Alport's Syndrome, Goodpasture's Syndrome, and Type IV Collagen

The
new england journal
of
medicine
review article
mechanisms of disease
Alports Syndrome, Goodpastures Syndrome,

and Type IV Collagen
Billy G. Hudson, Ph.D., Karl Tryggvason, M.D., Ph.D.,
Munirathinam Sundaramoorthy, Ph.D., and Eric G. Neilson, M.D.
asement membranes form a complex surface on which epithelial cells reside. These membranes provide morphogenic cues that determine
the fate of cells, the polarization of subcellular constituents, and the location of
cell receptors and transporters.1-3 Basement membranes are assembled through an interweaving of type IV collagen (collagen IV) with laminins, nidogen, and sulfated proteoglycans.4,5 Collagen IV belongs to a family of collagenous proteins that has at least 25
distinct members. The COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, and COL4A6
genes6-13 encoding the six chains of collagen IV a1(IV) through a6(IV) are selectively expressed in different membranes at various stages of embryonic development.14
This selectivity accounts for the location of disease and the clinical consequences of injury to collagen IV. Damage to collagen IV due to mutation (in Alports syndrome) or an
immune attack (in Goodpastures syndrome) disrupts the function of attached epithelia and leads to organ impairment.
In 1927, Alport reported that deafness was a feature of a previously described familial nephropathy that caused uremia in males but spared females.15 Splitting of the
glomerular basement membrane, hematuria, interstitial nephritis, and progressive kidney failure explain the renal aspects of the disorder.16 The cause of Alports syndrome
was unknown17 until mutations were discovered in the COL4A3, COL4A4, and COL4A5
collagen genes.18-20 Some carriers of a mutant collagen IV gene are thought to have a
variant of Alports syndrome termed benign familial hematuria or thin glomerular basement membrane disease.18,21-24
In 1958, Stanton and Tange25 described nine patients with a pulmonaryrenal disorder they called Goodpastures syndrome after an earlier report by Ernest Goodpasture.26 The classic presentation of Goodpastures syndrome is explosive lung hemorrhage with nephritis that is often crescentic; the syndrome is rapidly fatal if left
untreated.27,28 It is an immune disorder with serum antibodies directed against particular regions of the a3(IV) chain of collagen IV in lung and kidney.29-33
For many years, a connection between the two syndromes was suspected, because
most glomeruli from the kidneys of patients with Alports syndrome do not stain by
the immunofluorescent method with antibodies from patients with Goodpastures
syndrome.34 This curiosity focused attention on collagen IV, and today we know that
the pathogenesis of both diseases is linked to the same a3.a4.a5(IV) collagen protomer.14,35-37
From the Departments of Medicine (B.H.,

M.S., E.G.N.), Biochemistry (B.H., M.S.),
and Cell and Developmental Biology
(E.G.N.), Vanderbilt University School of
Medicine, Nashville; and the Department
of Medical Biochemistry and Biophysics,
Karolinska Institute, Stockholm, Sweden
(K.T.). Address reprint requests to Dr. Neilson at the Department of Medicine, D-3100
MCN, Vanderbilt University Medical Center, Nashville, TN 37232-2358, or at eric.
neilson@vanderbilt.edu.
N Engl J Med 2003;348:2543-56.
Copyright 2003 Massachusetts Medical Society.
structure and distribution of type iv collagen

Collagen IV was first isolated by Kefalides from glomerular basement membrane in
1966,38 and during the past 35 years, the structures of the six chains that assemble into
collagen IV molecules have been elucidated by numerous investigators.4,6-14,39-44 Each
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of the six chains of collagen IV has three domains:

there is a short 7S domain at the N-terminal; a
long, collagenous domain occupies the midsection of the molecule; and a noncollagenous domain
(NC1) is positioned at the C-terminal (Fig. 1). In spite
of many potential permutations, the six chains of
collagen IV apparently form only three sets of
triple helical molecules called protomers, which
are designated as a1.a1.a2(IV), a3.a4.a5(IV),
and a5.a5.a6(IV).35-37,39 These protomers create
collagenous networks by uniting two NC1 trimers
to form hexamers and uniting four 7S domains to
form tetramers with other protomers, as shown
in the a3.a4.a5(IV) network in Figure 2A. Only
three canonical sets of hexamers form networks:
a1.a1.a2(IV)a1.a1.a2(IV), a3.a4.a5(IV)a3.a4.
a5(IV), and a1.a1.a2(IV)a5.a5.a6(IV). The x-ray
crystallographic structure of the a1.a1.a2(IV) NC1
hexamer provides novel insight into the molecular
interactions that govern chain assembly and the
pathophysiological mechanisms underlying Goodpastures and Alports syndromes.48,49 A computergenerated, space-filling model of the a3.a4.a5(IV)
hexamer (Fig. 2B) shows how three NC1 domains
fold and associate as a trimeric cap for each protomer, which, in turn, interacts with the trimeric
cap of an adjoining protomer.36,48
Assembly of collagen IV networks is regulated
developmentally. The a1.a1.a2(IV)a1.a1.a2(IV)
network is a component of all basement membranes
of all animal phyla,50-53 whereas the a3.a4.a5(IV)
a3.a4.a5(IV) and a1.a1.a2(IV)a5.a5.a6(IV) net-
of
medicine
works have a restricted distribution in mammalian

tissues. The a3.a4.a5(IV) network occurs in the
kidney (in glomerular basement membrane and
some tubular basement membranes), lung, testis,
cochlea, and eye,47,54,55 and the a5.a5.a6(IV) network is a feature of skin, smooth muscle, esophagus, and kidney (Bowmans capsule).36,37,44,56,57
During embryonic development of human glomerular basement membrane, the a1.a1.a2(IV) network appears at the start of early capillary-loop
formation (by embryonic day 75 [E75]) but is gradually replaced by the a3.a4.a5(IV) network in the
mature glomerular capillary (by day E150)47,58,59
or by the a5.a5.a6(IV) network in Bowmans capsule.37,44,59 This developmental switch is a critical
step in the maturation of the kidney (Fig. 3A) and
perhaps other specialized tissues.
alports syndrome
Classically, Alports syndrome consists of hematuria, proteinuria (less than 1 to 2 g of protein excreted
per day), progressive renal failure, and sensorineural deafness.60 Lenticonus of the anterior lens capsule (positive oil droplet sign), retinopathy (dot
and fleck reflections), and rarely, mental retardation
or leiomyomatosis occur in some patients.61,62 Clinical variability among kindreds with Alports syndrome reflects the complexity of collagen genetics
(involving one of three loci with multiple sites for
mutation), inconsistency in the assembly of collagen IV protomers in selected tissues, and uneven
Type IV collagen chains
Protomers
2
1
1
1
2
a1.a1.a2
4
3
5
3
4
a3.a4.a5
6
5
5
5
6
NC1 monomer
a5.a5.a6
7S
NC1 trimer
Figure 1. Triple Helical Organization of the Type IV Collagen Family.

Six genetically distinct a chains are arranged into three triple helical protomers that differ in their chain composition. Each protomer has a 7S
triple helical domain at the N-terminal; a long, triple helical, collagenous domain in the middle of the molecule; and a noncollagenous (NC1)
trimer at the C-terminal. Interruptions in the GlyXaaYaa amino acid sequence at multiple sites along the collagenous domain (white rings)
confer flexibility, allowing for looping and supercoiling of protomers into networks. The selection of a chains for association into trimeric protomers is governed by molecular recognition sequences encoded within the hypervariable regions of NC1 domains. 35,37
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expression of these defects.18,19 New pedigrees usu- with autosomal recessive disease are either comally come to attention after clinical evaluation of a pound heterozygotes or have homozygous mutations in the COL4A3 or COL4A4 gene encoding the
patient for progressive deafness or hematuria.
a3(IV) or a4(IV) chain, respectively, on chromogenetics
some 2q3537.64,65 Rarely, some kindreds have an
In approximately 85 percent of patients with Alports autosomal dominant inheritance of dominant negsyndrome there is X-linked inheritance of muta- ative mutations in the COL4A3 or COL4A4 gene.18
tions in the COL4A5 gene encoding the a5(IV) col- The types of mutations in these genes include mislagen chain on chromosome Xq2648.20,63 In fe- sense mutations, premature stop codons, splice mumale carriers, penetrance is variable and depends tations, and in-frame deletions. Concomitant muon the type of mutation or degree of mosaicism fol- tations in the COL4A6 gene encoding the a6(IV)
lowing lyonization of the X chromosome. Patients chain are associated with leiomyomatosis.66-68
B
EA
EB
a5
7S
a4
a3
NC1
4
3
5
4
5
3
a4
a3
a5
Figure 2. Assembly and Network Organization of Collagen IV Protomers.

Protomers create basement-membrane networks with other protomers by uniting two NC1 trimers to form an interface hexamer at the C-terminal and by uniting four triple helical 7S domains at the N-terminal (Panel A). A network composed of a3.a4.a5(IV) protomers is illustrated,
showing end-to-end connections of individual protomer units, supercoiling and looping of the triple helixes, and disulfide cross-links between
triple helical domains.35-37,39 The structure of the NC1 hexamer is determined by the particular a chains that form a triple helical protomer
and by the particular canonical protomers that can connect to adjoining protomers (NC1 box). Molecular recognition sequences encoded
within NC1 domains govern the selection of partner chains for both protomer and network assembly. The 7S domains also play a key part in
determining the specificity, affinity, and geometry of the tetramer formed through the connection of four protomers (7S box). 39,45,46 Two other
networks are composed of pairs of a1.a1.a2(IV) hexamers or a1.a1.a2(IV)a5.a5.a6(IV) NC1 hexamers.35-37,39 The a3.a4.a5(IV)
a3.a4.a5(IV) network differs from the others in that it has a greater number of disulfide cross-links between triple helical domains, which increases its resistance to proteolysis.47
Panel B shows the three-dimensional model of the a3.a4.a5(IV) NC1 hexamer that is depicted in the NC1 box in Panel A. The three-dimensional structure and the location of epitopes were determined by computer modeling of the crystal structure of the a1.a1.a2(IV)
a1.a1.a2(IV) hexamer48 and the apparent quaternary structure of the a3.a4.a5(IV) hexamer.36 The hexamer is composed of two trimeric
caps, each derived from adjacent protomers. Each trimer consists of an a3 monomer (red), an a4 monomer (blue), and an a5 monomer
(green). The monomers have a novel tertiary structure with two homologous subdomains, each of which is characterized by b-sheet motifs.
The model depicts the location of the EA (yellow) and EB (gold) regions that encompass two dominant epitopes for Goodpasture antibodies.
The epitopes reside in the a3(IV) NC1 domain, near the triple helical junction, and they are partially sequestered by interactions with the
a5(IV) and a4(IV) NC1 domains, respectively.
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A
Embryonic
Immature
2
1
2
1
Mature
Developmental
switch
4
3
5
6
5
4
3
4
5
2
1
6
5
B
Embryonic
Immature
2
1
1
Mature
2
1
1
Developmental
switch
4
3
5
6
5
5
Childhood
Adulthood
Figure 3. Distribution and Switches of Collagen IV Networks in Glomerular Development.

During early embryonic development (Panel A, left), the a1.a1.a2(IV) network is present at all stages. In the mature glomerulus (Panel A,
right), this network is a component of Bowmans capsule, mesangial matrix, and glomerular basement membrane. In contrast, the a3.a4.a5(IV)
and a5.a5.a6(IV) networks first appear at the early capillary-loop stage. They appear to replace (dotted line) most of the a1.a1.a2(IV) network within the glomerular basement membrane and Bowmans capsule, respectively, and they persist in the mature glomerulus. In the
X-linked form of Alports syndrome (Panel B), the switch in networks is arrested (red Xs), as a result of mutations in the a5(IV) chain. These
mutations result in the persistence of the a1.a1.a2(IV) network and the absence of the a3.a4.a5(IV) and a5.a5.a6(IV) networks.
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Most evidence suggests that chain mutations

produce a post-translational defect in protomer assembly. The COL4A3 and COL4A4 genes69 and genes
that encode for nephrin, podocin, and CD2-associated protein, forming the glomerular slit diaphragm and allowing filtration,70 are regulated by
a transcription factor called LMX1B, which is mutated in patients with the nailpatella syndrome.
Carriers of a mutant LMX1B gene have a renal lesion of variable severity, which is consistent with a
reduction in the a3.a4.a5(IV) network in glomerular basement membrane71,72 and loss of the glomerular filtration barrier.70
pathogenesis
Mutations present in Alports syndrome that produce post-translational defects in a3(IV), a4(IV),
or a5(IV) chains may result in incorrect folding or
assembly of monomers; such defective monomers
are rapidly degraded. These mutations, therefore,
arrest the normal developmental switch (Fig. 3A)
and cause the persistence of a1.a1.a2(IV) networks
in glomerular basement membrane (Fig. 3B).47 In
patients with X-linked Alports syndrome, a3(IV),
a4(IV), and a5(IV) collagens in most glomeruli, tubules, and Bowmans capsules are undetectable by
immunostaining (female carriers can be mosaics).
In patients with autosomal recessive Alports syndrome, there is a5(IV) collagen in Bowmans capsule but no detectable a3(IV) or a4(IV) collagens in
glomerular or tubular basement membranes.73 The
reason for this difference is that the a5(IV) chain is
shared by two different protomers one in the glomerular basement membrane and the other in Bowmans capsule.36,57 Some a5(IV) mutations that allow for partial formation of a3.a4.a5(IV) networks
may produce less severe phenotypes.19
The replacement of the a1.a1.a2(IV) network
by the a3.a4.a5(IV) network during fetal development may be related to oxidative and physical stress
in renal basement membranes74 (and perhaps also
in the cochlea75 and the lens capsule76). In the kidney, as plasma traverses glomerular capillaries, the
protein content, including the levels of serum proteases, increases. The embryonic a1.a1.a2(IV) network is more susceptible to endoproteolysis than
the more heavily cross-linked a3.a4.a5(IV) network.47,74 It seems, then, that basement membranes that are more exposed to proteases or oxidants need the protection of a resistant collagen IV
network. Over time, patients with Alports syndrome
probably become more sensitive to selective base-
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ment-membrane proteolysis, which may explain

why their glomerular membranes thicken unevenly,
split, and ultimately deteriorate.47
The primary filtration barrier of the glomerular
capillary consists of the glomerular basement membrane and the outer slit diaphragm formed between
adjacent podocytes. Deterioration of the glomerular basement membrane produces mild proteinuria,
whereas loss of the slit diaphragm leads to massive
proteinuria.70 Proteinuria in Alports syndrome is
associated with damage to the glomerular basement
membrane that leads to sclerosis, rather than primary loss of the slit pore. In pedigrees with a history
of renal failure, disease usually progresses from concomitant interstitial nephritis and the renal fibrosis
that accompanies sclerosis of the glomerular basement membrane.78,79 Macrophages and lymphocytes are found in areas of disrupted tubular basement membrane,80,81 and fibroblasts are formed
by epithelialmesenchymal transition.82,83 This fibrogenic response destroys the renal architecture.
clinical presentation
Pedigrees with Alports syndrome vary in the rapidity of onset of organ failure (Table 1). In patients with nonsense or missense mutations, reading-frame shifts, or large deletions, renal failure
and sensorineural deafness generally develop by
30 years of age (in the juvenile form). In patients
with splice variants, exon-skipping mutations, or
missense mutations of glycines in the collagen
helix, health usually begins to deteriorate after 30
years of age (in the adult form), and these patients
have mild or late-onset deafness.19,84,85 A family
history of early, severe deafness or lenticonus portends a poor prognosis in young progeny at risk.86
The presenting sign of Alports syndrome is often hematuria. Members of kindreds with a strong
history of renal failure and deafness do not need to
undergo kidney biopsy. These patients usually require only an imaging study of the genitourinary
tract to rule out a tumor or other defect that could
cause hematuria. The mutations in families with
X-linked, recessive, or dominant Alports syndrome
are not confined to a few regions of the COL4A3,
COL4A4, or COL4A5 gene. Rather, they are scattered
throughout many exons, making it difficult to develop predictive genetic tests.
findings on kidney biopsy
When examined by electron microscopy, the lesions in kidney-biopsy specimens from patients
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Table 1. Clinical Pathophysiology of Alports and Goodpastures Syndromes.

Disease
Mechanism
Clinical Description
Some missense mutations or splice variants in the COL4A5 gene, producing a

reduction or distortion in a3.a4.a5(IV)
and a5.a5.a6(IV) networks
Deletions, nonsense mutations, or missense mutations in the COL4A5 gene,
producing a loss of a3.a4.a5(IV) and
a5.a5.a6(IV) networks
Delayed onset of renal failure (>30 yr of age),

with mild deafness in men; less severe
in female carriers
Leiomyomatosis
Deletions from the COL4A5 gene through

to the second exon of the COL4A6 gene,
producing a loss of a3.a4.a5(IV) and
a5.a5.a6(IV) networks and smoothmuscle tumors
Early onset of renal failure, with esophageal

dysfunction, genital leiomyomas, and
occasional posterior cataract
Recessive
Homozygous or compound heterozygous

nonsense mutations, missense mutations, frame shifts, small deletions, or
splice variants in COL4A3 or COL4A4
gene, producing a loss of the
a3.a4.a5(IV) network
Early onset of renal failure (<30 yr of age)

in both sexes
Dominant
Missense mutation in the COL4A4 gene;

splice variants or short in-frame deletions of the collagenous region; or
shortened signal-peptide sequences in
the COL4A3 gene; defects produce aberrations in the a3.a4.a5(IV) network
Renal failure of varying severity
Benign familial hematuria
Missense mutations in the COL4A3 gene

or splice variants, frame shifts, or missense mutations in the COL4A4 gene,
inherited in an autosomal dominant
fashion, producing a subtle decrease
in the a3.a4.a5(IV) network
Mild hematuria with thin basement membranes and rare hypertension or proteinuria that is nonprogressive; findings on
kidney biopsy have been relatively normal
Nailpatella syndrome
Autosomal dominant mutation in the

Variable penetrance, but some children have
LMX1B transcription factor, which regunephrotic syndrome and skeletal and nail
lates the COL4A3 or COL4A4 gene as
dysplasias
well as the genes encoding nephrin,
podocin, and CD2-associated protein
Alports syndromes
X-linked
Adult
Juvenile
Early onset of renal failure (<30 yr of age)

in men, with frank deafness and often
lenticonus
Goodpastures syndromes*
ANCA-negative (75%)
Autoantibodies to a3(IV) NC1 domain
Anemia, pulmonary infiltrates, focal necrosis,

or crescentic glomerulonephritis, with
or without hemoptysis; variable progression; prognosis better with early diagnosis and treatment
ANCA-positive (25%)
Autoantibodies to a3(IV) NC1 domain

plus antibodies to myeloperoxidase
May resemble ANCA-negative syndrome but

responds better to treatment and may be
a vasculitis-associated variant
Post-transplantation
Alports syndrome
Alloantibodies to a3(IV), a4(IV),

and a5(IV) NC1 domains
Seen in all patients with Alports syndrome

(except female carriers of the X-linked
syndrome) after transplantation; varying
degrees of nephritis
* ANCA denotes antineutrophil cytoplasmic autoantibody.
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with Alports syndrome are variable. The typically

thin glomerular basement membranes thicken over
time into multilamellations surrounding lucent areas that often contain granules of varying density
the so-called split basement membrane (Fig.
4A).16,87 In any one kidney from a patient with
Alports syndrome, there are areas of thinning and
splitting glomerular basement membrane. Tubules
drop out, segmental glomerular scars progress, and
the kidneys eventually fail because of interstitial fibrosis. Thin basement membranes are also found
in 5 to 10 percent of the normal population.88 In
these cases, the blood pressure is normal, there is
little proteinuria, and progression to renal failure
is rare. When such patients present with hematuria,
they often receive a diagnosis of benign familial hematuria.62 Many of these patients have mutations
in the same genetic loci that encode for the a3(IV)
or a4(IV) chains associated with autosomal recessive or dominant Alports syndrome,21,22 but thin
glomerular basement membranes are occasionally
seen in other forms of glomerulopathy.22 In kindreds with Alports syndrome, the carriers have thin
glomerular basement membranes and a phenotype
similar to that in patients with benign familial hematuria.24 For this reason, the boundary between
Alports syndrome and benign familial hematuria
has become increasingly vague.18,24
tive assays can detect these antibodies in the serum

of most transplant recipients, and they are nearly
always directed against multiple epitopes along the
a3(IV), a4(IV), or a5(IV) chain of collagen (Fig. 5
and Table 1).91,92 Female patients who are hetero-
treatment
Patients with Alports syndrome who have early

renal failure can be treated conservatively with antihypertensive drugs and angiotensin-converting
enzyme inhibitors to attenuate proteinuria and slow
progression, although the indications for treatment
in children are still unclear.89 Patients who require
dialysis are candidates for renal transplantation. Although the development of nephritis with antiglomerular basement membrane alloantibodies in the
transplanted kidney is not very common,90 sensi-
Figure 4. Histopathological Features of Kidneys

in Alports and Goodpastures Syndromes.
An electron micrograph of a glomerular capillary from a
patient with Alports syndrome and proteinuria (Panel A)
demonstrates the multilamellations and lucent spaces
resulting in the split appearance of the basement membrane (arrows). Panel B (hematoxylin and eosin) shows
focal, segmental necrosis of the glomerular tuft in a kidney from a patient with Goodpastures syndrome. Panel C
(hematoxylin and eosin) shows the crescent formation of
the glomerular tuft in such a kidney.
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Goodpasture
autoantibodies
4
Alport alloantibodies
after transplantation
Oxidant
4
3
4
5
Immune reaction T+B
4
3
5
4
5
3
Antiglomerular basement
membrane antibodies
Figure 5. Goodpasture Autoantibodies and Alport Alloantibodies, Which Target Different Epitopes of the a3.a4.a5(IV)
NC1 Hexamer.
Antiglomerular basement membrane antibodies derive from an antigen-specific T-cell and B-cell response (T+B). The
epitopes for the Goodpasture autoantibodies are inaccessible to antiglomerular basement membrane antibodies unless there is a dissociation of the hexamer, which may be caused by oxidative stress. These epitopes reside in the a3(IV)
NC1 domain and are partially sequestered by the adjacent a5(IV) NC1 and a4(IV) NC1 domains. In contrast, the
epitopes for the Alport alloantibodies are accessible on the hexamer surface and reside on the a3(IV), a4(IV), and a5(IV)
NC1 domains.
zygous for mutations in the COL4A5 gene occasionally have progression to renal failure. When they undergo transplantation, the donor kidney does not
develop antiglomerular basement membrane alloantibodies. Patients with Alports syndrome generally do no worse after renal transplantation than
patients with other forms of progressive renal failure.93 Lenticonus can be treated with lens implants,
as in cataract surgery.94
goodpastures syndrome
Patients with antiglomerular basement membrane antibodies in whom glomerulonephritis and
lung hemorrhage develop have Goodpastures syndrome.95 In the differential diagnosis of pulmonaryrenal syndromes, antiglomerular basement
membrane disease can be distinguished from un-
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derlying immune-complex nephritis or antineutrophil cytoplasmic autoantibody (ANCA)associated nephritis by the presence of antiglomerular
basement membrane antibodies, which, on staining of a renal-biopsy specimen, appear in a linear
pattern in inflamed glomeruli along the glomerular basement membrane.27
genetics
Goodpastures syndrome is a multigenic disorder.

Hudson and coworkers identified the a3(IV) NC1
domain as the Goodpasture autoantigen.29,96 This
target antigen must be present as a component of
the native a3.a4.a5(IV) network (Fig. 2 and 5) of selected basement membranes in order for pulmonary
and renal disease to develop. Consequently, there
are no reported cases in patients with Alports syndrome. In mice, the induction of antiglomerular
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basement membrane disease is limited to selected

strains that express susceptibility genes in the major histocompatibility complex (MHC).97
Goodpastures syndrome in humans is restricted by the MHC; HLA-DRB1*1501 and DRB1*1502
alleles increase susceptibility, whereas HLA-DR7
and DR1 are protective.98 The thymus expresses
a3(IV) NC1 peptides that can cause elimination
of autoreactive CD4+ helper T cells,99 but a few
such T cells escape deletion and can subsequently
engage in the production of antiglomerular basement membrane antibodies.100 The immunologic
specificity of the antibodies is notable, since antibodies against a1.a1.a2(IV) NC1 domains do not
cause antiglomerular basement membrane nephritis.101-103
pathogenesis
Human antiglomerular basement membrane antibodies can initiate glomerulonephritis when infused into primates104 or when human allografts
are transplanted into patients with active Goodpastures syndrome.105 In genetically engineered mice
that produce human IgG antibodies, immunization
with a3(IV) NC1 domains results in the production
of human antiglomerular basement membrane
antibodies and proliferative glomerulonephritis.106
Human antiglomerular basement membrane antibodies, usually of the IgG class (or, rarely, IgA), are
of particularly high affinity and remain attached to
glomerular basement membrane for prolonged
periods107; the antiglomerular basement membrane antibodies eluted from tissues faithfully represent the antiglomerular basement membrane
antibodies found in serum.33
Two dominant epitopes (EA and EB) have been
identified in the a3(IV) NC1 domain.108-112 Both
are inaccessible for antibody binding unless dissociation of the hexamer occurs (Fig. 5). The EA and EB
epitopes are located in close proximity to each other, near the triple helical junction (Fig. 2B),36 and
they are sequestered at the interface between NC1
domains within a triple helical protomer, rather than
between adjacent protomers.36,48 Although there
are several subpopulations of antiglomerular basement membrane antibodies in the serum of patients
with Goodpastures syndrome,109,113,114 immunologic specificity for the two dominant epitopes is
most important.109,110
Since the a3(IV) NC1 epitope is hidden within the a3.a4.a5(IV) protomer,110,114,115 it is presumed that an environmental factor, such as ex-
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posure to hydrocarbons116 or tobacco smoke,117

is required in order to reveal cryptic epitopes to the
immune system (Fig. 5). Endogenous oxidants can
open this privileged site,74 as can certain subpopulations of antiglomerular basement membrane
antibodies.110
Anti-a3(IV) NC1 antibodies are structurally
similar118 and are highly regulated by T cells.119
Lymphocytes and macrophages are present in the
kidneys of mice with antiglomerular basement
membrane disease,120,121 and in rats, T cells can
transfer disease in the absence of antibody.122,123
Moreover, the antiglomerular basement membrane
alloantibodies produced after renal transplantation
in patients with Alports syndrome91 or the anti
glomerular basement membrane antibodies produced in patients with Goodpastures syndrome124
may not always be sufficient for the development of
nephritis. In this regard, transfer of antiglomerular basement membrane antibodies into mice that
are deficient in ab T-cell receptors fails to produce
glomerulonephritis, suggesting that T cells are
also effectors of the inflammatory response.97
The mechanism of renal injury in Goodpastures
syndrome is complex. When antiglomerular basement membrane antibodies bind glomerular basement membrane, they activate complement125 and
proteases126; such activation disrupts the filtration
barrier and Bowmans capsule, causing proteinuria and facilitating crescent formation. CD4+ and
CD8+ T cells and intrinsic renal epithelium induce
the migration of macrophages and neutrophils
into the kidney.121,123,127-129 Interleukin-12 and
interferon-g mediate crescent formation.130,131
The initial inflammatory reaction in the glomerulus
produces proteinuria with attendant downstream
consequences for tubular epithelium,132 the development of interstitial nephritis, and the subsequent
appearance of fibrosis.79
clinical presentation
Goodpastures syndrome occurs primarily in young

men in their late 20s and in men and women over
60 years of age.28 In the younger age group, the
disease is usually eruptive, with hemoptysis, a sudden decrease in the hemoglobin level, pallor, cough,
fever, dyspnea, hematuria, non-nephrotic proteinuria, and red-cell casts. Chest radiography shows
diffuse alveolar infiltrates. Hemoptysis is largely
confined to smokers.117 Goodpastures syndrome is
generally detected earlier in patients who present
with lung hemorrhage, and such patients may do
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better than those who present with silent renal in- As these lesions progress, there is concomitant injury alone. Presentation with oliguria is a particu- terstitial nephritis with fibrosis and tubular atrophy.
larly bad sign.133,134
treatment
antiglomerular basement membrane
antibodies
The prognosis at presentation is worse if there is

oliguria, advanced fibrosis or more than 50 percent crescents on renal biopsy, a serum creatinine
concentration of more than 5.7 mg per deciliter
(500 mol per liter), or a need for dialysis.134 Most
patients with advanced disease do not have a response to plasmapheresis or immunosuppression.
Patients with end-stage kidney disease who present
with hemoptysis, however, should be treated for
lung hemorrhage, which does respond to plasmapheresis.133 Patients who have the fewest features
known to predict a poor outcome typically have a
response when given 8 to 10 treatments with plasmapheresis during the first two weeks, accompanied by oral prednisone and cyclophosphamide
therapy. Although the evidence is largely experiential, those who have a response to treatment involving an enduring absence of antiglomerular basement membrane antibodies can have their dose of
prednisone tapered after a few months, while continuing to receive cyclophosphamide for varying
periods of up to a year. Kidney transplantation is
possible, but because there is a risk of recurrence,
experience has suggested that patients should wait
for six months and certainly until antiglomerular basement membrane antibodies are undetectable in serum.124
Almost all antiglomerular basement membrane

antibodies from patients with Goodpastures syndrome are directed against the a3(IV) NC1 domain;
a few patients also produce antibodies against the
a1(IV) or a4(IV) NC1 domain (Table 1).30 Commercial assays for antiglomerular basement membrane antibodies have varying degrees of sensitivity
and specificity; often, immunofluorescent staining
of a kidney-biopsy specimen for antiglomerular
basement membrane antibody and C3 complement
is needed for confirmation. Kidney-biopsy specimens from 2 to 3 percent of patients with Goodpastures syndrome that appear on standard assays
to contain no circulating antiglomerular basement
membrane antibodies show linear staining for antia3(IV) NC1 antibody along the glomerular basement membrane; circulating antibodies in these
patients are detectable only with the use of a highly
sensitive biosensor.135
In testing serum in antiglomerular basement
membrane assays, it is important that the a3(IV)
NC1 domain be used as the sole target, because assays that use all collagen IV fragments cannot distinguish Goodpasture antibodies from antibodies
against the a1(IV) NC1 domain in patients with a
paraneoplastic syndrome.102 Approximately 25 percent of patients with Goodpastures syndrome also
summary
produce ANCA, mainly against myeloperoxidase
(Table 1).136 Patients in this subgroup probably have The family of type IV collagens continues to provide
a vasculitis-associated variant for which the prog- an important source of new information about basenosis is surprisingly good with treatment.137
ment-membrane molecules in epithelial tissues.
Given the additional knowledge available today, we
findings on kidney biopsy
propose renaming the a3.a4.a5(IV) protomer the
The performance of an urgent kidney biopsy rather Goodpasture protomer. This change honors the
than a lung biopsy (lung tissue can have a great cornerstone role of the Goodpasture antigen in endeal of autofluorescence) is important in suspected larging our knowledge of collagen IV biochemistry
cases of Goodpastures syndrome in order to estab- and relates the molecular understanding of prolish the diagnosis and the degree of irreversible tomer assembly to the pathogenesis of Goodpasdamage. Renal biopsies typically show focal or seg- tures and Alports syndromes.
mental glomerular necrosis (Fig. 4B), which later,
The insights provided by the work completed
with destruction of the glomerular basement mem- to date suggest that a number of therapeutic adbrane and cellular proliferation, leads to crescent vances may be forthcoming. Recognition that baseformation (Fig. 4C). Breakdown of the Bowmans ment membranes in patients with Alports syncapsule by periglomerular inflammation is of con- drome are particularly susceptible to proteolysis47
cern, and vasculitis on renal biopsy suggests the si- may eventually lead to the prophylactic use of spemultaneous presence of ANCA-related disease.136 cific protease inhibitors or even gene-replacement
2552
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therapy.138 Work with experimental models of undoubtedly provide a new understanding of colantiglomerular basement membrane disease al- lagen-related diseases.
Supported in part by grants (DK-46282 and DK-55926, to Dr.
ready predicts a role for costimulatory blockade of
DK-18381 and DK-53763, to Dr. Hudson; and DK-62524,
T-cell activation,139 immune modulation with in- Neilson;
to Dr. Sundaramoorthy) from the National Institutes of Health and
terleukin-4 and interleukin-10,121 or inhibition of a grant (to Dr. Tryggvason) from the Swedish Medical Research
macrophage migration.140 If nothing else, the fu- Council.
We are indebted to Larry Howell for assistance in the preparation
ture will be interesting, and work in this area will of the
figures.
references
1. Gumbiner BM. Cell adhesion: the molec-
ular basis of tissue architecture and morphogenesis. Cell 1996;84:345-57.

2. Davies JA, Garrod DR. Molecular aspects
of the epithelial phenotype. Bioessays 1997;
19:699-704.
3. Schock F, Perrimon N. Molecular mechanisms of epithelial morphogenesis. Annu
Rev Cell Dev Biol 2002;18:463-93.
4. Yurchenco PD, Smirnov S, Mathus T.
Analysis of basement membrane self-assembly and cellular interactions with native and
recombinant glycoproteins. Methods Cell
Biol 2002;69:111-44.
5. Aumailley M, Gayraud B. Structure and
biological activity of the extracellular matrix.
J Mol Med 1998;76:253-65.
6. Soininen R, Haka-Risku T, Prockop DJ,
Tryggvason K. Complete primary structure
of the alpha 1-chain of human basement
membrane (type IV) collagen. FEBS Lett
1987;225:188-94.
7. Hostikka SL, Tryggvason K. The complete primary structure of the alpha 2 chain
of human type IV collagen and comparison
with the alpha 1(IV) chain. J Biol Chem 1988;
263:19488-93.
8. Mariyama M, Leinonen A, Mochizuki T,
Tryggvason K, Reeders ST. Complete primary structure of the human alpha 3(IV) collagen chain: coexpression of the alpha 3(IV)
and alpha 4(IV) collagen chains in human
tissues. J Biol Chem 1994;269:23013-7.
9. Leinonen A, Mariyama M, Mochizuki T,
Tryggvason K, Reeders ST. Complete primary structure of the human type IV collagen
alpha 4(IV) chain: comparison with structure and expression of the other alpha (IV)
chains. J Biol Chem 1994;269:26172-7.
10. Hostikka, SL, Eddy RL, Byers MG,
Hoyhtya M, Shows TB, Tryggvason K. Identification of a distinct type IV collagen alpha
chain with restricted kidney distribution
and assignment of its gene to the locus of
X chromosome-linked Alport syndrome.
Proc Natl Acad Sci U S A 1990;87:1606-10.
11. Myers JC, Jones TA, Pohjolainen ER, et
al. Molecular cloning of alpha 5(IV) collagen
and assignment of the gene to the region of
the X chromosome containing the Alport
syndrome locus. Am J Hum Genet 1990;46:
1024-33.
12. Zhou J, Ding M, Zhao Z, Reeders ST.
Complete primary structure of the sixth
chain of human basement membrane collagen, alpha 6(IV): isolation of the cDNAs
for alpha 6(IV) and comparison with five
other type IV collagen chains. J Biol Chem

1994;269:13193-9.
13. Oohashi T, Sugimoto M, Mattei MG,
Ninomiya Y. Identification of a new collagen
IV chain, alpha 6(IV), by cDNA isolation and
assignment of the gene to chromosome
Xq22, which is the same locus for COL4A5.
J Biol Chem 1994;269:7520-6.
14. Hudson BG, Reeders ST, Tryggvason K.
Type IV collagen: structure, gene organization, and role in human diseases: molecular
basis of Goodpasture and Alport syndromes
and diffuse leiomyomatosis. J Biol Chem
1993;268:26033-6.
15. Alport AC. Hereditary familial congenital haemorrhagic nephritis. BMJ 1927;1:
504-6.
16. Spear GS. Pathology of the kidney in
Alports syndrome. Pathol Annu 1974;9:93138.
17. Idem. Alports syndrome: a consideration of pathogenesis. Clin Nephrol 1973;
1:336-7.
18. Longo I, Porcedda P, Mari F, et al.
COL4A3/COL4A4 mutations: from familial
hematuria to autosomal-dominant or recessive Alport syndrome. Kidney Int 2002;61:
1947-56.
19. Jais JP, Knebelmann B, Giatras I, et al.
X-linked Alport syndrome: natural history in
195 families and genotype-phenotype correlations in males. J Am Soc Nephrol 2000;11:
649-57.
20. Barker DF, Hostikka SL, Zhou J, et al.
Identification of mutations in the COL4A5
collagen gene in Alport syndrome. Science
1990;248:1224-7.
21. Lemmink HH, Nillesen WN, Mochizuki
T, et al. Benign familial hematuria due to
mutation of the type IV collagen alpha4
gene. J Clin Invest 1996;98:1114-8.
22. Buzza M, Wilson D, Savige J. Segregation
of hematuria in thin basement membrane
disease with haplotypes at the loci for Alport
syndrome. Kidney Int 2001;59:1670-6.
23. Badenas C, Praga M, Tazon B, et al.
Mutations in the COL4A4 and COL4A3 genes
cause familial benign hematuria. J Am Soc
Nephrol 2002;13:1248-54.
24. Dagher H, Buzza M, Colville D, et al.
A comparison of the clinical, histopathologic, and ultrastructural phenotypes in carriers of X-linked and autosomal recessive
Alports syndrome. Am J Kidney Dis 2001;
38:1217-28.
25. Stanton MC, Tange JD. Goodpastures
syndrome: pulmonary hemorrhage associ-
n engl j med 348;25
www.nejm.org
ated with glomerulonephritis. Austr Ann

Med 1958;7:132-44.
26. Goodpasture EW. The pathology of
pneumonia accompanying influenza. U S
Naval Med Bull 1919;13:177-97.
27. Kluth DC, Rees AJ. Anti-glomerular basement membrane disease. J Am Soc Nephrol
1999;10:2446-53.
28. Savage CO, Pusey CD, Bowman C, Rees
AJ, Lockwood CM. Antiglomerular basement
membrane antibody mediated disease in the
British Isles 1980-4. Br Med J (Clin Res Ed)
1986;292:301-4.
29. Saus J, Wieslander J, Langeveld JP, Quinones S, Hudson BG. Identification of the
Goodpasture antigen as the alpha 3(IV)
chain of collagen IV. J Biol Chem 1988;263:
13374-80.
30. Kalluri R, Wilson CB, Weber M, et al.
Identification of the alpha 3 chain of type IV
collagen as the common autoantigen in antibasement membrane disease and Goodpasture syndrome. J Am Soc Nephrol 1995;6:
1178-85.
31. Gunwar S, Bejarano PA, Kalluri R, et al.
Alveolar basement membrane: molecular
properties of the noncollagenous domain
(hexamer) of collagen IV and its reactivity
with Goodpasture autoantibodies. Am J Respir Cell Mol Biol 1991;5:107-12.
32. Butkowski RJ, Wieslander J, Kleppel M,
Michael AF, Fish AJ. Basement membrane
collagen in the kidney: regional localization
of novel chains related to collagen IV. Kidney
Int 1989;35:1195-202.
33. Kalluri R, Melendez E, Rumpf KW, et al.
Specificity of circulating and tissue-bound
autoantibodies in Goodpasture syndrome.
Proc Assoc Am Physicians 1996;108:134-9.
34. McCoy RC, Johnson HK, Stone WJ, Wilson CB. Absence of nephritogenic GBM
antigen(s) in some patients with hereditary
nephritis. Kidney Int 1982;21:642-52.
35. Boutaud A, Borza DB, Bondar O, et al.
Type IV collagen of the glomerular basement
membrane: evidence that the chain specificity of network assembly is encoded by the
noncollagenous NC1 domains. J Biol Chem
2000;275:30716-24.
36. Borza DB, Bondar O, Todd P, et al. Quaternary organization of the Goodpasture
autoantigen, the a3(IV) collagen chain:
sequestration of two cryptic autoepitopes
by intraprotomer interactions with the a4
and a5 NC1 domains. J Biol Chem 2002;277:
40075-83.
37. Borza DB, Bondar O, Ninomiya Y, et al.
june 19, 2003

2553
The
new england journal
The NC1 domain of collagen IV encodes a

novel network composed of the alpha 1,
alpha 2, alpha 5, and alpha 6 chains in
smooth muscle basement membranes.
J Biol Chem 2001;276:28532-40.
38. Kefalides NA. A collagen of unusual
composition and a glycoprotein isolated
from canine glomerular basement membrane. Biochem Biophys Res Commun 1966;
22:26-32.
39. Timpl R, Wiedemann H, van Delden V,
Furthmayr H, Kuhn K. A network model for
the organization of type IV collagen molecules in basement membranes. Eur J Biochem 1981;120:203-11.
40. Yurchenco PD, Furthmayr H. Self-assembly of basement membrane collagen. Biochemistry 1984;23:1839-50.
41. Tryggvason K, Robey PG, Martin GR.
Biosynthesis of type IV procollagens. Biochemistry 1980;19:1284-9.
42. Butkowski RJ, Langeveld JP, Wieslander
J, Hamilton J, Hudson BG. Localization of
the Goodpasture epitope to a novel chain of
basement membrane collagen. J Biol Chem
1987;262:7874-7.
43. Gunwar S, Saus J, Noelken ME, Hudson
BG. Glomerular basement membrane: identification of a fourth chain, alpha 4, of type
IV collagen. J Biol Chem 1990;265:5466-9.
44. Peissel B, Geng L, Kalluri R, et al. Comparative distribution of the alpha 1(IV),
alpha 5(IV), and alpha 6(IV) collagen chains
in normal human adult and fetal tissues and
in kidneys from X-linked Alport syndrome
patients. J Clin Invest 1995;96:1948-57.
45. Langeveld JP, Noelken ME, Hard K, et al.
Bovine glomerular basement membrane:
location and structure of the asparaginelinked oligosaccharide units and their potential role in the assembly of 7 S collagen IV
tetramer. J Biol Chem 1991;266:2622-31.
46. Nayak BR, Spiro RG. Localization and
structure of the asparagine-linked oligosaccharides of type IV collagen from glomerular basement membrane and lens capsule.
J Biol Chem 1991;266:13978-87.
47. Kalluri R, Shield CF, Todd P, Hudson
BG, Neilson EG. Isoform switching of type
IV collagen is developmentally arrested
in X-linked Alport syndrome leading to
increased susceptibility of renal basement
membranes to endoproteolysis. J Clin Invest
1997;99:2470-8.
48. Sundaramoorthy M, Meiyappan M,
Todd P, Hudson BG. Crystal structure of
NC1 domains: structural basis for type IV
collagen assembly in basement membranes.
J Biol Chem 2002;277:31142-53.
49. Than ME, Henrich S, Huber R, et al. The
1.9-A crystal structure of the noncollagenous (NC1) domain of human placenta collagen IV shows stabilization via a novel type
of covalent Met-Lys cross-link. Proc Natl
Acad Sci U S A 2002;99:6607-12.
50. Guo XD, Johnson JJ, Kramer JM. Embryonic lethality caused by mutations in basement membrane collagen of C. elegans.
Nature 1991;349:707-9.
2554
of
medicine
51. Zhang X, Hudson BG, Sarras MP Jr.
Hydra cell aggregate development is blocked

by selective fragments of fibronectin and
type IV collagen. Dev Biol 1994;164:10-23.
52. Netzer KO, Suzuki K, Itoh Y, Hudson
BG, Khalifah RG. Comparative analysis of
the noncollagenous NC1 domain of type IV
collagen: identification of structural features important for assembly, function, and
pathogenesis. Protein Sci 1998;7:1340-51.
53. Fowler SJ, Jose S, Zhang X, Deutzmann
R, Sarras MP Jr, Boot-Handford RP. Characterization of hydra type IV collagen: type IV
collagen is essential for head regeneration
and its expression is up-regulated upon exposure to glucose. J Biol Chem 2000;275:
39589-99.
54. Kalluri R, Gattone VH II, Hudson BG.
Identification and localization of type IV collagen chains in the inner ear cochlea. Connect Tissue Res 1998;37:143-50.
55. Cosgrove D, Samuelson G, Meehan DT,
et al. Ultrastructural, physiological, and
molecular defects in the inner ear of a geneknockout mouse model for autosomal Alport
syndrome. Hear Res 1998;121:84-98.
56. Yoshioka K, Hino S, Takemura T, et al.
Type IV collagen alpha 5 chain: normal distribution and abnormalities in X-linked
Alport syndrome revealed by monoclonal
antibody. Am J Pathol 1994;144:986-96.
57. Ninomiya Y, Kagawa M, Iyama K, et al.
Differential expression of two basement
membrane collagen genes, COL4A6 and
COL4A5, demonstrated by immunofluorescence staining using peptide-specific monoclonal antibodies. J Cell Biol 1995;130:121929.
58. Miner JH, Sanes JR. Collagen IV alpha 3,
alpha 4, and alpha 5 chains in rodent basal
laminae: sequence, distribution, association
with laminins, and developmental switches.
J Cell Biol 1994;127:879-91.
59. Harvey SJ, Zheng K, Sado Y, et al. Role of
distinct type IV collagen networks in glomerular development and function. Kidney Int
1998;54:1857-66.
60. Williamson DAJ. Alports syndrome of
hereditary nephritis with deafness. Lancet
1961;2:1321-3.
61. Grunfeld JP. Contemporary diagnostic
approach in Alports syndrome. Ren Fail
2000;22:759-63.
62. Kashtan CE. Familial hematuric syndromes Alport syndrome, thin glomerular basement membrane disease and Fechtner/Epstein syndromes. Contrib Nephrol
2001;136:79-99.
63. Martin P, Heiskari N, Zhou J, et al. High
mutation detection rate in the COL4A5 collagen gene in suspected Alport syndrome
using PCR and direct DNA sequencing. J Am
Soc Nephrol 1998;9:2291-301.
64. Lemmink HH, Mochizuki T, van den
Heuvel LP, et al. Mutations in the type IV collagen alpha 3 (COL4A3) gene in autosomal
recessive Alport syndrome. Hum Mol Genet
1994;3:1269-73.
65. Mochizuki T, Lemmink HH, Mariyama
n engl j med 348;25
www.nejm.org
M, et al. Identification of mutations in the

alpha 3(IV) and alpha 4(IV) collagen genes
in autosomal recessive Alport syndrome. Nat
Genet 1994;8:77-81.
66. Antignac C, Zhou J, Sanak M, et al. Alport
syndrome and diffuse leiomyomatosis: deletions in the 5' end of the COL4A5 collagen
gene. Kidney Int 1992;42:1178-83.
67. Zhou J, Mochizuki T, Smeets H, et al.
Deletion of the paired alpha 5(IV) and alpha
6(IV) collagen genes in inherited smooth
muscle tumors. Science 1993;261:1167-9.
68. Zhang X, Zhou J, Reeders ST, Tryggvason K. Structure of the human type IV collagen COL4A6 gene, which is mutated in
Alport syndrome-associated leiomyomatosis. Genomics 1996;33:473-9.
69. McIntosh I, Dreyer SD, Clough MV, et al.
Mutation analysis of LMX1B gene in nailpatella syndrome patients. Am J Hum Genet
1998;63:1651-8.
70. Hamano, Y, Grunkemeyer JA, Sudhakar
A, et al. Determinants of vascular permeability in the kidney glomerulus. J Biol Chem
2002;277:31154-62.
71. Miner JH, Morello R, Andrews KL, et al.
Transcriptional induction of slit diaphragm
genes by LMX1B is required in podocyte differentiation. J Clin Invest 2002;109:106572.
72. Morello R, Zhou G, Dreyer SD, et al. Regulation of glomerular basement membrane
collagen expression by LMX1B contributes
to renal disease in nail patella syndrome.
Nat Genet 2001;27:205-8.
73. Kashtan CE, Kleppel MM, Gubler MC.
Immunohistologic findings in Alport syndrome. Contrib Nephrol 1996;117:142-53.
74. Kalluri R, Cantley LG, Kerjaschki D,
Neilson EG. Reactive oxygen species expose
cryptic epitopes associated with autoimmune
Goodpasture syndrome. J Biol Chem 2000;
275:20027-32.
75. Huang T, Cheng AG, Stupak H, et al.
Oxidative stress-induced apoptosis of cochlear sensory cells: otoprotective strategies.
Int J Dev Neurosci 2000;18:259-70.
76. Reddan JR, Steiger CA, Dziedzic DC,
Gordon SR. Regional differences in the distribution of catalase in the epithelium of the
ocular lens. Cell Mol Biol (Noisy-le-grand)
1996;42:209-19.
77. Gunwar S, Ballester F, Noelken ME,
Sado Y, Ninomiya Y, Hudson BG. Glomerular basement membrane: identification of a
novel disulfide-cross-linked network of
alpha3, alpha4, and alpha5 chains of type IV
collagen and its implications for the pathogenesis of Alport syndrome. J Biol Chem
1998;273:8767-75.
78. Kim KH, Kim Y, Gubler MC, et al. Structural-functional relationships in Alport syndrome. J Am Soc Nephrol 1995;5:1659-68.
79. Remuzzi G, Bertani T. Pathophysiology
of progressive nephropathies. N Engl J Med
1998;339:1448-56.
80. Zeisberg M, Bonner G, Maeshima Y, et
al. Renal fibrosis: collagen composition and
assembly regulates epithelial-mesenchymal
june 19, 2003

transdifferentiation. Am J Pathol 2001;159:

1313-21.
81. Zeisberg M, Maeshima Y, Mosterman
B, Kalluri R. Renal fibrosis: extracellular
matrix microenvironment regulates migratory behavior of activated tubular epithelial
cells. Am J Pathol 2002;160:2001-8.
82. Strutz, F, Okada H, Lo CW, et al. Identification and characterization of a fibroblast
marker: FSP1. J Cell Biol 1995;130:393-405.
83. Iwano, M, Plieth D, Danoff TM, Xue C,
Okada H, Neilson EG. Evidence that fibroblasts derive from epithelium during tissue
fibrosis. J Clin Invest 2002;110:341-50.
84. Gross O, Netzer KO, Lambrecht R, Seibold S, Weber M. Meta-analysis of genotypephenotype correlation in X-linked Alport
syndrome: impact on clinical counselling.
Nephrol Dial Transplant 2002;17:1218-27.
85. Hasstedt SJ, Atkin CL, San Juan AC Jr.
Genetic heterogeneity among kindreds with
Alport syndrome. Am J Hum Genet 1986;
38:940-53.
86. Colville DJ, Savige J. Alport syndrome:
a review of the ocular manifestations. Ophthalmic Genet 1997;18:161-73.
87. Rumpelt HJ. Alports syndrome: specificity and pathogenesis of glomerular basement membrane alterations. Pediatr Nephrol 1987;1:422-7.
88. Dische FE, Anderson VE, Keane SJ,
Taube D, Bewick M, Parsons V. Incidence of
thin membrane nephropathy: morphometric investigation of a population sample.
J Clin Pathol 1990;43:457-60.
89. Adler L, Mathew R, Futterweit S, et al.
Angiotensin converting enzyme inhibitor
therapy in children with Alport syndrome:
effect on urinary albumin, TGF-beta, and
nitrite excretion. BMC Nephrol 2002;3:2.
90. Byrne MC, Budisavljevic MN, Fan Z, Self
SE, Ploth DW. Renal transplant in patients
with Alports syndrome. Am J Kidney Dis
2002;39:769-75.
91. Kalluri R, Torre A, Shield CF III, et al.
Identification of alpha3, alpha4, and alpha5
chains of type IV collagen as alloantigens for
Alport posttransplant anti-glomerular basement membrane antibodies. Transplantation 2000;69:679-83.
92. Hudson BG, Kalluri R, Gunwar S, et al.
The pathogenesis of Alport syndrome
involves type IV collagen molecules containing the alpha 3(IV) chain: evidence from
anti-GBM nephritis after renal transplantation. Kidney Int 1992;42:179-87.
93. Kashtan CE, McEnery PT, Tejani A, Stablein DM. Renal allograft survival according
to primary diagnosis: a report of the North
American Pediatric Renal Transplant Cooperative Study. Pediatr Nephrol 1995;9:679-84.
94. van Setten G. Anterior lenticonus: histological evaluation and approach for cataract
surgery. J Cataract Refract Surg 2001;27:
1071-5.
95. Wilson CB, Dixon FJ. Anti-glomerular
basement membrane antibody-induced glomerulonephritis. Kidney Int 1973;3:74-89.
96. Wieslander J, Barr JF, Butkowski RJ, et
al. Goodpasture antigen of the glomerular

basement membrane: localization to noncollagenous regions of type IV collagen.
Proc Natl Acad Sci U S A 1984;81:3838-42.
97. Kalluri R, Danoff TM, Okada H, Neilson
EG. Susceptibility to anti-glomerular basement membrane disease and Goodpasture
syndrome is linked to MHC class II genes and
the emergence of T cell-mediated immunity
in mice. J Clin Invest 1997;100:2263-75.
98. Phelps RG, Rees AJ. The HLA complex
in Goodpastures disease: a model for analyzing susceptibility to autoimmunity. Kidney Int 1999;56:1638-53.
99. Wong D, Phelps RG, Turner AN. The
Goodpasture antigen is expressed in the
human thymus. Kidney Int 2001;60:1777-83.
100. Salama AD, Chaudhry AN, Ryan JJ, et
al. In Goodpastures disease, CD4(+) T cells
escape thymic deletion and are reactive with
the autoantigen alpha3(IV)NC1. J Am Soc
Nephrol 2001;12:1908-15.
101. Bolton WK, Luo AM, Fox PL, May WJ,
Sturgill BC. Study of EHS type IV collagen
lacking Goodpastures epitope in glomerulonephritis in rats. Kidney Int 1995;47:40410.
102. Kalluri R, Petrides S, Wilson CB, et al.
Anti-alpha 1 (IV) collagen autoantibodies
associated with lung adenocarcinoma presenting as the Goodpasture syndrome. Ann
Intern Med 1996;124:651-3.
103. Sado Y, Boutaud A, Kagawa M, Naito I,
Ninomiya Y, Hudson BG. Induction of antiGBM nephritis in rats by recombinant alpha
3(IV)NC1 and alpha 4(IV)NC1 of type IV collagen. Kidney Int 1998;53:664-71. [Erratum,
Kidney Int 1998;54:311.]
104. Lerner RA, Glassock RJ, Dixon FJ. The
role of anti-glomerular basement membrane
antibody in the pathogenesis of human glomerulonephritis. J Exp Med 1967;126:9891004.
105. Almkuist RD, Buckalew VM Jr, Hirszel
P, Maher JF, James PM, Wilson CB. Recurrence of anti-glomerular basement membrane antibody mediated glomerulonephritis
in an isograft. Clin Immunol Immunopathol
1981;18:54-60.
106. Meyers KE, Allen J, Gehret J, et al.
Human antiglomerular basement membrane
autoantibody disease in XenoMouse II. Kidney Int 2002;61:1666-73.
107. Rutgers A, Meyers KE, Canziani G, Kalluri R, Lin J, Madaio MP. High affinity of
anti-GBM antibodies from Goodpasture and
transplanted Alport patients to alpha3(IV)
NC1 collagen. Kidney Int 2000;58:115-22.
108. Netzer KO, Leinonen A, Boutaud A, et
al. The Goodpasture autoantigen: mapping
the major conformational epitope(s) of
alpha3(IV) collagen to residues 17-31 and
127-141 of the NC1 domain. J Biol Chem
1999;274:11267-74.
109. Hellmark T, Burkhardt H, Wieslander
J. Goodpasture disease: characterization of
a single conformational epitope as the target
of pathogenic autoantibodies. J Biol Chem
1999;274:25862-8.
n engl j med 348;25
www.nejm.org
110. Borza DB, Netzer KO, Leinonen A, et

al. The Goodpasture autoantigen: identification of multiple cryptic epitopes on the
NC1 domain of the alpha3(IV) collagen
chain. J Biol Chem 2000;275:6030-7.
111. David M, Borza DB, Leinonen A, Belmont JM, Hudson BG. Hydrophobic amino
acid residues are critical for the immunodominant epitope of the Goodpasture autoantigen: a molecular basis for the cryptic
nature of the epitope. J Biol Chem 2001;276:
6370-7.
112. Gunnarsson A, Hellmark T, Wieslander
J. Molecular properties of the Goodpasture
epitope. J Biol Chem 2000;275:30844-8.
113. Neilson EG, Kalluri R, Sun MJ, et al.
Specificity of Goodpasture autoantibodies for
the recombinant noncollagenous domains
of human type IV collagen. J Biol Chem 1993;
268:8402-5.
114. Kalluri R, Sun MJ, Hudson BG, Neilson EG. The Goodpasture autoantigen:
structural delineation of two immunologically privileged epitopes on alpha3(IV) chain
of type IV collagen. J Biol Chem 1996;271:
9062-8.
115. Wieslander J, Langeveld J, Butkowski
R, Jodlowski M, Noelken M, Hudson BG.
Physical and immunochemical studies of
the globular domain of type IV collagen: cryptic properties of the Goodpasture antigen.
J Biol Chem 1985;260:8564-70.
116. Stevenson A, Yaqoob M, Mason H, Pai
P, Bell GM. Biochemical markers of basement membrane disturbances and occupational exposure to hydrocarbons and mixed
solvents. QJM 1995;88:23-8.
117. Donaghy M, Rees AJ. Cigarette smoking and lung haemorrhage in glomerulonephritis caused by autoantibodies to glomerular basement membrane. Lancet 1983;2:
1390-3.
118. Meyers KE, Kinniry PA, Kalluri R, Neilson EG, Madaio MP. Human Goodpasture
anti-alpha3(IV)NC1 autoantibodies share
structural determinants. Kidney Int 1998;
53:402-7.
119. Derry CJ, Ross CN, Lombardi G, et al.
Analysis of T cell responses to the autoantigen in Goodpastures disease. Clin Exp
Immunol 1995;100:262-8.
120. Remuzzi G, Zoja C, Bertani T. Glomerulonephritis. Curr Opin Nephrol Hypertens
1993;2:465-74.
121. Tipping PG, Kitching AR, Huang XR,
Mutch DA, Holdsworth SR. Immune modulation with interleukin-4 and interleukin-10
prevents crescent formation and glomerular
injury in experimental glomerulonephritis.
Eur J Immunol 1997;27:530-7.
122. Wu J, Hicks J, Ou C, Singleton D, Borillo
J, Lou YH. Glomerulonephritis induced by
recombinant collagen IV alpha 3 chain
noncollagen domain 1 is not associated
with glomerular basement membrane antibody: a potential T cell-mediated mechanism. J Immunol 2001;167:2388-95.
123. Wu J, Hicks J, Borillo J, Glass WF II,
Lou YH. CD4(+) T cells specific to a glomer-
june 19, 2003

2555
ular basement membrane antigen mediate

glomerulonephritis. J Clin Invest 2002;109:
517-24.
124. Netzer KO, Merkel F, Weber M. Goodpasture syndrome and end-stage renal failure to transplant or not to transplant?
Nephrol Dial Transplant 1998;13:1346-8.
125. Sheerin NS, Springall T, Carroll MC,
Hartley B, Sacks SH. Protection against antiglomerular basement membrane (GBM)mediated nephritis in C3- and C4-deficient
mice. Clin Exp Immunol 1997;110:403-9.
126. Baricos WH, Cortez SL, Le QC, et al.
Evidence suggesting a role for cathepsin L in
an experimental model of glomerulonephritis. Arch Biochem Biophys 1991;288:468-72.
127. Timoshanko JR, Kitching AR, Holdsworth SR, Tipping PG. Interleukin-12 from
intrinsic cells is an effector of renal injury in
crescentic glomerulonephritis. J Am Soc
Nephrol 2001;12:464-71.
128. Kitching AR, Ru Huang X, Turner AL,
Tipping PG, Dunn AR, Holdsworth SR. The
requirement for granulocyte-macrophage
colony-stimulating factor and granulocyte
colony-stimulating factor in leukocyte-mediated immune glomerular injury. J Am Soc
Nephrol 2002;13:350-8.
129. Holdsworth SR, Kitching AR, Tipping
PG. Th1 and Th2 T helper cell subsets affect
patterns of injury and outcomes in glomerulonephritis. Kidney Int 1999;55:1198-216.

130. Kitching AR, Tipping PG, Holdsworth
SR. IL-12 directs severe renal injury, crescent
formation and Th1 responses in murine glomerulonephritis. Eur J Immunol 1999;29:
1-10.
131. Timoshanko JR, Holdsworth SR, Kitching AR, Tipping PG. IFN-gamma production
by intrinsic renal cells and bone marrowderived cells is required for full expression
of crescentic glomerulonephritis in mice.
J Immunol 2002;168:4135-41.
132. Isbel NM, Hill PA, Foti R, et al. Tubules
are the major site of M-CSF production in
experimental kidney disease: correlation
with local macrophage proliferation. Kidney
Int 2001;60:614-25.
133. Lockwood CM, Peters DK. Plasma
exchange in glomerulonephritis and related
vasculitides. Annu Rev Med 1980;31:167-79.
134. Levy JB, Turner AN, Rees AJ, Pusey CD.
Long-term outcome of anti-glomerular basement membrane antibody disease treated
with plasma exchange and immunosuppression. Ann Intern Med 2001;134:1033-42.
135. Salama AD, Dougan T, Levy JB, et al.
Goodpastures disease in the absence of
circulating anti-glomerular basement membrane antibodies as detected by standard
techniques. Am J Kidney Dis 2002;39:

1162-7.
136. Kalluri R, Meyers K, Mogyorosi A,
Madaio MP, Neilson EG. Goodpasture syndrome involving overlap with Wegeners
granulomatosis and anti-glomerular basement membrane disease. J Am Soc Nephrol
1997;8:1795-800.
137. Bosch X, Mirapeix E, Font J, et al. Prognostic implication of anti-neutrophil cytoplasmic autoantibodies with myeloperoxidase specificity in anti-glomerular basement
membrane disease. Clin Nephrol 1991;36:
107-13.
138. Heikkila P, Tibell A, Morita T, et al.
Adenovirus-mediated transfer of type IV collagen alpha5 chain cDNA into swine kidney
in vivo: deposition of the protein into the
glomerular basement membrane. Gene Ther
2001;8:882-90.
139. Reynolds J, Tam FW, Chandraker A, et
al. CD28-B7 blockade prevents the development of experimental autoimmune glomerulonephritis. J Clin Invest 2000;105:643-51.
140. Lan HY, Bacher M, Yang N, et al. The
pathogenic role of macrophage migration
inhibitory factor in immunologically induced
kidney disease in the rat. J Exp Med 1997;
185:1455-65.
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Alport's Syndrome, Goodpasture's Syndrome, and Type IV Collagen

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