antibodies Review Anti-Idiotypic Agonistic Antibodies: Candidates for the Role of Universal Remedy Aliya K. Stanova 1, Varvara A. Ryabkova 1 , Sergei V. Tillib 2,3, Vladimir J. Utekhin 1, Leonid P. Churilov 1,4,* and Yehuda Shoenfeld 1,5 1 Department of Pathology and Laboratory of the Mosaic of Autoimmunity, Saint Petersburg State University, 199034 Saint Petersburg, Russia; [email protected] (A.K.S.); [email protected] (V.A.R.); [email protected] (V.J.U.); [email protected] (Y.S.) 2 Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; [email protected] 3 Institute of Gene Biology, Russian Academy of Sciences, 119334 Moscow, Russia 4 Saint Petersburg Research Institute of Phthisiopulmonology, 191036 Saint Petersburg, Russia 5 Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to Tel Aviv University School of Medicine, Tel-Hashomer, Ramat Gan 52621, Israel * Correspondence: [email protected] Received: 30 April 2020; Accepted: 26 May 2020; Published: 28 May 2020 Abstract: Anti-idiotypic antibodies (anti-IDs) were discovered at the very beginning of the 20th century and have attracted attention of researchers for many years. Nowadays, there are five known types of anti-IDs: α, β, γ, ", and δ. Due to the ability of internal-image anti-IDs to compete with an antigen for binding to antibody and to alter the biologic activity of an antigen, anti-IDs have become a target in the search for new treatments of autoimmune illnesses, cancer, and some other diseases. In this review, we summarize the data about anti-IDs that mimic the structural and functional properties of some bioregulators (autacoids, neurotransmitters, hormones, xenobiotics, and drugs) and evaluate their possible medical applications. The immune system is potentially able to reproduce or at least alter the effects of any biologically active endogenous or exogenous immunogenic agent via the anti-idiotypic principle, and probably regulates a broad spectrum of cell functions in the body, being a kind of universal remedy or immunacea, by analogy to the legendary ancient goddess of universal healing Panacea (Pανα´κεια, Panakeia in Greek) in the treatment and prevention of diseases, possibly including non-infectious somatic and even hereditary ones. Keywords: anti-idiotypic antibodies; agonistic autoantibodies; autacoid; drug; hormone; neurotransmitter 1. Introduction In 1900, London and Besredka demonstrated the existence of physiologic antihemolysins. In fact, these were anti-idiotypic autoantibodies (anti-IDs) against hemolysins. The authors immediately suggested their regulatory role [1]. Much later experimental anti-IDs were obtained by Kryzhanovsky et al. (1960) [2] and by Oudin (1963) [3]. In 1973, Lindenmann speculated that some anti-IDs may serve as homobodies or internal immunological mirror images of appropriate antigens [4]. The interest in anti-IDs started to increase with the proposal of the network theory of the immune system by Jerne in 1974 [5]. The main idea was that Ab can both recognize an antigen and in turn also be recognized by another Ab towards its paratope (Figure1). Antibodies 2020, 9, 19; doi:10.3390/antib9020019 www.mdpi.com/journal/antibodies Antibodies 2020, 9, x FOR PEER REVIEW 2 of 15 Antibodies 2020, 9, 19 2 of 15 Antibodies 2020, 9, x FOR PEER REVIEW 2 of 15 Figure 1. Scheme of idiotypic/anti-idiotypic interactions. Figure 1. Scheme of idiotypic/anti-idiotypic interactions. Figure 1. Scheme of idiotypic/anti-idiotypic interactions. The mechanism of the formation of Jerne’s network is the following: An antigen stimulates the The mechanism of the formation of Jerne’s network is the following: An antigen stimulates the productionThe mechanism of Abs (Ab1). of the The formation active centers of Jerne’s of Abnetwor1 arek recognized is the following: by the Ansecond antigen class stimulates of Abs—anti- the production of Abs (Ab1). The active centers of Ab1 are recognized by the second class of Abs—anti-IDs productionIDs (Ab2). Inof theirAbs (Ab1). turn, Ab2 The servesactive ascenters an antigen of Ab 1for are the recognized third class by of the Abs second (Ab3)—anti-anti-IDs, class of Abs—anti- and (Ab2). In their turn, Ab2 serves as an antigen for the third class of Abs (Ab3)—anti-anti-IDs, and so on [6]. IDsso on(Ab2). [6]. TheIn their network turn, Ab2finally serves appeared as an antigento be not for endless, the third because class of Ab3 Abs may (Ab3)—anti-anti-IDs, be identical or close and in The network finally appeared to be not endless, because Ab3 may be identical or close in their recognizing sotheir on [6].recognizing The network properties finally to appeared Ab1. The to system be not is endless, self-balanced because and Ab3 follows may be thermodynamically identical or close inLe properties to Ab1. The system is self-balanced and follows thermodynamically Le Châtelier’s principle theirChâtelier’s recognizing principle properties of shift to Ab1.compensation The system (Le is self-balanced Châtelier′s principleand follows states thermodynamically that if a dynamic Le of shift compensation (Le Châtelier s principle states that if a dynamic equilibrium is disturbed by Châtelier’sequilibrium principle is disturbed of shiftby changing compensation0 the conditions, (Le Châtelier the position′s principle of equilibrium states that shifts if toa counteractdynamic changing the conditions, the position of equilibrium shifts to counteract the change to reestablish equilibriumthe change tois disturbedreestablish by equilibrium), changing the hence conditions, the appearance the position of any of equilibriumnew antigenic shifts specificity to counteract “X“ or equilibrium), hence the appearance of any new antigenic specificity “X” or an increase in the amount thean changeincrease to in reestablish the amount equilibrium), of any existing hence Ab the te appearancends to make of the any system new antigenic respond specificityby increasing “X“ theor of any existing Ab tends to make the system respond by increasing the production of anti-X- or anti-Ab anproduction increase inof theanti-X- amount or anti-Ab of any sp existingecificities. Ab In te thisnds interpretation,to make the system the immune respond system by increasing does not carethe specificities. In this interpretation, the immune system does not care about the self- or non-self-character productionabout the self-of anti-X- or non-self-character or anti-Ab specificities. of recogniz In thisable interpretation, antigens, and the rather immune keeps system the idiotype–anti-does not care of recognizable antigens, and rather keeps the idiotype–anti-idiotypic balance. Moreover, according to aboutidiotypic the balance.self- or non-self-characterMoreover, according of torecogniz Jerne’sable theory antigens, it is nothing and ratherbut autoimmunity, keeps the idiotype–anti- which serves Jerne’s theory it is nothing but autoimmunity, which serves as the key point of the physiologic idiotypicas the key balance. point of Moreover, the physiologic according autoregulation to Jerne’s theory of the it immuneis nothing system. but autoimmunity, which serves autoregulation of the immune system. as theAnti-IDs key point are of directedthe physiologic against authetoregulation idiotype of ofAb the1 and immune may represent system. its mirror replica. It seems Anti-IDs are directed against the idiotype of Ab1 and may represent its mirror replica. It seems that Anti-IDssome of themare directed can recognize against the idiotypesame structur of Abes1 andas the may antigen represent does. its Paul mirror Ehrlich replica. was It the seems first that some of them can recognize the same structures as the antigen does. Paul Ehrlich was the first thatwho some pointed of them out in can Latin: recognize “Corpora the nonsame facit structur nisi fixataes as”—“ theThe antigen bodies does. cannot Paul act Ehrlichby other wasmeans the than first to who pointed out in Latin: “Corpora non facit nisi fixata”—“The bodies cannot act by other means than whobind ”pointed [7]. The out recognition in Latin: “ Corporaof the same non facitstructures nisi fixata both”—“ byThe an bodies antigen cannot and act by by its other anti-IDs means in than living to to bind”[7]. The recognition of the same structures both by an antigen and by its anti-IDs in living bindsystems” [7]. mayThe elicitrecognition similar of inform the sameational structures and signaling both by consequences. an antigen and If anti-IDs by its anti-IDsdo recognize in living and systems may elicit similar informational and signaling consequences. If anti-IDs do recognize and systemsbind like may their elicit primary similar antigens, informational they might and signalingto a certain consequences. degree act asIf theanti-IDs antigen, do recognizeand imitate and or bind like their primary antigens, they might to a certain degree act as the antigen, and imitate or bindcompetitively like their blockprimary some antigens, (or even they all) mightbiological to a effects certain of degree primary act antigens as the antigen,(hormones, and xenobiotics, imitate or competitively block some (or even all) biological effects of primary antigens (hormones, xenobiotics, competitivelyneurotransmitters, block autacoids,some (or even and aldrl)ugs). biological This option effects gives of primary an over antigenswhelming (hormones, hope that xenobiotics, the immune neurotransmitters, autacoids, and drugs). This option gives an overwhelming hope that the immune neurotransmitters,system