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of July 28, 2017.
Comment on ''Spontaneous Autoimmunity
Sufficiently Potent to Induce Diabetes
Mellitus Is Insufficient to Protect against
Insulinoma''
Dan E. H. Andersson and Åke Sjöholm
J Immunol 2009; 183:3559-3560; ;
doi: 10.4049/jimmunol.0990069
http://www.jimmunol.org/content/183/6/3559.2
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References
Letters to the Editor
Comment on “Impaired Priming
and Activation of the Neutrophil
NADPH Oxidase in Patients
with IRAK4 or NEMO
Deficiency”
W
*Laboratory of Human Immunology
Department of Immunology
Institute of Biomedical Sciences
University of São Paulo
São Paulo, São Paulo, Brazil
†
Laboratory of Human Genetics of Infectious Diseases
The Rockefeller University
New York, NY 10065
‡
Laboratoire de Génétique Humaine des Maladies Infectieuses
Faculté de Médicine Necker
Paris, France
§
Department of Pediatrics and Pharmacology
Center for Investigation in Pediatrics
State University of Campinas Medical School
Campinas, São Paulo, Brazil
¶
Department of Pediatric Hematology/Oncology
University of Massachusetts Medical School
Worcester, MA 01655
References
1. Singh, A., K. A. Zarember, D. B. Kuhns, and J. I. Gallin. 2009. Impaired priming and
activation of the neutrophil NADPH oxidase in patients with IRAK4 or NEMO deficiency. J. Immunol. 182: 6410 – 6417.
2. Ghosh, S., M. J. May, and E. B. Kopp. 1988. NF-␬B and Rel proteins: evolutionarily
conserved mediators of immune responses. Annu. Rev. Immunol. 16: 225–260.
3. Moynagh, P. N. 2005. The NF-␬B pathway. J. Cell Sci. 118: 4589 – 4592.
4. Anrather, J., G. Racchumi, and C. Iadecola,. 2006. NF-␬B regulates phagocytic
NADPH oxidase by inducing the expression of gp91phox. J. Biol. Chem. 281:
5657–5667.
5. Condino-Neto, A., C. Whitney, and P. E. Newburger. 1988. Dexamethasone but not
indomethacin inhibits human phagocyte nicotinamide adenine dinucleotide phosphate
oxidase activity by down-regulation expression of genes encoding oxidase components.
J. Immunol. 161: 4960 – 4967.
6. Luengo-Blanco, M., C. Prando, J. Bustamante, W. C. Aragão-Filho, P. V. S. Pereira, J.
Rehder, C. Padden, J.-L. Casanova, P. E. Newburger, and A. Condino-Neto. 2006.
Essential role of nuclear factor-␬B for NADPH oxidase activity in normal and anhidrotic ectodermal dysplasia leucocytes. Blood 112: 1453–1460.
www.jimmunol.org/cgi/doi/10.4049/jimmunol.0990068
Comment on “Spontaneous
Autoimmunity Sufficiently Potent
to Induce Diabetes Mellitus Is
Insufficient to Protect against
Insulinoma”
W
FIGURE 1. Superoxide release by 30 nM PMA-stimulated mononuclear cells. Cells were derived as follows: lane 1, four healthy donors; lane
2, four patients with EDA-ID. Superoxide generation by EDA-ID mononuclear cells was significantly lower compared with cells from healthy
donors (p ⬍ 0.05, n ⫽ 4; Mann-Whitney U test).
e have read with great interest the article by
Zwicker et al. (1). The authors, employing a double
transgenic murine model on a NOD background,
reported that conferment of autoimmunity that is sufficiently
potent to induce diabetes does not prevent the formation of
insulinoma.
We would like to discuss the potential clinical implications of
their findings. To the best of our knowledge, only one case of
insulinoma has hitherto been published in type 1 diabetes (from
our hospital; Ref. 2). This patient, who had insulin-dependent
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e have read with interest the article published by
Singh et al. in the May 4, 2009 issue of The Journal of Immunology (1). NF-␬B is an essential
transcription factor for multiple genes related to the immune
response and development (2, 3). Previous studies by our
group and others also support the concept that NF-␬B activation is essential for NOX2 activity, both in vitro and in
vivo. Anrather et al., using a murine model, observed a lack
of NADPH oxidase activity in leukocytes, fibroblasts, and
neural cells after overexpression of I␬B␣ and in a p65/RelA
knockout (4). Our previous studies with dexamethasone, a
steroid that inhibits NF-␬B function, demonstrated inhibition of the phagocyte NADPH oxidase system at the transcriptional level (CYBB and NCF1 genes) in THP-1 myelomonocytic cells (5). Using U937 cells with a stable
transfected repressor of NF-␬B (I␬B␣-S32A/s36a) and
EBV-transformed B cells from two patients with ectodermal
dysplasia and immunodeficiency (EDA-ID), we found that
proper binding of NF-␬B is necessary for human CYBB and
NCF1 gene expression and normal NADPH oxidase activity
(6). Recently, our group observed that mononuclear cells
from patients with EDA-ID produce less superoxide than
normal control cells (Fig. 1). Taken together, our current
and previous observations (5, 6), and those of Singh et al. (1)
all corroborate the essential role of NF-␬B for proper function of the human phagocyte NADPH oxidase system.
Paolo Ruggero Errante,* Carolina Prando,†
Jacinta Bustamante,‡ Walmir Cutrin Aragão Filho,*
Paulo Vitor Soelio Pereira,* Jussara Rehder,§
Jean Laurent Casanova,† Peter Newburger,¶ and Antônio
Condino Neto*
3560
Dan E. H. Andersson and Åke Sjöholm
Department of Clinical Science and Education
Division of Internal Medicine
Karolinska Institute
Stockholm, Sweden
References
1. Zwicker, K., C. Chatten, K. Gratton, D. Demetrick, P. Serra, A. Shameli, P. Santamaria, and O. F. Bathe. 2009. Spontaneous autoimmunity sufficiently potent to induce
diabetes mellitus is insufficient to protect against insulinoma. J. Immunol. 183:
1705–1714.
2. Svartberg, J., M. Stridsberg, E. Wilander, D. E. Andersson, and B. Eriksson. 1996.
Tumour-induced hypoglycaemia in a patient with insulin-dependent diabetes mellitus.
J. Intern Med. 239: 181–185.
www.jimmunol.org/cgi/doi/10.4049/jimmunol.0990069
Response to Comment on
“Spontaneous Autoimmunity
Sufficiently Potent to Induce
Diabetes Mellitus Is Insufficient to
Protect against Insulinoma”
W
e thank Drs. Andersson and Sjöholm for sharing
their interesting clinical observations, which appear pertinent to our experimental model. Their
account of a case of insulinoma that developed despite autoimmune diabetes mellitus (DM) (1) certainly evokes consideration of potential parallels to our observations.
Drs. Andersson and Sjöholm suggest that the insulinomas in
the two patients they encountered were derived from ␤-islet
cells that survived autoimmunity, perhaps by some alteration in
Ag presentation. In our experimental model, we could not identify any evidence of selection of Ag loss variants or of downregulation of MHC class I expression, even though the immune
response was heavily biased by the TCR transgene to target
islet-specific glucose-6-phosphatase catalytic subunit-related
protein (IGRP). Indeed, the fact that one of the patients de-
scribed had persistently high titers of autoantibodies against
GAD-65 is evidence that there is some degree of immunity
against the insulinoma (which likely still expresses GAD-65)
and that this immune response is rendered ineffective by other
mechanisms. It is possible that, like our model, the immunosuppressive factors may reside in the tumor itself.
The clinical cases described also prompt another question:
what led to the emergence of insulinoma in the first place? Even
in individuals without autoimmune DM, insulinoma is uncommon. We would speculate that the likelihood of developing
insulinoma is considerably reduced following the autoimmune
destruction of a sufficient number of ␤-islet cells to induce DM.
In our RIPTAg model, a tumor developed because of a genetic
proclivity for ␤-islet cell transformation. In humans, a small
proportion of insulinomas are familial, typically associated with
mutations in the multiple endocrine neoplasia-1 (MEN1) gene
(encoding menin) (2). However, from the description, the two
clinical cases appear to be of the more common sporadic type.
MEN1 gene mutations are not seen in sporadic insulinomas
(3). The development of insulinoma in the setting of autoimmune DM is remarkable, and it supports the hypothesis that a
(yet unproven) predisposing genetic event irrevocably transforms ␤-islet cells (2).
Finally, we are led to wonder about the connection of tumor
immunity and autoimmunity itself, which is not as simple as
once thought. Our initial hypothesis was that autoimmunity
would confer protection against tumor, and that did not prove
correct. Indeed, melanoma progresses despite concurrent vitiligo (4); and the chronic inflammation of pernicious anemia is a
risk factor for gastric cancer (5). It is also possible to induce tumor immunity without autoimmunity (6, 7). Tumor immunity and autoimmunity are therefore not necessarily synchronous phenomena. Understanding how tumor immunity and
autoimmunity are uncoupled will represent a significant advance for oncologists and for physicians treating autoimmunity.
Oliver F. Bathe and Christa Chatten
Department of Surgery
University of Calgary
Calgary, Alberta, Canada
References
1. Svartberg, J., M. Stridsberg, E. Wilander, D. E. Andersson, and B. Eriksson. 1996.
Tumour-induced hypoglycaemia in a patient with insulin-dependent diabetes mellitus.
J. Intern. Med. 239: 181–185.
2. Pelengaris, S., and M. Khan. 2001. Oncogenic co-operation in ␤-cell tumorigenesis.
Endocr. Relat. Cancer 8: 307–314.
3. Cupisti, K., W. Hoppner, C. Dotzenrath, D. Simon, I. Berndt, H. D. Roher, and P. E.
Goretzki. 2000. Lack of MEN1 gene mutations in 27 sporadic insulinomas. Eur.
J. Clin. Invest. 30: 325–329.
4. Ram, M., and Y. Shoenfeld. 2007. Harnessing autoimmunity (vitiligo) to treat melanoma: a myth or reality? Ann. NY Acad. Sci. 1110: 410 – 425.
5. Hsing, A. W., L. E. Hansson, J. K. McLaughlin, O. Nyren, W. J. Blot, A. Ekbom, and
J. F. Fraumeni, Jr. 1993. Pernicious anemia and subsequent cancer: a population-based
cohort study. Cancer 71: 745–750.
6. Ramirez-Montagut, T., M. J. Turk, J. D. Wolchok, J. A. Guevara-Patino, and A. N.
Houghton. 2003. Immunity to melanoma: unraveling the relation of tumor immunity
and autoimmunity. Oncogene 22: 3180 –3187.
7. Bowne, W., R. Srinivasan, J. Wolchok, W. Hawkins, N. Blachere, R. Dyall, J. Lewis,
and A. Houghton. 1999. Coupling and uncoupling of tumor immunity and autoimmunity. J. Exp. Med. 190: 1717–1722.
www.jimmunol.org/cgi/doi/10.4049/jimmunol.0990070
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and ketosis-prone type 1 diabetes since the age of 13, developed
a highly malignant, metastatic, and intractable insulinoma at
age 33, i.e., some 20 years after her type 1 diabetes was
diagnosed.
While not directly addressed (although tumor tissue is still
available), there may have been a small subset of ␤ cells, surviving for unknown reasons in the face of long-standing type 1
diabetes, that might have altered their Ag presentation to
thereby escape destruction and then undergo neoplastic transformation into insulinoma cells. Unraveling the mechanisms
underlying this phenomenon may offer unique insights into
therapeutical possibilities by which endogenous or transplanted
␤ cell survival can be improved by genetic immune manipulation in type 1 diabetes.
We also have another relevant case (yet unpublished), a 60year old nondiabetic woman with benign insulinoma and
grossly elevated plasma levels of C peptide, proinsulin, and insulin who also shows persistent high titers of autoantibodies
against GAD-65, the prime ␤ cell Ag in human type 1 diabetes.
LETTERS TO THE EDITOR