Comment; Good summary article, even though it’s 6 years old, this material is widely unknown in
“traditional” medical circles. So many organ systems involved, so many diseases that are poorly understood. Shame!

Theoharis C. Theoharidesa,b,c,*, David E. Cochraned
a Department of Pharmacology and Experimental Therapeutics, Tufts-New England Medical Center, Boston, MA, USA
b Department of Biochemistry, Tufts-New England Medical Center, Boston, MA, USA
c Department of Internal Medicine, Tufts-New England Medical Center, Boston, MA, USA
d Department of Biology, Tufts University, Medford, MA, USA
Received 2 July 2003; received in revised form 15 October 2003; accepted 16 October 2003


Mast cells are not only necessary for allergic reactions, but recent findings indicate that they are also involved in a variety of
neuroinflammatory diseases, especially those worsened by stress. In these cases, mast cells appear to be activated through their Fc receptors
by immunoglobulins other than IgE, as well as by anaphylatoxins, neuropeptides and cytokines to secrete mediators selectively without overt
degranulation. These facts can help us better understand a variety of sterile inflammatory conditions, such as multiple sclerosis (MS),
migraines, inflammatory arthritis, atopic dermatitis, coronary inflammation, interstitial cystitis and irritable bowel syndrome, in which mast
cells are activated without allergic degranulation.
D2003 Elsevier B.V. All rights reserved.

  1. Selective release of mast cell mediators

Mast cells derive from a distinct precursor in the bone
marrow (Rodewald et al., 1996) and mature under local
tissue microenvironmental factors (Galli, 1993). Mast cells
are necessary for the development of allergic reactions,
through crosslinking of their surface receptors for IgE
(FcqRI), leading to degranulation and the release of vaso-
active, pro-inflammatory and nociceptive mediators that
include histamine, cytokines and proteolytic enzymes
(Kobayashi et al., 2000; Galli et al., 2002). The multitude
of mediators that could be secreted has given rise to new
speculations about the possible role of mast cells in immune
responses (Gurish and Austen, 2001), whether it is acquired
immunity (Marone et al., 2002) or in response to bacteria
(Malaviya and Abraham, 2001). As the spectrum of diseases
that may involve mast cells increases, so do the questions
concerning the triggers and the mechanisms through which mast cells may be able to participate in such diverse
conditions without the ‘‘classic’’ degranulation by exocyto-
sis typical of anaphylactic reactions.
A main aspect of mast cell physiology that had been
largely ignored until recently is that mast cells can secrete
mediators without overt degranulation (Theoharides and
Douglas, 1978), through differential or selective release
(Theoharides et al., 1982), this process is probably regulated
by the action of distinct protein kinases on a unique phos-
phoprotein (Theoharides et al., 1980; Sieghart et al., 1978).
Unlike allergic reactions, mast cells are rarely seen to
degranulate during autoimmune (Benoist and Mathis, 2002)
or inflammatory processes (Woolley, 2003); moreover, the
‘‘mast cell stabilizer’’ disodium cromoglycate (cromolyn)
may be ineffective as a therapeutic modality (Okayama et
al., 1992). Instead, mast cells appear to undergo ultrastruc-
tural alterations of their electron dense granular core indi-
cative of secretion, but without overt degranulation, a process
that has been termed ‘‘activation’’ (Dimitriadou et al., 1990;
Dimitriadou et al., 1991; Theoharides et al., 1995a) ‘‘intra-
granular activation’’ (Letourneau et al., 1996) or ‘‘piece-
meal’’ degranulation (Dvorak et al., 1992a,b). Such
‘‘subtle’’ activation may be associated with the ability of
mast cells to release some mediators selectively (Kops et al., 1984, 1990; Van Loveren et al., 1984), as shown for
serotonin (Theoharides et al., 1982), eicosanoids (Benyon
et al., 1989; Levi-Schaffer and Shalit, 1989; van Haaster et
al., 1995) and IL-6 (Leal-Berumen et al., 1994; Marquardt et
al., 1996; Gagari et al., 1997; Hojo et al., 1996). In fact, we
recently showed that interleukin-1 (IL-1) can stimulate
human mast cells to release IL-6 selectively without de-
granulation , through a unique process utilizing 40– 80-nm
vesicles unrelated to the secretory granules (800 –1000 nm)
(Kandere-Grzybowska et al., 2003b).
These findings suggest that mast cells may also be
involved in inflammatory diseases (Theoharides, 1996) that
include multiple sclerosis (MS) (Theoharides, 1990),
migraines (Theoharides, 1983), arthritis (Woolley, 1995),
cardiovascular disease (Constantinides, 1995), interstitial
cystitis of the urinary bladder (Theoharides and Sant,
1994), and irritable bowel syndrome (IBS) (Weston et al.,
1993). In fact, many of these diseases (Table 1) appear to
occur concomitantly, as in interstitial cystitis (Koziol et al.,
1993; Alagiri et al., 1997).

Dr. Raymond Oenbrink