Background
Malaria is the most serious and widespread parasitic disease in humans, occurring widely throughout the tropical areas of the world. In 2012, 207 million cases of malaria were reported, with 627,000 deaths [
1]. The process of malaria pathogenesis is very complex, mainly involving the effects of cytoadhesion and sequestration of parasitized red blood cells (PRBCs) in the vital organs [
2] and the induction of soluble cytokines [
3,
4]. The major complications of severe
Plasmodium falciparum malaria include cerebral malaria, pulmonary oedema, acute kidney injury, severe anaemia, bleeding, acidosis and hypoglycaemia [
5]. These complications can develop rapidly and progress to death within hours or days [
6].
Mast cells (MCs) are pivotal effector cells in allergic diseases, and play a role in the body’s inflammatory response and immunity. These immune cells are abundant in tissues exposed to the external environment, including the skin [
7,
8]. MCs can be activated by various stimuli including cytokines, chemokines and neuropeptides. The biological effects of MCs depend on the release of preformed and
de novo-synthesized mediators such as histamine, proteases, leukotrienes, and various cytokines [
9]. MCs are best known for immunoglobulin (Ig) E-mediated immediate-type hypersensitivity reactions [
10]. In
P. falciparum infection, the significant elevation of the blood concentrations of IgE, IgE-anti-malarial antibodies and histamine have been associated with disease severity in human [
11] and animal models [
12]. Morphologically, MCs have not been evaluated in malaria. This study aimed to investigate the response of MCs in the skin of patients with
P. falciparum malaria.
Discussion
MCs have been implicated in the inflammatory response and allergic process by releasing various cytokines, associated with IgE-mediated immediate-type hypersensitivity reactions [
9,
15]. This study is the first to investigate the response of MCs in the skin tissues of
P. falciparum malaria-infected patients. MCs were localized mostly in the papillary layer, which correlated with blood vessel density and contributed to an immediate defense against stimuli [
16]. MC degranulation is a characteristic pattern of immunological and morphological changes after activation [
17]. Generally, an increase in degranulated MCs can result in MC activation syndrome (MCAS). The syndrome includes a range of manifestations, involving the skin, gastrointestinal, cardiovascular, respiratory, and neurological system [
18]. In malaria infection, studies have shown that IgE level is associated with malaria severity [
19,
20]. In addition, malaria antigens have been reported to activate macrophages and monocytes to produce various cytokines, such as tumour necrosis factor (TNF)-alpha [
20,
21] and interleukin-1 beta [
22]. These cytokines, which are classified as MC secretagogues, may activate MCs through FcεRI receptors. The increased level of these cytokines is related to malaria severity, and is hypothesized to affect the response of MCs. MCs provide a potential source of TNF during the early phase of infection. In an animal malaria model, a study showed an association between MCs and the elevation of serum TNF, which could contribute to malaria protection [
23]. Increases in the number of MCs, and MC degranulation, have been documented in diseases such as renal amyloidosis [
24], interstitial lung fibrosis [
25], gastrointestinal disease [
26] and myocardial infarction [
27]. The changes correlated with pathological alterations, and are relevant to MC mediators.
Artemisinin derivatives were the drugs of choice used to treat all malaria cases. A previous report has documented that artemisinin can decrease MC degranulation by blocking IgE-induced MC degranulation in an anaphylactic animal model [
16]. However, in this study, the number of MC degranulations remained elevated at seven days post-treatment. Thus, artemisinin may not prevent MC degranulation in malaria
in vivo. Quinine and tetracycline have also been reported to cause MC degranulation [
28]. Mefloquine was recently reported to function as an anti-mast cell agent, inducing apoptosis through a granule-mediated pathway [
29]. The effects of anti-malarial drugs on mast cell degranulation need to be further investigated to determine the physiological action and pathways involved. Moreover, some antibiotics, including penicillins, cephalosporins, sulphonamides, as well as some antiepileptic drugs can cause MC degranulation by acting through IgE receptors on MCs, triggering degranulation [
28].
Changes in the number of MCs have been reported in wound healing [
30], keloid formation [
31], chronic inflammation [
32], parasitic infestation [
33], urticaria, atopic eczema, lichen planus, psoriasis, pretibial myxedema, scleroderma, neural tumour and mycosis fungoides [
17]. The factors involved in the increased number of MCs in such conditions remain unclear [
34]. In addition, percentage MC degranulation correlated positively with initial parasite count (
r
s
= 0.66,
p <0.0001), indicating that MCs are activated in severe
P. falciparum malaria. Normally, MCs can undergo repeated rounds of degranulation and regranulation [
35-
38]. An
in vitro human lung MC culture showed late recovery (18–48 hr) from IgE-induced MC degranulation [
39]. In addition, mouse MCs recovered from degranulation at 30 min after activation [
40]. However, another study reported MCs regenerated from horseradish peroxidase induced MC degranulation after six weeks [
41]. At day 7 post-treatment, MC degranulation of uncomplicated (day 0 = 31.35% ± 3.29, day 7 = 23.93% ± 1.07,
p = 0.091) and complicated
P. falciparum (day 0 = 43.72% ± 1.44, day 7 = 40.32 ± 1.81%,
p = 0.349) remained elevated. The process of MC regranulation at day 7 was not observed in the study, indicating that MC regranulation in the skin of
P. falciparum is a delayed response (over seven days).
Parenchymatous changes, including RBC extravasation, perivascular oedema and leukocytic infiltration were significantly increased in the malaria groups. It can be speculated that RBC extravasation and perivascular oedema are secondary to endothelial cell damage, following cyto-adhesion and sequestration of PRBCs, and the local effects of MC cytoplasmic granules, such as TNF, histamine, heparin, and proteases [
42]. In addition, histamine, the major MC mediator in malaria, causes increased vascular permeability and subsequent extensive vascular damage to endothelial cells [
43]. Inflammatory reactions can also be related to immune responses during malaria infection.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
PW carried out the histopathology work and preliminary data analysis. RN wrote and analyzed the first draft of the manuscript. PV conceptualized the research idea, supervised, and revised the final manuscript. All authors read and approved the final manuscript.