CHAPTER ‘ Hypothesis’ and Development of Immunity

32 Bidyut Kumar Das, Aditya K Panda

INTRODUCTION have shown that migrants from areas with low incidence It is a concept based on the premise that reduced exposure of suffer more from these diseases to microorganisms would result in increased immune when they migrate to higher incidence areas. reactivity promoting allergic and autoimmune disorders. and autoimmune diseases result from an This has been evident in Western countries where high exaggerated host immune response against self . quality of has drastically reduced exposure Several factors such as genetic susceptibility, immune of the population to micro-organisms presumed to have dysregulation and environmental triggers have been contributed to the ‘silent epidemic’ of autoimmune implicated in the causality of autoimmune diseases. disorders in first world countries. This premise is Genetic factors are unlikely candidates for this surge since supported by epidemiological, experimental and clinical mutations associated with disease susceptibility requires evidence. Incidence of has increased significantly a long time span to manifest and the observations on HH in children in the last 3-4 decades and similarly there is are only several decades old. Environmental factors, like increased prevalence of inflammatory bowel disease parasite , play an important role in protection (IBD),Type-1 diabetes (T1D), (MS) in the against allergy and autoimmune diseases since they past 50 years. Interestingly, such increased incidences of modulate the host for their own survival. allergy and autoimmune diseases have not been reported Excessive attention to hygiene and sanitation has resulted in low-income tropical countries where infections are in a parasite free environment that has resulted in loss of most frequent indicating a possible reciprocal association control over a hyperactive host immune system. between and allergy/autoimmune diseases which forms the basis of hygiene hypothesis (HH). Experimental Evidence The HH has been subjected to analysis through experimental models and there is robust evidence to The concept of ‘Hygiene Hypothesis’ (HH) was for the support the premise enumerated earlier. first time introduced by Strachan in 1989 based on the observation of an inverse correlation between sibling The beneficial nature of infections against different size and risk of allergy: more the sibling sizing less was autoimmune disorders through their immunomodulating the chance of developing allergic disorders. This was activity has been demonstrated in animal models. Murine further validated in other studies in different populations. model of colitis induced by trinitrobenzene sulfonic acid Furthermore, a meta-analysis of 32 studies revealed (TNBS) or dextran sodium sulfate (DSS) is significantly decreased risk of atopic in infants or children reduced after exposure to S. mansoni soluble egg exposed to pet , those consuming less antibiotics and through enhancement of IL-4, IL-10 and reduction of in those who grew up in rural areas. IFN-γ . Furthermore, infection of mice with T. spiralis cercariae antigen significantly reduces severity of disease Besides susceptibility to allergy, the HH is also valid for when colitis is induced subsequently. autoimmune diseases. Interestingly, persons from similar ethnic background living in two different environmental The administration of helminthic products also showed conditions showed six fold higher prevalence of T1D in promising results in experimental autoimmune areas with good sanitary conditions. These observations encephalitis (EAE), a model for MS(multiple sclerosis). have been attributed to varied infection rates in two Before the onset of EAE, administration of S. mansoni diverse geographical areas: reduced exposure to infection antigen or its cercariae reduced the severity and increases autoimmune response to self, facilitating incidence of EAE through decreased TNF-α, IL-12, susceptibility to T1D. Prevalence of IBD is higher in IFN-γ and increased TGF-β,IL-4 and IL-10. In addition, US compared to sub Saharan Africa, and increased transfer of splenic T-cells from T. spiralis infected rats into helminth infection in Africa has been attributed to play experimental model significantly protected them from a modulatory role in preventing IBD. In India, an inverse disease onset. correlation between filarial infection and autoimmune In collagen induced arthritis (CIA) model, akin to disorders such as systemic lupus erythematosus and RA, effectiveness of ES-62, a filarial parasite (A. vitae) rheumatoid arthritis has been observed. Interestingly, execretory glycoprotein molecule has been established. SLE is more frequent in African Americans compared ES-62 interfered with initiation, progression and severity to West African. Furthermore, human migration studies of CIA by diminishing Th-1 and Th-17 immune responses. 146 4, IL-5, IL-9, Il-10 and IgE. Experimental models infected models Experimental IgE. and Il-10 IL-9, IL-5, 4, to atopicdisorders through increased production ofIL- islinked Th2 response The cytokines. proinflammatory autoimmune diseases cells through production of distinct Th1 responsehasbeenlinked tothepathogenesisof Th1 andTh2subsetshaving distinctlyoppositefunction. their requirement.T-helper cellsfurtherpolarizeinto on based cells Treg or Th into differentiate T-cells Naïve vital inantigenpresentationtoTcells. towards amoretolerogenicsubset.Dendriticcellsare immune hoemostasis,andchangeofdendritic cells and B-regcells,pivotalinmaintaining (Treg) regulatory T of amplification , cells Th-2 of elevation differentiation, have helminth properties includingrepressionofT-helper-(Th)1/Th17 of effects been extensively investigated. Ithasseveral important immunomodulatory The feasible application. remains tobeseeniftheseobservationsit into translate to RAandSLE.But products inreducingsusceptibility been postulated as a mechanism of action of filarial worm negative correlation of IL-17 and filarial antigen levels has and autoimmunedisease such asSLE and RA.Recently,a infection filarial between association negative significant Some robust datafrom Indian populationshowed a helminth derived productsfortherapyinthesediseases. products in RAandT1D there arenoclinicaltrialsusing suggest a possible therapeutic role for helminths or its models and experimental Although epidemiologicaldata without infections. anti-inflammatory IFN-γ and IL12 in infected MS patients compared to those the TGF-b, lower IL-10, and cytokine, levels like cytokines inflammatory of of levels higher without helminthinfections.Investigation revealed resonance activity imagingcompared to MS patients scores, lower number of relapse and improved magnetic who harboredhelminthinfectionhadreduceddisability controls. Theobservation suggestedthatMSpatients infections (c)helminthsinfectedsubjectsand(d)healthy with naturallyinfectedhelminths,(b)MSpatientswithout important follow-upstudycomprising of (a) MS patients failed to demonstrate effectiveness of TSO against CD. An rate. However, arecentphase-2clinical trial in 2013, of respondersandenhancedremission increased number severity, of disease reduction significant revealed have (Crohn’s disease) andrefractoryUC() Clinical trialsofTrichurissuis(TSO)inCD therapy. helminth of effectiveness and safety assess to out carried been have trials clinical Several community. scientific the or modulateautoimmunedisorders has takenthefancyof protect to products parasite of effect the of trials Human with infection by diabetes non- manifest progression from to rapid mice (NOD) diabetic obese of protection indicates evidence experimental Several IL-4 andIL-13,theanti-inflammatorycytokines. through expansion of TGF-b and increased production of IL-10, CLINICAL EVIDENCE CLINICAL THE IMMUNOLOGICAL BASIS OF HYGIENE HYPOTHESIS S. mansoni S. ecra antigens cercariae into therapeuticapplication. translated be could which spinoff beneficial a as allergy could preventimmune responsethat autoimmunityand host immunesystemthroughsuppressionofactive relationship. Itssurvival is depended on evasion of the the humanhostover millionsofyear hasasymbiotic It isapparentthatworms, which has co-evolved with non-inflammatory phenotype. by promotingIL10 production from macrophage M2, the reduces sinensis Clonorchis with infection dextran-sodium-sulfate (DSS)-inducedcolitismicemodel, higher expressionofIL10,TGF-bandarginase-1.In and IL12 lower with phenotype anti-inflammatory and macrophages are characterizedbyimmunosuppressive classical M1 activation oralternative M2activation. M2 Based on externalstimulimacrophagesundergo drives theadaptive immuneresponseisthemacrophage. immune systemthat The otherimportantcelloftheinnate lectin receptors. parasite products through tolllikereceptororCtype towards tolerogenicphenotypehasbeenstimulatedby beneficial have role against autoimmune diseases. Polarization of DC DC Tolerogenic responses). Treg (Th2, immunogenic (Th1, Th17 phenotype) or tolerogenic antigen toT-cells. DC directs T cells polarization towards of dendritic cells are tocapture,process and present system and inautoimmune diseases. Important functions Dendritic cells playapivotalrole in theinnateimmune of IL10was observed injointsofCIAmodel been reported in MS, IBD and CIA model and restoration proliferation ofB reg cells by helminthinfectionhave and (Breg) andincreaseproductionofIL10.Generation cells Helminths promoteproliferationofBregulatory immune responsetowards Th2type. in humansuppressIL17productionandpossiblypolarize infection filarial Interestingly, IL10). (IL-4, cytokines Treg by suppressingTh1/Th17cytokines,andincreasingTh2/ induced arthritismodelimproves diseasepathogenesis collagen a to product helminth ES-62 of Administration inflammatory cells that regulatesthebalancebetween Th1andTh2. mediated TGF-b. Furthermore,itenhancesproliferationofTreg Th1/Th17 disorders through increasedproductionandIL-10 regulate down helminths of diseasepathogenesis.Infectionwith outcome final the in Treg and Th17 as such factors other disease manifestations.Thisindicatestheimportanceof in experimental models but itdoes not translateinto Thus helminth infectionsshould leads to atopicdisorder with helminthshaveimmune response. shownaTh2type innate andadaptive immune system, down regulating products in immune modulation. It actsonboththe emerging from the roleplayed by helminths andits disorders has beencritically evaluated with evidence Its impact on several autoimmune diseases and allergic and clinicalobservations.epidemiological, experimental Hygiene hypothesis has beenvalidated through CONCLUSION CHAPTER 32 147 Nature Clinical 2016; 22:481-486 BMC Medicine 2015; BMC Medicine 13: DOI: 10.1186/s12916- Versini M, Jeandel P, Bashi T,Bizzaro G, M, Shoenfeld Blank Bashi T,Bizzaro Jeandel P, M, Versini and of helminthes Hypothesis Hygiene the Unraveling Y. and clinical pathophysiology, origins, : applications. 015-0306-7 control the and infections helminth Parasitic RM. Maizels disorders. autoimmune and allergic human of Microbiology and Infection Microbiology Weinstock Weinstock JV. Autoimmunity: the worm returns. 2012; 491:183-185 Ben-Ami Shor, Harel M,Ellakim to hygiene their ova theory harnessing helminthes and R, Shoenfield Y. Allergy Immunol 2013; 45:211- Clin Rev treat autoimmunity. The 216 4. 5. 6. 7. 2014; 23:1553-1554 2016; DOI: 10.1177/0961203316662722 Panda AK, Das BK. Diminished IL-17A levels may Das BK. Diminished IL-17A levels AK, Panda protect filarial infected individuals from development of and systemic lupus erythematosus. rheumatoid arthritis Lupus Panda AK, Das BK. Rheumatoid arthritis patients are free arthritis AK, Das BK. Rheumatoid Panda of filarial infection in an area where filariasis is endemic: et al. Arthritis and Pineda on the article by comment 2013; 65:1402-1406. Rheumatism AK, Absence Das of BK. filarialPanda infection in patients of systemic lupus erythematosus (SLE) in filarial endemic role. Lupus area: a possible protective REFERENCES 3. 1. 2. the inflammatoryphenotype. Human clinical parasite new exciting will provide decades the coming trials in diseases. of autoimmune the treatment for molecules