Autoimmunity in Acute Poststreptococcal GN: A Neglected Aspect of the Disease

Abstract

Acute poststreptococcal GN (APSGN) is the prototype of immune complex GN and is associated with manifestations of autoimmune reactivity that have been neglected as epiphenomena. Recently, studies have demonstrated transient antifactor B autoantibodies that activate the alternative complement pathway, bringing self-immunity to a central position in the pathogenesis of APSGN. Therefore, examining other manifestations of autoimmunity that have been reported in association with poststreptococcal GN is of interest. This article reviews the renal and extrarenal manifestations of autoimmune reactivity in APSGN and considers their potential relevance in modifying the usually benign clinical course of the disease. It also discusses related aspects of the nephritogenic antigens, complement activation, and genetic elements associated with immune reactivity and their potential relevance to the familial incidence of the disease.

The existence of autoimmune reactivity in APSGN has been known for several decades,¹ but it has been considered epiphenomena that occasionally aggravate the usually clinically benign course of the disease. The recent demonstration in patients with APSGN of antifactor B autoantibodies that stabilize C3 convertase and are pivotal to the activation of the alternative complement pathway² adds critical insight into the pathogenicity of the glomerular immune-complex deposition and brings to center stage the role of streptococcal-induced autologous immunity in the pathogenesis of APSGN. Although APSGN’s global incidence has decreased considerably, it nevertheless is significant in countries of middle and lower socioeconomic development^3,4 and remains the most common form GN in children.⁵

The purpose of this review is to examine the various manifestations of autoimmune reactivity reported in patients with this disease. It also updates the increasing number of streptococcal types that have been associated with nephritis, addresses the persistent questions about nephritogenic antigens, considers the less recognized activation of the lectin complement pathway in APSGN, and discusses some genetic aspects of potential autoimmune relevance.

Streptococcal Infections and Nephritogenic Antigens

For a long time, GN was considered a complication of group A β-hemolytic streptococci M types 49, 55, 57, and 60 (skin infections) and M types 1, 2, 4, and 12 (upper respiratory infections).⁶ This notion was on the basis of robust evidence obtained in epidemics, and a recent systematic review listed 23 M types, of which M types 1, 2, 4, 12, 49, 55, 63, and 73 were cultured from eight or more specimens from patients with APSGN and 19 more types were cultured from single specimens.⁷

However, it is now recognized that group A streptococci do not have the monopoly on nephropathogenicity. Studies of isolated cases, clusters of cases, and epidemics have now demonstrated that GN may follow infections of Streptococcus zooepidemicus,^8,9 Streptococcus pneumonia,^10,11 Streptococcus constellatus,¹² and Streptococcus anginosus,¹³ and the identity of nephritogenic streptococcal antigen(s) continues to be a matter of dispute. The association of APSGN with acute rheumatic fever in the same patients, while occasionally reported,¹⁴ remains a rare event, and second episodes of APSGN are exceptional, if they occur at all. The contrasting features of the “one-hit” attack of APSGN and the recurrent activation of humoral and cellular autoimmunity in rheumatic fever and rheumatic heart disease have been authoritatively discussed by Martin et al.¹⁵ These observations have long suggested a single nephritogenic antigen and the development of long-lasting protective antibodies in the disease.

Accumulated evidence gives strong support to the claims of the nephritis-associated plasmin receptor (NAPlr), identified as glyceraldehyde-3-phosphate dehydrogenase,¹⁶ and to the cationic cysteine proteinase streptococcal pyrogenic exotoxin B (SPEB),⁶ as the antigen(s) causing nephritis. High titers of antibodies to NAPlr and SPEB are present in the convalescent sera of patients with APSGN, and they have been colocalized with plasmin (NAPlr) and with complement and IgG (SPEB) in the glomeruli of biopsies from patients with the disease. Furthermore, these antigens induce the production of monocyte chemoattractant protein 1 and IL-6 in mesangial cells in association with overexpression of adhesion molecules; they also promote release of IL-6, TNF-α, IL-8, and TGF-β from peripheral blood leukocytes.⁴ NAPlr activates C3,¹⁶ and SPEB¹⁷ degrades complement factors. Experimental hyperimmunization with SPEB induces GN, leukocyte infiltration, and complement activation; the generated anti-SPEB antibodies have crossreactivity with HSP70 and thioredoxin, which suggested to the authors¹⁸ that this antigen was driving autoimmune reactivity. In addition, SPEB modulates the recruitment of complement regulatory proteins factor H and factor H–like protein 1 that are part of the mechanisms of immune evasion activated in streptococcal infection.¹⁹

Although significant evidence supports the nephritogenicity of these streptococcal antigens, the gene encoding SPEB was absent in strains of the most recent epidemic in the Brazilian municipality Nova Serrana.²⁰ Therefore, if it played a role in this epidemic, it cannot be the causative molecule in all patients. These findings point to the possibility of several nephritogenic antigens eliciting long-lasting immune responses or the existence of an as yet unidentified culprit of APSGN.

Complement Activation in APSGN

The activation of the complement system is a central event in the pathogenesis of APSGN. The acute phase of the disease almost universally features a reduction in the circulating level of C3, which usually returns to normal levels within a month. Because C1 and C4 are usually within normal limits, the reduction of C3 is assumed to be the result of a transient activation of the alternative pathway of the complement system.

The activation of the classic pathway of complement is suppressed by chemokine-binding evasins secreted by Streptococcus bacteria (discussed later) and by proteins on the streptococcal surface that bind a C4b-binding protein (C4BP).^21,22 Studies have found “atypical” cases of postinfectious GN with persistent proteinuria and hematuria and progression to CKD to be associated with persistent activation of the alternative pathway of the complement system, related to mutations in complement-regulating proteins and to antibodies to the C3 convertase.²³

The mechanism of activation of the alternative pathway of complement was unknown until the recent demonstration of antifactor B antibodies,² but it is important to keep in mind that there is also evidence of participation of the lectin complement pathway in poststreptococcal immune sequelae. Polymorphisms of the genes of the lectin pathway are risk factors for rheumatic heart disease,¹⁵ and activation of the lectin pathway has been shown to occur in patients with APSGN. Although normal C1q levels are found to be almost universal in APSGN, occasionally low C4 levels that are part of both the classic and lectin complement pathways have been reported in APSGN. Kholer and Ten Bensel²⁴ studied six patients with APSGN, and they found that one had a low-normal C4 value and two had low C4 values that increased to normal over 7–12 days. Cameron et al.²⁵ found low C4 levels in association “with very low C3 concentrations” in six of 32 patients with acute GN (28 of them poststreptococcal). Lewis et al.²⁶ reported low C4 levels in four of 14 patients with APSGN. Wyatt et al.²⁷ found activation of C4 (as determined by a high C4d-C4 ratio) in eight of 14 patients with APSGN, but only one patient had low C4 levels. Ohsawa et al.²⁸ first demonstrated, in the renal biopsy of a 16-year-old patient with APSGN, an intense mesangial staining for the lectin pathway starter molecule mannose-binding lectin (MBL), in association with immunostaining for C4d and for the associated serine protease MASP-1. They noted that MBL recognizes mannose as well as N-acetyl-glucosamine, which are antigenic determinants present in cell wall polysaccharides of group A streptococci. They also noted that MBL recognizes, although to a lesser extent, galactosamine radicals that could be exposed by streptococcal neuraminidase.

Hisano et al.²⁹ extended these observations in 18 patients with APSGN and found that glomerular deposits of C3c, C4, factor B, C4-bp, C5b-9, CD59, MBL, and MASP-1 were present in seven patients. Furthermore, glomerular deposits of C4-bp, an indicator of C4 consumption, were also positive in all of the patients in whom MBL and MASP-1 deposits were not detected. Skattum et al.³⁰ used ELISA to study the serum concentrations of MBL and found that although the median concentration of MBL was higher in patients with APSGN, the proportion of patients with APSGN and controls with low levels of MBL did not differ. They also found that some patients with MBL deficiency developed nephritis, indicating that MBL was not indispensable in the pathogenesis of the disease. Taken together, these studies indicate that in addition to the alternative pathway, the complement lectin pathway is activated in significant numbers of patients with APSGN. However, in contrast with the increased severity of IgA nephropathy associated with the activation of the lectin complement pathway,³¹ among patients with APSGN, the clinical (hematuria, proteinuria, and hypertension), biochemical (serum creatinine), and histologic characteristics were similar in those with or without glomerular MBL/MASP-1 deposits.²⁹

The interactions of Streptococcus with the complement pathways as they relate to APSGN are shown in Figure 1. These interactions include activation of the alternative and lectin pathways and the suppression of complement activity by evasins, directed to escape immune recognition and prevent phagocytic uptake.³² Of relevance to this review, soluble evasins are, at least in part, responsible for the lack of activation of the classic complement pathway in APSGN, despite a robust antibody response to streptococcal antigens. C3 is continuously generated in the alternative pathway (a process called “tick over”). Hydrolyzed C3 is formed spontaneously or after contact with surfaces³³ and reacts with factor B, which is then susceptible to cleavage by factor D into fragments Ba and Bb. Interaction of the active Bb fragment with C3 generates C3bBb (alternative pathway C3 convertase). C3bBb is critical for the regeneration of C3b, which feeds back for the formation of more C3bBb convertase complex (an amplification loop). The participation of complement is a critical element in the generation of inflammation by the immune complexes deposited in the glomerulus. Factor B autoantibodies² developed in APSGN are transient, stabilize the amplification loop, and maintain the activation of the alternative complement pathway (Figure 1).

Figure 1.

Activation of the complement system in acute poststreptococcal glomerulonephritis. Streptococcal relationships with the complement system related to the pathogenesis of APSGN. Streptococcal interactions with the complement pathways are activating (arrows) and suppressing (“evasins” to protect bacterial virulence shown in interrupted lines with end blocks). Secreted evasins suppress the activation of several elements of the classic complement pathway, whereas surface-bound evasins block the action of complement on the bacterial surface by several means.³² The lectin complement pathway is initiated by interaction of polysaccharide ligands in the bacterial surface with pattern recognition molecules (MBL, ficolins, and collectins) that react with mannose-binding lectin–associated serine proteases (MASPs) and subsequently activates C4 and then C2 to form C4b2a (classic pathway C3 convertase). Generation of antifactor B autoantibodies may result from neoepitopes resulting from the interaction of the Streptococcus with the alternative complement pathway or from conformational epitopes shared between factor B and Streptococcus. Antifactor B autoantibodies play a major role in the activation of the alternative complement pathway in APSGN because stabilizes C3bBb (alternative pathway convertase) and maintains the amplification loop (circle) that regenerates C3 from the cleaved active C3b fragment. Consumption of C3 and increase in terminal complement components are a consequence of C3bBb activity. Complement activation is critical for the nephritogenic inflammatory reactivity of the streptococcal antigen-antibody complexes deposited in the glomerulus. C3(H₂O), hydrolized C3; Endo O, endopeptidase O; Endo S, endopeptidase S; FH, complement Factor H; IdeS/Mac-1, Mac-2, Ig degrading enzyme with homology to the α-subunit of human Mac-1 and Mac-2 (CD11b/CD18, CR3); MAC, membrane attack complex.

Autoimmune Reactivity in APSGN

A large number of autoantibodies have been demonstrated in patients with APSGN.

Anticomplement Antibodies

Antifactor B Antibodies

Chauvet et al.² studied sera from 34 children with APSGN and low serum C3 levels and compared their anticomplement autoantibodies with the findings in children with C3 glomerulopathy and persistent hypocomplementemia. Their aim was to demonstrate differences in the complement activation between these two entities, which share some clinical features and C3 activation but have a very different prognosis. They found that 31 of 34 patients with APSGN and only four of 28 patients with C3 glomerulopathy had antifactor B antibodies, mainly of the IgG1 subclass. Antifactor B autoantibodies in the diagnosis of APSGN had sensitivity and specificity of 95% (95% confidence interval, 85% to 99%) and 82% (95% confidence interval, 66% to 93%), respectively.² The antifactor B autoantibodies were transient and inversely correlated with plasma levels of C3 and directly correlated with levels of C5b-9 (Figure 1). Furthermore, they showed that antifactor B autoantibodies enhanced the activity of the alternative pathway C3 convertase and identified antibody binding sites in factor B. The APSGN-associated antifactor B autoantibodies did not stabilize a C3 convertase formed on red blood cells; therefore, these autoantibodies are different from the C3 nephritic factor (C3NeF) antibodies in C3 glomerulopathy, which have a pathogenesis likely unrelated to infection and recognize an epitope of C3bBb in red blood cells. These findings indicate that APSGN has a different mechanism of alternative pathway activation compared with C3 glomerulopathy³⁴ and underline the potential clinical usefulness of factor B autoantibodies in the differential diagnosis of APSGN (with limitations, as discussed in the editorial by Noris and Remuzzi³⁵).

Anti-C1q Antibodies

Anti-C1q antibodies have been found in several autoimmune diseases, most notably in hypocomplementemic urticarial vasculitis and in systemic lupus erythematosus (SLE). In SLE, these antibodies are associated with proliferative GN.³⁶ The pathogenic role of anti-C1q antibodies is likely related to immune complex (C1q–anti-C1q) deposition because the administration of C1q monoclonal antibodies to naive mice results in glomerular deposition of C1q and C1q antibodies but not in overt kidney disease.³⁷

Kozyro et al.³⁸ studied anti-C1q antibodies by ELISA in 112 children with newly diagnosed GN, and they reported that eight of 24 patients with APSGN had autoantibodies to C1q and differed from the rest in having more pronounced proteinuria and hypertension, as well as delayed renal recovery. The researchers subsequently extended these observations in 50 children with APSGN, 19 of whom were found to have anti-C1q antibodies.³⁹ The patients with anti-C1q antibodies exhibited more severe subnephrotic proteinuria, higher levels of creatinine, and severe hypertension. In addition, these patients had more profoundly depressed C3 levels and a more prolonged course of the disease, manifested by hematuria, proteinuria, and elevated serum creatinine for 3 months or longer. There was a negative correlation between the C1q levels and the anti-C1q antibodies. The authors noted that streptococcal protein H activates C1q-mediated complement consumption and suggested that anti-C1q antibodies had only a mild effect in the classic complement pathway. There do not appear to be subsequent studies on C1q antibodies and their association with a more severe and prolonged clinical course in APSGN.

Anticonvertase Antibodies (C3 Nephritic Factors)

As early as 1972, researchers reported that the sera of patients with APSGN have factors that induce breakdown of C3 in normal sera.⁴⁰ In 1994, Frémeaux-Bacchi et al.⁴¹ described three children with APSGN who had C3NeF activity in the serum. C3NeF activity, determined by assessing the ability of purified IgG to stabilize the cell-bound C3bBb convertase, disappeared a few months after the plasma complement levels normalized, and the researchers suggested that transient C3NeF generation was the cause of activation of the alternative complement pathway in APSGN. Nineteen years later, Sethi et al.²³ described 11 patients with postinfectious GN (one with confirmed preceding streptococcal infection)—cases that were considered atypical because they presented with unregulated activity of the alternative complement pathway. Seven of these patients had positive C3NeF activity (autoantibodies to C3 convertase), and four had mutations in the complement genes. The common element in these cases is that both the complement gene mutations and the C3NeF(s) prolong the t_1/2 of C3 convertase and drive sustained complement activation and the glomerular deposition of complement proteins and breakdown products. The patients had persistent hematuria, proteinuria, or both 4–48 months after the kidney biopsy. Kidney biopsy samples showed diffuse endocapillary GN (in five patients), mesangioproliferative GN (in four patients), membranoproliferative GN (in one patient), and crescentic GN (in one patient), with glomerular C3 deposition and less intense IgG staining. Electron microscopy showed subepithelial electron-dense “hump”-like deposits, as well as mesangial and subendothelial deposits. Serum C3 levels eventually normalized in four patients. A similar patient with prolonged course of APSGN was found to have a heterozygous sequence variant of the complement factor H–related protein 5 gene.⁴² The overlapping characteristics between these patients with atypical postinfectious GN and the patients with C3 glomerulopathy are not surprising because abnormalities in the alternative pathway of complement are present in both entities.

Table 1 compares some characteristics of APSGN and C3 nephropathy.^43–52 Renal biopsy in a patient suspected of having APSGN is indicated when there is progressive deterioration of renal function or when low C3 levels and significant proteinuria persist for >1 month. The absence or near absence of glomerular IgG deposition in association with strongly positive C3 deposits would make the diagnosis of C3 glomerulopathy more likely. Other characteristics are less useful because diffuse endocapillary proliferative GN and subepithelial electron-dense deposits are features that also may be present in C3 glomerulopathy (Table 1). Whether transient generation of C3NeF is a feature of the short-term activation of the alternative pathway in some patients with APSGN remains to be determined. It is also relevant to determine if persistent C3NeF(s) or complement mutations are driving the development of CKD in the occasional patient whose condition departs from the usual benign course of APSGN.⁴

Table 1.

APSGN and C3 nephropathy

Characteristics	C3 Nephropathy	APSGN
Annual incidence	Approximately 1–3/1,000,00043	90–280/1,000,0003,4
Preceding infection	Upper respiratory infection frequent44	Streptococcal infection
Clinical picture	Hematuria, proteinuria, hypertension43,45	Hematuria, hypertension, edema, proteinuria (subclinical disease four to ten times more frequent)6
Prognosis	Progression to ESKD >50%43,45	ESKD exceptional, risk factor for two-hit damage46
Autoantibodies to complement factors	C3Nef (50%–80%), C4Nef (20%), C5Nef (10%–40%), anti-C3bBb (59%), antifactor H (21%), antifactor B (14%), anti-C3b (9%)47–49	Transient antifactor B (91%),a anti-C3bBb (32%), antifactor H (0%), anti-C3b (12%)2
Light histology	MPGN, mesangial proliferative GN, endocapillary proliferative GN, crescentic GN, sclerosing GN43	Diffuse proliferative endocapillary and mesangial GN, MPGN (occasionally in resolving phase), rarely crescentic
Immunofluorescence	C3 dominant (Ig negative or two orders of magnitude less than C3)50	C3 (all), IgG (91%), IgM (68%)51,52
Electron microscopy	Subendothelial, mesangial, and subepithelial deposits; osmiophilic sausage-shaped deposits in the GBM (dense deposit disease)43	Subepithelial, subendothelial, and mesangial deposits

Some characteristics of APSGN and C3 nephropathy. Important differences are highlighted in bold. MPGN, membranoproliferative GN; GBM, glomerular basement membrane.

^aAntifactor B autoantibodies in APSGN, in contrast to C3 nephropathy, are transient because the streptococcal infection is limited in time and different from C3Nef because they are unable to stabilize a C3 convertase on red blood cells (see text).

Anti-Ig Antibodies

The search for anti-Igs in APSGN originated from experimental studies by McIntosh et al.,⁵³ who demonstrated that streptococcal neuraminidase induced desialization of human IgG and autologous anti-IgG antibodies. Furthermore, they showed that anti-IgG antibodies were deposited in the glomeruli of rabbits infected with β-hemolytic streptococci.⁵⁴ Subsequent studies showed that anti-IgG and anti-IgM autoantibodies were present in a large number of patients with APSGN in the first week of the disease. Specifically, within this time frame, IgG-rheumatoid factor was demonstrated in the sera of 32%–43% of patients with APSGN and IgM-rheumatoid factor in 15% of such patients.^55,56 Glomerular anti-IgG deposits were found in the glomeruli of 19 of 22 biopsies,⁵¹ and IgG with anti-IgG reactivity was eluted from the kidneys of an individual with a fatal case of APSGN.⁵⁷

The development of anti-IgG autoantibodies has been attributed to autoantigenic characteristics of neuraminic acid–depleted IgG resulting from streptococcal neuraminidase.^58,59 Alternatively, anti-IgG reactivity may develop from IgG binding in the streptococcal wall. Type 2 receptors in groups A, C, and G streptococci bind avidly to the Fc fragment of IgG, and group A streptococci cultured in medium containing autologous serum and injected into rabbits result in the development of circulating anti-IgG antibodies and their deposition in glomeruli.⁶⁰ Experimental nephritogenicity has been found in streptococcal strains capable of binding to immune complexes.⁶¹ Other studies have confirmed anti-IgG, anti-IgM, and anti-IgA autoantibodies in APSGN⁶²; their deposition in the glomeruli⁶³; and their relationship with circulating immune complexes.⁵⁶ However, there has been no evidence that anti-Ig reactivity modifies the clinical course of the disease. The streptococcal neuraminidase may remove neuraminic acid from circulating leukocytes, and neuraminic acid–depleted neutrophils have a predilection for glomerular deposition, which may induce an “exudative” pattern in the GN of APSGN.^64,65 Again, however, the clinical significance of these findings is uncertain.

Antiglomerular Heparan Sulfate Antibodies

Antikidney autoantibodies in the sera of patients with acute GN were first reported in 1958, detected by hemagglutination tests using human kidney digest as antigen.⁶⁶ Subsequently, patients with progressive GN were found to have increased cellular reactivity to streptococcal cell membranes.⁶⁷ Also, cellular immune reactivity to altered (glycosidase-treated and neuraminidase-treated) glomerular basement membrane was demonstrated in patients with GN, particularly with the proliferative histologic pattern.⁶⁸ Fillit et al.⁶⁹ expanded these studies and focused on APSGN in 1985, demonstrating antiglomerular proteoglycan antibodies in the sera of patients with APSGN. The major antigenic determinant was glomerular heparan sulfate, and there was crossreactivity with streptococcal hyaluronate. The authors suggested that autoimmunity to glomerular heparan sulfate resulted from the crossreactivity to streptococcal capsular hyalonate and noted the likelihood that persistent autoimmune reactivity could drive the progression to chronicity in some patients.⁶⁹ Unfortunately, there are no studies evaluating the incidence of antiglomerular proteoglycan antibodies in patients with APSGN or their potential association with disease progression.

Anticardiolipin Antibodies

Although anticardiolipin (ACL) antibodies have been reported in as many as 48% of patients with APSGN, patients with pyodermitis without GN had similar incidence, and ACL-positive and ACL-negative cases did not exhibit clinical or histopathologic differences.⁷⁰ Antiphospholipid syndrome has a global incidence of two patients per 100,000 population per year,⁷¹ and ACL antibodies have been found in 25% of healthy children, possibly associated with unspecified infections.⁷² Occasionally, ACL antibodies have been reported in patients with APSGN in association with hemolytic anemia.^73–75 Relating ACL antibodies to any characteristic of ASPGN is difficult, and thrombotic microangiopathy has not been reported in association with APSGN.

Autoimmune Hemolytic Anemia and Thrombocytopenia

In a systematic review of the literature, Bertola et al.¹⁴ found 16 patients with hemolytic anemia, thrombocytopenia, or both that presented in association with or was preceded by APSGN. Coombs-positive hemolytic anemia, with or without cold agglutinins, has been found in patients with APSGN.^74,75 Anti-I antibodies were reported in two children with APSGN and associated with hemolytic anemia (cold agglutinin disease).⁷⁴ An adult patient also presented with hemolytic anemia in association with thrombocytopenia and ARF; renal biopsy showed no evidence of thrombotic microangiopathy but instead, was consistent with APSGN.⁷⁶ Researchers also reported finding platelet-associated Ig attributed to autoimmune reactivity in one patient.⁷⁷

ANCAs

Ardiles et al.⁷⁸ reported that 9% of 210 patients with APSGN were ANCA positive using an indirect immunofluorescence assay on ethanol-fixed normal human neutrophils. The pattern was diffuse in 14 patients and perinuclear in four patients. Antibodies against myeloperoxidase (MPO) were present in four cases, but none of the samples exhibited reactivity against proteinase-3. Patients with impetigo without nephritis were uniformly ANCA negative. ANCA-positive patients had more severe disease, manifested by elevated serum creatinine levels and glomerular crescent formation independent of the MPO reactivity. Others have reported the existence of MPO-ANCA and antielastase antibodies in patients with APSGN,⁷⁹ and Kanai et al.⁸⁰ confirmed the association of MPO-ANCA with crescentic APSGN in a patient who improved clinically but remained ANCA positive, despite treatment with azathioprine and prednisone. ANCA-positive crescentic GN is associated with other infections, particularly staphylococcal infections, so this feature of aggressive autoimmunity is likely dependent on bacterial characteristics. APSGN may also be associated with ANCA-negative vasculitis that was attributed to the release of neutrophil extracellular traps by the streptococcal infection.⁸¹

Anti-DNA Antibodies

Single- and double-stranded anti-DNA antibodies were reported in two patients with APSGN.⁸² The authors suggested pathogenic relevance to these findings; however, because the DNA–anti-DNA complexes persisted for 15 or 21 months, whereas the clinical picture resolved rapidly, it is difficult to assign significance to the anti-DNA reactivity.

Table 2 shows a summary of autoimmune reactivity reported in APSGN.

Table 2.

Autoimmmune reactivity in acute poststreptococal GN

Autoimmune Reactivity	Incidence in APSGN (n/Total Cases)	Potential Relevance/Association
Anticomplement antibodies
Antifactor B	91% (31/34)	Pathogenic relevance2
Anti-C1q	33.3% (8/24)	Prolonged and severe disease38,39
C3NeF	63.6% (7/11)	Persistent disease23,41
Anti-Ig	32%–80% (anti-IgG), 15% (anti-IgM)	Uncertain significance (association with exudative GN?)a55,56
ANCA	9% (18/210, 4 anti-MPO)b	Crescentic disease78
Antiglomerular proteoglycans	Unknown	Disease progression68,69
ACL	Patient reports	Hemolytic anemia70,73–75
Anti-I	Patient reports	Hemolytic anemia74
Anti-DNA	Patient reports	Uncertain significance82

Autoimmune reactivity in APSGN.

^aAnti-IgG reactivity has been associated with streptococcal neuraminidase, and peripheral blood neutrophils desialized by streptococcal neuraminidase (sialidase) have preferential glomerular infiltration (exudative GN; in the text^55,56).

^bAnti-MPO was detected in four patients (no reactivity to proteinase 3 or cathepsin-G).⁷⁸

Genetic Associations between APSGN and Autoimmune Disease

The first observation of the familial incidence of APSGN dates from 1812, when Wells⁸³ commented that prevalence of postscarlatinal dropsy was elevated among the family members of index cases and attributed it to “constitutional similarities.” Prospective studies in 77 siblings of index cases demonstrated a APSGN familial incidence of 37.8%⁸⁴; this is higher than the attack rates found in outbreaks among the general population, which range from 28.3% after skin streptococcal infections to 4.5% after throat streptococcal infections.⁸⁵ A prospective study of 15 families (61 siblings of index cases) found a proportion consistent with a single autosomal recessive trait.⁸⁶

Although genetic associations with an elevated likelihood of developing APSGN have remained elusive, studies have shown that among patients with APSGN, there is a high incidence of HLA-Dw4 in Venezuela,⁸⁷ of HLA-D in Japan,⁸⁸ and of HLA-DRB10311 in Egypt.⁸⁹ A report from Turkish researchers indicates a higher risk of APSGN for carriers of the “a” allele of the endothelial nitric oxide synthase gene intron 4a/b.⁸⁹ The associations with HLA-D genes are relevant to this discussion because of their relationship with autoimmune reactivity.⁹⁰ Specifically, HLA-Dw4 is associated with the synthesis of anti-IgG autoantibodies in patients with rheumatoid arthritis,^91–93 and its high incidence in patients with APSGN suggests an association with the previously mentioned anti-Ig reactivity. ANCA-related MPO is associated with HLA-DQ.⁹⁴ These genetic associations in APSGN require confirmation, and their potential relationship with autoimmune reactivity and the clinical course of the disease awaits evaluation.

Validating the findings of Chauvet et al.² in further studies is important because the absence of antifactor B autoantibodies in a patient suspected of having APSGN might be an indication for renal biopsy that would establish the diagnosis of C3 glomerulopathy and raise the consideration of anticomplement therapies. In addition, some manifestations of autoimmunity in APSGN merit specific attention. These include the following: (1) the relation of more severe disease (including crescentic GN) and progression to CKD associated with anti-C1q antibodies, ANCA, antiglomerular proteoglycan antibodies, and genetic mutations of complement; (2) the role of autoimmune reactivity associated with other risk factors in worse prognosis of APSGN in adult patients; and (3) genetic associations (possibly HLA-D) with APSGN susceptibility.

Disclosures

The author has nothing to disclose.

Funding

B. Rodriguez-Iturbe is a recipient of the Cátedra Salvador Zubirán Scholarship, Universidad Nacional de Mexico and Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán,” Mexico.