Parasitic Infections’ Immunomodulatory Effects and Autoimmune Diseases

The hygiene hypothesis has been implicated in the dramatic increase in autoimmune and allergic diseases noticed in recent decades, especially in developed countries. This growth was associated with lesser exposure to diverse immunoregulatory infectious agents. This hypothesis has been proved by many potent epidemiological and experimental studies. The results of these studies along with the analysis of the western world’s microbiome helped us to have a greater idea about microorganisms shared in the hygiene hypothesis, as well as their main mechanisms that have an effect on the immune system. Protozoal infections have been proved to have remarkable immunomodulatory changes in different autoimmune diseases. Helminths and their derivatives were proved to have a protective role. Helminths’ broad immunomodulatory effects have been tested in clinical trials of autoimmune diseases, including inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and type-1 diabetes. In this review, we discussed particular parasitic infections and their immunomodulatory effects on some autoimmune diseases.


INTRODUCTION
This increase in the prevalence of autoimmune and allergic diseases has been attributed to the relatively better hygiene standards that are present in the western world. Those standards included the reduction of exposure to different pathogens, including parasites. Parasites were proved to have multiple anti-inflammatory and immunomodulatory mechanisms for the immune system.
The hygiene hypothesis was the most proposed reason for the disease-dampening effects reported in the different studies analyzing the relationship between parasitic infections and autoimmunity. In this review, we discussed the current studies concerning parasites as potent immunomodulators in autoimmune diseases.
Chronic autoimmune diseases affecting various organs have remarkably increased all over the world in the last few years. During the last decades, epidemiological studies had pointed to a special increase in the incidence of chronic autoimmune-inflammatory CNS diseases such as multiple sclerosis and autoimmune encephalomyelitis ((Trapp and Nave, 2008;Ramagopalan and Sadovnick, 2011).

Hygiene Hypothesis:
The hygiene hypothesis is a term that supported the theory of a potent relationship between infectious disease prevalence with allergic and autoimmune (AI) diseases (Bach, 2002).The prevalence of allergic diseases such as bronchial asthma has increased in the last decades. It reached more than 15% in countries such as the United Kingdom, New Zealand and Australia (Eder et al., 2006). Additionally, atopic dermatitis prevalence has been also elevated in developed countries, as about 2-10% of adults and 15-30% of children were affected (Bieber, 2008).It has been also noted that the prevalence of autoimmune diseases had marked elevation in European countries. It was reported that the prevalence of type 1 diabetes (T1D) among children (0-4 years) was increased in Finland (Harjutsalo et al., 2008).
In addition, a remarkable increase in Crohn's disease, ulcerative colitis and biliary cirrhosis was noticed in the last years (Rautiainen et al., 2007).In the developed countries, after the industrial progress, great care for hygiene was achieved such as water sanitation, and good food preservation. Moreover, vaccination programs for common childhood diseases were initiated. That resulted in a reduction in the incidence of infectious diseases like hepatitis A virus. Widespread usage of anti-pathogenic medications has also contributed to the elimination of many parasitic diseases like schistosomiasis and filariasis (Zaccone et al., 2006).
Studies had demonstrated the protective effect of exposure to infectious agents in early childhood life against allergic and AI diseases. Riedler et al. (2001) showed that exposure to farming and cowsheds in early life protected against asthma.Regarding exposure to parasitic diseases and their impact on the incidence of allergic diseases, Flohr et al. (2006) documented that schistosomiasis could protect against allergic dermatitis among Vietnamese children. Another study reported the inverse relationship between parasitic infections and the incidence of allergic dermatitis (van den Biggelaar et al., 2004).
It was noted that the incidence of immune-based diseases was about 100% in mice bred in specific pathogen-free (SPF) conditions, while it was very low in mice grown in conventional sanitary conditions, suggesting a strong association with the development of atopic diseases (Bach, 2002).Parasitic infection induction was found to reduce the severity of the disease attacks in multiple sclerosis patients. It was documented that there was an elevation in interleukin (IL) 10 and transforming growth factor (TGF)-β in patients' blood samples (Correale and Farez, 2007).
Trichuris suis ova infection in ulcerative colitis patients resulted in improvement of the symptoms. The same positive effect was also documented in Crohn's disease patients (Summers et al., 2005a, b). The larval stage of hookworm, Necator americanus was injected intradermally to treat Crohn's disease and produced remarkable effects (Croese et al., 2006). Studies from many countries such as Venezuela (Lynch et al., 1993), Vietnam (Flohr et al., 2006) and Gabon (van den Biggelaar et al., 2004) showed that parasitic diseases elimination had resulted in a higher incidence of atopic diseases such as atopic dermatitis.
In general, infectious agents, especially parasites, might have biological importance for the pharmacological and therapeutic values for treating allergic and AI diseases. Nevertheless, after removing the parts causing the infectious diseases and their pathology, then using the molecules responsible for treating or alleviating the symptoms of the immune-based diseases (Osada and Kanazawa, 2010). Parasitic infections were documented to have therapeutic effects against many autoimmune diseases and will be discussed in this review in detail.

Autoimmune Diseases and Parasitic Infections: Rheumatoid Arthritis:
Rheumatoid arthritis (RA) is an AI disease characterized by an inflammatory chronic progressive course that affects peripheral joints symmetrically resulting in their damage, irreversible deformities and reduced life expectancy (Mota et al., 2012).
RA affects about 0.2-1 % of the worldwide population. It is more common in females, with its highest incidence among the aged between 30 to 50 years. Its outcome affects both, the patient and society. It affects the life quality of the patients and the productivity of society (De Azevedo et al., 2008).The process begins with the loss of the normal mechanism of self-tolerance to auto-antigens and identifying joint antigens as foreign molecules, which resulted in synovitis and joint destruction. The synovial membrane in this process is the tissue of the target where mononuclear cellular infiltrates occur that lead to synovial hyperplasia, proinflammatory cytokines release, and vascular proliferation. Synovial hyperplasia is the nucleus for synovial plannus that causes bone erosion, cartilage, tendons and ligaments destruction resulting in joint damage (Mota et al., 2012).
Innate immune cells, which participate in the inflammatory infiltrate of the synovium, are; mast cells, neutrophils, natural killer cells and the most important cells are macrophages. Macrophages have a dual action in this pathology; they release pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-23) as a part of being antigenpresenting cells (APCs), and produce prostanoids and extracellular matrix metalloproteinases (Mota et al., 2012).Concerning disease affecting cytokines, TNF-α has a unique role. It activates macrophages and lymphocytes resulting in exacerbating synovitis. It also stimulates the release of other inflammatory mediators. TNF-α also acts directly on bone resorption by stimulating the receptor activator of nuclear factor kappa-B ligand (RANKL) that activates monocytes into osteoclasts and inhibiting their apoptosis (Schett et al., 2005).
RA is defined as Th17 immunemediated disease. IL-17 is the main cytokine of this pathway that stimulates the expression of RANKL triggering and exacerbating bone resorption. Antiapoptotic cytokines like IL-2, IL-4, and IL-15 were elevated in RA which explains the inhibition of T cell apoptosis in this disease (Andersson et al., 2008).Rheumatoid factor was detected in 70-80% of RA patients. B cells also could act as class II APCs with a production of cytokines (Andersson et al., 2008).
In Nigerian villages where there was a higher prevalence of parasitic diseases, the rheumatoid factor seropositivity was detected in many patients. However, interestingly, they had lesser severe clinical and radiological manifestations than parasite-free RA patients (Greenwood et al., 1970).Collagen-induced arthritis (CIA) is characterized by the production of CIIspecific antibodies, which is a common feature of RA (Nandakumar, 2010). In addition, rheumatoid factor (RF) was detected in CIA as in RA (Tarkowski et al., 1989). Trentham et al. (1977) injected the rats with CII emulsified in complete Freund's adjuvant (CFA) that produced polyarthritis with an autoimmune course and an erosive nature. Consequently, other researchers developed CIA in mice and non-human primates (Cathcart et al., 1986).
Schistosoma mansoni infection of male DBA⁄ 1 mice two weeks prior to injection with type II collagen (IIC) significantly decreased the severity of arthritis. Anti-IIC IgG and IgG2a levels were lower in infected rather than in uninfected mice. Concerning the cytokineproducing potentials in the infected mice, the downregulation of Th1 (IFN-c) and proinflammatory cytokines (TNF-a and IL-17A) was observed (Osada et al., 2009). In addition, an upregulation of Th2 (IL-4) and an anti-inflammatory cytokine (IL-10). Schistosoma mansoni infection reduced the severity of autoimmune arthritis through systemic and local reduction of proinflammatory mediators, indicating the potential of parasite-derived materials as therapeutic agents against rheumatoid arthritis (Osada et al., 2009).
Filarial nematodes secrete phosphorylcholine-containing 62-kDa glycoprotein, excretory-secretory-62 (ES-62), which has immunomodulatory activities. This glycoprotein was found to have an anti-inflammatory action in the murine CIA model and human rheumatoid arthritis-derived synovial tissue cultures, as a first step to developing (ES)-62-based drugs. It was documented that ES-62 could inhibit Th1-type responses and reduce antigen-specific IgG2a (a Th1-promoting antibody subclass), with no modulation of IgG1, IgG3 and IgM levels (Harnett et al., 2008).
Schistosoma japonicum attenuated CIA via a similar mechanism like Schistosoma mansoni up-regulated Treg cells (Song et al., 2011).
Hymenolepis diminuta infection was found to reduce arthritis development in CIA mice through T and B cells dependent mechanisms. The immunemodulatory effect was abolished in T and B cells deficient mice (Shi et al., 2011).
Nippostrongylus brasiliensis infection decreased clinical arthritis incidence and severity in spontaneous arthritis in MRL/lpr mice through enhanced IL-4 production (Salinas-Carmona et al., 2009).
Toxoplasma gondii prevented spontaneous arthritis development in the IL-1R antagonist-deficient mice model through Th1 polarization with consequent Th17 inhibition (Washino et al., 2012). A similar effect was reported with gammairradiated Toxoplasma gondii in decreasing adjuvant arthritis in mice by declined production of pro-inflammatory cytokines (Hafez et al., 2020).
Leishmania purified proteins from amastigotes reduce arthritis scoring in CIA mice model (O'Daly et al., 2010). A similar effect was reported using Leishmania major, Leishmania analog of the receptors for activated C kinase (LACK). This effect was attributed to increased IL-4 production while decreased production of proinflammatory cytokines; IL-6 and IL-17 (Yang et al., 2018).

Inflammatory Bowel Disease:
Clinical trials were conducted using Trichuris suis ova and that treatment was effective in relieving Crohn's disease manifestations in more than 70% of the patients (Summers et al., 2005b).
Necator americanus infection improved the clinical condition of patients with inflammatory bowel disease that increased with time (Croese et al., 2006).
Heligmosomoides polygyrus attenuated colitis via tolerogenic DC that affect T cell response and led to decreased IL-17 production (Blum et al., 2012).

Celiac Disease:
Necator americanus infection depressed the inflammatory response in the patients through reduced IFN-γ and IL17A production (McSorley et al., 2011).

Multiple Sclerosis (MS):
Trichuris suis ova was used in MS patients, and this treatment was successful to inhibit new magnetic resonance imaging (MRI) detected lesions. This was attributed to Treg and Breg enhanced activity in helminthic infections, which increased IL-10 and decreased IL-12 production in infected patients. This effect was confirmed when anti-helminthic therapy was used, deteriorated clinical presentation and radiological lesions occur (Correale and Farez, 2007). Necator americanus, Hymenolepis nana, Ascaris lumbricoides, Enterobius vermicularis, Trichuris trichura and Strongyloides stercoralis infections were tried in clinical studies to compare symptoms between MS parasitic-infected and non-infected patients. The studies showed reduced relapses, disability scores and MRI lesions in infected patients (Correale and Farez, 2007).

Autoimmune Encephalitis:
Schistosoma mansoni reduced the incidence and the severity of experimental autoimmune encephalitis (EAE) disease. This effect was achieved via the affection of inflammatory cytokines profile; increased IL-4 and IL-10 while decreased TNF-α and IL-12, resulting in reduced CNS inflammatory cell infiltration (La Flamme et al., 2003).

Systemic Lupus Erythematosus (SLE):
Schistosoma mansoni infection trials in MRL/lpr mice were effective to turn the glomerulonephritis phenotype from diffuse proliferative to the membranous pattern. It was achieved via increased IL-4, IL-5, IL-10, and TGF-β (Miyake et al., 2014).
Plasmodium chabaudi infection of female BWF1 lupus mice (SLE model) was successful in the protection of lupus nephritis through reduced nitric oxide (NO) and hydrogen peroxide (H2O2) in both kidney and liver of infected mice (Al-Quraishy et al., 2013).
Dirofilaria immitis prevented diabetes development in NOD mice through an IgE-dependent mechanism and abrogated class switch from IgM to IgG anti-insulin autoantibodies (Imai et al., 2001).
Heligmosomoides polygyrus alleviated and suppressed the severity of diabetes in NOD mice through reduced expression of TNF-α and IL-1β in the pancreas (Osada et al., 2013).

CONCLUSION
Numerous experimental and clinical studies have documented that infection with the parasites could reduce the severity of some autoimmune disorders. Most of these studies depended on the use of parasitic infections as prophylactic strategies. Particular parasites could be used to treat certain human autoimmune diseases; therefore, these controlled infections could be used as an adjuvant treatment. Nevertheless, the isolation of the effective molecules from the parasites could offer a better prospect in the context of parasitic infections as protective or treatment strategies for autoimmune diseases.  (2)