1260?The?Journal?of?Clinical?Investigation http://www.jci.org Volume 121 Number 4 April 2011
or nitrite can increase plasma cGMP and
reduce blood pressure (15, 17, 18). However,
like any potential therapy, there are poten-
tial adverse effects (15, 18). Dietary supple-
mentation of nitrites can cause methemo-
globinemia and interfere with oxygenation
of the blood. Furthermore, dietary nitrite
and nitrate can contribute to the formation
of potentially carcinogenic nitrosamines,
although the epidemiological association of
dietary nitrogen oxides with cancer has been
questioned (19). Accordingly, until there is
more guidance from larger, randomized
clinical trials, direct supplementation of the
diet with nitrite or nitrate salts seems inad-
visable. Adherents of the hypothesis may
be served best by generous helpings of leafy
The authors thank Jonathan Stamler for
comments on this work. This work was
supported in part by grants from the NIH
(RC2HL103400, 1U01HL100397, and K12
HL087746) and by the Tobacco-Related
Disease Research Program of the Univer-
sity of California (18XT-0098).
Address correspondence to: John P. Cooke,
Stanford Cardiovascular Institute, 300 Pas-
teur Drive, A260 MC 5319, Stanford, Cali-
fornia 94305, USA. Phone: 650.723.6459;
Fax: 650.723.8392; E-mail: john.cooke@
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Neutrophils give us a shock
Clifford A. Lowell
Department of Laboratory Medicine, UCSF, San Francisco, California, USA.
I turned to Wikipedia when I was search-
ing for a way to explain the basics of ana-
phylaxis and came across the following
statement: “True anaphylaxis is caused by
degranulation of mast cells or basophils
mediated by immunoglobulin E (IgE).”
This is the classic teaching, present in all
the immunology textbooks, but the paper
in this issue of the JCI by Jönsson et al.
(1) informs us that this view is, at best,
incomplete. Instead, we learn that ana-
phylaxis can be mediated by neutrophils
recognizing IgG/antigen complexes. In
addition to turning around our under-
standing of anaphylaxis, this paper adds
to the growing list of neutrophil func-
tions besides just bacterial killing and
protease production (2). Lately we have
learned that neutrophils are major sourc-
es of cytokines and chemokines (3, 4).
They play a direct role in influencing the
recruitment and activation of monocytes/
macrophages, T cells, and NK cells dur-
ing inflammation (5–7). Neutrophils have
been implicated as the primary initiators
of immune complex–mediated diseases
(8, 9). And now the shocking news (pun
intended!) that they are major players in
The history of anaphylaxis
Anaphylaxis is an acute, multisystem,
severe type I hypersensitivity reaction
that develops in minutes to hours follow-
ing antigen exposure (10). In its mildest
forms, it results in rashes (hives), wheez-
ing, and some gastrointestinal symptoms
(cramping, bloating). In its more severe
forms, patients develop bronchoconstric-
tion with hypoventilation, systemic vaso-
dilation (leading to frank shock), cardiac
dysrhythmias, and central nervous system
abnormalities. Anaphylaxis most often
Conflict?of?interest: The author has declared that no
conflict of interest exists.
Citation?for?this?article: J Clin Invest. 2011;