INNOVATIONS IN ISRAEL ,0$-ǯ92/21ǯ0$5&+2019 Helminth-Related Tuftsin-Phosphorylcholine Compound and its Interplay with Autoimmune Diseases Miri Blank PhD1 and Yehuda Shoenfeld MD FRCP MasACR1,2 1Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 2Mosaic of Autoimmunity, St. Petersburg University, St. Petersburg, Russian Federation and Th17 and modified Th2) [5]. Long-lived parasites such ABSTRACT: The hygiene theory represents one of the environmental as helminthes have the ability to immunomodulate the host facets that modulate the risk for developing autoimmune immune network. Therefore, treatment with helminthes or diseases. There is a reverse correlation between the presence their ova ameliorate murine experimental models and patients of helminthes and flares of autoimmune diseases, which with autoimmune diseases. The aim of the helminth is to explains the rise in incidence of certain autoimmune diseases survive inside the host environment by protecting itself from in developed countries. The protective properties of certain eradication by the host immune system [4-6]. This review will helminthes are attributed to their secretory compounds which immunomodulate the host immune network in order to shed light on helminth secretory immunomodulatory small survive. Thus, the helminthes use an array of mechanisms. One molecules, focusing on tuftsin-phosphorylcholine (TPC). of the major mechanisms enabling manipulation of the host– helminth interaction is by targeting the pattern recognition HELMINTH TREATMENT IN PATIENTS AND MURINE receptors (PRRs)-dependent and -independent mechanisms, EXPERIMENTAL MODEL which include toll-like receptors, C-type lectin receptors, and Diving deep into the parasite world, Cox [7] revealed an inter- the inflammasome. The current review provides a glimpse of esting view of its history. This was evident already in the period numerous helminth secreted products which have a role in the of ancient Egypt, from 3000 to 400 BC, particularly in the Ebers immunomodulation of the host immune network, focusing on papyrus, an Egyptian medical tome of herbal knowledge dis- bifunctional tuftsin-phosphorylcholine (TPC). TPC is a natural covered at Thebes [8]. Some worm-related diseases emerged, as compound based on phosphorylcholine of helminth origin that described in the Old Testament when the Israelites crossed the was used in the past to cover stents and tuftsin, a self-peptide Red Sea on their exodus from Egypt in 1250 to 1200 BC [9], derived from the spleen. TPC was proven to be efficient in and in Hippocrates’ writings [10]. The helminthes and their three murine experimental models (lupus, colitis, and arthritis) products, being pathogenic or protective, raised researchers’ and ex vivo in giant cell arteritis. curiosity in ancient times as well as today. IMAJ 2019; 21: 158–162 Helminthes (parasitic worms) in certain geographic areas KEY WORDS: animal models, autoimmunity, helminth, exist in reverse correlation with the flare of autoimmune dis- immunomodulation, tuftsin-phosphorylcholine (TPC) eases and inflammatory conditions. During recent decades, accumulating evidence showed the effectivity of therapy with helminthes and their ova in reducing inflammation and in the clinical score of autoimmune diseases, such as multiple scle- eoepidemiological studies show a reverse correlation rosis (MS), rheumatoid arthritis (RA), type I diabetes mellitus G between less developed countries and the incidence of (T1DM), and inflammatory bowel diseases (IBD) [6,11-13]. autoimmune diseases [1]. There are more than 80 autoimmune Patients with active ulcerative colitis and Crohn’s disease were diseases whose occurrence increased dramatically in the last treated with an ingestion of live helminth eggs, Trichuris suis, few decades [1]. One of the major hypotheses to explain this and their disease remitted [14-16]. The helminth therapy was trend is the hygiene hypothesis [3]. According to this theory, not associated with side effects or serious complications attrib- early and repeated exposure to infections enrich the innate utable to the therapeutic agent [17]. and adaptive immune network, whereas improved sanitation Since MS, an inflammatory and demyelinating disease increases autoimmunity (for example, there is no lupus in affecting the central nervous system, is mediated via a Th1 pre- malaria-infected areas) [3,4]. A low parasite burden leads to dominant immune mechanism, researchers assumed that MS a high-inflammatory condition (e.g., activation of Th1, Th2, patients could benefit from helminthes by inducing a Th2 shift and Th71), fibrosis and chronic pathology, while a high parasite [18,19]. A prospective double-cohort study was performed in burden results in a low-immune pathology (inhibition of Th1 12 MS patients who presented with eosinophilia and parasitic 158 ,0$-ǯ92/21ǯ0$5&+2019 INNOVATIONS IN ISRAEL infection with Hymenolepis nana, Trichuris trichiura, Ascaris pathway spleen tyrosine kinase (Syk) in intestinal DCs from lumbricoides, Strongyloides stercoralis, or Enterobius vermicu- H. polygyrus bakeri-infected mice. DCs sense gut flora and laris. Infected patients showed a significant improvement in damaged epithelium via expression of C-type lectin receptors. clinical MS manifestations, as well as an increased myelin Focusing on a C-type lectin (CLEC) 7A, which encodes for the basic protein-specific T cell secretion of anti-inflammatory dectin-1 receptor on DCs and drives Th1/Th17 development, cytokines [interleukin 10 (IL-10) and transforming growth the authors provided evidence that soluble worm products can factor-beta (TGFβ)], and reduction in inflammatory cytokines block CLEC7A and Syk mRNA expression in gut DCs from [IL-12 and interferon-gamma (IFNγ)]. Likewise, the number uninfected mice after a brief in vitro exposure. Inhibition of of T regulatory cells were increased [18]. In another study, 16 Syk expression and phosphorylation in intestinal DCs may be MS patients with relapsing-remitting multiple sclerosis (RRMS) one mechanism through which helminthes induce regulatory were assessed for safety and brain magnetic resonance imag- DCs that down-modulate colitis [30]. ing (MRI) activity during oral administration of ova from the Another example of helminth secretory products that porcine whipworm, Trichuris suis (TSO). The study was per- modulate the host immune response was introduced by formed during 5 months of screening observation, 10 months another group [31-33]. They described a glycoprotein, ES62, of treatment, and 4 months of post-treatment surveillance [19]. secreted by the parasitic worm Acanthocheilonema viteae in No serious symptoms or adverse events occurred during treat- which phosphorylcholine is presented as a moiety by glycans ment. A trend was consistent, with a 35% diminution in active on the protein. This secretory molecule exerts anti-inflamma- lesions when observation MRIs were compared with MRIs of tory activity in murine models of chronic asthma, lupus and the treated subjects; at the level of individuals, 12 of 16 subjects arthritis affecting T cells, B cells, macrophages, dendritic cells improved during TSO treatment associated with expansion of (DCs), and mast cells [31]. This research group has produced T regulatory cells during TSO treatment [19]. a synthetic analog for ES62. This synthetic small molecule Employing experimental autoimmune models, ameliora- manipulates the pro-inflammatory scenario by inhibiting tion of disease activity was achieved by administration of TLR2, 4, and 9 expression via the MYD88 pathway, inhibiting helminthes or their ova. Studies with non-obese diabetic NF-κB, which occurs as a result of inhibition of pro-inflam- (NOD) mice showed that inoculation with Trichinella spiralis, matory cytokine production [32,33]. Heligmosomoides polygyrus, or Schistosoma mansoni using In parallel, Donnelly et al. [34,35] found a 68-mer peptide, egg antigen or the worm antigen markedly reduced the rate of helminth defense molecule FhHDM-1, secreted by the hel- experimental type I diabetes mellitus (T1DM) and suppressed minth Fasciola hepatica, which potently modulates the host lymphoid infiltration in pancreas islets [16,19-22]. Amelioration immune response. This peptide ameliorated disease in two of experimental autoimmune encephalomyelitis (EAE) was autoimmune murine models, type 1 diabetes, and relapsing- achieved following helminth treatment [23]. Schistosome remitting immune-mediated demyelination. In this case the worm infections prevented colitis, shifting the immune response secretory peptide had no effect on T cell response in the con- towards Th2 phenotype [24,25].Syphacia obvelata-infected rats text of cytokine production and specific T cell response, but developed less severe arthritis than uninfected rats. Extracts it reduced the clinical score. The FhHDM-1 peptide affects of the nematode Ascaris suum, Schistosoma mansoni and the host immune network via interaction with macrophages, Acanthocheilonema viteae were also found to reduce the severity reducing their capacity to secrete pro-inflammatory cytokines of collagen-induced arthritis (CIA) in mice [26-28]. such as TNFα and IL-6 [34,35]. FhHDM-1 is a cathelicidin- Ingestion of parasitic worms ameliorated experimental like peptide that binds to macrophages, internalizes into autoimmune diseases via several mechanisms, mostly by endolysosomes, inhibits its acidification, and diminishes the