review http://www.kidney-international.

org
& 2007 International Society of Nephrology

Pathogenesis of poststreptococcal
glomerulonephritis a century after Clemens von
Pirquet
B Rodrı́guez-Iturbe1 and S Batsford2
1
Instituto Venezolano de Investigaciones Cientı́ficas (IVIC-Zulia), Hospital Universitario de Maracaibo and Centro de Investigaciones
Biomédicas, Maracaibo, Venezuela and 2Department of Immunology, Institute of Medical Microbiology, Freiburg University, Freiburg,
Germany

Considerable insight has been gained into the It has been known for a long time that scarlatina nephritis
etiopathogenesis of poststreptococcal glomerulonephritis appears as a rule in the third week. None of the hypothesis
since the landmark theoretical construct of Clemens von thus far advanced is able to account satisfactorily for the fact
Pirquet postulated that disease-causing immune complexes that nephritis occurs just at that time.
were responsible for the nephritis that followed scarlet fever. von Pirquet C. Allergy. Arch Int Med 7:259–288, 382–436,
Over the years, molecular mimicry between streptococcal 1911.
products and renal components, autoimmune reactivity and Acute poststreptococcal glomerulonephritis (APSGN) is
several streptococcal antigens have been extensively studied. an ancient and well-defined renal disease. Recent decades
Recent investigations assign a critical role to both in situ have seen a reduction in the incidence of the disease
formation and deposition of circulating immune complexes for reasons not entirely clear, but likely associated with
that would trigger a variety of effector mechanisms. earlier recognition and effective treatment of streptococcal
Glomerular plasmin-binding activity of streptococcal infections. Nevertheless, epidemics and clusters of cases
glyceraldehyde-3-phosphate-dehydrogenase may play a role continue to appear in several regions of the world and
in nephritogenicity and streptococcal pyrogenic exotoxin B sporadic cases of APSGN account for 21% (4.6–51.6%) of
and its zymogen precursor may be the long-sought children admitted to the hospital with acute renal failure in
nephritogenic antigen. developing countries.1
Kidney International (2007) 71, 1094–1104; doi:10.1038/sj.ki.5002169; In the 18th century, it was recognized that ‘edematous
published online 7 March 2007 swelling with scanty, dark and at times totally suppressed
KEYWORDS: immune complex disease; streptococcal antigens; strepto- urine’ was a feared complication of the convalescent period
coccal GAPDH; plasmin receptor; exotoxin B; zymogen of scarlet fever,2 but it was Wells3 who, in 1812 published
a classic paper, actually delivered 6 years before to the Society
for the Improvement of Medical and Chirurgical Knowledge,
defining the limits of the latent period and the characteristics
of the edema, giving evidence that the urine contained
the ‘red matter’ as well as ‘the serum of the blood’ and
emphasized that this complication occurred more frequently
in siblings than in the general population. This communica-
tion preceded by more than 10 years the landmark
clinicopathological contributions of Richard Bright,4 which
established the connection between dropsy and coagulable
urine, and by more than six decades the finding of ‘glome-
rulitis’ in postscarlatinal nephritis5 and the report of Reichel6
that gave a clear description of the glomerular lesions in
a fatal cases of the disease subsequently expanded on by
Osman et al.7
Correspondence: B Rodriguez-Iturbe, Servicio de Nefrologı́a, Hospital Despite the fact that both the clinical features and the
Unversitario, Ave Goajira s/n, Maracaibo, Estado Zulia, Venezuela. E-mail: renal pathology of the disease were well known, the reasons
[email protected] for the association between this clearly non-infectious
Received 23 August 2006; revised 9 November 2006; accepted (‘reactive’) complication of an infectious and, at that time,
12 December 2006; published online 7 March 2007 epidemic disease remained elusive until the seminal work of

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B Rodrı́guez-Iturbe and S Batsford: Etiopathogenesis of poststreptococcal nephritis review

Clemens von Pirquet.8 In 1903, von Pirquet, then a 29-year- EXPERIMENTAL MODELS OF PSGN
old pediatrics resident, purely on the basis of clinical Following the demonstration of the etiologic role of the
observations, postulated the existence of antibody-driven group A streptococcus in induction of acute nephritis, many
pathogenic, rather than beneficial immune reactions that he attempts were made to induce experimental glomerulone-
named allergy (‘altered reactivity’). Interestingly, in an phritis in animals, including rabbits, rats, mice, and monkeys.
unusual method of claiming scientific priority for a concept, The major difficulty is clear: group A streptococci are
he outlined his theory in a sealed letter sent to the Academy specific human pathogens. Injections of dead streptococci,
of Sciences in Vienna that was only to be opened at his toxic extracellular products, and streptococcal vaccines, deep
request. This was in fact done in 1908 when the letter was and superficial infections produced by inoculations with
read in a session of the Academy.9 live bacteria, and implantation of diffusion chambers have
The term poststreptococcal glomerulonephritis became been tried by many authors in attempts to reproduce the
usage following the demonstration that the b-hemolytic characteristics of PSGN seen in humans.20–24 In relation to
streptococcus was the cause of scarlet fever, based on the experimental infection, Reed and Matheson25 as well as
experimental work of Dick and Dick,10 the clinical work of Becker and Murphy26 were able to induce albuminuria and
Dochez and Sherman11 and particularly reports in the first hematuria, and occasionally hypertension and azotemia.
half of the 20th century that identified cases of glomerulo- Unfortunately, these careful and laborious investigations did
nephritis following upper respiratory and skin infections not consistently produce glomerulonephritis and did not
owing to streptococci. Among such reports, the work of permit evaluation of putative nephritogenic antigens.
Little et al.,12 who identified bacteriologic and or serological More recently, Nordstram et al.27 explored streptococcal
evidence of streptococcal infections in 109 of 116 consecutive nephritogenicity in a series of elegant studies using steel cages
cases of acute glomerulonephritis and the association of and osmotic pumps implanted subcutaneously in rabbits
glomerulonephritis with pyodermitis and streptococcal and in mice. They found clinical and histological evidence
wound infections reported by Futcher,13 deserve specific of nephritis when the cages were filled with nephritis-
mention. associated bacterial isolates and subsequently implicated
The next important theoretical concept was that of streptokinase as a nephritogenic factor,28,29 these results are
‘nephritogenic’ streptococcal strains. This notion was advan- discussed later.
ced initially by Seegal and Earle,14 who noted that rheumatic
fever and PSGN, both nonsuppurative complications of IMMUNE COMPLEX DISEASE AND COMPLEMENT ACTIVATION
streptococcal infection, did not coexist in the same patient, Immune complexes represent the ‘toxic bodies’ proposed to
differed in geographical location, in sex incidence (2:1 be responsible for the symptoms by von Pirquet.8 Although
male:female predominance in PSGN), and propensity to the identity of the nephritogenic antigen remained con-
healing (PSGN) rather than to relapsing attacks (rheumatic troversial, general agreement existed in the 1960s and 1970s
fever). Although recognizing that host differences ‘may play a with respect to the nephritogenic role of circulating immune
definite role’ in explaining these contrasting characteristics, complexes because of similarities between PSGN and the
they championed a straightforward explanation, namely the acute (‘one-shot’) serum sickness model.30,31
existence of hemolytic streptococcal strains that caused Glomerular trapping of immune complexes is facilitated
rheumatic fever (hence rheumatogenic strains) and other by various factors. Among these, appropriate size
strains that caused glomerulonephritis (nephritogenic (300–500 000 Da), antigen:antibody relationship (combining
strains). Subsequent investigations15–18 were considered to ratios near equivalence), type of antibody (class and affinity
validate this concept and laid the foundations for the determine half-life in plasma and ability to activate
search for nephritogenic antigens in group A streptococcal complement), and the efficiency of the reticuloendothelial
strains isolated from patients with nephritis. As reviewed system in clearing the complexes are relevant.30–32
elsewhere,19 Rebecca Lancefield’s M types 1, 2, 4, 12, 18, and It was accepted that immune complexes of appropriate
25 were strains with nephritogenic potential usually reco- size32 (300–500 000 Da), could deposit in the glomeruli,
vered from the upper respiratory tract whereas M types 49, activate the complement system and local coagulation
55, 57, and 60 were usually associated with impetigo- mechanisms, and induce glomerulonephritis. In acute serum
associated nephritis.18 More recently, the production of a sickness, as in PSGN, there is a full recovery of the renal
lipoproteinase that makes serum opaque (opacity factor) has lesions and a transient reduction in serum complement
been used to subdivide M proteins into class I (opacity factor levels.31,33 With respect to circulating immune complexes, as
negative) corresponding to serotypes that cause rheumatic many as 2/3 of PSGN patients had serum antigen–antibody
fever and class II (opacity factor positive) that corresponds to complexes,34 but these were also present in controls and in
serotypes that cause pyoderma and acute glomerulonephri- patients with uncomplicated streptococcal infections.35
tis.19 Although these associations were the foundation of Furthermore, there was no correlation between the presence
much research, accumulated evidence (see below) has or the amount of circulating immune complexes and the
demonstrated that M protein is not the decisive factor in clinical or pathological characteristics of the disease,36 so
streptococcal nephritogenicity. these findings lacked clinical significance.

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The critical role played by an in situ immune reaction glomeruli and tubulointerstitial regions in APSGN,47 and
resulting from antibody meeting free antigen deposited in the Rastaldi et al.48 showed that the intensity of intraglomerular
glomeruli was suspected as early as 1976.37 This possibility and tubulointerstitial intercellular adhesion molecule-1
was emphasized by the difficulties of inducing glomerulone- staining correlated with the intensity of macrophage infiltra-
phritis and the near impossibility of inducing subepithelial tion in glomeruli and the interstitium, respectively. Further-
immune deposits (humps), which represent the prototype more, the number of intraglomerular leukocytes correlated
lesion in PSGN,38,39 with preformed immune complexes. with proteinuria.
Large amounts of preformed immune complexes may Increased circulating levels of IL-6, IL-8, tumor necrosis
produce glomerulonephritis but this is leukocyte-mediated, factor-a, and monocyte chemotactic protein-1 have been
and the localization of the immune deposits is largely found in APSGN49,50 and a correlation between proteinuria
subendothelial. The landmark experiments of Vogt et al.,40 and urinary monocyte chemotactic protein-1 excretion has
who showed that cationic antigens could be attracted to been demonstrated.51
and effortlessly penetrate the negatively charged glomerular From the evidence listed above, it can be concluded that
basement membrane to induce prominent subepithelial infiltrating immune cells play a role in the development and
electron-dense deposits and severe glomerulonephritis, severity of the inflammatory glomerular damage in PSGN.
suggested that cationic streptococcal antigens might have However, the lack of a suitable animal model makes it
a role in acute PSGN. Obviously, charge alone does not difficult to explore the relative importance of cell-mediated
govern in immune complex deposition in the glomeruli, immune reactivity and the good prognosis of APSGN makes
as highlighted by the fact that patients with vasculitis and it unnecessary to consider the use of immunosuppressive
myeloperoxidase (cationic):anti-myeloperoxidase immune drugs in uncomplicated cases of the disease.
complexes have a pauci-immune glomerulonephritis.
Complement activation is a central feature in APSGN and STREPTOCOCCAL NEPHRITOGENICITY
the alternate pathway is preferentially activated. New insights We will now consider potential pathogenetic mechanisms in
into the activation of complement have been gained by the PSGN, including molecular mimicry between streptococcal
demonstration that immunoglobulin (Ig)-binding proteins fractions and renal structural constituents, autoimmune
in the streptococcal surface bind C4BP (a C4b-binding reactivity (in particular anti-IgG activity), plasminogen/
protein), thereby interfering with the classical pathway of plasmin binding by streptococcal surface proteins, and
complement activation.41,42 Relevant for a putative nephrito- finally, glomerular immune complex formation involving
genic antigen (extracellular cysteine proteinase (streptococcal streptococcal antigenic components (Table 1).
pyrogenic exotoxin B, SpeB)) that will be discussed later,
Wei et al.43 have recently shown that complement regulatory MOLECULAR MIMICRY
proteins (FH and FHL-1), used for immune evasion by Several investigators have studied structural similarities
Streptococcus pyogenes, are bacterial surface proteins that may between soluble fractions of streptococci and components
be removed by SpeB, suggesting that this protease may of the human glomerulus as a possible cause of nephri-
modulate FH and FHL-1 recruitment during infection. togenicity. Kefalides et al.52 reported antibodies to laminin,
Additional information on complement activation in
PSGN was provided by Ohsawa et al.44 who found that the
lectin pathway of complement activation may be activated in Table 1 | Streptococcal nephritogenicity
PSGN, probably by the recognition of glucosamine residues Molecular mimicry
in the bacterial wall by the mannan-binding lectin-starter Cross-reactivity of streptococcal products with laminin, collagen,
molecule; however, recent evidence shows that individuals GBM etc.
deficient in mannan-binding lectin may still develop
Anti-Ig reactivity
glomerulonephritis45 and the participation of this pathway Streptococcal neuraminidase
of complement activation in PSGN remains a matter of Streptococcal Ig-binding receptors
speculation.
Streptococcal-related glomerular plasmin-binding activity
Streptokinase
CELLULAR IMMUNE MECHANISMS IN PSGN zSpeB/SpeB
The presence of immunocompetent cells in biopsies of PSGN Enolase
was recognized more than two decades ago. Macrophages and NAPlr–GAPDH
T helper cells were shown to infiltrate the glomeruli in early Streptococcal nephritogenic antigens
biopsies.46 Infiltration of mononuclear cells may be pro- M protein
moted by chemotactic factors of the complement system, but Histone-like proteins
infiltration by immune cells is not correlated with comple- NAPlr–GAPDH
zSpeB/SpeB
ment deposition.
GBM, glomerular basement membrane; GAPDH, glyceraldehyde-3-phosphate-
Overexpression of the intercellular adhesion molecule-1 dehydrogenase; Ig, immunoglobulin; NAPLr, nephritis associated plasmin receptor;
and lymphocyte function-associated antigen-1 was seen in SpeB, streptococcal pyrogenic exotoxin B; zSpeB, zymogen precursor of SpeB.

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B Rodrı́guez-Iturbe and S Batsford: Etiopathogenesis of poststreptococcal nephritis review

collagen, and other molecules in the sera of patients with clinical picture.76 Despite this evidence, it should be noted
PSGN. Several authors found shared antigenic determinants that the capacity to produce neuraminidase is not a unique
between M12 streptococcal protein and glomerular basement characteristic of nephritogenic streptococci; in fact, rheuma-
membrane,53–55 vimentin,56 and mesangial proteins,57 and togenic streptococci also produce this enzyme.68
Kraus and Beachey58 found M protein epitopes of potential Anti-Ig production could also be the result of Ig binding
renal autoimmune relevance. to receptors in the streptococcal wall. Type II receptors in
However, there are little, if any, differences in the cross- groups A, C, and G streptococci have been demonstrated by
reactivity patterns of streptococci with rheumatogenic several authors.77–79 These receptors bind avidly to the Fc
potential compared with those with nephritogenic poten- fragment of IgG and anti-IgG antibodies are systematically
tial.59 An extensive review of the experiments reporting cross- produced by the injections of group A streptococci cultured
reactivity between mammalian tissues and streptococci by in medium containing autologous serum.80 Anti-IgG activity
Christensen et al.60 concluded that most of the preparations induced by streptococci with Ig-binding receptors is
used likely contained streptococcal Ig receptors or tissue IgG associated with enhanced tissue deposition of IgG and
Fc receptors or, in those studies where sera were involved, immune complexes in rabbits, causing inflammatory glo-
anti-Igs; furthermore, they emphasized the near impossibility merular changes.81,82 Streptococcal receptors with affinity for
to induce disease with injections of cross-reactive antigens. IgM have also been described.83,84
Ig-binding capacity by streptococcal components may
AUTOIMMUNE REACTIVITY IN PSGN have additional nephritogenic relevance. Protein H, a surface
The existence of autoimmune mechanisms triggered by protein of S. pyogenes interacting with the constant Fc region
streptococci capable of causing nephritis was championed by of IgG, is known to be released from the streptococcal surface
McIntosh et al.23,61,63,64 in the early 1970s. They showed that by cysteine proteinase (SpeB) produced by the bacteria. Berge
cryoglobulins had a role in experimental nephritis induced by et al.85 have shown that addition of protein H to human
type 12 streptococcus,23 that streptococcal neuraminidase serum produces complement activation with dose-dependent
could eliminate the sialic acid of IgG, and that such autologous cleavage of C3. Protein H–IgG complexes released from the
desialized IgG was capable of inducing anti-IgG reactivity and streptococcal surface may then be relevant not only as
glomerular lesions.61 IgG-rheumatoid factor was subsequently modulators of complement activation but also as inducers of
demonstrated in the serum of 32–43% of patients with PSGN anti-IgG reactivity. The latter suggests a link between a
and IgM-rheumatoid factor in 15% of the patients,33,62 putative nephritogenic antigen (SpeB – see later) and anti-
particularly in the first week of the disease.63 In addition, IgG reactivity in PSGN.
anti-Ig deposits were demonstrated in the glomeruli of 19 of In addition to anti-IgG, other autoimmune reactivity has
22 biopsies64 and IgG with anti-IgG reactivity was eluted from been found in patients with PSGN. DNA–anti-DNA com-
the kidneys of a fatal case of PSGN.65 More evidence of anti- plexes86 and antineutrophil-cytoplasmic antibodies have also
IgG activity was found with the skin-window technique, which been detected. The latter are present in as many as 2/3 of the
showed that patients with PSGN reacted to normal human patients in whom there is azotemia and in 70% of the
IgG with a lymphocytic infiltrate similar to the recognition patients that develop crescentic glomerulonephritis after
reaction observed in response to antigens to which the patient streptococcal infection.87
had had previous exposure.66 From the evidence listed above, it may be concluded that
Two mechanisms have been advanced to explain the autoimmune reactivity and, particularly, anti-IgG antibodies
development of anti-IgG activity in PSGN: neuraminidase- in serum and in glomerular deposits are frequently present in
induced desialization of Ig and IgG-binding proteins in the PSGN. As these autoimmune phenomena do not define a
streptococcal wall. Although neuraminidase production was specific clinical course of the disease, it is possible that they
reported in streptococci of M types 1, 4, and 12,67 there are represent epiphenomena; however, it is not unreasonable to
conflicting reports on its frequency among isolates.68–70 likely consider that in some patients, severe autoimmune reactivity
owing to loss of neuraminidase production by bacteria after may modulate the course of PSGN.
repeated subculturing.69
Serum neuraminidase activity and free neuraminic (sialic) NEPHRITOGENIC STREPTOCOCCAL ANTIGENS
acid levels were found in PSGN patients by us71 and others.72 The lack of a suitable animal model for PSGN made it
Additional evidence in favor of a nephritogenic role for necessary to focus attention on selected streptococcal
neuraminidase was presented in experiments that showed fractions and their potential to deposit in the glomeruli
that desialized leukocytes have an affinity for the glomeruli73 and cause injury. In parallel, studies were directed to detect
and by the demonstration of glomerular-binding sites for these putative antigens in renal biopsies of patients with
Arachys hypogea (peanut agglutinin), presumably identifying APSGN and the corresponding antibody response.
free galactosamine radicals exposed by the loss of sialic acid
from deposited Igs74 and desialized leukocytes.75 The M PROTEINS
association of APSGN and thrombotic microangiopathy in Several early investigations reported M proteins in human
a patient suggested a role of neuraminidase in the combined renal biopsies,88–90 but the results were inconsistent.91,92 The

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review B Rodrı́guez-Iturbe and S Batsford: Etiopathogenesis of poststreptococcal nephritis

discrepancies were attributed to impurities of the strepto- been removed from the list of candidate nephritogenic
coccal fractions used to produce the antisera and to variation antigens in PSGN. Nevertheless, streptokinases are proteins
in the timing of the biopsy, but also free antigen unmasked by secreted by streptococci with the capacity to convert
antibody is more likely to be present in early biopsies.90,93 plasminogen to plasmin107,108 and both Poon-King et al.109
Experimentally, it could be shown that complexes of M and Nordstrom et al.27 suggested that binding of strepto-
protein and fibrinogen could localize in the glomerulus94,95 kinase could convert plasminogen to active plasmin, which
and mild, self-limited renal lesions were induced by repeated could cause degradation of extracellular matrix proteins,
injections of M protein, either alone or in combination with activation of matrix metalloproteinases, and local activation
fibrinogen.96 of the complement and coagulation pathways. Plasmin-
In the following years, evidence against a primary role of initiated tissue injury could assist deposition of, and promote
M protein accumulated. First is the fact that recurrence of further damage by immune complexes. This notion was
PSGN is extremely rare, if it occurs at all, which is compatible subsequently embraced by Yoshizawa et al.110,111 in their
with the notion of ubiquitous antigen(s) conferring long- studies on the streptococcal glyceraldehyde-3-phosphate-
lasting immunity and conflicts with the mounting number of dehydrogenase (GAPDH) plasmin receptor (see below). This
putative nephritogenic M-proteins types that do not confer pathogenic mechanism may also be triggered by other
lifetime immunity. In addition, Treser et al.97 showed that streptococcal antigens with the capacity to activate and bind
convalescent sera, presumably containing antibody against plasmin (see later). Interestingly, mouse plasminogen is not
the specific nephritogen, could recognize free antigenic sites activated by streptokinase,112 which would imply a different
in early biopsies, but this staining was not prevented by mechanism for the streptokinase-induced nephritis observed
preabsorbing the sera with M protein. Interestingly, attempts in the mouse cage model.
to evaluate the specificity of IgG eluted from the kidney in a
fatal case of PSGN did not show anti-M type streptococcal STREPTOCOCCAL HISTONE-LIKE PROTEINS
reactivity.65 Finally, in recent years, it has been shown that Bacterial histone-like proteins (HlpA) of streptococci may
not only group A streptococci have nephritogenic potential, contribute to the virulence of infections by promoting
as Streptococcus zooepidemicus (group C), known to be the monocytes/macrophages to synthesize and release proin-
cause of equine ‘strangles (fever, mucopurulent nasal flammatory cytokines.113 HlpA are highly cationic and
discharge, lymphadenitis, and submandibular abscesses) selective binding of HlpA to proteoglycans in the rabbit
and mastitis in cows, has been responsible for recent glomerular basement membrane has been reported,114 and
epidemic outbreaks and clusters of cases of PSGN in different this binding might initiate in situ immune complex
parts of the world.98,99 formation.115 The potential nephritogenicity of HlpA has
been suggested because it is released into the circulation by
STREPTOKINASE group A streptococci in vivo and it elicits an antibody
In 1979, Villarreal et al.100 described a protein in nephrito- response.116 To our knowledge, determination of anti-HlpA
genic streptococci that was present in glomerular deposits in antibodies in patients with poststreptococcal sequelae and
most biopsies from patients with APSGN and was recognized streptococcal histone localization in the glomeruli of PSGN
by the majority of sera of patients with PSGN.101 Subsequent patients has not been reported, thus its role in PSGN is
experiments identified this protein as streptokinase102 and, speculative.
following this lead, Nordstrand et al.27 using the mouse
tissue-cage model induced glomerular lesions with strepto- NEPHRITIS-ASSOCIATED STREPTOCOCCAL PLASMIN
kinase-producing streptococci and showed that deletion of RECEPTOR
the gene encoding a streptokinase variant associated with Identification of nephritis-associated streptococcal plasmin
nephritis resulted in loss of nephritogenicity.29 In addition, receptor (NAPlr) as a putative nephritogen is the culmina-
they identified streptokinase in the glomeruli of some tion of a long series of studies initiated in the 1960s by Treser,
infected mice by the immunogold silver-staining technique.28 Lange, Yoshizawa.97,110 The current focus of investigations
However, production of this streptokinase variant was not is a plasmin-binding protein on the surface of nephritogenic
invariably associated with nephritis in the mouse cage streptococci.117 These studies followed the identification of a
model29 and anti-streptokinase antibody titers do not offer fraction obtained in the supernatant of pressure-disrupted
critical information on streptococcal infections associated streptococci named endostreptosin118 or preabsorbing
with nephritis.103,104 Furthermore, streptokinase alleles that antigen.119 Early biopsies of PSGN presented sites that stain
were thought to be present mainly in nephritogenic strains positive with fluorescein isothiocyanate-labeled Ig from con-
are just as common in non-nephritogenic streptococci.105 In valescent sera presumably identifying free antigenic sites. The
subsequent experiments, the group that had originally preabsorbing antigen was so-named because it was shown to
proposed streptokinase as a nephritigenic antigen concluded preabsorb the staining capacity of convalescent sera. How-
that there was no unique reactivity to streptokinase in PSGN ever, it was later shown that convalescent sera had anti-IgG
patients and that there were no streptokinase deposits in reactivity33,62 that could be responsible for the positive
human renal biopsy material.106 Therefore, streptokinase has stainings found in PSGN biopsies. Repeated injections of

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B Rodrı́guez-Iturbe and S Batsford: Etiopathogenesis of poststreptococcal nephritis review

preabsorbing antigen in rabbits resulted in glomerular C3 been suggested for a-enolase.123 Nevertheless, plasmin-
staining and mild proliferative changes with minimal or no related nephritogenicity requires the participation of im-
proteinuria or hematuria.120 Recent reports deal with an mune complexes and the demonstration of the colocalization
NAPlr of 43 kDa, initially identified by Winram and of the putative antigen and the complement and Ig is a
Lottenberg,121 which is a glycolytic enzyme with glyceralde- dependable characteristic of such immune reactivity. The
hyde-3-phosphate-dehydrogenase (GAPDH) activity.113 different sites of glomerular localization for NAPlr and C3
Streptococcal plasminogen-binding proteins may facilitate and Ig104 would speak against its role as the nephritogenic
bacterial invasion since, as mentioned earlier, surface-bound antigen.
plasmin activates both metalloproteinases and collagenases,
which can induce local inflammation. SpeB/zSpeB
Studies by Yoshizawa et al.104 showed that NAPlr activated SpeB is a cationic cysteine proteinase that belongs to the
the alternate complement pathway, that high antibody titers group of exotoxins (SpeA, SpeB, SpeC, and SpeD) produced
to NAPlr (as determined by Western blot in comparison with by pyogenic streptococci. One of these ‘erythrogenic’ toxins10
normal controls) were present in 92% of PSGN patients and was found by Elliot in 1945124 to be an active proteinase of
60% of uncomplicated streptococcal infections remaining 28 kDa generated by proteolysis following reduction of an
elevated for at least 10 years, and that renal NAPlr deposits extracellular zymogen precursor of B40 kDa produced by
were found in all renal biopsies of patients with APSGN group A streptococci. The proteinase (SpeB) and its
taken in the first 14 days of the disease. In a follow-up precursor (zSpeB) were subsequently identified by Gerlach
investigation,111 the same authors demonstrated prominent et al.125 and the crystal structure and integrin-binding
glomerular plasmin-like activity in patients who had APSGN properties were defined by Kagawa et al.126
and in whom glomerular NAPlr was positive, whereas it was SpeB is present in all S. pyogenes isolates and is the
absent or weak in patients who had APSGN and in whom predominant extracellular protein, accounting for more than
glomerular NAPlr was negative. The distribution of glomeru- 90% of the total secreted protein. Patients with infections
lar plasmin-like activity was identical to that of NAPlr. with several M types seroconvert to SpeB, indicating that
Importantly, the distribution of the deposits of NAPlr did not the molecule is made in vivo in the course of strepto-
coincide with the distribution of complement or IgG coccal infections.127 SpeB is a plasmin-binding receptor
deposits111 and therefore the authors postulated that protein128,129 that is capable of degrading human fibronectin,
nephritogenicity of NAPlr is related to its plasmin-binding activating a 66-kDa matrix metalloproteinase and of releasing
capacity, which was likely to facilitate immune complex active kinins.130,131 zSPEB and SpeB are cationic with pKs of
deposition. 8.2 and 9.3, respectively.
Several questions remain to be answered in relation to The possibility that SpeB/zSpeB could be a nephritogenic
these detailed investigations. First is the possibility of cross- antigen was raised after studies from Vogt et al.132 showed
reactivity with human GAPDH. This needs to be considered, that cationic antigens were present in the glomeruli in
because the staining of certain structures, particularly APSGN. These glomerular deposits were later identified as
infiltrating leukocytes, in the biopsies presented by the zymogen/streptococcal proteinase.40
authors,104 is a regular feature in biopsies stained with anti- Poon-King et al.109 in 1993 showed that streptococcal
human GAPDH (unpublished data from our laboratories). nephritogenic strains produced a plasma-binding protein
In addition, a recent multicentric investigation revealed identified as zSpeB and two simultaneous and independent
different results; as evaluated by both enzyme-linked studies133,134 provided evidence for a role of SpeB and zSpeB
immunosorbent assay and Western blot, anti-NAPlr anti- in APSGN. Cu et al.134 showed that 12 of 18 renal biopsies of
bodies were a rare occurrence and glomerular deposition of patients with PSGN had deposits of SpeB and high anti-SpeB
streptococcal NAPlr was infrequent in PSGN.122 One possible antibody levels were present in patients with PSGN, but not
reason for the contrasting observations in these studies is the in patients with uncomplicated streptococcal infections or in
different genetic background of the patients in the cited patients with acute rheumatic fever. Parra et al.133 did a
studies: the patients in the study of Batsford et al.122 had multicentric study of 153 patients with APSGN, 23 patients
many different genetic backgrounds, whereas the patients in with uncomplicated streptococcal infections and 93 controls
the studies by Yoshizawa et al.104 were drawn from a relatively in Venezuela, Chile, and Argentina and found that anti-zSpeB
homogeneous Japanese population. titers of 1:800–1:3200 had a likelihood ratio (sensitivity/
Also unanswered is the relationship between plasmin- 1-specificity) for the detection of streptococcal infections
binding activity and nephritogenicity. It is intellectually associated with glomerulonephritis of 2.0–44.2 and that
appealing to assign a pathogenic role to the capacity to bind receiver operating characteristic curves showed that anti-
activated plasmin to the glomeruli and this mechanism could zSpeB titers were consistently superior to anti-streptolysin
be operating in relation to several streptococcal fractions, in O titers and anti-DNAase B titers.
addition to NAPlr–GAPDH; for instance, streptokinase, In a more recent study, Batsford et al.122 evaluated NAPlr
SpeB, and enolase. In fact, the latter has the strongest and zSpeB/SpeB in biopsies and sera obtained from the
plasmin-binding activity and a nephritogenic potential has patients with PSGN in Venezuela, Chile, and Switzerland.

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review B Rodrı́guez-Iturbe and S Batsford: Etiopathogenesis of poststreptococcal nephritis

They found SpeB deposits in 12 of 17 biopsies and circulating example, the putative nephritogenic antigens SpeB/zSpeB
anti-SpeB antibodies in 53 of 53 sera examined. In contrast, as well as NaPlr are found in virtually all S. pyogenes
circulating antibodies to NAPlr were detected in five of isolates, including those strains associated with rheumatic
47 sera and unequivocal glomerular deposits of NaPlr in fever reviewed in Batsford et al.138 but only a minority of
only one biopsy (borderline in 2). Importantly, these studies patients develops nephritis. Particular properties of the
showed colocalization of SpeB and complement and IgG in bacteria are rather essential but not sufficient for induction
the glomeruli (Figure 1b) and, in addition, they demon- of disease. Based on such observations, it has long been
strated the existence of immunogold-labeled SpeB deposits accepted that host factors must play a major and decisive
inside the electron-dense subepithelial deposits (‘humps’) role in determining who gets poststreptococcal nephritis.
(Figure 1e) that are the histological hallmark of APSGN. As In fact, as early as 1812, the ‘constitutional differences’
discussed in earlier sections, other streptococcal antigens among families were assumed to be responsible for a familial
have been localized in the glomeruli and previous studies had predisposition to PSGN.3 Subsequent studies showed that
shown intra-hump Ig;135 however, this is the first time that 20139–38%140 of siblings of patients with sporadic PSGN
streptococcal antigens have been demonstrated within this developed clinical or subclinical nephritis. Nevertheless,
particular lesion. Not surprisingly, this was attributed to studies on human lymphocyte antigen antigen distribution
charge-facilitated penetration of SpeB, as is the case with have failed to define a specific association with PSGN.141,142
other cationic antigens that can induce similar electron-dense Multiple factors are likely in play in the genetic predisposi-
subepithelial lesions experimentally.136,137 tion to PSGN.

HOST FACTORS RESPONSIBLE FOR NEPHRITOGENICITY CONCLUDING REMARKS

Careful scrutiny of all the publications on PSGN fails to A number of pathways by which streptococci could initiate
identify properties of group A streptococci that are closely and perpetuate glomerular injury have been delineated
correlated with the appearance of glomerulonephritis. For above. It seems unlikely that a single mechanism will be
responsible in all cases, although at this time we favor the
view that glomerular-immune complex formation is the
a b critical step in the initiation of the disease that as it evolves
recruits a variety of effector mechanisms. As PSGN develops
in a minority of the patients infected with nephritogenic
strains, it is clear that host factors are critical to determine
who gets and who does not get nephritis. What these factors
are is not clear at present.
It may be noted that nephritogenicity, understood as the
c P
d P
capacity for generating renal inflammation, is not the same as
BM
hump nephritogenic antigen–antibody reactivity. The first may well
C3 result from plasmin-binding characteristics, whereas the later
hump may involve colocalization of the putative antigen with
BM IgG complement and Ig, as has been shown for streptococcal
SpeB (Figure 2). Further studies are required to elucidate the
participation of these elements in the pathogenesis of
e P f BM P poststreptococcal glomerulonephritis.
BM
From the standpoint of diagnosis of nephritogenic
streptococcal infections, rising antibody titers to SpeB/
hump zSpeB or NaPlr represent the best evidence presently
SPE B
available, but they are not available in clinical practice. Yet,
C3
IgG it is likely that they may be used to improve the etiologic
SPE B diagnosis of patients with acute nephritic syndrome in the
Figure 1 | SpeB is colocalized with complement and Ig and shown future.133
inside the subepithelial electron-dense deposits in APSGN. (a) A Clearly, in the 20th century we have gained great insight
light microphotograph of a glomerulus of APSGN (PAS staining, into the pathogenesis of antigen–antibody reactions and
original magnification  400) and (b) a merge microphotograph in poststreptococcal nephritis, yet, to quote Wolfgang von
which zSpeB (fluorescein isothiocyanate-labeled, green) and C3
colocalization is shown in orange. The set of immune electron Goethe, ‘if you miss the first buttonhole you will not succeed
microphotographs show a biopsy of APSGN in which the same in buttoning up your coat’ (Wer das erste Knopfloch verfehlt,
subepithelial electron-dense deposit (‘hump’) shows (c) C3, (d) IgG, kommt mit dem Zuknöpfen nicht zu Rande. From ‘Maximen
and (e) SpeB as immunogold-positive specs inside the hump. (f) a
composite in which the gold specs are substituted by colored spots is
und Reflektionen no. 900’) and it is fitting to give credit to
shown. The microphotographs and electronmicrophotographs are Clemens von Pirquet, a century after his sealed communica-
reproduced from Batsford et al.122 tion to the Vienna Academy of Sciences, for finding for us the

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B Rodrı́guez-Iturbe and S Batsford: Etiopathogenesis of poststreptococcal nephritis review

Nephritogenic streptococcus Nephritogenic streptococcus

GAPDH (NAPIr) zSpeB/SpeB

Mesangial and GBM binding Anti-zSeB/SpeB antibodies

Plasmin entrapment
and sustained activity (SpeB-antiSpeB)

Inflammatory reactivity (PMN,Mo) zSpeB, SpeB

degradation of GBM
anti-SpeB

+
Ic pentration through damaged GBM Circulating (SpeB-antiSpeB) depostion
and in situ SpeB-antiSpeB formation

Immune complex-mediated glomerulonephritis

Figure 2 | Etiopathogenesis of PSGN. Nephritogenicity of streptococcal NAPlr–GAPDH (left side) may be related to its plasmin-binding
activity that would induce inflammatory reactivity and glomerular basement membrane (GBM) degradation as, as demonstrated by
Oda et al.,111 it colocalizes in glomeruli with plasmin, but not with IgG or complement. SpeB and zSpeB (right side) may induce
immune-complex-mediated glomerulonephritis as SpeB deposits colocalizes with complement and IgG and is present in the subepithelial
humps that are the hallmark lesion of PSGN.122

elusive first buttonhole of this immune-mediated renal 9. Wagner R. Clemens von Pirquet: His Life and Work. Baltimore: Johns
Hopkins Press, 1968. Cited in Silverstein AM. Clemens Freiherr von
disease. Pirquet: explaining immune complex disease in 1906. Nat Immunol
2000; 1: 453–455.
ACKNOWLEDGMENTS 10. Dick GF, Dick GH. Experimental scarlet fever. J Am Med Assoc 1923; 81:
Research in Professor Rodriguez-Iturbe’s lab is supported by FONACIT 1166–1167.
Grant F-2005000283, Venezuela. 11. Dochez AR, Sherman L. The significance of Streptococcus hemolyticus
in scarlet fever and the preparation of a specific antiscarlatinal serum
by immunization of the horse to Streptococcus hemolyticus scarlatinae.
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