Lupus: Open Access
Open Access

Malariotherapy: The Old-Renewed Immunotherapeutic Candidate for Systemic Lupus Erythematosus

Mostafa A. Abdel-Maksoud^1,2* and Saleh Al-Quraishy^{1 *}Correspondence: PhD in Immunology. Mostafa A. Abdel-Maksoud, Zoology Department, College of Science, P.O. Box 2455, Riyadh – 11451, Saudi Arabia, Tel: 00966507927800, Fax: 0096614679781, Email:

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Malaria As A Lethal Disease

Malaria is considered as one of the most dangerous lifethreatening diseases that can be transmitted to human through the bites of infected female Anopheles mosquitoes [1]. According to the 2017 World Malaria Report, there were two hundred and sixteen million cases of malaria in 2016, up from two hundred and eleven million cases in 2015. This has resulted in a number of deaths reached approximately four hundred and forty-five thousand in 2016 [2]. The parasite species that are able to cause malaria infection in humans are five, and two of these species P. falciparum and P. vivax pose the greatest threat [3]. The time period between the infective mosquito bite and the appearance of symptoms in a non-immune individual, is usually ranging from ten to fifteen days. Unfortunately, early malaria symptoms like – fever, headache and chills may be misdiagnosed and subsequently delay the treatment regimen [4]. The most aggressive one, P. falciparum if not treated within twenty-four hours, the infection can progress to severe illness, and ultimately to death [5]. It is noteworthy that Partial immunity against malaria infection is developed over years of exposure, and despite it never provides complete protection, it can reduce the disease severity [6]. For this reason, the majority of malaria deaths in Africa occur in young children, whereas in areas with less transmission, all age groups are at equivalent grade of risk [7]. Antimalarial medicines still having a huge problem due to the drug resistance and the evolution of drug-resistant genes in malaria parasites is still challenging issue [8]. Mosquirix–is an injectable vaccine that offers partial protection against malaria infection in young children. It has been evaluated in many parts of Africa as a complementary malaria control tool that could be added to the WHO-recommended preventive and treatment measures. [9]. Indeed, the war between malaria parasites and the host immune system is multifactorial and highly sophisticated.

That’s why some chronic infections end with death and others have been abrogated. Even after the malaria recovery, Postmalaria neurological syndrome (PMNS) could arise which is a complication that has been reported after recovery from a severe Plasmodium falciparum attack [10]. Autoimmune haemolytic anaemia due to P. vivax malaria or following its treatment with artesunate was also recorded [11,12]. Hemograms from some malaria-infected patients have showed deep thrombocytopenia and macrocytic normochrome anemia [13]. Also, acute pancreatitis and subdural haematoma were presented in a patient with severe falciparum malaria [14]. Meanwhile, there is another point of view which deals with this war as a positive event from which the host can gain benefits. Surprisingly, when some patients suffering from general paralysis of the insane (GPI) or paralytic dementia have been treated with malaria, they have expressed a significant amelioration in their neurological abnormalities and hence the term malariotherapy has been introduced [15].

The Other Face: Malariotherapy Of Psychiatric Diseases

Malaria infection was historically associated with reductions in aggressiveness of symptoms among the patients suffering from mental illness who have recurrent malaria infection [16]. The malaria-associated psychiatric effects, have introduced it as proposed therapeutic candidate in the treatment of neurosyphillis [17] a debilitating condition then is now commonly known as “general paresis of the insane” (GPI) for which no effective treatments were available [18]. According to the first published description of the practical application of the malariotherapy, for which its author has win the Nobel Prize in medicine [19], GPI patients were intentionally inoculated with the blood-stage of malaria benign forms, allowing approximately ten cycles of intermittent fever prior to treatment of the infection with available anti-malarial drugs [20]. Later on, this approach was applied on a larger number of GPI patients and pronounced improvements in psychiatric symptoms including aggression, mania, reduced irritability, psychosis, amnesia, confusion, and disorientation following this malaria treatment was reported [21,22]. Although remissions in up to a third of patients were documented by some authors [23], it still represents a surprising effect in the remaining patients. On the other hand, some reports claimed that the risk behind malaria infection may exceed the beneficial effects associated with it and the success rates are not satisfactory [24-29]. In spite of the fact that mosquito inoculation is associated with a higher risk than blood-stage inoculation, [30], the growing popularity of malariotherapy for the treatment of non-syphilitic psychiatric patients, together with the possibility of cross-contamination with Treponema pallidum, led to increasing use of direct mosquito inoculation for the purpose [31]. Indeed, the clinical outcomes of malariotherapy for neuropsychiatric disorders are controversial. Despite the results of treatment of some psychiatric disorders (including chronic “dementia praecox” or schizophrenia, as well as manic-depressive psychosis) perceived as less successful [32], a group of diseases have been also suggested to be significantly improved by applying malariotherapy [33-36]

The Current Malariotherapy For Autoimmune Diseases

After the first introduction of the term malariotherapy by the Austrian psychiatrist Julius Wagner-Jauregg, there was a debate about the concept that lethal parasites could have beneficial effects to their hosts. No any attempts were done to investigate the mechanisms behind the malaria- associated neurocurable effects after Wagner innovation. At 1969, Greenwood has noticed that there is a low incidence of the autoimmune disease, rheumatoid arthritis, in western Nigeria where malaria infection is frequent [37]. Afterwards, his group has showed suppressed spontaneous autoimmune disease in BWF1 mice that have been infected with plasmodium berghei [38]. Similar results were obtained when Gerrard et al. [39] have observed a lower prevalence of allergy in native populations in Northern Canada compared to other populations. Later on, Strachan [40] has postulated what's called "Hygiene Hypothesis" according to which the increase in the autoimmune diseases (ADs) in industrialized world is directly associated with the lack of recurrent infections and the hygienic conditions in these countries. Conversely, as greenwood has noticed, low incidence of ADs is associated with poor countries where infections especially malaria are endemic [41]. Similarly, Matricardi et al. [42] have correlated exposure to childhood infections with the reduced risk of atopy later in life. As another face of the hygiene hypothesis, the "old-friend hypothesis" has been introduced by Graham Rook [43] when he suggested that Mycobacteria and other environmental organisms can act as immunomodulators for immunoregulatory disorders. The "ole friend hypothesis" and its supporting, "microflora hypothesis” have attracted investigators later on to discover such surprising relationship between harmful infections and aggressive ADs. Ege et al. [44] have reported a wider range of microbial exposures and lower prevalence of asthma and atopy in children growing up on farms. Two years later, our group have tried the story in experimental models of ADs rather than humans. We have infected the animal model of human lupus, female BWF1 mice with plasmodium chabaudi- infected erythrocytes and investigated the consequences of infection on the disease parameters. We have found that malaria infection has altered the redox state in kidney and liver tissues and confers protection against lupus nephritis [45]. After that, we have investigated the mechanism through which malaria infection could ameliorate the lupus- associated pathology. It was interesting that malaria infection attenuated B-Cell auotreactivity through modulating the CXCL12/CXCR4 Axis and its downstream Signals PI3K/ AKT, NFκB and ERK [46]. The infection has also diminished plasma immune complexes and ameliorated the histopathological alterations in different organs of female BWF1 lupus mice [47]. In the renal tissue of lupus mice, the malaria infection has increased the rate of renal immune complexes deposition [48] with concomitant increased total antioxidant capacity [49]. Conversely, malaria infection has increased oxidative stress and apoptosis in splenic tissue of lupus-prone (NZB/NZW) F1 mice [50]. The detailed mechanism behind this surprising phenomenon still been unresolved and the results obtained are still controversial but this situation has attracted many research groups around the world to deeply study this mysterious relationship. Many neurologists have focused on the malariotherapy for neurosyphillis and other mental disorders and sometimes they called it as pyro therapy or fever therapy [51-56]

Conclusion

The term malariotherapy, despite being old and forgotten since nearly eighty years returns to the scientific world potentially after both the human and the animal experimental data that supports it. This term may be the key for the solution of the problematic greatly mysterious in curable category of diseases named autoimmune diseases. This surprising relationship between malaria infection and the autoimmune condition, SLE returns back the postulation that parasitic infections could be double edged swards having both positive and negative consequences.

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