2. cellular players in glomerular disease, using selected
illustrative examples. Figure 2 summarizes some of
the ways in which glomerular injury can occur, with
individual diseases that will be discussed below and
in later articles in this series.
The Cellular Composition of the Glomerulus: Intrinsic
Glomerular Cells
Mesangial Cells: Matrix Homeostasis and a Glomerular
Scaffold
Mesangial cells provide support for the glomerular cap-
illary network and help maintain the homeostasis of the
mesangial matrix by secreting soluble factors. When injured,
mesangial cells can develop an activated phenotype or die
(via apoptosis or other mechanisms) (5). Circulating soluble
factors or metabolites can induce these responses directly, or
cause mesangial cells to secrete factors that elicit these
responses in an autocrine manner (6). In a process analogous
to wound healing, mesangial cell injury without ongoing
injurious stimuli may result in healthy remodelling of the
glomerulus, with mesangial cell migration, proliferation of
mesangial cell precursors in the juxta-glomerular apparatus,
and production of appropriate mesangial matrix (7).
Mesangial cell activation commonly results in hyper-
trophy and proliferation, excessive matrix production, and
the production of reactive oxygen species (5). Activated
mesangial cells produce chemokines and cytokines, which
act on mesangial cells themselves and on other resident
glomerular cells or leukocytes. These nearby cells in turn
secrete mediators that act on mesangial cells, forming a
paracrine loop (3). PDGFB is a potent mesangial cell mito-
gen. Its production by glomerular endothelial cells is es-
sential for mesangial cell development (5) and its
expression is upregulated in IgA nephropathy and other
proliferative forms of GN (8). Mesangial matrix expansion
Figure 1. | Basic structure of the glomerulus and the glomerular filtration barrier. (A) Each glomerulus is composed of an afferent arteriole,
which supplies the glomerular capillaries, and an efferent arteriole, into which they drain. Mesangial cells and mesangial matrix provide
structural support for the glomerular capillaries, lined by specialized fenestrated endothelium, and then the glomerular basement membrane.
On the urinary side of the glomerular basement membrane are podocytes, with foot processes that wrap around the glomerular capillaries. The
urinary space is lined by a cup-like layer of parietal epithelial cells which adhere to the basement membrane of Bowman’s capsule. (B) The
glomerular filtration barrier is a specialized molecular sieve, with properties that aid filtration of small solutes from the blood to the urine, while
limiting the passage of macromolecules such as albumin.
2 Clinical Journal of the American Society of Nephrology
3. and the release of vasoactive mediators results in de-
creased glomerular surface area and altered glomerular
hemodynamics, with decreased GFR (3,5). If mesangial
cell activation is ongoing, ECM accumulation in the inter-
stitial space leads to interstitial fibrosis, followed by glo-
merulosclerosis (9).
Mesangial cells are targets both in immunologic injury
and in metabolic disease. Mesangial IgA deposition is the
hallmark of IgA nephropathy. In this disease, current models
imply a multihit pathogenesis with immune complexes
of anti-glycan autoantibodies and galactose-deficient
IgA1 being deposited in the mesangium, resulting in
mesangial cell injury and proliferation (10). Mesangial cell
hypertrophy and matrix expansion are histologic fea-
tures of diabetic nephropathy, mediated by metabolic
and hemodynamic changes in the setting of diabetes.
These include hyperglycemia, advanced glycation end
products, oxidized free fatty acids, and angiotensin II
(5). Acquired or genetic abnormalities of the GBM may
also influence the phenotype and activation status of
mesangial cells, with mesangial matrix expansion and
subsequent glomerular sclerosis, as in experimental Alport
disease (11).
Glomerular Endothelial Cells: Adapted for Selective
Permeability
Glomerular endothelial cells are uniquely adapted for
selective permeability and filtration. Although the glomerular
endothelium is continuous, it contains fenestrations, which
cover up to 50% of the glomerular surface area (12). On
conventional electron microscopy these fenestrations
appear as ovoid transcellular “holes”, 60–70 nm in
diameter (12). However, the fenestrations (and the glo-
merular endothelium itself) are covered by glycocalyx, a
carbohydrate-rich, gel-like mesh with important roles in
capillary permeability, regulation of the interactions be-
tween leukocytes and endothelial cells, and transduction
of shear stress (12).
In some disease states, endothelial injury leads to altered
microvascular permeability and albuminuria. Inflamma-
tory stimuli increase permeability by widening endothelial
cell-cell junctions, and in some instances, inducing trans-
cellular holes (13). Endothelial disease is a feature of rap-
idly progressive forms of GN, including ANCA-associated
GN, anti-GBM GN, and class 3 and 4 lupus nephritis.
However, reduced GFR also occurs in association with a
loss of endothelial fenestral area in other diseases, such as
preeclampsia (14) and diabetic nephropathy (15). Glomerular
endothelial cells are particularly vulnerable to injury medi-
ated by complement dysregulation, for example in atypical
hemolytic uremic syndrome (16). Podocyte-derived
vascular endothelial growth factor (VEGF) is critical
to the maintenance of endothelial cell structure and
function. Anti-VEGF therapies are associated with pro-
teinuria in humans, and mice with a podocyte-
specific VEGF deletion develop proteinuria (17). The
glomerular endotheliosis and proteinuria seen in preeclamp-
sia is associated with increased placental production of
soluble fms-like tyrosine kinase-1, an endogenous VEGF
antagonist (18).
The endothelial glycocalyx is predominantly composed
of proteoglycans, with their negatively charged glycos-
aminoglycan (GAG) chains covalently bound to the cell
surface, and sialoproteins, with adsorbed components
Table 1. Key functions and responses of intrinsic glomerular cells
Cell Type
Normal Function and
Features
Responses to Injury
Relevant Glomerular
Diseases (Examples)
Mesangial
cells
Maintain structural architecture
of glomerulus
Lysis with healthy remodeling IgA nephropathy
Mesangial matrix homeostasis
Apoptosis Diabetic nephropathy
Regulate filtration surface area
Hypertrophy
Phagocytose apoptotic cells
Proliferation and matrix expansion
leading to glomerulosclerosis
Glomerular
endothelial
cells
Fenestrations and glycocalyx
facilitate selective permeability
and filtration
Apoptosis ANCA-associated GN
Loss of fenestrations Lupus nephritis
(class 3 and 4)Widening of cell-cell junctions,
transcellular holes Hemolytic uremic
syndrome
Glycocalyx damage, loss of GAG
synthesis
Diabetic nephropathy
Podocytes Foot processes wrap around
capillaries
Apoptosis Minimal change disease
Adherence to GBM
Foot process effacement FSGS
Slit diaphragm regulates filtration
Detachment from GBM, podocyte
loss
Diabetic nephropathy
Loss of slit diaphragm
Parietal
epithelial
cells
Line Bowman’s capsule Apoptosis Crescentic GN
Several subsets of cells likely
with different functions
Migration to glomerular tuft,
production of ECM proteins
leading to glomerulosclerosis
FSGS
Subset of cells may be able to
differentiate into podocytes
and play a reparative function
Proliferation leading to crescent and
pseudocrescent formation
GAG, glycosaminoglycan; GBM, glomerular basement membrane; ECM, extracellular matrix.
Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2016 Cells Involved in Glomerular Disease 3
4. Figure 2. | Simplified diagrammatic representation of a selection of mechanisms of glomerular injury. (A) Antibody-mediated glomerular
injury. From left to right, (i) neutrophils (shown) and macrophages induce injury after anti-a3(IV)NC1 autoantibodies bind to the GBM in anti-
GBM GN; (ii) in membranous glomerulopathy autoantibodies against PLA2R1 (and other antigens) on podocytes are deposited subepithelially,
with the involvement of complement; (iii) antibodies can bind to antigens lodged in the glomerulus (grey dots) with recruitment of macrophages
(shown) and neutrophils, and the activation of complement; (iv) circulating immune complexes can be deposited in glomeruli, activate
complement, and recruit leukocytes; (v) ANCA, (with complement) activates neutrophils and enables their recruitment to the glomerulus. Not
shown, but important, is IgA deposition in mesangial areas. (B) Cell-mediated immune mechanisms. (i) Effector CD41 cells (often Th1 or Th17
type) recognize antigens that can be intrinsic to or planted in the glomeruli. This occurs via their T cell receptor recognizing MHC class II
peptide complexes (several cell types could possibly be involved in this process). Activated T cells produce cytokines (IL-17A and IFN-g as
examples) that have direct effects on intrinsic kidney cells and activate, together with costimulatory molecules (e.g., CD154/CD40), innate
leukocytes such as macrophages. Not shown are interactions between intrinsic renal cells and T cells that include costimulation and cytokines.
(ii) CD81 cells can recognize antigenic peptides with MHC class I on intrinsic cells and secrete cytokines or induce cell death. (C) Metabolic,
vascular, and other mechanisms of injury. Podocyte and foot process injury and dysfunction occurs due to (i) genetic abnormalities of slit
diaphragm proteins and (ii) in minimal change disease and FSGS due to circulating permeability factors. Metabolic factors such as (iii) systemic
and intraglomerular hypertension and (iv) hyperglycemia and its consequences are common, and affect both the cells and the structural
components of the glomerulus. Both glomerular endothelial cell and podocyte injury are important consequences of preeclampsia, involved a
number of mediators including soluble fms-like tyrosine kinase-1. C3 glomerulopathy, as well as some types of atypical hemolytic uremic
syndrome (vi), can be induced by autoantibodies to, or genetic abnormalities in, complement regulatory proteins, resulting in complement
activation. a3(IV)NC1, the non-collagenous domain of the a3 chain of type IV collagen; FLT1, fms-like tyrosine kinase-1; GBM, glomerular
basement membrane; Mac, macrophage; M-type PLA2R1, phospholipase A2 receptor 1; Th, T helper; VEGF, vascular endothelial growth
factor.
4 Clinical Journal of the American Society of Nephrology
5. such as albumin (12). The net negative charge of the glyco-
calyx is thought to play a role in the charge selectivity of
the GFB, helping restrict the passage of the negatively
charged macromolecule, albumin (12). While some data
does not support this ‘charge selectivity’ theory (19), it is
likely that the glycocalyx, functioning as a hydrogel,
forms a physical barrier that is important for permselectiv-
ity (12,20). The development of albuminuria in experimen-
tal models of diabetes is associated with changes in the
glycocalyx, including loss of GAGs (12), which may occur
due to hyperglycemia-induced disruption of GAG synthe-
sis (21). Damage to any of the three layers of the GFB (en-
dothelium, GBM, or podocyte) can result in the presence of
high molecular weight proteins in the urine (22). However,
because changes in component of the GFB often affect the
other elements, the contribution of each individual com-
ponent to the filtration barrier is not easy to discern (22).
Additionally, even in health, a significant amount of al-
bumin may pass through the GFB and be retrieved by the
proximal tubule, mediated by the neonatal Fc receptor,
FcRn (19,23). The relative importance of these two
pathways in glomerular diseases remains the subject
of debate and may differ in individual diseases and
patients (23).
Glomerular endothelial cell injury may promote tubu-
lointerstitial fibrosis, leading to ESRD in CKD (24). Shear
stress is necessary for glomerular endothelial function and
with poor glomerular perfusion, decreased survival sig-
nals from endothelial cells induce regression and rarefac-
tion of the peritubular capillary network (24). This reduced
microvascular blood flow results in chronic tubulointersti-
tial hypoxia and fibrosis, with inflammation from damaged
tubular epithelial cells propagating further endothelial cell
injury (24).
Podocytes: Critical to Maintaining the Filtration Barrier
Podocytes possess multiple foot processes that wrap
around the glomerular capillaries, with filtration slits
between adjacent processes (25). Although sometimes de-
scribed as a specialized epithelial cell, the podocyte is a
uniquely differentiated cell with some mesenchymal fea-
tures (4,26). Diseased podocytes may exhibit actin cytoskel-
etal rearrangement, loss of the slit diaphragm, a more
cuboidal morphology (27), and may dedifferentiate in dis-
ease along epithelial or mesenchymal pathways, termed
‘podocyte disease transformation’ (26). Podocytes have lim-
ited capacity for repair or regeneration, with podocyte loss
being a feature of many conditions that lead to glomerulo-
sclerosis (28). As podocytes are lost from glomeruli, the
GFB is compromised; experimentally, when .20% of po-
docytes are lost, progressive glomerulosclerosis ensues
(29). Evidence that the extent of podocyte loss determines
outcome is consistent with the “podocyte depletion” hy-
pothesis (30). This hypothesis unifies a variety of glomeru-
lar diseases by postulating that the degree of podocyte
depletion induced by injurious processes is a critical deter-
minant of progression to glomerulosclerosis.
The term ‘podocytopathy’ describes disease that feature
podocyte dysfunction as the primary manifestation of the
disease process and that result in significant proteinuria.
Podocytopathies commonly occur due to circulating fac-
tors or inherited deficiencies of podocyte genes (4,31), and
include minimal change disease and FSGS. However, po-
docyte injury and loss can also occur due to other envi-
ronmental cues, including indirectly, due to abnormalities
in the paracrine, ECM, and GBM-mediated signaling nec-
essary for normal podocyte function (4,25). Both intact
junctions between podocyte foot processes at the slit di-
aphragm and adhesion of podocytes to the GBM are es-
sential for the function of the GFB (25). Podocyte
detachment occurs due to increased shear stress either in
glomerular hypertension or hyperfiltration, or to impaired
podocyte adhesion, more commonly occurring in inflam-
matory glomerular diseases (28). Podocyte adhesion to the
GBM involves a range of regulatory and scaffold proteins.
As well as serving as a mechanical anchor, adhesion is
an interface for the bidirectional transmission of signals
concerning cell growth, differentiation, and survival (32).
Podocyte transmembrane receptors bind to the GBM, with
the extracellular domain binding to a specific GBM protein
(e.g., collagen or laminin), and the intracellular domain re-
cruiting effector proteins linked to components of the podo-
cyte cytoskeleton, most commonly actin. Integrins are a
major family of such transmembrane receptors, with muta-
tions in integrins and changes in activation status implicated
in a number of diseases, including FSGS (33,34).
Podocyte foot processes are connected by the podocyte
intercellular junction, commonly called the slit diaphragm
due to its appearance on electron microscopy. This junction
is a necessary component of the GFB that determines
glomerular permeability characteristics. Within the kid-
ney, nephrin and podocin are unique to the podocyte and
essential for its function (25). Inactivating mutations of the
genes encoding nephrin and podocin causes nephrotic
syndrome with diffuse collapse of podocyte foot processes
(35,36). Both proteins are also involved in signal transduc-
tion (37), and signaling via adaptor proteins has a major
influence on the function of the podocyte actin cytoskele-
ton (25). Lastly, podocytes may act as “immune cells” (38)
that under some circumstances, present antigenic pep-
tides to CD41 T cells (39).
Glomerular PECs: Not Merely Lining Cells
PECs adhere in a monolayer to Bowman’s capsule, and
in humans are morphologically similar to squamous epi-
thelial cells (1). Several subpopulations of PECs exist in
humans, expressing combinations of podocyte, progenitor,
or tubular markers, although no consensus has been
reached on the nomenclature and function of these cell
types (1). Although podocytes and PECs are derived
from a common mesenchymal progenitor, PECs proliferate
under normal conditions, whereas terminally differenti-
ated podocytes have limited ability to regenerate (1).
Some studies suggest that some PECs can differentiate
into podocytes (1,40), supported by in vivo imaging studies
in mice showing not only migration of PECs to the visceral
layer of the glomerular tuft, but also nanotube “bridges”
between podocytes and PECs, and podocyte migration to
the Bowman’s capsule epithelial layer (41). While PECs
may be able to play a reparative role, they can also con-
tribute to injury after conversion. Activated PECs can pro-
liferate and contribute to crescent formation in rapidly
progressive GN (1), or participate in the formation of pseu-
docrescents and sclerotic lesions, as in certain forms of
Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2016 Cells Involved in Glomerular Disease 5
6. FSGS, with PECs migrating to the glomerular tuft and pro-
ducing ECM matrix proteins (1).
Leukocytes and the Glomerulus in Health and Disease
Leukocytes participate in many forms of glomerular
disease. They can influence disease by inducing, damp-
ening, or resolving systemic immune responses that lead to
glomerular disease. Alternately, leukocytes may act locally
within the glomerulus to mediate inflammation, or poten-
tially to resolve inflammation and mediate repair, or
contribute to homeostasis within normal glomeruli. Fig-
ure 3 shows leukocytes within glomeruli in GN. The sys-
temic actions of a range of innate and adaptive leukocytes
are critical to glomerular diseases discussed in articles
later in this series. The pathogenesis of these diseases
are intimately related to leukocyte behavior and activity
systemically, for example, the loss of tolerance and the
generation of nephritogenic autoimmunity in secondary
lymphoid organs (42–46).
Leukocytes in the Normal Glomerulus
Cross-sections of glomeruli from humans without renal
disease show few leukocytes, suggesting that the glomerulus
may not, under steady state conditions, support substantial
leukocyte recruitment. However, viewing normal mouse
glomeruli in vivo in three dimensions over time shows that
leukocytes patrol the normal glomerulus (Figure 4A) (47).
Patrolling monocytes in glomeruli are phenotypically sim-
ilar to monocytes that survey other blood vessels, and
although they may have homeostatic functions, they
could also promote renal and glomerular inflammation
by sensing danger (48).
Glomerular Leukocyte Recruitment: Specialized and
Potentially Damaging
A variety of leukocytes are recruited to glomeruli in
inflammatory glomerular disease. Generally speaking,
leukocyte recruitment is mediated by adhesion molecules
and chemokines (Figure 4B). Adhesion of leukocytes in glo-
merular capillaries does not follow the traditional selectin-
mediated rolling paradigm that exists in postcapillary
venules in other tissues. On recruitment, leukocytes halt
suddenly in glomerular capillaries (49), with some re-
maining static and others migrating bidirectionally (47).
The specific adhesion molecules that mediate this arrest
and migration are context-dependent, both in terms of
the leukocyte type involved and the process inducing the
recruitment. Also critical to leukocyte recruitment are
chemokines, with some specialization in that specific
chemokines are associated with specific chemokine
receptor-expressing leukocytes (e.g., CXCL8/IL-8 and
CXCR2-expressing neutrophils). Activated products of
complement, C3a and C5a, are chemoattractants, while
other mediators are more specialized, e.g., leukocytes that
express Fcg receptors, monocyte/macrophages, and neutro-
phils, are recruited via IgG deposited in glomeruli (50).
Neutrophils and the Glomerulus: First Responders with a
Damaging Phenotype
Neutrophils, the most abundant immune cells, are first-
line responders in inflammation and in a variety of
Figure 3. | Leukocytes in glomeruli of patients with rapidly progressive GN. High powered photomicrographs as illustrative examples of
leukocyteswithinglomeruliinANCA-associatedGN. Inallpanelscell nucleiarestainedwith49,6-diamidino-2-phenylindole(blue).(A)CD451cells
(green, CD45isacommonleukocytemarker)in theglomerulus,(B) CD31Tcells(green), (C)CD681macrophages(green),and (D)myeloperoxidase
(red) expressing leukocytes (neutrophils or macrophages) in a segmental glomerular lesion with local loss of CD34 (green), an endothelial cell lesion.
Nephrin (marking podocytes) is in white. Magnification: (A), (C ) and (D) x400; (B) x600. Photomicrographs from Ms. Kim O’Sullivan.
6 Clinical Journal of the American Society of Nephrology
7. glomerular diseases. On activation, neutrophils produce
and release reactive oxygen species, proteases, cytokines,
and chemokines. Neutrophils are activated systemically
(51,52), or locally by proinflammatory mediators gener-
ated or deposited in the kidney, such as immune com-
plexes (47). Proinflammatory products of neutrophils
directly damage the GFB. In addition, in some forms of
GN (such as ANCA-associated GN and lupus nephritis)
neutrophils generate neutrophil extracellular traps, web-like
structures of histones decorated with proteases, peptides,
and enzymes that are also likely to be injurious (53). In
vivo microscopy reveals that a neutrophil can influence in-
jury over a considerable proportion of the glomerulus by
crawling within glomerular capillaries, in one disease
model covering an average of 150 mm/hour (47).
Monocytes, Macrophages, and the Glomerulus: Diverse
and Important
Innate cells of the monocyte/macrophage lineage have
multiple roles in tissues. Macrophages can adopt proin-
flammatory (M1) or anti-inflammatory (M2) phenotypes,
although these phenotypes exist on a continuum (46).
These phenotypes are plastic in vivo, with macrophages
responding to cues in the tissue microenvironment. In
the initial phases of experimental AKI, due to ischemia
reperfusion injury, macrophages in the interstitium are
proinflammatory and damaging (54). After the injurious
stimulus subsides, the same cells take on a healing and
reparative role (54). There is no intrinsic reason why intra-
glomerular leukocytes, in some situations, are not also
anti-inflammatory. While these reparative roles are
healthy if injury is self-limited, when pathologic processes
are ongoing, macrophages function as “frustrated” healing
cells and contribute to progressive fibrotic injury. In auto-
immune kidney disease, both humoral and cell-mediated
effector responses use macrophages as effector cells. Glo-
merular IgG activates macrophages via Fc-FcgR interac-
tions, while effector T helper 1 (Th1) and T helper 17
(Th17) cells activate these cells both by cytokines and via
cell-cell contact.
Figure 4. | Leukocyte recruitment and behavior in the glomerulus. (A) In health, neutrophils and monocytes (and potentially other leukocytes)
patrol the glomerulus. While some are static, the majority migrate bidirectionally within glomerular capillaries. (B) In acute disease, leukocytes
can be recruited and retained in glomeruli via a number of molecular processes. Examples are given with reference to the neutrophil (from left
to right). Neutrophils can be recruited via direct FcgR-Fc interactions. Adhesion molecules participate in recruitment, migration, and retention,
with, for example, Mac-1 (CD11b/CD18) on neutrophils slowing migration and inducing retention. P-selectins is not constitutively expressed
by glomerular endothelial cells, but in some situations P-selectin can participate in forming bridges with recruited platelets (pink oval) to
recruit neutrophils. Lastly, chemokines, for example CXCL8 (IL-8) secreted by endothelial cells, podocytes, mesangial cells (not shown), or
other leukocytes (not shown), attract leukocytes expressing appropriate chemokine receptors down a concentration gradient. Other
mechanisms, for example complement (not shown), can also attract leukocytes to the glomerulus. FcgR, Fcg receptor; ICAM-1, intercellular
adhesion molecule 1.
Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2016 Cells Involved in Glomerular Disease 7
8. Dendritic Cells: The Interstitium, and the Glomerulus As
Well?
Systemically, dendritic cells (DCs), specialized leuko-
cytes that present antigen to T cells, play a key role in
adaptive immune responses that cause GN. In the kidney,
DCs form an extensive interstitial network (55), where they
help maintain tolerance to filtered self-peptides (56) and
act innately as pro- or anti-inflammatory renal mononu-
clear phagocytes. These interstitial DCs are largely acutely
protective. However, in inflammatory states, recruited in-
flammatory monocytes differentiate into proinflammatory
DCs, while activated resident DCs carry antigen to drain-
ing lymph nodes and activate naïve T cells. In contrast to
the interstitial DC network, DCs are rarely present in nor-
mal glomeruli (57) and only uncommonly in acute disease.
While human biopsy studies are divided as to the presence
of DCs in glomeruli in more established injury, in estab-
lished rapidly progressive GN, DCs within injured glo-
meruli may participate in T cell recruitment and
activation (43).
Mast Cells: More than Just Mediators of Allergy
While mast cells traditionally are considered as media-
tors of anaphylaxis and allergy, they are tunable cells that
contribute to, and regulate inflammation and autoimmu-
nity. In addition to histamine and other mediators of
allergy, mast cells secrete both stored and newly synthe-
sized pro- and anti-inflammatory cytokines. Mast cells
are present within the kidney in GN in both the tubuloin-
terstitium and the glomerulus. Intrarenal mast cells are
proinflammatory, with the capacity to degranulate (58),
while in secondary lymphoid organs they are anti-
inflammatory, acting with regulatory T cells to help maintain
tolerance (59,60).
T Lymphocytes: Subsets Directing Immunity and
Glomerular Disease
Conventional CD41 and CD81 T lymphocytes have a
wide range of ab T cell receptors that can recognize a huge
variety of antigenic peptides. T cells are instrumental in
protection from infectious threats but in disease, T cells
mediate a number of forms of inflammatory and autoim-
mune glomerular disease. CD41 cells orchestrate adaptive
immunity, differentiating into subsets that direct the sub-
sequent components of the immune response. These sub-
sets, while somewhat plastic, are definable by their
signature cytokines, transcription factors, and to some
degree, chemokine receptors (44). In glomerular disease,
T follicular helper cells promote T cell–dependent anti-
body production. In contrast, Th1 and Th17 cells recognize
antigens intrinsic to, or planted in glomeruli, and act as
local effectors of glomerular injury in experimental rapidly
progressive forms of GN (61). Th1 cells are particularly
associated with macrophage activation, and Th17 cells
are associated with neutrophil recruitment and activation.
Temporally, at least in responding to foreign antigens,
Th17 cells act earlier in immune responses and over time
convert to a mixed Th1/Th17 or Th1 phenotype (44). Th2
cells support eosinophils, important in allergic interstitial
nephritis and in glomerular disease in sub-Saharan Africa
(62). CD81 cells are cytotoxic, killing cells that express
their cognate peptide with MHC class 1, but also secrete
cytokines and may act in a proinflammatory manner (63).
B Lymphocytes: Antibodies As Key Mediators of Glomerular
Disease
B cells and their terminally differentiated progeny, antibody-
secreting plasma cells, are critical cells in humoral im-
munity. Within lymphoid organs, they produce antibodies
that impact the glomerulus in different ways in many forms
of GN. In autoimmunity and after some infections, Igs can
form circulating immune complexes that are deposited in
glomeruli, including IgA1 complexes in IgA nephropathy.
Alternately, in situ immune complexes form when anti-
bodies bind to antigens that are intrinsic to the glomerulus
or antigens that have been “planted” in the glomerulus. In
malignant conditions, such as multiple myeloma, single
clones of antibodies or light chains can be deposited in
glomeruli, while cryoglobulins (both IgM and IgG) lodge
in glomeruli in infectious, autoimmune, and malignant
diseases. Antibody production by the B cell/plasma cell
lineage is not the only possible role for B cells. In GN, B cell
aggregates in the interstitium could secrete cytokines and,
especially in established autoimmune responses, autoreactive
B cells may assist in antigen recognition by concentrating
autoantigenic peptides derived from autoantigens internalized
by their own cognate B cell receptor (64).
Immunoregulatory Immune Cells: T Cells, Macrophages,
and More
A variety of immune cells, including some CD41 and
CD81 T cells, macrophages, and DCs, dampen both sys-
temic immunity and local inflammation. The best de-
scribed subset is the CD41CD251foxp31 regulatory T
cell (Treg) that maintains tolerance and dampens inflam-
mation via soluble mediators and cell-cell contact. Both
endogenous and exogenous Tregs regulate experimental
glomerular disease (65,66) by inhibiting systemic immu-
nity, and probably also via local effects. Studies using reg-
ulatory CD81 T cells in experimental membranous
nephropathy illustrate their anti-inflammatory role (67),
with transfer of regulatory macrophages and DCs also lim-
iting experimental glomerular disease (68,69), including
progressive and chronic fibrotic injury. Given the potential
plasticity of many of these cells, future cell therapy trials
would need to consider the question of the stability of
transferred immune cells.
Innate Lymphoid Cells and Other T Lymphocytes:
Unconventional and Interesting
Other potentially important leukocytes include natural
killer (NK) cells, other innate lymphoid cells, and uncon-
ventional T cells: gd T cells, NK T cells, MR1-restricted
mucosal associated invariant T cells, and MHC class
1b–reactive T cells (70). Some unconventional T cells inter-
act with MHC class I/II-peptide complexes, but in a manner
distinct to that of classical T cells, while others recognize
glycolipids, vitamin B metabolites, and modified peptides.
Unlike conventional ab cells, whose T cell receptors un-
dergo somatic recombination, unconventional T cells have
relatively restricted patterns of antigen recognition (70).
Little is known about these cells in glomerular disease.
8 Clinical Journal of the American Society of Nephrology
9. However, for example, NK cells and their ligands are pre-
sent in the kidney in human lupus nephritis (71). Experi-
mentally, deficiency of invariant natural killer T cells
exacerbated GN (72,73), while proinflammatory gd T cells
are present in kidneys after passive antibody transfer (74).
Some of these subsets are particularly relevant to mucosal
immunity, with clear potential relevance not only for IgA
nephropathy but also for other forms of glomerular disease.
Intrinsic Glomerular Cells and Leukocytes Interact in
Glomerular Disease
Interactions between leukocytes and resident glomerular
cells in immune glomerular disease are dynamic and sub-
stantial, going beyond the simplistic paradigm of glomerular
cells merely being the target of leukocyte-mediated injury.
Cytokines, chemokines, and costimulatory molecules from
intrinsic glomerular cells activate (and regulate) leukocytes
locally, and it is possible that effector T cells recognize
antigenic peptides displayed by intrinsic glomerular cells.
There are many examples of these interactions: chemokines
derived from toll-like receptor 4–expressing glomerular
endothelial cells recruit neutrophils in experimental
ANCA-associated GN (75), while cytokines and costimula-
tory molecules expressed by intrinsic renal cells participate
in local activation of effector CD41 T cells in experimental
GN (76,77).
Summary and Conclusions
The glomerulus is vulnerable to injury from inflamma-
tory, metabolic, and other disease processes, which not
uncommonly involve the “dark side” of innate and adap-
tive immunity. In recent years we have made great prog-
ress in understanding glomerular disease. We now better
understand systemic disease processes that direct glomer-
ular injury; the local cellular, humoral, metabolic, genetic,
and molecular responses that induce injury; the detail of
the pathologic appearances of human glomerular disease;
and some of the prognostic indicators. This knowledge
allows us to take a more integrated view of glomerular
disease. Key challenges in the future include not only
identifying common local pathways for intervention and
regulating systemic processes that mediate glomerular
disease, but also developing more specific and less toxic
therapies specific to individual glomerular diseases, and
subsets of patients (or even individual patients) with a
specific disease.
Acknowledgments
Ms. Kim O’Sullivan is thanked for the photomicrographs in
Figure 3. We apologize to the many excellent researchers whose
work we have not discussed and cited.
Research performed by A.R.K in glomerular disease is funded by
Project Grants from the National Health and Medical Research
Council of Australia (NHMRC) (nos. 1048575, 1045065, 1046585,
1064112, and 1084869). H.L.H. is funded by an NHMRC Post-
graduate Scholarship (no. 1075304).
Disclosures
A.R.K. has been a member of an advisory board for Roche
Products, Australia. No Roche studies (that the authors are aware
of) are reported or discussed in the manuscript. H.L.H. declares no
conflicts of interest.
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