances IgA1 production and alters
terminal glycosylation of secreted IgA1 (Fig. 2a) [50, 51].
The latter might be a result of down-regulation of C1GALT1
activity due to inhibition of both C1GALT1 and its molecular
chaperone C1GALT1C1 expression [50, 51]. IL-4 promotes
hypermethylation of CpG islands in C1GALT1C1 gene
promoter leading to the down-regulation of C1GALT1C1
mRNA and related higher secretion of aberrantly glycosylated IgA1 from B cells [52]. What is more, B cells from
IgAN patients seem to be more sensitive to IL-4 because
the decrease in C1GALT1C1 mRNA level induced by IL-4
was higher in IgAN B cells than in lymphocytes of both
healthy children and children with other renal diseases [52].
IL-17 exhibits a similar mechanism of action; expression
of C1GALT1 and C1GALT1C1 mRNA was significantly
lower in B cell line stimulated by IL-17 [53]. Hypoglycosylation of IgA1 induced by IL-4 or IL-17 is reversed by
5-azacytidine [52, 53], proving that Th2- and Th17-derived
interleukins disturb galactosylation of IgA1 through an epigenetic mechanism. Also IL-6, another pro-inflammatory
Clinical and Experimental Nephrology (2019) 23:291–303
295
Fig. 1 Involvement of T cells and their cytokines in posttranslational
modification of IgA1 hinge region. The process starts with addition
of N-acetylgalactosamine (GalNAc) to serine or threonine located
in hinge region. Physiologically the process is continued by active
C1GALT1, which adds galactose to GalNAc. Addition of sialic acid
by ST6GALNAC2 prevents further galactosylation of GalNAc. In
IgAN, IL-4 (Th2-type interleukin), IL-17 (Th17-type interleukin) and
TGF-β are associated with decreased expression of C1GALT1 and
its chaperon (C1GALT1C1). Additionally, IL-6 increases expression
of ST6GALNAC2 and decreases expression of C1GALT1. All mentioned cytokines stimulate production of Gd-IgA1. Violet arrays—
epigenetic mode of action; black arrays—unknown mode of action
cytokine, promotes hypogalactosylation of IgA1; stimulation of IgA1-secreting cells from IgAN patients with IL-6
increased ST6GALNAC2 activity and decreased activity of
C1GALT1 through analogical changes in their genes expression [51].
The serum concentrations of both IgA and Gd-IgA1 are
significantly higher for the IgAN patients compared with
chronic kidney disease (CKD) patients or healthy people
[54, 55]. Subpopulation of T cells—Tfh—might participate
in elevated synthesis of IgA and Gd-IgA1 through IL-21
(Fig. 2a) [17]. This crucial interleukin upregulates in the
mature B cells the expression of the activation-induced
cytidine deaminase (AID), DNA-editing enzyme, which
mediates IgA class switching during the differentiation of
activated B cells into plasma cells [17, 56]. T-cell-dependent IgA class switching in B cells of IgAN patients can
be stimulated also by TGF-β, cytokine produced by many
cell types, e.g., γδ T cells and Tregs [20]. What is more
important, TGF-β significantly decreases the mRNA levels of C1GALT1 and C1GALT1C1, and thus contributes to
the higher production of Gd-IgA1 (Fig. 1) [57]. However,
TGF-β does not affect sialylation of IgA1 [57]. Meng et al.
observed in IgAN patients very strong positive correlations
between the serum concentration of TGF-β1 on one side and
serum concentrations of total and secretory IgA and GdIgA1 on the other [32]. Toyabe et al. also reported a positive
correlation between the proportion of γδ T cells and proportions of IgA-producing-B cells and serum IgA level in IgAN
patients [20]. Less-specific T-cell-dependent mechanism of
IgA switching is mediated via CD40L. This membranebound cytokine is present after activation on all investigated
Th subsets (Th1, Th2, Tfh, Th17 cells), but not on Tregs [56,
58]. Besides the abovementioned T-cell-depended IgA class
switching, the T-cell-independent manners of IgA switching may be involved in the intensive production of IgA and
Gd-IgA1 in IgAN patients. This kind of IgA switching is
mediated through molecules such as tumor necrosis factor ligand superfamily members 13 [59] and 13b [60, 61]
(called April and BAFF, respectively) which are important
for B cell development. Authors found out that serum levels
of April and BAFF were increased in IgAN patients [59,
60]. Moreover, they have demonstrated that April induce
an overproduction of Gd-IgA1 in cultured lymphocytes of
IgAN patients [59].
However, some authors question the origin of circulatory Gd-IgA1 in IgAN; they argue that contrary to the
common understanding, it is not the galactose-deficient
IgA1 (problem in post-translation modification), but a
misdirected normal mucosal form of IgA1 secreted into
the circulation [5]. Pathological secretion of such IgA1
into the circulation is probably a result of defective trafficking during B cell maturation; plasma cells migrate into
13
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Clinical and Experimental Nephrology (2019) 23:291–303
Fig. 2 Involvement of T
cells and their interleukins
in the pathogenesis of IgAN.
a Mucosal infection can
stimulate the immune system
to produce various cytokines,
which beside participation
in immune response against
infection, may participate in
the IgAN pathophysiology.
IL-21 (Tfh-type interleukin)
enhances IgA1 production and
might participate in stimulation
of anti-Gd-IgA1 production.
IL-4 (Th2-type interleukin) and
TGF-β enhance both IgA1 production and IgA1 glycosylation
alteration. Both numerically
and functionally deficient iTreg
population cannot effectively
suppress the defective immune
response leading to formation
of immune complexes. All these
processes lead to the formation of circulating immune
complexes. b Deposition of
circulating immune complexes
in glomeruli results in many
pathological processes—such as
T cells infiltration—that initiate
and exacerbate the glomerulonephritis. Additionally, infection
might result in hematuria
through stimulation of transendothelial migration of cytotoxic
effector cells (Tc and γδ T cells)
from circulation to glomeruli.
Solid and dashed lines represent
confirmed and hypothetical
links, respectively
the bone marrow instead of settling down in the mucosa
[5]. Batra et al. reported a similar homing pattern of Th
cells; based on higher expression of integrin characterized
for systemically homing cells (α4β1) rather than mucosal
homing cells (α4β7) authors concluded that systemic homing Th cells may direct the aberrant systemic Gd-IgA1 production observed in IgAN [62]. Two places are frequently
mentioned to be the site of lymphocyte activation in IgAN:
tonsillar and gastrointestinal mucosa; the former is a reason of popularity of tonsillectomy in IgAN treatment. In
accordance with the concept of T-cell-priming in tonsils,
novel network meta-analysis showed that tonsillectomy
(with steroids) was effective in inducing the remission
13
of IgAN [63]. However, the same meta-analysis failed to
show an efficacy of tonsillectomy (alone or with steroids)
in either prevention of ESRD or doubling of serum creatinine levels. It might be a result of genetic and epigenetic
make-up of entire T-cell population (not only in tonsils,
but also in respiratory and intestinal mucosa). Therefore,
tonsillectomy does not protect from both the activation of
T cells in other mucosal compartments and the aggravation
of IgAN. Indeed, high T cell infiltration in small intestine
lamina propria was observed and strongly correlated with
the serum IgA concentration in IgAN patients [64]. Additionally, a diminished repertoire of mucosal γδ T cells was
observed in the guts of IgAN patients [65].
Clinical and Experimental Nephrology (2019) 23:291–303
Production of anti‑Gd‑IgA1 autoantibodies
stimulated by Tfh
The seconnd hit in the IgAN pathogenesis is the production
of autoantibodies against Gd-IgA1, predominantly in the
IgG2 subclass [66]. Aberrantly glycosylated IgA1 might be
recognized as an autoantigen, and thus the immune response
against it may lead to the production of anti-IgA1-antibodies
[67]. However, Novak et al. noticed that some pathogens,
such as viruses and Gram-positive bacteria associated with
upper respiratory infections, possess GalNAc-containing
structures on their surfaces, which can mimic the GalNAc
in the hinge region of Gd-IgA1 [67, 68]. Hence, such infections might stimulate the production of antibodies with
cross-affinity to Gd-IgA1 which may lead to the formation
of pathological immune complexes.
Further studies confirmed that anti-Gd-IgA1 autoantibodies did not originate from a rare germline variant, but
from somatic hypermutation (SHM) of VH gene segments
in anti-Gd-IgA1-producing cells [69]. IL-21 may promote
SHM through increases of AID expression in the B cells of
IgAN patients [17].
Renal injury—Th2, Th17, Th22 and Treg cells
participation in the last hit
Immunohistochemical staining of renal biopsies in IgAN
indicates that kidneys are infiltrated mainly by αβ T cells,
and additionally by γδ T cells in progressive IgAN [70, 71].
Multivariate analyses showed that tubulointerstitial T cell
infiltration is independently associated with the progression
of IgAN, which would suggest that T cells participate in
renal injury in IgAN [72, 73].
Why do T cells infiltrate renal tissue? It turns out that
Gd-IgA1 stimulates mesangium cells to produce chemokines
for Th17 (CCL20) and Th22 cells (CCL20, CCL22 and
CCL27): [74, 75]. Moreover, Th2 polarization might
Table 2 Correlations between
immunological and clinical
features among IgAN patients
297
intensify the response of glomerular cells to IgA immune
complexes and both directly and indirectly decrease glomerular filtration rate (GFR) [49]. Gan et al. confirmed
higher renal expression of CCL20, CCL22, and CCL27 in
IgAN patients; the elevation was even more pronounced in
patients with accompanying tonsillitis [16]. Moreover, elevation of Th22 cells in patients’ peripheral blood was associated with worse histologic renal images; the percentage
of Th22 cells was positively correlated with MEST scores.
Authors concluded that tonsillitis aggravated renal injury
in IgAN through induction of Th22 lymphocytosis, infiltration of renal tissue, and promotion of renal fibrosis by Th22
[16, 76].
On the other hand, using an animal model of IgAN,
Huang et al. have evidenced that Tregs of IgAN patients
cannot effectively suppress the deposition of IgA in the
mesangial region, the expansion of the mesangial matrix,
or the extensive proliferation of glomerular mesangial cells
[33]. Additionally, the histological severity of the renal
biopsy of IgAN patients tended to be worse in parallel with
the decrease of blood Tregs frequency [34]. Therefore, it is
hypothesized that the numerically and functionally defective
Treg population cannot effectively suppress the renal injury
in IgAN [34].
Clinical correlations with T cell alterations
Majority of T cell subpopulations and interleukins alterations have been associated with clinical features of IgA
nephropathy, such as the occurrence and severity of proteinuria, elevated serum creatinine concentration and reduced
GFR, and hematuria (summarized in Table 2).
The severity of 24-h proteinuria is positively correlated
with serum IL-21 [17] and IL-17A [13]. Proteinuria-positive
patients have a higher frequency of Th22 cells than proteinuria-negative IgAN patients and healthy people [14]. Moreover, higher proteinuria was observed in the patients possessing polymorphisms that caused a decreased expression of
Clinical feature
Immunological feature
Coefficient of determination (r2)
References
Severity of 24-h proteinuria
Tonsillar Th1/Th2 ratio
miR-155 level in PBMC
Serum IL-21
Frequency of activated Tregs
Serum IL-17A
sIL-2Ra level
Frequency of activated Treg
Tfh cells
0.6162
0.5270
0.4755
0.3364
0.1225
0.0576
0.4624
0.2824
[21]
[15]
[17]
[13]
[13]
[77]
[13]
[78]
Severity of 24-h albuminuria
Estimated GFR
The power of clinical severity determination is represented by coefficient of determination (r2)
13
298
CTLA-4, immunosuppressive protein expressed on Tregs
[40]. On the other hand, negative correlations were observed
between the severity of 24-h proteinuria and tonsillar Th1/
Th2 ratio [21], miR-155 level in PBMC [15], and frequency
of activated Tregs [13]. Moreover, 24-h albuminuria is positively associated with sIL-2Ra level, a marker of continuous
T cells activation [77].
Estimated GFR level is positively correlated with the frequency of activated Treg subset [13], and negatively with
Tfh cells [78].
The density of Tc and Th cells in the renal interstitium
is associated with the severity of erythrocyturia [79]. Cox
et al. demonstrated that antigenic stimuli enhance CX3C
chemokine receptor 1 (CX3CR1) expression on circulating
blood cytotoxic effector cells (Tc and γδ T cells) of IgAN
patients, which promotes glomerular transendothelial migration of lymphocytes and leads to a break in the continuity of
the glomerular capillary wall, and subsequently to hematuria
(Fig. 2b) [80]. CX3CR1-positive Tc cells are more frequent
not only in the blood of IgAN patients with hematuria, but
also in tonsils of IgAN patients [81]. Moreover, a synthetic
analog of bacterial DNA upregulates the CX3CR1 expression on tonsillar Tc cells of IgAN patients [81]. Patients with
significantly higher amount of glomerular and urinary fractalkine, the only ligand of CX3CR1, had recurrent episodes
of gross hematuria [80]. Furthermore, disappearance of
hematuria after tonsillectomy was associated with decrease
in number of blood CX3CR1-positive Tc cells, while in
patients with persistent hematuria the number of CX3CR1positive Tc cells stayed unchanged [81].
Some of the biomarkers associated with T cells were analyzed in the context of renal outcome in the follow-up. As
we mentioned, the degree of renal tubulointerstitial T cells
infiltration is an independent prognostic biomarker of IgAN
progressive course [72, 73]. Van Es et al. found in multiple
regression analysis that intraepithelial Tc positive for natural
killer cell granule protein 7 (expressed in activated T cells,
in kidney, liver, lung and pancreas) was associated with the
progression of IgAN in patients with normal or near-normal eGFR [82]. Additionally, high level (in the upper third
tertile) of continuous T cell activation biomarker, sIL-2Ra,
predicted IgAN progression to the combined end point, even
after adjustment for the main clinical risk factors: time average albuminuria and GFR at baseline [77].
Clinical correlations and prognostic value of T cells’ biomarkers support the hypothesis that T cells, especially Tc,
Th17, Th22 and Tfh, play a vital role in the pathogenesis and
pathophysiology of IgAN.
13
Clinical and Experimental Nephrology (2019) 23:291–303
T cells as a therapeutic target of traditional
and biological therapy
According to Kidney Disease: Improving Global Outcomes
(KDIGO) Clinical Practice Guideline for Glomerulonephritis 2012, treatment of IgAN patients may include therapy
with renin–angiotensin system (RAS) blockers, fish oil, corticosteroids, and non-steroidal immunosuppressive agents
(cyclophosphamide, azathioprine and cyclosporine) [2]. One
recently published study suggests that renoprotection (RAS
blockers) is effective in preventing the progression of IgAN
only if clinical and morphological risk factors are missing
or modest [83]. It highlights the need for more aggressive
treatment in patients with risk factors for the appearance of
ESRD, such as proteinuria, hypertension, decreased eGFR,
and severe histological lesions [84].
Considering a number of adverse effects, immunosuppression should be prescribed only for patients at the highest
risk of developing ESRD [85]. Al-Lawati et al. suggested
that immunosuppressive drugs in IgAN ought to modulate
immune responses, including Gd-IgA1 production, glomerular and tubulointerstitial inflammation, and mesangial and
endothelial cell proliferation [85]. All mentioned processes
are dependent on the activity of T cells and their cytokines,
which has been clearly demonstrated in our paper. What is
more, even though B cells are more frequently described in
the context of IgAN than T cells, recently published results
of randomized, controlled trial of rituximab (anti-CD20 antibody) in IgAN, showed an inefficiency in the reduction of
proteinuria, serum levels of Gd-IgA1 or antibodies against
Gd-IgA1 [86]. This may encourage the nephrology community to focus on other targets: T cells and their interleukins.
Corticosteroids
The most commonly used immunosuppression agents are
corticosteroids. According to current guidelines, patients
with GFR > 50 ml/min/1.73 m2 who fail to achieve levels of
proteinuria below 1 g/day despite 3–6 months of optimized
supportive care (including RAS blockers) are candidates
for a 6-month course of systemic corticosteroid therapy [2].
The majority of recently published randomized controlled
trials (RCTs) support the claim that corticosteroids reduce
proteinuria and the probable progression of kidney function
decline, but at the same time are associated with a number
of adverse effects [87].
The knowledge about the precise effect of corticosteroids on T cells in IgAN is limited. Generally, corticosteroids are considered to inhibit production of both Th1- and
Th2-type cytokines; probably with a more pronounced effect
on Th1 cytokines in prolonged treatment [88]. In contrast,
Zhang et al. observed elevation of IL-4 and IL-10 serum
Clinical and Experimental Nephrology (2019) 23:291–303
concentrations, Th2- and Treg-type cytokines, after 8–12
weeks of prednisone therapy in IgAN patients. Additionally,
such corticosteroid treatment reduced the frequency of Tfh
cells and the serum concentration of IL-21 [78].
To sum up, corticosteroids are an effective treatment for
high risk patients with IgAN and the mechanism is at least
partially T cell-dependent. However, given the elevation of
IL-4, changes in T cell populations after treatment with corticosteroids seem to be not optimal for IgAN patients, thus
more targeted therapeutics are needed. Admittedly, prednisone therapy can significantly reduce the levels of total
IgA and Gd-IgA1 [89, 90] but, as Kosztyu et al. highlighted,
levels of these immunoglobulins did not reach normal values
[90].
Azathioprine and cyclophosphamide
KDIGO guidelines suggest using corticosteroids combined
with cyclophosphamide or azathioprine in IgAN patients
only if there is crescentic IgAN with rapidly deteriorating
kidney function [2]. However, the impact of these drugs on
the course of IgAN is currently poorly documented. Studies
on azathioprine in autoimmune diseases other than IgAN
revealed reduction in γδ T [91] and Th17 cells but also an
unfavorable reduction of Treg suppressive activity [92].
Reduction of number and suppressive activity of Treg was
also reported for low dose cyclophosphamide; it seems that
Tregs are more sensitive to cyclophosphamide compared
with Th and Tc cells [93, 94]. On the contrary, administered
intravenously high-dose cyclophosphamide (100–200 mg/
kg divided over 2–4 consecutive days) is immunosuppressive through affecting all T cell subpopulations [95].
Unfortunately, clinical trials testing effectiveness of cyclophosphamide in IgAN treatment used low-dose protocols
(about 1.5 mg/kg/day for 2–6 months) [2], which, according to current knowledge, might be responsible for its low
effectiveness.
Calcineurin inhibitors (CNIs): cyclosporine
and tacrolimus
Recently published meta-analysis of seven RCTs indicates
that the combination of CNIs and medium/low-dose corticosteroid is more effective in reducing proteinuria compared
with the treatment with corticosteroid alone, suggesting a
synergistic effect between CNIs and corticosteroids but
without significant improvement in eGFR and higher incidents of gastrointestinal, neurological, and musculoskeletal
symptoms [96].
Tacrolimus effectively inhibits key T cell activation pathways in T cells after kidney transplant [97]. A rat model of
IgAN treated with tacrolimus revealed that usage of CNIs
leads to an improvement of clinical features, along with
299
reduction of serum concentration of TGF-β1, Th2-type
cytokines (IL-4, IL-5), but elevation of Th1-type cytokine
IFN-γ, which might have a protective role against the development of IgAN [98]. Median regression analysis of GdIgA1 serum changes in IgAN patients before transplantation
and up to 6 months after transplantation revealed that the
degree of exposure to the tacrolimus therapy correlated with
a decrease of IgA1, but not Gd-IgA1 [89].
Anti‑thymocyte globulin (ATG)
Transplanted patients receive induction therapy just after
transplantation to lower the risk of acute rejection during the early posttransplantation period. One of the commonly used and effective drugs is rabbit anti-thymocyte
globulin (ATG) [99]. Studies have shown that ATG can
effectively reduce the risk of recurrence of primary IgAN
after renal transplantation [100, 101]. This observation
will be verified after completion of an ongoing prospective, multicenter, randomized, open trial with a followup 5-year period called PIRAT (Prevention in Recipients
With Primary IgA Nephropathy of Recurrence After Kidney Transplantation: ATG-F versus Basiliximab as Induction Immunosuppressive Treatment) [102].
The anti-inflammatory mechanism of ATG is based on
induction of T cell apoptosis, while increasing the number of Treg cells and improving their function [103, 104].
The latter is attributed to elevated production of IL-4 and
IL-13, Th2-type cytokines [105]. Also, renal recipients
receiving ATG have prolonged depletion of Tfh cells
[106].
Table 3 Proposed T-cell-dependent targets of biological therapeutics
Target
Mechanism of action
IL-4
Neutralization of IL-4
IL-4R/IL-13R Antagonism of IL‑4/IL-13
receptor
IL-5
Neutralization of IL-5
IL-6
Neutralization of IL-6
IL-6R
Antagonism of IL‑6 receptor
IL-12, IL-23 Inhibition of Th1 and Th17
differentiation through p40
inhibition
IL-17A
Neutralization of IL-17A
IL-21
IL-22
TGF-β
TGF-βR
Neutralization of IL-21
Neutralization of IL-22
Neutralization of TGF-β
Antagonism of TGF-β receptor
Drug
Pascolizumab
Dupilumab, Pitakinra
Mepolizumab
Sirukumab
Tocilizumab
Ustekinumab
Secukinumab
Ixekizumab
NNC0114-0006
Fezakinumab
Fresolimumab
Galunisertib
13
300
New targeted biological therapeutics
Advances in understanding IgAN pathobiology encourage us to target T cells and T cell cytokines in a more
precise manner. Optimal immunotherapy in IgAN ought
to reduce the activity of Th2, Tfh, Th17 and Th22 cells,
while improving the function of Treg cells. All potential
therapeutic targets with dedicated biologic drugs are summarized in Table 3. According to T cells’ participation
in multi-hit pathogenetic process, clinical trials with the
drugs included in Table 3, but currently untested in the
IgAN context, would be desirable. Following reported correlations between T-cell interleukins and clinical severity of IgAN (summarized in Table 2), antibodies against
IL-21 or inhibitors of IL-21 receptors should be especially
tested.
Final conclusions
Excessive activity of T cells, especially the Th2, Tfh, Th17
and Th22 subpopulations, not only plays an important role
in IgAN pathogenesis, but also is correlated with its clinical
severity. The fact that 15–20% of patients within 10 years
and 30–40% of patients within 20–30 years after the first
clinical presentation progress to ESRD encourage us to
a more aggressive treatment in patients with risk factors.
However, the currently used immunosuppressive drugs for
the treatment of IgAN are unspecific because they target
all populations of T cells. In our opinion, optimal immunotherapy in IgAN should reduce the activity of specific
subpopulations by modulation of cytokine levels or inhibition cytokine receptors, while simultaneously improving
the function of Treg cells. Therefore, clinical trials with the
drugs targeting the imbalance of the T cells compartment
are highly desirable.
Acknowledgements All figures were made using draw.io and Paint.
NET software. This work was supported by Polish Ministry of Science and Higher Education statutory grAnt 02-0058/07/262 to Jacek
M. Witkowski.
Compliance with ethical standards
Conflict of interest The authors have declared that no conflict of interest exists.
Ethical standards This article does not contain any studies with human
participants or animals performed by any of the authors.
Informed consent Informed consent was not involved.
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat
ivecommons.org/licenses/by/4.0/), which permits unrestricted use,
13
Clinical and Experimental Nephrology (2019) 23:291–303
distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made.
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