2379-6367 PPIJ

Pharmacy & Pharmacology International Journal
Volume 6 Issue 2 - 2018
Antibodies, prophylaxis, transmission
Pierre Lutgen*
IFBV-BELHERB, Luxembourg
Received: January 08, 2018 | Published: February 08, 2018
*Corresponding author: Pierre Lutgen, IFBV-BELHERB, BP 98 L-6905, Niederanven, Luxembourg; Email:
Citation: Lutgen P (2018) Antibodies, prophylaxis, transmission. Pharm Pharmacol Int J 6(2): 00155. DOI: 10.15406/ppij.2018.06.00155


Elevated levels of immunoglobulin IgE are found in many infections and allergies. IgE is increased in the majority of individuals living in areas of high malaria endemicity. Sotiriades, in 1917, reported clinical improvement in the condition of a patient with acute malaria following the inoculation of 10 ml of serum obtained from a “chronic” case. Kauders confirmed this finding by observing that beneficial effects resulted in 9 of 12 patients who received small quantities of serum from a person difficult to infect with malaria. Plasmodium can give rise to IgE in the absence of other pathogens, such as helminths or other intestinal protozoan parasites, which also are known to induce IgE elevation. IgE in association with monocytes or platelets may trigger reactions that are protective and/or pathogenic. Most children and adults living in areas where the endemicity of Plasmodium falciparum malaria is high, have significantly elevated levels of both total IgE antibodies and specific antimalarial IgE bodies in blood. IgE containing immune complexes are known to give rise to monocyte activation via the NO (Nitrous oxide) transduction pathway. A recent study in Nigeria shows that the malaria infection specifically raises IgE, but that IgG and IgM remain virtually stable. There is a strong positive correlation between IgE and parasite density. IgE rises almost exponentially with the severity of the disease [1-9].

An interesting piece of work on this topic comes from Egypt. This study investigated the effect of breast-feeding in protection against protozoan infection in infants with persistent diarrhea. There was a significant positive correlation between the infection intensity and the serum levels of IgE. The levels of IgE and TNF-α were significantly lower in the breast-fed group than in the non-breast-fed group. The percentage of protozoan infections was significantly lower in breast-fed infants [10]. IgE elevations are the expression of CD4+ cells and we have been able to demonstrate that these are increased by the administration of Artemisia annua and Artemisia afra. CD4+ cells are already induced in the pre-erythrocytic stages of malaria. This leads to a wide range of antibodies including some specific against the circumsporozoite protein (CSP) [11,12]. The elevation of specific Plasmodium falciparum antibodies is age dependent. The prolonged and repeated exposure to malaria parasites is necessary for the induction of these specific antibodies and there is a significant correlation between their level and the number of malaria attacks [13]. The ability to resist Plasmodium falciparum malaria is an important adaptive trait of human populations living in endemic areas. The detection of significant differences in the expression of this trait and the identification of the factors involved should improve the understanding of the host-parasite relationship and might lead to advances in control strategies. In a study in Tanzania it was clearly demonstrated that high anti-Plasmodium falciparum IgE levels were associated with reduced acute risk of acute malaria in all age groups, independently of the total IgE level. High levels of IgG either weren’t associated with a reduced risk to succumb to a new clinical episode [14].

Reactions to mosquito bites, being immunological in nature, lead to swelling, wheal and flare of the skin. They are due to the mosquito salivary proteins. Mosquito saliva contains many biological materials, anticlotting and antiplatelet factors and vasodilators which presumably increase the speed at which blood from the host is imbibed. But also immunomodulators, allergens which bind to IgE and induce histamine release. Sporozoites express α-gal (galactose-alpha-1,3-galactose), and the bite of mosquitoes like the bite of ticks may lead to an overload with immunoglobulin E antibodies. The molecule α-gal is also present on Trypanosoma and Leishmania parasites [15,16]. Allergens are present in the saliva of most of the mosquitoes, even those which are not infected. A study has shown in a murine model that bites from uninfected mosquitoes prior to Plasmodium yoelii infection influences the local and systemic immune responses and limits parasite development within the host. The difference in liver parasite burdens becomes evident at 20 hours post infection. Another strange way to achieve vaccination! Although the mechanism has yet to be completely elucidated, a similar phenomenon has been noticed: repeated infestation with Ixodes scapularis ticks induces resistance to Borrelia burgdorferi transmission. And multiple exposure to bites from uninfected sand flies prior to infection confer resistance to Leishmania major [17,18]. Repeated exposure to malarial infection could potentially lead to a broadening of antibody specificity. It leads to the boosting of antibodies that are shared by the various parasite strains [19].

In endemic areas specific antibodies develop not only against the blood stages parasites but also specific against sporozoites and the circumsporozoite protein (CSP). Results show that a single sporozoite inoculation does not induce antibodies, but that a single inoculation repeated every year would after 10 to 15 years at least induce detectable but low levels of sporozoite-specific antibodies. Conversely, multiple inoculations per year induce a strong humoral immune response within 2 years [20]. Immunoglobulins are associated with protection against malaria inoculation, by activating monocytes. The role of monocytes in malaria prophylaxis was first proposed by a research team from Uganda. Monocytes have a limited life span. In the absence of appropriate stimuli, they undergo apoptosis, but under the influence of survival signals, these cells differentiate into macrophages or dendritic cells. It has been shown that ligation of IgE on human monocytes markedly reduces the apoptosis. A cooperative, synergistic effect between immunoglobulins and monocytes was demonstrated. The addition of monocytes from healthy individuals to Plasmodium falciparum cultures in the presence of serum from immune individuals markedly inhibits the proliferation of the parasite in vitro. The activity of monocytes alone and immunoglobulins alone was moderate and inconsistent [21,22]. Immunoglobulins protect efficiently by targeting α-gal on sporozoites immediately after inoculation by Anopheles mosquitoes; but not against the disease once the erythrocytic stage of malaria is established. IgE also interferes with the 14-3-3 ε protein during the invasion of hepatocytes by sporozoites. Antibodies are capable of blocking infection of the liver by Plasmodium falciparum. They could block infection at the pre-erythrocytic stage in several ways, either by neutralizing sporozoites directly, opsonizing sporozoites for phagocytosis or blocking invasion of sporozoites into hepatozoites [23-27].

In a mice model it was shown that prior exposure to saliva had no detectable effect on the rate of migration of the sporozoites away from the skin. The applicability of these results to humans remains to be confirmed as mice do not exhibit the typical wheal and flare reaction characteristic of humans [28]. The inhibition of sporozoites cell traversal activity seems to be an import element. The immunoglobulin 3D11 for example neutralizes 90% of the sporozoite infectivity by interacting with CSP. Circumsporozoite protein is the antigenic target of RTS, S and of other pre-erythrocytic malaria vaccines currently undergoing clinical trials [29,30]. A similar protection mechanism by IgE has been documented for leishmaniasis. IgE antibodies bind strongly to promastigotes [31]. It happens that Artemisia infusions are less efficient for non-immune Caucasians. It is probably not related to genetic strains, but to the absence of acquired immunity. In sub-Saharan Africa most people are almost continuously infected by Plasmodium falciparum parasites, and the majority of infected adults rarely experience overt disease. In naïve individuals Plasmodium falciparum infection is almost always symptomatic and clinical symptoms can be observed at very low parasitemia levels [32]. A study involving several African ethnic groups, some of Caucasian ascent, others of the negroid type, was unable to detect genetic factors able to explain the significant differences in immune response [33]. But in an Indian study no circulating free antibodies were detected in some individuals. The significance of this trait present in some individuals deserves to be studied in depth [34,35]. The total IgE level in a population is strongly related to the malaria endemicity in that area. In a study from the Uppsala University in Sweden it was found that the total level of IgE in the Swedish population was much lower at 8ng/ml than for adult donors from Liberia (2123 ng/ml), Madagascar (301ng/ml) and Thailand (647ng/ml), areas where malaria transmission and endemicity is high. None of the donors had malaria when blood was taken.

IgE titers are negatively correlated with gametocyte carriage and this may be an important factor in a area of high endemicity [36,37]. During stage II to V gametocytes hide in the bone marrow for their development. IgE is well present in the bone marrow; it is even generated there in case of stress (anemia, drugs, parasites, bacteria…). Also mast cells originate from a bone marrow progenitor and subsequently develop different phenotype characteristics locally in tissues. Mast cells play an important protective role, are involved in wound healing, immune tolerance, defense against pathogens and blood-brain barrier functions. These cells are known to accumulate at sites of inflammation in response to parasite and bacterial infections. There they degranulate and set free histamines, IgE and TNF-alpha. Degranulation is proportional to parasitemia, increasing from virtually 0 to 40% in the case of complicated malaria. It is difficult to understand why gametocytes hide in the bone marrow for their development. Mast cells express a high affinity for IgE. Often mast cells are coated with IgE [38-42]. Artesunate is antagonistic with the formation of IgE and its mechanisms of action against parasites [43,44]. Worse even, a 5-fold increase in gametocytogenesis in Plasmodium falciparum has been documented for chloroquine in vitro [45].

It is shocking to read in a recent paper that while chloroquine may significantly reduce mortality, but whether it will interfere with the host immune system is currently unknown. And the authors demonstrate in a mice model that a single dose of chloroquine soon after malaria infection significantly suppresses both the cellular and humoral immunity of the host. The authors conclude that chloroquine only is efficient in the well established erythrocytic stage by inhibiting hemozoin formation, but, if used in prophylaxis, may have dramatic impacts on the immune system and malaria prevalence [46]. This is not surprising as chloroquine reduces CD4+ activation [47]. Is it criminal negligence not to have studied in the European Institutes of Tropical Medicine and elsewhere the impact of this inhibition of the immune system might have on prophylaxis and transmission and to have alerted the African communities against these risks. Chloroquine is still massively sold in Africa and the second most preferred medicine after ACTs (Artemisinin Combined Therapies).



Conflict of Interest



  1. Sotiriades D (1917) Serotherapy tests in malaria. Greece Med 19: 27-28.
  2. Kauders O, Dattner B (1924) Clinical and experimental studies on therapeutic vaccine malaria. Jb Psych Neurol 43: 40525.
  3. McGregor IA (1964) The Passive Transfer of Human Malarial Immunity. Am J Trop Med Hyg 13: 237-239.
  4. Perlmann P, Perlmann H, Looareesuwan S, Krudsood S, Aikawa M, et al. (2000) Contrasting functions of IgG and IgE antimalarial antibodies in uncomplicated and severe Plasmodium falciparum malaria. Am J Trop Med Hyg 62(3): 373-377.
  5. Mgbeoma E, Serekara C (2016) Immunoglobulin levels in Plasmodium falciparum malaria infected subjects in Port Harcourt, Nigeria. Int J Adv Multidiscip Res 3(5): 49-55.
  6. Johansson SG, Mellbin T, Vahlquist B (1968) Immunological levels in Ethiopian preschool children with special reference to high concentrations of IgE. Lancet 1(7552): 1118-1121.
  7. Seka SJ, Brouth Y, Yapo Crezoit AC, Atseye NH (2004) The role of serum immunoglobulin E in the pathogenesis of Plasmodium falciparum malaria in Ivorian children. Scand J Immunol 59(2): 228-230.
  8. Calissano C, Modiano D, Sirima BS, Konate A, Sanou I, et al. (2003) IgE antibodies to Plasmodium falciparum and severity of malaria in children of one ethnic group living in Burkina Faso. Am J Trop Med Hyg 69(1): 31-35.
  9. Brummer KH, Lappalainen P, Reunala T, Palosuo T (1994) Detection of mosquito saliva-specific IgE and IgG4 antibodies by immunoblotting. J Allergy Clin Immunol 93(3): 551-555.
  10. Abdel Hafeez EH, Belal US, Abdellatif MZ, Naoi K, Norose K (2013) Breast-Feeding Protects Infantile Diarrhea Caused by Intestinal Protozoan Infections. Korean J Parasitol 51(5): 519-524.
  11. Tchandema CK, Lubumbashi, Rdcongo, Pierre Lutgen (2016) In vivo trials on the therapeutic effects of encapsulated Artemisia annua and Artemisia afra. Global Journal for Research analysis 5(6): 228-234.
  12. Perez-Mazliah D, Langhorne J (2015) CD4 T-cell subsets in malaria: TH1/TH2 revisited. Front Immunol 5: 671.
  13. Khusmith S, Panitchakorn J, Krudsood S, Wilairatana P, Looareesuwan S (2001) IgE Elevation and anti-Plasmodium falciparum IgE antibodies: association of high level with malaria resistance. Southeast Asian J Trop Med Public Health 32(4): 696-702.
  14. Bereczky S, Montgomery SM, Troye Blomberg M, Rooth I, Shaw MA, et al. (2004) Elevated anti-malarial IgE in asymptomatic individuals is associated with reduced risk for subsequent clinical malaria. Int J Parasitol 34(8): 935-942.
  15. Avila JL, Rojas M, Galili U (1989) Immunogenic Gal alpha 1-3Gal carbohydrate eptopes are present on pathogenic American Trypanosoma and Leishmania. J Immunol 142(8): 2828-2834.
  16. Peng Z, Simons FE (1997) Cross-reactivity of skin and serum specific IgE responses and allergen analysis for three mosquito species with worldwide distribution. J Allergy Clin Immunol 100(2): 192-198.
  17. Donovan MJ, Messmore AS, Scrafford DA, Sacks DL, Mc Dowell MA, et al. (2007) Uninfected mosquito bites confer protection against infection with malaria parasites. Infect Immun 75(5): 2523-2530.
  18. Kamhawi SY, Belkaid G, Modi G, Rowton E, Sacks D (2000) Protection against cutaneous leishmaniasis resulting from the bites on uninfected sand flies. Science 290(5495): 1351-1354.
  19. Kusi KA, Manu EA, Manful Gwira T, Kyei Baafour E, Dickson EK, et al. (2017) Variations in the quality of malaria-specific antibodies with transmission intensity. PloS One 12(9): e0185303.
  20. Druilhe P, Pradier O, Marc JP, Miltgen F, Mazier D, et al. (1986) Levels of antibodies to Plasmodium falciparum sporozoite surface antigens reflect malaria transmission rates and are persistent in the absence of reinfection. Infect Immun 53(2): 393-397.
  21. Ogwang PE, Ogwal JO, Kasasa S, Olila D, Ejobi F, et al. (2012) Artemisia annua L. Infusion Consumed Once a Week Reduces Risk of Multiple Episodes of Malaria: ARandomised Trial in a Ugandan Community. Tropical Journal of Pharmaceutical Research 13(3): 445-453.
  22. Khusmith S, Druilhe P (1983) Cooperation between antibodies and monocytes that inhibit in vitro proliferation of Plasmodium falciparum. Infect Immun 41(1): 219-223.
  23. Duarte J, Herbert F, Guiyedi V, Franetich JF, Pied S, et al. (2012) High levels of immunoglobulin E autoantibody to 14-3-3 epsilon protein correlates with protection against severe Plasmodium falciparum malaria. J Inf Dis 206(11): 1781-1789.
  24. Orlandi Pradines E, Almeras L, Barbe S, Remoue F, Rogier C, et al. (2007) Antibody response against saliva antigens of Anopheles gambiae and Aedes aegypti in travellers in tropical Africa. Microbes Infect 9(12-13): 1454-1462.
  25. Waitayakul A, Somsri S, Sattabongkot J, Looareesuwan S, Cui L, et al. (2006) Natural human humoral response to salivary gland proteins of anopheles mosquitoes in Thailand. Acta Trop 98(1): 66-73.
  26. Tapchaisri P, Asavanich A, Limsuwan S, Tharavanij S, Harinasuta KT (1985) Antibodies against malaria sporozoites in patients with acute uncomplicated malaria and patients with cerebral malaria. Am J Trop Med Hyg 34(5): 831-836.
  27. Katoh N, Kraft S, Wessendorf JH, Biebeer T (2000) The high affinity IgE receptor (FcεRI) blocks apoptosis in normal human monocytes. J Clin Invest 105(2): 183-190.
  28. Chahnaz K, Tatiana V, Jerome V (2011) Neither Mosquito Saliva nor Immunity to Saliva Has a Detectable Effect on the Infectivity of Plasmodium Sporozoites Injected into Mice. Infect Immun 78(1): 545-551.
  29. Mishra S, Nussenzeig RS, Nussenzeig V (2012) Antibodies to Plasmodium circumsporozoite protein (CSP) inhibit sporozoite’s cell traversal activity. J Immunol Methods 377(1-2): 47-52.
  30. Ferreira A, Monimoto T, Altszuler R, Nussenzweig V (1987) Use of DNA probe to measure the neutralization of Plasmodium berghei sporozoites by a monoclonal antibody. J Immunol 138(4): 1256-1259.
  31. Lynch NR, Malave C, Turner KJ, Infante B (1986) IgE antibody against surface antigens of Leishmania promastigotes in American cutaneous leishmaniasis. Parasite Immunol 8(2): 109-116.
  32. Doolan DL, Dobano C, Baird JK (2009) Acquired immunity in malaria. Clin Microbiol Rev 22(1): 13-36.
  33. Modiano D, Petrarca V, Sirima BS, Nebié I, Coluzzi M, et al. (1996) Different response to Plasmodium falciparum malaria in West African sympatric ethnic groups. Proc Natl Acad Sci 93(23): 13206-13211.
  34. Biswas S, Saxena QB, Roy A (1990) The natural occurrence of circulating antibodies in populations of endemic malarious disease. Indian J Malariol 27(3): 139-148.
  35. Perlmann H, Helmby H, Hagstedt M, Carlson J, Larsson PH, et al. (1994) IgE elevation and anti-malarial antibodies in Plasmodium falciparum malaria. Clin Exp Immunol 97(2): 284-292.
  36. Lawaly R, Konate L, Laurence M, Dia I, Paul R, et al. (2012) Impact of mosquito bites on asexual parasite density and gametocyte prevalence in asymptomatic chronic Plasmodium falciparum infections and correlation with IgE and IgG titers. Infect Immun 80(6): 2240-2246.
  37. Baird JK, Jones TR, Purnomo, Masbar S, Leksana B, et al. (1991) Evidence for specific suppression of gametocytemia by Plasmodium falciparum in residents of hyperendemic Irian Jaya. Am J Tro Med Hyg 44(2): 183-190.
  38. Lee J, Veatch SL, Baird B, Holowka D (2012) Molecular mechanisms of spontaneous and directed mast cell motility. J Leukoc Biol 92(5): 1029-1041.
  39. Wilainam P, Nintase R, Parnpen V (2015) Mast cell activation in the skin of Plasmodium falciparum malaria patients. Malaria Journal 14: 67.
  40. Furuta T, Kikuchi T, Iwakura Y, Watanabe N (2006) Protective roles of mast cells and mast cell-derived TNF in murine malaria. J Immunol 177(5): 3294-3302.
  41. Corrado A, Tipton C, Wise S, Chiang KY, Waller E, et al. (2016) Human IgE Plasma cells in the blood, nasal polyp and the bone marrow. Am J Resp Crit Care Med 193: A6696.
  42. Mac Dermott RP, Jendrisak GA, Nash GS, Schreiber S, Bertovich MJ, et al. (1991) Human rib bone marrow mononuclear cells spontaneously synthesize and secrete IgE in vitro. Clin Exp Immunol 83(1): 163-168.
  43. Cheng C, Ng DS, Chan TK, Guan SP, Ho WE, et al. (2013) Anti-allergic action of anti-malarial drug artesunate in experimental mast cell-mediated anaphylactic models. Allergy 68(2): 195-203.
  44. Wei M, Xie X, Siao C, Xiaofeng Y, Mingfeng G, et al. (2013) Dihydroartemisinin suppresses ovalbumin-induced airway inflammation and reduces IgE in a mouse allergic asthma model. Immunopharmacol Immunotoxicol 35(3): 382-389.
  45. Buckling A, Ranford Cartwright LC, Miles A, Read AF (1999) Chloroquine increases Plasmodium falciparum gametocytogenesis in vitro. Parasitology 118(Pt 4): 339-346.
  46. Qin X, Chen G, Feng Y, Zhu X, Du Y, et al. (2014) Early Treatment with Chloroquine Inhibits the Immune Response against Plasmodium yoelii infection in Mice. Tohoku J Exp Med 234(4): 271-280.
  47. Ralf LJ Schmidt, Sabrina J, Katrin G, Nadine W, Marlene CG (2017) Chloroquine inhibits human CD4+ T-cell activation by AP-1 signaling modulation. Sci Rep 7: 42191.
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