Induction of IgA against Haemophilus parainfluenzae Antigens in
Tonsillar Mononuclear Cells from Patients with IgA Nephropathy
Shigeharu Fujieda,*
,1
Satoru Suzuki,† Hiroshi Sunaga,* Hideyuki Yamamoto,*
Mizue Seki,* Hidehiro Sugimoto,† and Hitoshi Saito*
*Department of Otorhinolaryngology and †Department of Clinical and Laboratory Science,
Fukui Medical University, Matsuoka, Yoshida, Fukui 910-1193, Japan
Much evidence suggests that IgA production in vivo
and in vitro is enhanced in patients with IgA nephrop-
athy (IgAN). We have demonstrated glomerular depo-
sition of the outer membranes of Haemophilus para-
influenzae (HP) antigens (OMHP) and the presence of
HP-specific IgA in the serum of patients with IgAN. In
this study, we investigated the production of IgA and
several cytokines by tonsillar mononuclear cells
(TMC) from IgAN patients induced by stimulation
with OMHP. The spontaneous production of total IgA
and TGF-

by TMC from IgAN patients was higher
than that by TMC from patients with chronic tonsilli-
tis (CT) (P < 0.05). Stimulation with OMHP in vitro
enhanced the production of HP-specific IgA by TMC
from IgAN patients (P < 0.01), but not by TMC from CT
patients. OMHP stimulation also enhanced the pro-
duction of TGF-

and IL-10 byTMC from IgAN patients
(P < 0.001). These results suggest that the infection of
HP in the tonsil may be involved in the etiology of
IgAN.
© 2000 Academic Press
Key Words: IgA nephropathy; IgA; Haemophilus
parainfluenzae; TGF-

; IL-10.
INTRODUCTION
Immunoglobulin A (IgA)
2
is the predominant immu-
noglobulin effector molecule of mucosal immunity and
functions as the first line of specific immunologic de-
fense against many viral and microbial pathogens (1).
However, a common glomerular disease, IgA nephrop-
athy (IgAN), is characterized by the presence of IgA
deposits, predominately in the glomerular mesangium,
and by mesangial proliferative glomerulonephritis (2,
3). The deposited IgA is likely to consist of antibodies
against viruses (4–7), food (8, 9), or bacteria (10–13),
but the pathogenesis remains unclear.
We have hypothesized that Haemophilus parainflu-
enzae (HP) in the tonsil and the pharynx plays an
important role in the production of IgA in patients with
IgAN (11–13). We believe this is true because (1) HP is
detected at higher levels in the pharynx of patients
with IgAN than in those with other renal diseases, (2)
glomerular deposition of the outer membranes of HP
antigens (OMHP) is observed, and (3) the serum con-
centration of IgA against OMHP in patients with IgAN
is higher than that in patients with other diseases
(11–13). In addition, the acute onset of IgAN is associ-
ated with a mucosal infection such as tonsillitis or
pharyngitis (14).
The tonsils are lymphoepithelial structures that pro-
vide a protective immunological ring at the openings of
both the digestive and respiratory tracts. The functions
of the tonsils are closely connected not only to funda-
mental immunological processes but also to the patho-
genesis of a wide variety of diseases (15). Tonsillectomy
has been reported to be an efficient therapeutic method
for IgAN (16, 17). Tonsillectomy combined with ste-
roids, cyclophosphamide, anti-platelet drugs, and war-
farin was found to result in reduced proteinuria and
improved renal functions in patients with IgAN during
a 5-year follow-up period compared to treatment with
steroids, cyclophosphamide, anti-platelet drugs, and
warfarin (16). In IgAN patients with tonsillectomy,
hematuria, proteinuria and serum IgA were decreased
after the tonsillectomy (17).
In this study, we performed tonsillectomy in patients
with IgAN for the treatment of IgAN and investigated
three points: (1) whether tonsillar mononuclear cells
(TMC) produce IgA against HP antigens, (2) whether
HP-specific IgA production is enhanced by in vitro
stimulation with HP antigens, and (3) whether TMC
produce IgA-related cytokines (TGF-

, IL-6, IL-10) in
response to in vitro stimulation with HP antigens.
1
To whom correspondence and reprint requests should be ad
-
dressed at Department of Otorhinolaryngology, Fukui Medical Uni-
versity, Shimoaizuki, Matsuoka, Yoshida, Fukui, 910-1193, Japan.
Fax: 81 (Japan)-776-61-8118. E-mail: sfujieda@fmsrsa.fukui-
med.ac.jp.
2
Abbreviations used: IgAN, IgA nephropathy; HP, Haemophilus
parainfluenzae; OMHP, outer membranes of HP; PA, Pseudomonas
aeruginosa; OMPA, outer membranes of Pseudomonas aeruginosa;
TMC, tonsillar mononuclear cells; CT, chronic tonsillitis; PBMC,
peripheral blood mononuclear cells; Ig, immunoglobulin.
Clinical Immunology
Vol. 95, No. 3, June, pp. 235–243, 2000
doi:10.1006/clim.2000.4864, available online at http://www.idealibrary.com on
1521-6616/00 $35.00
Copyright © 2000 by Academic Press
All rights of reproduction in any form reserved.
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