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T cell help and antiphospholipid antibody immunogenesis.

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at present, the number is higher, considering the increasing use
of this drug in RA and other arthritides. We also agree with the
prophylactic use of folic acid in MTX-treated patients, although its effectiveness in preventing serious hematologic
adverse events remains to be determined.
The data presented by all the authors are quite clear
and underscore the need for greater awareness of the risk of
severe hematologic side effects, including death, in rheumatic
disease patients treated with low-dose oral weekly MTX.
Luis R. Espinoza, MD
Sergio Gutierrez-Urefia, MD
JosC F. Molina, MD
Cesar 0. Garcia, MD
Marta L. CuCllar, MD
Louisiana State University
New Orleans, L A
1. Gutierrez-Ureila S, Espinoza LR: Methotrexate: the agent of
choice for chronic inflammatory disorders: a perspective ten years
later. Clin Exp Rheumatol 13:281-284, 1995
2. Feagan BG, Rochon J, Fedorak RN, Irvine EJ, Wild G, Sutherland
L, Steinhart AH, Greenberg GR, Gillies R: Methotrexate for the
treatment of Crohn’s disease. N Engl J Med 332:292-297, 199.5
3. Dumitrescu CR, Brandao L, Natour J: Monitoring methotrexate in
rheumatoid arthritis: current concepts and literature review. Braz J
Rheumatol 36:37-41, 1996
4. Berthelot JM, Maugars Y, Hamidou M, Chiffoleau A, Barrier J,
Grolleau JY, Prost A: Pancytopenia and severe cytopenia induced
by low-dose methotrexate: eight reports and a review of one
hundred cases from the literature (with twenty-four deaths). Rev
Rhum Engl Ed 62:477-486, 1995
5. Urbina-Joiro H, Cardiel MH, Alarcon-Segovia D, Kraus A: Factors
associated with severe cytopenias in rheumatoid arthritis. A casecontrol study (abstract). Arthritis Rheum 38 (suppl 9):S289, 199.5
6. Myllykangas-Luosujari R, Aho K, Isomaki H: Death attributed to
antirheumatic medication in a nationwide series of 1,666 patients
with rheumatoid arthritis who have died. J Rheumatol 22:22142217. 199.5
T cell help and antiphospholipid antibody
To the Editor:
Blank et a1 (1) recently reported the results of an
experiment in which they demonstrated the ability to transfer
antiphospholipid antibody (aPL) syndrome (APS) by bone
marrow transplantation in a BALB/c mice model. Of note,
however, Blank et a1 found that T cell-depleted bone marrow
(TDBM) failed to transfer the disease, indicating an essential
role for T cell help in the production of pathogenic aPL by B
In contrast, a similar study by Mizutani and coworkers,
which was not referred to by Blank et al, found that TDBM
transplants could induce autoimmuflity (2). The animal model
used by Mizutani et al involved (W/B)F, mice that develop
lupus-like syndromes with an unusually high incidence of
coronary vascular disease (CVD) (2). When the TDBM of the
(W/B)Fl mice was transplanted into autoimmune-resistant
B6C3Fl mice, lupus was induced in 60% of the recipient mice,
and 33% of these mice developed CVD. In addition, the
B6C3F, recipients that developed CVD had a significantly
higher titer of aPL. Thus, in this murine model of lupus,
genetic abnormalities in the hematopoietic B stem cells contributed to the synthesis of autoantibodies, including aPL, and
presumably, the latter activated prothrombotic mechanisms
that led to the development of CVD.
This variability in the dependence of T cell help for
aPL generation may be related to the different mouse models
employed by the 2 laboratories. Blank et al’s system involved
an experimentally induced APS in BALB/c mice by immunization with human monoclonal antibodies reactive against the
phospholipid cardiolipin or a pathogenic anti-DNA idiotype
(l),whereas Mizutani et al’s model involved genetically crossbred mice that spontaneously develop the disease.
An alternative explanation may yet highlight another
example of the heterogeneity of aPL, in this case, the division
of different subpopulations of aPL on the basis of the antibody’s pathogenicity and immunogenesis. The rationale for
this suggestion is derived from the fact that one main clinical
featurc of Blank et al’s mice was a high frequency of fetal
resorption, whereas, as stated, CVD was predominant in
Mizutani et al’s animals. We therefore believe that the inducing antigen may have been different in these models and,
thus, the production of antibody against the corresponding
target antigen may have been either T cell dependent or
Certainly, a population of T cell-independent aPL can
be produced. Recently, we detected IgG aPL in athymic nude
mice, and the specific aPL was inhibited using cardiolipin in
enzyme-linked immunosorbent assay (ELISA) (3). Control
sera from SCID mice were nonreactive. In normal human sera,
we have been interested in a subpopulation of naturally
occurring aPL, which are masked by heat-sensitive serum
coinhibitors, and which require a simple heat treatment to
releasc detectable aPL by ELISA (4). Interestingly, this natural
cryptic IgG aPL is predominantly IgG, (S), a subclass that is
produced largely independent of T cell help (6) and, thus, the
antibody synthesis may solely involve B cell activation.
It is increasingly being recognized that natural aPL
could have an important immunophysiologic role in the pathogenesis of A P S (4). As such, the finer definition of T cell help
in aPL immunogenesis will be useful, since the information
may enable specific immunotherapeutic intervention to modulate autoimmune disease activity.
Hwee-Ming Cheng, MD
Kuala Lurnpur, Malaysia
Christine Hu, MPhil
National University of Singapore
1. Blank M, Krause I, Lanir N, Vardi P, Gilburd B, Tincani A, Tomer
Y , Shoenfeld Y: Transfer of experimental antiphospholipid syndrome by bone marrow cell transplantation: the importance of the
T cell. Arthritis Rheum 38:11.5-122, 199.5
2. Mizutdni H, Engelman RW, Kinjoh K, Kurata Y, Ikehara S, Good
RA: Prevention and induction of occlusive coronary vascular disease in autoimmune (W/B)F, mice by haploidentical bone marrow
transplantation: possible role for anticdrdiolipin autoantibodies.
Blood 82:3091-3097, 1993
3. Cheng HM, Hu C: Presence of antiphospholipid autoantibody in
nudc mice. J Rheumatol 22:2006-2007, 1995
4. Cheng HM: Cryptic antiphospholipid autoantibodies and serum
coinhibitors. Autoimmunity 19:127-133, 1994
5. Cheng HM, Sam C K Bacterial immunity and immunogenesis of
normal salivary IgA and serum IgG, antiphospholipid autoantibody-a link? Immunol Lett 26:7-10, 1990
6. Papadea C, Check IJ: Human IgG and IgG subclasses. Crit Rev
Clin Lab Sci 27:27-58. 1989
To the Editor:
We thank Dr. Cheng for his valuable comments related
to our bone marrow transplantation model of A P S (1). Indeed,
we missed the article by Mizutani et a1 (1). Dr. Cheng is right
indicating that the APS in (B/W)F, mice is a basically genetically determined model, while our model is induced following
active immunization (2). Therefore, a T cell activation must be
involved in this process. Indeed, we (3) and others (4)have
previously shown the transfer of this specific model via T
cell lines (specific for the idiotype), while suppressing its
induction with specific T suppressor cells (5) and anti-CD4
antibodies (6).
We also believe that in humans, some autoimmune
diseases may emerge after infection following endogenous
idiotypic stimulation, with the pathogenic idiotype being harbored on some of the antibacterial antibodies (7-9). In subjects
prone to autoimmunity (due, for example, to genetic background, hormonal suitability, or immunologic deficiencies),
the idiotypic cascade will progress into antibody 3 (anti-antiid), thus simulating antibody 1 in its (auto)antigen binding
characteristics (10,ll).
We also agree that natural antibodies may be pathogenic, as we have shown with both anti-DNA (12) as well as
with anti-cardiolipin antibodies (13). Thus, it is conceivable
that multiple mechanisms may be involved in the pathogenesis
of APS.
Yehuda Shoenfeld, MD
Chaim Sheba Medical Center
Tel-Hashomer, Israel
1. Mizutani H, Engelman RW, Kinjoh K, Kurata Y, Ikehara S, Good
RA: Prevention and induction of occlusive coronary vascular
disease in autoimmune (W/B)F, mice by haploidentical bone
marrow transplantation: possible role for anticardiolipin autoantibodies. Blood 82:3091-3097, 1993
2. Bakimer R, Fishman P, Blank M, Sredni B, Djaldetti M, Shoenfeld
Y: Induction of primary antiphospholipid syndrome in mice by
immunization with a human monoclonal anti-cardiolipin antibody
(H-3). J Clin Invest 89:1558-1663, 1992
3. Blank M, Mendlovic S, Mozes E, Coates ARM, Shoenfeld Y:
Induction of SLE in naive mice with T cell lines specific for human
anti-DNA antibody SA-1 (1616 Idt) and for mouse tuberculous
antibody (TB168) antibody (1616 Id+). Clin Immunol Immunopathol 60:471-483, 1991
4. Fricke H, Mendlovic S, Blank M, Shoenfeld Y, Ben-bassat M,
Mozes E: Idiotype specific T cell lines inducing experimental SLE
in mice. Immunology 73:421-427, 1991
5. Blank M, Ben-Bassat M, Shoenfeld Y: Modulation of SLE induction in naive mice by specific T cells with suppressor activity to
pathogenic anti-DNA antibody idiotype. Cell Immunol 137:474486, 1991
6. Tomer Y, Blank M, Shoenfeld Y: Suppression of experimental
antiphospholipid syndrome and systemic lupus erythematosus in
mice by anti-CD4 monoclonal antibodies. Arthritis Rheum 37:
1236-1244, 1994
Shoenfeld Y: Idiotypic induction of autoimmunity: a new aspect of
the idiotypic network. FASEB J 8:1296-1301, 1994
Shoenfeld Y: Idiotypic induction of autoimmunity: do we need an
autoantigen? Clin Exp Rheumatol 12 (suppl ll):S37-S40, 1994
Shoenfeld Y: Anti-DNA antibodies: is DNA a self antigen or shelf
antigen or are autoimmune rheumatic diseases immunogen
driven? Rheumatol Europe 24 (suppl 2):17-20, 1995
Shoenfeld Y: Idiotypic network, pathogenic autoantibodies and
autoimmunity. Clin Exp Immunol 101 (suppl):26-28, 1995
George J, Shoenfeld Y: Infections, idiotypes and SLE. Lupus
4:333-335, 1995
Mendlovic S, Brocke S, Shoenfeld Y, Ben-Bassat M, Meshorer A,
Bakimer R, Mozes E: Induction of a SLE-like disease in mice by
a common anti-DNA idiotype. Proc Natl Acad Sci U S A
85:2260-2264, 1988
Cohen J, Bakimer R, Blank M, Valesini G, Shoenfeld Y: Pathogenic natural anti-cardiolipin antibodies: the experience from
monoclonal gammopathy. Clin Exp Immunol97:181-186, 1994
Recall of brand-name gold sodium thiomalate: are
generics reliable?
To the Editor:
I recently received a letter from Merck & Co. noting
that they would no longer manufacture gold sodium thiomalate
(Myochrysine). Previously, they had instituted a recall of this
product when it was feared that it might not conform to
“criteria for antimicrobial effectiveness.” Because they would
“be required to assure conformance to the compendia1 specifications,” they stated that they would have to remove the
product from the market for “an extended period” and therefore were instead ceasing production entirely. They noted the
“availability of other therapies” but did not mention that
Myochrysine has been available elsewhere as a generic product. The other injectable gold product, Solganal, remains
available only from Schering.
If I had told my Merck representative a year ago that
I might get a generic form of Myochrysine, he would have told
me of the superiority of branded products and the necessity of
using brands because of the reliability and concern of researchoriented companies like Merck. Physicians who are convinced
of the superiority of branded products (generic gold sodium
thiomalate was not recalled) might consider whether there are
any lessons to be learned from Mercks behavior.
Lonnie B. Hanauer, MD, FACP
Millbum, NJ
To the Editor:
Merck‘s decision to discontinue manufacturing Myochrysine (gold sodium thiomalate) was made reluctantly, and
only after we determined that a variety of effective therapies
remained available to patients with rheumatoid arthritis.
Merck discontinued Myochrysine after determining
that new U S , Pharmacopeia standards related to the preservative content would require extensive, time-consuming, and
costly modifications to our manufacturing process. The development and regulatory approval time needed to make these
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antibody, antiphospholipid, immunogenesis, help, cells
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