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Finding a valid model for human Wegener's granulomatosisComment on the article by Tomer et al.

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Vol. 39, No. 7, July 1996. pp 1262-1266
0 1996. American College of Rheumatology
Finding a valid model for human Wegener‘s
granulomatosis: comment on the article by
Tomer et a1
To the Editor:
We read with interest the report by Tomer et a1 on the
characterization of mice that were induced to make antineutrophil cytoplasmic antibodies (ANCA) (1). In that report,
mice immunized with human IgG ANCA generated antiidiotypic antibodies as well as anti-antiidiotypic antibodies (murine
ANCA). The murine ANCA reacted with alpha fraction of
human neutrophils containing proteinase-3 (PR3) and induced
activation of the respiratory burst in human neutrophils. An
unspecified number of the ANCA-immunized mice demonstrated nonspecific foci of perivascular mononuclear cell infiltrates in the lungs that were thought to be suggestive of
vasculitis. From these data the authors concluded that their
results suggested a pathogenic role for ANCA in Wegener’s
granulomatosis (WG).
W G is a systemic vasculitis histologically defined by the
presence of necrotizing vasculitis, granulomas, and pauciimmune glomerulonephritis (2,3). Although the immunized
mice demonstrated foci of perivascular mononuclear cell infiltrates in the lungs, they did not have histologic evidence of
vasculitis, giant cells, granulomatous inflammation, or pauciimmune glomerulonephritis. Thus, it appears that these mice
had none of the clinical or histopathologic features of W G
despite the presence of high-titer ANCA. We question the
authors’ conclusions that their findings suggest a pathogenic
role of ANCA in WG. In fact, one might legitimately draw the
opposite conclusion from these studies (i.e., that ANCA does
not play a pathogenic role in WG).
A possible explanation for why these mice with hightiter ANCA did not develop clinical or histopathologic features
of W G is that the ANCA induced by this technique do not
recognize murine PR3. While the authors adequately demonstrated that the induced murine ANCA recognized human
PR3 and activated human neutrophils, they provided no
evidence that these antibodies recognized murine PR3 and
activated the respiratory burst in murine neutrophils. This is a
critical point. If the murine ANCA did not react with murine
PR3 and did not induce activation of murine neutrophils, then
these mice may not be a valid model for human WG.
Many of the results in the current report by Torner et
a1 were published previously by the same group of investigators
(4). In the earlier report, mice immunized with human ANCA
were found to have glomerular IgG deposits suggestive of
immune complex-mediated glomerulonephritis; yet, the authors do not describe this feature in the current article (1). The
hallmark of glomerulonephritis in humans with W G is the
absence of IgG deposits in the affected glomeruli (pauciimmune glomerulonephritis). The finding of glomerular IgG
deposits, if real, may be taken as further evidence that the
disease induced in mice by immunization with human ANCA is
fundamentally different from human W G and other ANCAassociated syndromes.
Carol A. Langford, MD, MHS
Michael C. Sneller, MD
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, MD
1. Tomer Y, Gilburd B, Blank M, Lider 0, Hershkoviz R, Fishman P.
Zigelman R, Meroni P-L, Wiik A, Shoenfeld Y: Characterization of
biologically active antineutrophil cytoplasniic antibodies induced in
mice: pathogenetic role in experimental vasculitis. Arthritis Rheum
38:1375-1381, 1995
2. Lie JT, Members and Consultants of the American College of
Rheumatology Subcommittee on Classification of Vasculitis: Illustrated histopathologic classification criteria for selected vasculitis
syndromes. Arthritis Rheum 33:1074-1087, 1990
3. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS,
Travis WD, Rottem M, Fauci AS: Wegener granulomatosis: an
analysis of 158 patients. Ann Intern Med 116:488-498, 1992
4. Shoenfeld Y, Tomer Y, Blank M: A new experimental model for
Wegener’s granulomatosis. Isr J Med Sci 31:13-16, 1995
To the Editor:
W e appreciate the comments of Drs. Langford and
Sneller regarding our article on the characterization of biologically active ANCA induced in mice. The authors ask
whether, indeed, by active immunization with ANCA (Abl)
and induction of mouse ANCA (Ab3), we induced experimental WG. O n e should keep in mind that, usually, experimental
autoimmune models do not completely mirror their human
counterparts. For example, experimental allergic encephalomyelitis, regarded as the model for multiple sclerosis (MS), is
characterized by a monophasic attack of paralysis in the
susceptible animal, with a complete recovery and resistence to
further induction, while MS in humans is typically expressed
by remissions and exacerbations. The same holds for our
models that are induced by idiotypic dysregulation (1-4). In
contrast to experimental systemic lupus erythematosus and
antiphospholipid syndrome, which have been previously reported by us (2,3), in our 2 reports on the induction of mouse
ANCA (1) and their characterization (current report), we were
cautious enough not to include experimental W G in the titles
because we were aware of the partial homology to the human
Yet, since we were able to demonstrate infiltration of
perivascular lymphocytes in the lungs and Ig deposits in the
kidneys only in mice immunized with ANCA that developed
mouse ANCA, but not in those immunized with irrelevant
control Ig, we raised the possibility of the induction of experimental vasculitis. In addition, in our previous study ( l ) ,
several of the ANCA-immunized mice, but not the controls,
died earlier with sterile lung microabscesses. We believe that
W G is an autoimmune disease with a long incubation period
(following infection); similarly, over a longer study period we
might expect to see a more comparable experimental model of
vasculitis in our mice or even a full clinical picture of WG.
several mediators of inflammation, including sPLA,, play an
important role in RA.
Y . Tomer, MD
Y . Shoenfeld, MD
Sheba Medical Center
W. Pruzanski, MD, FRCPC, FACP
P. Vadas, MD, PhD
The Wellesley Hospital
Toronto, Ontario, Canada
1. Blank M, Tomer Y, Stein N, Kopolovic J, Wiik -4, Meroni P-L,
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Weaver AL, Sebba AI, Appelrouth DJ, Hudson NP, Gordon GV,
Gordon RD, Ludivico CL, Austin MC, Sanders Kh4, Schuette PT,
Moidel RA, Kraska AR, Ting N, Shanahan WR Jr, Loose LD:
Tenidap in rheumatoid arthritis: a 24-week double-blind comparison with hydroxychloroquine-plus-Piroxicam,and Piroxicam
alone. Arthritis Rheum 38:1447-1456, 1995
2. Pruzanski W, Kennedy BP, van den Bosch H, Stefanski E, Wloch
M, Vadas P: Tenidap sodium inhibits secretory non-pancreatic
phospholipase A, synthesis by foetal rat calvarial osteoblasts.
Mediat Inflamm 4:67-70, 1995
3. Vadas P, Browning J, Edelson J, Pruzanski W: Extracellular
phospholipase A, expression and inflammation: the relationship
with associated disease states. J Lipid Mediat Cell Signal 8:l-30,
4. Bomalaski JS, Clark M A Phospholipase A, and arthritis. Arthritis
Rheum 36:190-198, 1993
5. Pruzanski W, Scott K, Smith G, Rajkovic I, Stefanski E, Vadas P:
Enzymatic activity and immunoreactivity of extracellular phospholipase A, in inflammatory synovial fluids. Inflammation 16:451457, 1992
6. Pruzanski W, Koo Seen Lin M, Vadas P Secretory phospholipase
A, in rheumatic diseases. In, Phospholipase A2 in Clinical Inflammation: Molecular Approaches to Pathophysiology. Edited by KB
Glaser, P Vadas. Boca Raton, FL, CRC Press, 1995
7. Vadas P, Pruzanski W, Kim J, Fornasier V: The proinflammatory
effect of intra-articular injection of soluble human and venom
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8. Bomalaski JS, Lawton P, Browning J: Human extracellular recombinant phospholipase A, induces an inflammatory response in
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Inhibition of human group I1 phospholipase A, by C-reactive
protein in vitro. J Lipid Mediat Cell Signal 11:187-200, 1995
10. Pruzanski W, de Beer FC, de Beer MC, Stefanski E, Vadas P:
Serum amyloid A protein enhances the activity of secretory
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Conforti G, Shoenfeld Y : Immunization with anti-neutrophil cytoplasmic antibody (ANCA) induces the production of mouse ANCA
and perivascular lymphocyte infiltration. Clin Exp Immunol 102:
120-130, 1995
2. Mendlovic S, Brocke S , Shoenfeld Y, Ben-Bassat M, Meshorer A,
Bakimer R: Induction of an SLE-like disease in mice by a common
anti-DNA idiotype. Proc Natl Acad Sci U S A 85:2260-2264, 1988
3. Bakimer R, Fishman P, Blank M, Sredni B, Djaldetti M, Shoenfeld
Y : Induction of primary antiphospholipid syndrome in mice by
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Tenidap in rheumatoid arthritis: comment on the
article by Blackburn et a1
To the Editor:
We read with interest the article by Blackburn et al
describing the efficacy of tenidap in the treatment of rheumatoid arthritis (RA) (1). The authors state in the introduction
that the mechanism of action of tenidap is mediated by its
inhibition of cyclooxygenase and the modulation of the release
of several cytokines, such as interleukin-1, tumor necrosis
factor a,and interleukin-6. They found that in tenidap-treated
RA patients, the levels of circulating C-reactive protein (CRP)
and serum amyloid A (SAA), 2 well-known acute-phase reactants, decrease. We would like to suggest that in addition to the
above observations, another mechanism plays an important
role in the antiinflammatory activity of tenidap. We reported
recently that tenidap markedly inhibits the synthesis of proinflammatory type I1 secretory phospholipase A, (sPLA,) (2). It
was found that tenidap inhibits sPLA, expression at the
post-transcriptional level ( 2 ) .
There is compelling evidence that sPLA, plays an
important role in the induction/propagation of the inflammatory process in RA (3,4). Secretory PLA, is highly concentrated in inflammatory synovial fluids (5),and its activity in the
circulation significantly correlates with disease activity in patients with RA (6). In animal experiments, intraarticular
injections of purified (7) or recombinant human (8) sPLA,
induce dose- and time-dependent synovitis, which can be
attenuated by sPLA, inhibitors (7,8). Of interest is the fact that
CRP was found to act as an inhibitor of sPLA, (9), whereas
S A A increased sPLA, activity (10). The fact that tenidap is
effective in the therapy of RA is important not only for the
value of this agent as an addition to the armamentarium of
antiarthritic drugs, but also as a further line of evidence that
To the Editor:
We appreciate the comments of Drs. Pruzanski and
Vadas regarding our recent report. We agree that tenidap is
effective therapy in RA and is an important addition to the
treatment armamentarium for this and perhaps other inflammatory disorders. At this point, the intracellular mechanisms
by which tenidap’s effects are mediated have not been fully
elucidated. Certainly, inhibition of certain cytokines and the
cyclooxygenase pathway have been demonstrated in vivo. As
Drs. Pruzanski and Vadas point out, there may be additional
mechanisms, such as inhibition of sPLA,. Further investigation
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