Archive for février 2018

Immunoglobulins and malaria prophylaxis

février 11, 2018

Immunoglobulins and malaria prophylaxis

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. Plasmodium can give rise to IgE in the absence of other pathogens, such as helminths which also are known to induce IgE elevation. IgE in association with monocytes or platelets may give rise to 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 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 raises almost exponentially with the severity of the disease. The increase is the same for males and females as has been shown in several studies.
P Perlmann, M Aikawa. Contrasting functions of IgG and IgE antimalarial antibodies in uncomplicated and severe Plasmodium falciparum malaria. Am J TropMed Hyg, 2000, 62, 373-377.
Eze Evelyn Mgbeoma, C Serekara. Immunoglobulin levels in Plasmodium falciparum malaria infected subjects in Port Harcourt, Nigeria. Int J Adv Multidipl Res, 2016. 3, 49-55
SGO Johansson, Immunological levels in Ethiopian preschool children with special reference to high concentrations of IgE. The Lancet, 1968 291, 1118-1121
J Seka-Seka, Y Brouth. The role of serum immunoglobulin E in the pathogenesis of Plasmodium falciparum malaria in Ivorian children. Scandinavian J of Immunol, 2004, 59, 228-230.
C Calissano, D Modiano, B Sodiomon, IgE antibodies to Plasmodium falciparum and severity of malaria in children of one ethnic group living in Burkina Faso. Am J Trop Med Hyg, 2003, 69, 31-35
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).
Constant Kansango Tchandema, Pierre Lutgen. In vivo trials on the therapeutic effects of encapsulated Artemisia annua and Artemisia afra. Global Journal for Research analysis 2016, 6, 228-234
D Perez-Mazliah, J Langhorne. CD4 T-cell subsets in malaria revisited: Frontiers in Immunology, 2015,5, article 671.
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.
Srisin Khusmith, J Panitchakorn. IgE Elevation and anti-Plasmodium falciparum IgE antibodies: association of high level with malaria resistance. Southeast Asian J trop Med Public Health 2001, 32, 4, 696-702
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 weren’t associated eiher with a reduced risk to succumb to a new clinical episode.
Bereczky S, Montgomery SM. Elevated anti-malarial IgE in asymptomatic individuals is associated with reduced risk for subsequent clinical malaria. Int J Parasitol. 2004 Jul;34(8):935-42.
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 sat 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.
Avila JL, Rojas M, Immunogenic Gal alpha 1 eptopes are present on pathogenic American Trypanosoma and Leishmania. J Immunol 1989, 142, 2028-2834
Peng Z, Simons FE, Cross-reactivity of skin and serum specific IgE responses and allergen analysis for three mosquito species with worldwide distribution. J Allergy Clin Immunol, 1997, 100, 192-8.
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! And it may explain why people living in countries with dense Anopheles populations are immunized by these bites. And even if regular consumption of Artemisia infusion or vaccines have a prophylactic action the IgE related immunity does not decrease because people are continuously biten by mosquitoes with the concommittant injection of saliva. Although most of these people are asymptomatic, they do not develop high levels of parasitemia and fever because the saliva of the mosquitoes maintains a high level of IgE.
There are also seasonal increases in IgE, after the rainy season. They are absent or low in the absence of bites
Palosuoa K, Reunula T. Seasonal increase in human IgE and IgG4 antisaliva antibodies to Aedes mosquito bites. Int Arch Allergy Immunol 1997 114, 367-72
F Remoue, E Alix, IgE and IgG4 antibody responses to Aedes saliva in African children. Acta Tropica, 2007, 108-115
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.
MJ Donovan, AS Messmore, MA McDowell, Uninfected mosquito bites confer protection against infection with malaria parasites, Infection and Immunity, 2007, 75, 2523-2530
Kamhawi SY, Belkaid G, Sacks D. Protection against cutaneous leishmaniasis resulting from the bites on uninfected sand flies, Science, 290:1351-1354
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.
Patrick E Ogwang, Jasper O Ogwal, 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 June 2012; 13 (3): 445-453
S Khusmith, P Druilhe. Cooperation between antibodies and monocytes that inhibit in vitro proliferation of Plasmodium falciparum. Infection and Immunity, 1983, 219-223
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 interfers 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.
Duarte J. Herbert F, Pied S, High levels of immunoglobulin E autoantibody to 14-3-3 epsilon protein correlate with protection against severe Plasmodium falciparum malaria, J Inf Dis 2012, 206, 1781-9
Orlandi-Pradines E, Almeras L, Rogier C, Antibody response against saliva antigens of Anopheles gambiae and Aedes aegypti in travellers in tropical Africa. Microbes Infect, 2007, Oct 9, 1454-62
Waitayakul A, Somsri S, Natural human humoral response to salivary gland proteins of anopheles mosquitoes in Thailand. Acta Trop 2008 Apr 98 66-73
Tapchaisri P, Asavanich A, Limsuwan S, Tharavanij S, Harinasuta KT. Antibodies against malaria sporozoites in patients with acute uncomplicated malaria and patients with cerebral malaria. Am J Trop Med Hyg. 1985 Sep;34(5):831-6.
N Katoh, S Kraft, T Biebeer. The high affinity IgE receptor (FcεRI) blocks apoptosis in normal human monocytes, Journal of Clinical Investigation, Jan 2000
The inhibition of sporozoite’s 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.
S Mishra, R Hussenzeig. Antibodies to Plasmodium circumsporozoite protein CSP inhibit sporozoite’s cell traversal activity. J Immunol Methods 2012 377, 47-52.
Ferreira A, Monimoto T Use of DNA probe to measure the neutralization of Plasmodium berghei sporozoites by a monoclonal antibody. J Immunol 1987 138 , 1256-9
A similar protection mechanism by IgE has been documented for leishmaniasis. IgE antibodies bind strongly to promastigotes.
Lynch NR, Malavé C, Infante B, IgE antibody against surface antigens of Leishmania promastigotes in American cutaneous leishmaniasis, Parasite Immunol, 1986 8, 109-16.
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.
D Doolan, C Dobano, JK Baird. Acquired immunity in malaria: Clinical Microbiology Reviews. Jan 2009, 13-36.
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.
D Modiano, V Petrarca, M Coluzzi, Different response to Plasmodium falciparum malaria in West African sympatric ethnic groups. Proc Natl Acad sci 1996 93, 13206-11.
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.
Biswas S, Saxena QB, The natural occurrence of circulating antibodies in populations of endemic malarious disease. Indian J Malariol, 1990 27, 139-48
The total IgE level in a population is strongly related to the malaria endemicity in that area.

Country IgE ng/ml
Sweden 8
Madagascar 301
Thailand 647
Liberia 2134

H Perlmann, H Helmby, IgE elevation and anti-malarial antibodies in Plasmodium falciparum malaria. Cl
IgE titers are negatively correlated with gametocyte carriage and this may be an important factor in a area of high endemicity.
R Lawaly, L Konate, R Paul. Impact of mosquito bites on asexual parasite density and gametocyte prevalence in asymptomatic chronic Plasmodium falciparum infections and correlation with IgE and IgG titers. Infection and Immunology, 2012, 80. 2240-2246.
Baird JK, Jones Tr, Leksana B. Evidence for specific suppression of gametocytemia by Plasmodium falciparum in residents of hyperendemic Irian Jaya. Am J Tro Med Hyg, 1991, 44, 183-90.
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
Lee J, Veatch SL, Baird B, Holowka D. Molecular mechanisms of spontaneous and directed mast cell motility. J Leukoc Biol. 2012 Nov;92(5):1029-41. doi: 10.1189/jlb.0212091. Epub 2012 Aug 2.
P Wilainam, R Nintase, Mast cell activation in the skin of Plasmodium falciparum malaria patients. Malaria Journal, 2015, 14-67
Naohiro Watanabe, Takahisa Furuta. Cell-Derived TNF in Murine Malaria Protective Roles of Mast Cells and Mast J Immunol 2006; 177:3294-3302
A Corrado C Tipton, E Waller, Human IgE Plasma cells in the blood, nasal polyp and the bone marrow. Am J Resp Crit Care Med 193:2016:A6696
MacDermott RP, Jendrisak GA, Nash GS. Human rib bone marrow mononuclear cells spontaneously synthesize and secrete IgE in vitro. Clin Exp Immunol. 1991 Jan;83(1):163-8.
Artesunate is antagonistic with the formation of IgE and its mechanisms of action against parasites.
Cheng C, Wong WS, Anti-allergic action of anti-malarial drug artesunate in experimental mast cell-mediated anaphylactic models. Allergy, 2013, 68, 195-203
Wei M, Xie X, Dihydroartemisinin suppresses ovalbumin-induced airway inflammation and reduces IgE in a mouse allergic asthma model. Immunopharmacol Immunotoxicol. 2013 Jun;35(3):382-9. doi: 10.3109/08923973.2013.785559.
Worse even, a 5-fold increase in gametocytogenesis in Plasmodium falciparum has been documented for chloroquine in vitro.
Buckling A, Read AF. Chloroquine increases Plasmodium falciparum gametocytogenesis in vitro. Parasitology, 1999, 118, 339-46.
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.
Xiaosong Qin, Yaming Cao, Guang Chen Early Treatment with Chloroquine Inhibits the Immune Response against Plasmodium yoelii Infection in Mice. 271 Tohoku J. Exp. Med., 2014, 234, 271-285; doi: 10.1620/tjem.234.271.
This is not surprising as chloroquine reduces CD4+ activation.

Ralf L. J. Schmidt, Sabrina Jutz, Katrin Goldhahn, Chloroquine inhibits human CD4+ T-cell activation by AP-1 signaling modulation. Sci Rep. 2017; 7: 42191.
Is is dramatic negligence not to have studied in the European Institutes of Tropical Medicine and elsewhere the impact this inhibition of the of the immune system might have on prophylaxis and transmission and not to have alerted the African communities against these risks. Chloroquine is still massively sold in Africa and the second most preferred medicine after ACTs.
Thousands of research papers have been written on artemisinin. But this molecule has no effect on sporozoites and gametocytes, on prevention and transmission. Curative and preventive strategies for malaria treatment should ideally target three malarial life-cycle stages: exoerythrocytic forms, the asexual blood stages, and the transmission stages.