Clin. exp. Immunol. (1980) 42, 247-254.

IgA glomerulonephritis (Berger's disease):

evidence of high serum levels of polymeric IgA

M. LOPEZ TRASCASA, J. EGIDO, J. SANCHO & L. HERNANDO Servicio

de Nefrologia, Fundaciin Jiminez Diaz, Madrid, Spain

(Accepted for publication 23 May 1980)

SUMMARY
Eleven out of 15 patients with IgA mesangial glomerulonephritis (Berger's disease) had
an increased proportion of serum IgA in 9-21S fractions on 5-40% sucrose density-
gradient ultracentrifugation; the heavier fractions decreased at acid pH. Serum IgA
purified by starch electrophoresis was subjected to reduction-alkylation yielding frag-
ments of lower molecular weight. J chain was detected on urea alkaline polyacrylamide
electrophoresis and the high-molecular weight IgA bound the human secretory compo-
nent. In six patients treated with phenytoin for 1 year there was a decrease in polymeric
IgA and an increase in monomeric IgA adopting a pattern similar to that of the controls.
Our results show the presence of a large amount of true IgA polymers, partially as
immune complexes, in the serum of patients with Berger's disease. These data together
with their normalization after phenytoin treatment may open a new pathogenic and
therapeutic approach to this entity.

INTRODUCTION
IgA glomerulonephritis, described by Berger & Hinglais (1968) and Berger (1969), is now a well
recognized entity. The significance of IgA and its role in this disease are not clear. The
demonstration in the glomerular mesangium of IgA and C3 in a granular pattern strongly
suggested mesangial deposition of immune complexes, raising the question of IgA's capacity to
function as antigen or antibody. However, Lowance, Mullins & McPhaul (1973) could not find
anti-IgA antibodies in patients with this disease. Tung et al. (1978) have been unable to
demonstrate circulating immune complexes using the Clq solid phase and Raji cell radioimmune
assays, although those tests are not suitable for the investigation of IgA complexes.
The high frequency of elevated serum IgA levels found in these patients (Lagrue et al., 1974;
Droz, 1976; Van der Peet et al., 1977) and the recurrence of this nephropathy in transplanted
kidneys (Bergeret al., 1975) has focused attention on serum IgA. Although the possibility of an
abnormal IgA has been suggested by some authors (Lagrue et al., 1974; Berger et al., 1975) a
detailed report studying the biochemical characteristics of IgA in Berger's disease is lacking. We
report evidence of a high proportion of polymeric IgA, partially as immune complexes, in the
serum of patients with Berger's disease. This nephropathy probably represents a new pathogenic
entity different from the classic models of glomerulonephritis. Furthermore, the decrease in
polymeric IgA after phenytoin treatment could represent a new therapeutic approach.
Correspondence: Dr J. Egido, Servicio de Nefrologia, Fundaci6n Jimenez Diaz, Avda Reyes Cat6licos 2,
Madrid 3, Spain.
0099-9104/80/1100-0247$02.00 © 1980 Blackwell Scientific Publications
247
248 M. Lopez Trascasa et al.

MATERIALS AND METHODS

The diagnosis of IgA nephropathy was based on the presence of IgA in the glomerular
mesangium with or without C3 and other immunoglobulins. Patients with clinical or biochemical
evidence of liver disease, systemic lupus erythematosus, Henoch-Schonlein purpura or other
systemic diseases were excluded. Sera from nine medical students and staff members matched for
age and sex with patients with IgA glomerulonephritis were used as controls. Venous blood
samples (without heparin) were allowed to clot at 370C for 1 hr and centrifuged at 2,000g at room
temperature for 15 min. The sera obtained plus 0-02% sodium azide were stored in small aliquots
at - 20'C for not longer than 1 week.
Informed consent of the patients was obtained before their inclusion in the phenytoin
therapeutic trial. The dose employed was 300 mg/day. During the time of the study, phenytoin
was the only drug taken by the majority of the patients. Three of them also received a thiazide
diuretic. A complete clinical, laboratory and immunological assessment was performed on each
hospital visit. Only the preliminary study of the phenytoin effects on serum IgA from eight
patients will be reported here.
Gel filtration studies. Serum samples from patients with IgA nephropathy (1 ml mixed with 1
ml of phosphate-buffered saline [PBS] containing 10% sucrose) were fractionated over Sephadex
G-200 superfine. Fractions of 1 2 ml were collected. The optical density was measured at 280 nm
by u.v. spectrophotometry. Immunoglobulins were located in the different fractions by double
diffusion with specific antibodies.
Qualitative measurement of serum IgA. (a) Analytical ultracentrifugation: Sucrose density
gradients (5-40%, w/v) were prepared in 5-ml polyallomer tubes. Sucrose was dissolved in 0 15 M
Tris-HCl, pH 7*4, or in 0- 15 M glycine HCl, pH 2- 8, buffer. Serum samples of 50 Al diluted 1/10
were applied. The gradients were centrifuged at 4°C for 16 hr at 170,000 g in a Spinco L-2
ultracentrifuge with a SW-50RI rotor. IgM (19S), IgG (7S) and bovine serum albumin (BSA;
4.5S) were used as markers. Fractions of approximately 200 ,ul were collected from the bottom.
Fractions in glycine HCI buffer were immediately neutralized to pH 7-4 by addition of 30,ul of 0 2
M Tris; 1.5 ml of 0*9% borate-buffered saline, pH 8, were added to each one and read by u.v.
spectrophotometry at 280 nm. Each fraction was assayed for IgA by a double-antibody
radioimmunoassay (see below). The ng/ml of IgA measured on gradient fractions were plotted
against the fraction number. The total surface and the areas of zones 5-9S, 9-13S, 13-17S and
17-21S, delimited by comparison with the position of markers, were measured by planimetry.
The areas were expressed in per cent of the total.
(b) Radioimmunoassay of IgA: This was carried out according to the general method of
Hunter (1978). One hundred microlitres of a rabbit anti-human a-chain was used at a dilution
which bound approximately 50% of the TCA-precipitable counts of the 1251 IgA. To this, 100,l of
each gradient fraction was added, the tubes were incubated for 2 hr at room temperature and then
0- 1 ml of 1251 IgA was added and further incubated for 2 hr at room temperature. The 1251 IgA
rabbit anti-IgA complex was precipitated by 100,ul of sheep anti-rabbit IgG added at equivalence
with respect to rabbit IgG. Normal rabbit serum was added to the buffer (0 15 M BBS-BSA 0*2%,
pH 8.0) to provide more antigen. Tubes were incubated for 16 hr at 4°C, centrifuged at 3,000
r.p.m. for 10 min, decanted and the precipitates were washed twice with 0- 15 M BBS-BSA 0 2%,
pH 8-0. The tubes were then counted for radioactivity. A standard inhibition curve was
constructed with unlabelled IgA. The assay conditions used permitted IgA to be measured in the
range of 200 to 8 5 ng/ml.
IgA purification. Twelve millilitres of serum from these patients were applied in a well on a
9 x 50 cm block of starch. The electrophoresis was performed for 26 hr at 4°C and constant
voltage of 400 V, the block was cut into about 12 fractions of 1 cm in width and the proteins were
extracted with 0-5 M PBS, pH 7A4. IgA was detected by double immunodiffusion. The IgA
molecular weight of fractions from the anodic and cathodic side was examined by gel filtration on
Sephadex G-200 superfine.
Reduction-alkylation of IgA samples. IgA from the anodic side was labelled with 1251 by the
 High polymeric IgA levels in Berger's disease 249
method of Hunter & Greenwood (1962). It was reduced with 0-04 M dithiothreitol for 1 hr at
370C in 0*15 M Tris buffer, pH 8, containing 0.15 M NaCi, 0-002 M EDTA and alkylated with 3-3
molar excess of iodoacetamide at room temperature for 45 min in the dark. The molecular size of
125I IgA fragments was examined before and after reduction-alkylation by gel filtration and
immunoprecipitation.
J chain examination. J chain was detected by alkaline urea acrylamide electrophoresis
(Reisfeld & Small, 1966). Samples of heavy IgA (300 ,ug) obtained either from anodic fractions
on starch electrophoresis or IgA from Ultrogel Ac A34 that did not contain IgM were reduced
with 10 mm mercaptoethanol in 10 M urea in a boiling water bath for 5 min. IgM from patients
with macroglobulinaemia before and after reduction and IgA before reduction were used as
controls. After reduction the samples were applied on polyacrylamide gels (4% gels) and
electrophoresed at 3 5 mA per tube until the bromophenol used as a marker was near the anodic
side. The proteins were fixed with sulphosalycic (5%) and trichloroacetic acid (5%) and stained
with Coomassie blue overnight. Gels were washed with acetic acid (5%).
Affinity ofthe secretory component for the polymeric IgA. Human secretory component (SC)
was isolated from human whey by affinity chromatography on IgM Sepharose adsorbent
(Underdown et al., 1977). The measurement of the affinity of the secretory component for
polymeric IgA was based upon the method of Brandtzaeg (1974). Briefly, samples of high
molecular weight IgA from patients and IgM and monomeric IgA used as controls were incubated
at 370C for 1 hr at 40C overnight with free SC labelled with 125I. The final molar SC: Ig ratio
averaged 1: 7 5 for the IgA fraction and 1: 2-5 for the IgM fraction. After incubation these
samples were centrifuged on 5-40% sucrose density gradients as described above, measuring the
c.p.m. in each fraction.
Phenytoin assay. The serum concentration of phenytoin was measured by commercially
available radioimmunoassay (Amersham, England).

RESULTS
Serum levels of IgA with different molecular weights
There was a significant difference in the relative distribution of IgA with high sedimentation
constants in the patients as compared to controls (Table 1), but four of 15 patients with IgA
mesangial glomerulonephritis showed an IgA distribution similar to the controls. Incubation at
pH 7-4 and 2-8 resulted in a decrease in fractions 13-21S, significant only in fractions 17-21S
(Table 2). The same studies were performed in five controls and there were no changes at any IgA
molecular weight (data not shown). The results are compatible with a covalent structure for these
forms of high molecular weight IgA.
To exclude the possibility that the high level of high molecular weight IgA was a consequence
of an increase in IgA serum levels, four patients with other glomerular nephropathies (post-
infectious acute proliferative glomerulonephritis, nephrotic syndrome with minimal histological
change, lupus diffuse proliferative glomerulonephritis and diabetic glomerulosclerosis) and high

Table 1. Distribution of proportion of IgA in serum of patients with IgA glomerulonephritis in ultracentri-
fugation fractions

n 5-9S 9-13S 13-17S 17-21S

Controls 9 75-08+3-17* 21-12+3-45 3-41±+0-95 0-38+0-16

Patients 15 58-68+13-74 32-80+10-59 7 65+4-68 0-91+0-66
P value <0-0025t <0-0025 <0-01 <0-025

*
Mean + standard deviation.
t Degrees of freedom for the t-test have been corrected for significantly different standard deviations.
250 M. Lopez Trascasa et al.
serum IgA levels were studied. The distribution of IgA was not significantly different from that of
controls. Several samples were repeatedly studied; the results were consistent.
Study ofpolymeric forms in high molecular weight IgA preparations
The IgA obtained from the cathodic side following starch gel electrophoresis was monomer
(Gavrilova, Egorov & Shakhanima, 1976). IgA samples from the anodic side were polymeric;
they contained a small protein of a-mobility but did not contain IgM or IgG. To establish the
covalent nature of this IgA, it was labelled with 125I and submitted to reduction-alkylation;
components of lower molecular weight resulted (Fig. 1).

Dextran
blue IgG BSA (a)

a) (b)
0'
-0

a1)

01)
0-

40 50 60 80 90
Elution volume (ml)
Fig. 1. Sephadex G-200 superfine elution profile of '25I IgA from the anodic side of a starch electrophoresis
chromatographed on a column (2.6 40 cm) equilibrated with PBS, pH 7-3. (a) Before and (b) after
X

reduction and alkylation (see details in Materials and Methods). Arrows denote the elution position of the
dextran blue (Vo), human IgG (mol. wt 150,000) and BSA (mol. wt = 68,000) used as markers.
=

J chain was detected by urea alkaline acrylamide electrophoresis in the fractions with high
molecular weight IgA of the four patients studied (Fig. 2). Affinity of the secretory component for
that IgA was also shown (Fig. 3b). IgM showed a strong affinity for "25I SC; all radioactivity after
density-gradient ultracentrifugation was located on the 19S zone (Fig. 3a). High molecular
weight IgA from patients with mesangial IgA glomerulonephritis showed an affinity for 12'I SC
lower than IgM; about 50% of radioactivity was bound as described in polymeric IgA from IgA
myeloma (Brandtzaeg, 1974, 1978). These data suggest a marked increase of polymeric IgA in
the sera of these patients in relation to normal human sera.

Effects of phenytoin treatment on levels of polymeric IgA

In six patients with high serum polymeric IgA levels the percentage distribution was established
before and after 1 year of phenytoin treatment. There was a decrease in polymeric IgA and an
increase in monomeric IgA adopting a pattern similar to the controls (Table 3). In two other
patients with a normal IgA percentage distribution treated for 6 months there was also a decrease
 High polymeric IgA levels in Berger's disease 251

;a

iAI LI ..
Fig. 2. Alkaline-urea polyacrylamide gel electrophoresis of the high molecular weight IgA. (A) IgA not
reduced; (B) IgA after reduction. J chain is shown.

13 S 5S
(a )

ot I

Q)
F
0

CL
.)_
0
0
>1

a)

-o
(c )
.0

6 8 10 12 14 16 18
Fraction number
Fig. 3. Distribution of radioactivity after sucrose density-gradient ultracentrifugation with IgM (a), high
molecular weight IgA from a patient with Berger's disease (b) and monomeric IgA (c) after incubation with
125I SC. All 125I SC bound to IgM, about 50% to patients' heavy IgA and none to monomeric IgA. Bottom of
gradient to the left.
252 M. Lopez Trascasa et al.
Table 2. Serum IgA distribution in six patients with IgA mesangial glomerulonephritis after ultracentrifuga-
tion in sucrose gradients at pH 7-4 and pH 2-8.

5-9S 9-13S 13-17S 17-21S

Per cent IgA at pH 7-4 47-25+11.19* 41-98+8-04 9-61+±611 1-14±0-90
Per cent IgA at pH 2-8 51-52±9-77 42-14+6-40 5-50+±401 0-25±0-11
P value n.s. n.s. n.s. <0-05

*
Mean ± standard deviation
n.s. = not significant

Table 3. Effect of phenytoin treatment on serum IgA percentage distribution after ultracentrifugation in
sucrose density gradients (pH 7-4) in patients with IgA mesangial glomerulonephritis

n 5-9S 9-13S 13-17S 17-21S

Before treatment 6 59-06±2-14* 32-55+2-04 8-43±2-74 0-74±0-17

P value <0-0025t <0-025 <0-025 n.s.
After 1 year of 6 77-32±5-18 20-33+5-33 1-94±0-87 0-4±0-31
treatment
Controls 9 75-08+2-98 21-12±3-25 3-41±0-89 0-37±0-15

* Mean ± standard deviation

t Paired t-test of difference - before and after

in polymeric forms (20-66+3-69 vs 14-65±+166 [9-13S]; 5-04+1-07 vs 2-03±+197 [13-17S]

and 0-76+0-09 vs 0-48±0-03 [17-21S]) and an increase in monomeric forms (73-51±+ 1-60 vs
82.84+3.65 [5-9S]) suggesting that the action of phenytoin could be more marked on the IgA of
high molecular weight. In these eight patients the serum phenytoin concentrations were in the
therapeutic range.

DISCUSSION

Most patients with IgA glomerulonephritis have an increase in serum IgA with sedimentation
constants between 9-21S. Acid treatment only partially reduced this proportion but reduction
yielded fragments of smaller size. These results are compatible with the presence of a large
amount of polymeric forms of serum IgA in patients with IgA glomerulonephritis.
How do these results fit with previous knowledge of the pathogenesis of IgA glomerulo-
nephritis? The demonstration of IgA and C3 fluorescence in a granular pattern strongly sug-
gested mesangial deposition of immune complexes, but our data are against the majority of high
molecular weight IgA being circulating immune complexes, though the changes produced at acid
pH in forms between 13-21 S (that represents around 10% of circulating IgA in the majority of
patients) are compatible with immune complexes. The presence of J chain in and the affinity for
the secretory component of the high molecular weight IgA supports the view that it is polymeric
IgA (Radl et al., 1974).
Why IgA is deposited in the glomerular mesangium of these patients is unknown. Immune
complexes-especially those formed at equivalence-are heavier and less soluble and may
deposit in the mesangium (Germuth & Rodriguez, 1975). The large amount of high polymeric
IgA levels found in the serum of patients with Berger's disease might follow the same route. The
possibility of intermittent existence of immune complexes in which the polymeric IgA is involved
 High polymeric IgA levels in Berger's disease 253
cannot be excluded. The normal serum IgA pattern found in four out of 15 patients studied could
suggest that polymerization may be transient. It is also possible that Berger's disease may include
more than one entity. A similar mesangial immunofluorescent pattern is found in Henoch-
Schonlein syndrome and alcoholic cirrhosis (Berger, Yaneva & Nabarra, 1977). The recent
demonstration by Kater et al. (1979) of IgA deposition in the liver, intestine, skin and kidney of
some patients with alcoholic hepatic disease could suggest that the reticuloendothelial system, by
removing protein aggregates, could be exhausted and the IgA deposits would then remain
persistently.
Several studies have failed to reveal glomerular localization of secretory IgA in Berger's
disease (Dobrin, Knudson & Michael, 1975; Whitworth et al., 1976), though others have
occasionally found it (McCoy, Abramowsky & Tisher, 1974). Preliminary results in our labora-
tory have shown the existence of polymeric IgA, measured by secretory component binding, at the
glomerular mesangium. Further studies will be needed to demonstrate the exact biochemical
relationship between serum and mesangial-deposited IgA as well as the possible pathogenic
connection between Berger's disease and the other IgA nephropathies. Interestingly, we have
observed that serum from patients with Berger's disease suppresses the polymorphonuclear
leucocyte chemotaxis (Egido et al., in preparation), an aspect previously described in polymeric
forms of myeloma IgA (Van Epps & Williams, 1976).
Recently Nomoto, Sakai & Arimori (1979) and Sakai, Nomoto & Arimori (1979) have
shown that patients with IgA nephropathy had a marked increase in IgA-bearing peripheral
blood lymphocytes and a significantly decreased IgA-specific suppressor T cell activity. Further-
more, certain family members of the patients with IgA nephropathy showed an increase in
IgA-bearing lymphocytes. These data and the findings of polymeric IgA in some relatives of these
patients (unpublished observation) suggest that a genetic factor could play a role.
The basic defect in these patients could consist in an abnormal tendency to a high degree of
IgA polymerization. This in relation with upper respiratory tract infections could form a certain
proportion of immune complexes. Polymeric IgA in the immune complexes formed in vitro or in
vivo was a prerequisite for experimental IgA nephropathy (Rifai et al., 1979).
Although many pathogenic aspects remain to be elucidated the existence of the elevated IgA
polymeric levels found in these patients could offer a new therapeutic approach. In this sense, we
are currently treating these patients with phenytoin, a drug that selectively decreases IgA levels
(Seager et al., 1975). The decrease in the high polymeric IgA levels observed after 1 year of
phenytoin treatment seems of particular interest. It is possible that the normalization of
polymeric IgA levels could decrease the load of abnormal IgA presented to the mesangium,
thereby allowing it to eliminate the polymeric IgA. We are presently evaluating whether
serum-induced suppression of polymorphonuclear leucocyte chemotaxis becomes normal after
the decrease of polymeric IgA levels following phenytoin treatment. Even though a complete and
careful clinical study, including iterative renal biopsies, is needed to prove whether this therapy is
valid, the IgA alterations herein described offer a new pathogenic approach to this interesting and
frequent entity.
This work was supported in part by a grant (No. 163-79) from the Instituto Nacional de Salud (Insalud). Dr
L6pez Trascasa and Jaime Sancho are respectively the recipients of a grant from Jimenez Diaz Foundation
and from Conchita RAbago Foundation.

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