continuous dual resetting of the immune repertoire as a...

Review ArticleContinuous Dual Resetting of the Immune Repertoire asa Basic Principle of the Immune System Function

Silvana Balzar

Department of Clinical Microbiology, Polyclinic Breyer, Zagreb, Croatia

Correspondence should be addressed to Silvana Balzar; [email protected]

Received 29 July 2016; Accepted 4 December 2016; Published 26 January 2017

Academic Editor: Andreia M. Cardoso

Copyright © 2017 Silvana Balzar.This is an open access article distributed under the Creative Commons Attribution License, whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Idiopathic chronic inflammatory conditions (ICIC) such as allergy, asthma, chronic obstructive pulmonary disease, and variousautoimmune conditions are a worldwide health problem. Understanding the pathogenesis of ICIC is essential for their successfultherapy and prevention. However, efforts are hindered by the lack of comprehensive understanding of the human immunesystem function. In line with those efforts, described here is a concept of stochastic continuous dual resetting (CDR) ofthe immune repertoire as a basic principle that governs the function of immunity. The CDR functions as a consequence ofsystem’s thermodynamically determined intrinsic tendency to acquire new states of inner equilibrium and equilibrium againstthe environment. Consequently, immune repertoire undergoes continuous dual (two-way) resetting: against the physiologiccontinuous changes of self and against the continuously changing environment. The CDR-based dynamic concept of immunitydescribes mechanisms of self-regulation, tolerance, and immunosenescence, and emphasizes the significance of immune system’scompartmentalization in the pathogenesis of ICIC. The CDR concept’s relative simplicity and concomitantly documentedcongruency with empirical, clinical, and experimental data suggest it may represent a plausible theoretical framework to betterunderstand the human immune system function.

1. Introduction

Although a remarkable progress has been made in under-standing immunity, a comprehensive general model of func-tion of the immune system has not been established. Whilenumerous elements of the immune machinery are identified,the key functional nodes, organizational hierarchy (if any),and how the immune system regulates itself are still not clear.

That is not just a theoretical problem. The lack of basicunderstanding of immune system’s function thwarts effortstoward successful treatments and prevention of steadilygrowing pandemics of chronic inflammatory conditions suchas allergy, asthma, chronic obstructive pulmonary disease(COPD), inflammatory bowel disease (IBD), and autoim-mune conditions. According to the World Health Orga-nization’s estimate (the global burden of disease, updatefor 2004), only the chronic respiratory diseases (allergicrhinitis, asthma, and COPD) affect more than 1.2 billionpeople. Although we have been aware of those idiopathicconditions for decades, their pathogenesis is still unknown.

Nevertheless, all are considered immunologic in origin[1, 2].

The current reductionism-driven research has been iden-tifying cellular and molecular mechanisms (such as TNF-𝛼, IL-5, and IL-4 pathways) associated with the previouslymentioned diseases. However, the subsequently developedimmunologicals, which target particular components of theinflammatory cascade, have been somewhat effective inreducing the symptoms, but not in resolving the pathology.Therefore, there is an urgent need to broaden the approachesand find the way to not only therapeutically control thoseimmune disorders, but also develop effective preventionstrategy and thus protect the health of future generations.The members of the recently formed trans-NIH Centerfor Human Immunology, Autoimmunity and Inflammation(CHI) have outlined these problems in the initiative tocomprehensively study the human immune system as a pan-NIH project, thus proposing a holistic approach to acquire adeeper understanding of the function of the immune system[1].

HindawiJournal of Immunology ResearchVolume 2017, Article ID 3760238, 13 pageshttps://doi.org/10.1155/2017/3760238

https://doi.org/10.1155/2017/3760238

2 Journal of Immunology Research

In line with those efforts, proposed here is a generalconcept of function of the immune system. The conceptbuilds on the fact that, due to living system’s continuous com-munication with the environment (energy exchange throughheat, food intake, waste excretion, etc.), the system under-goes continuous disturbances and fluctuations in molecularinteractions. Therefore, the system is forced to continuouslyreset itself toward appropriate equilibrium states. Such acontinuous equilibrium resetting in the system is a base forthe continuous dual (two-way: against self and against theenvironment) resetting of the immune repertoire (CDR) asa mode of the immune system function.

Description of the CDR-based concept (CDRc) will beginwith a brief summary of basic elements and current conceptsin immunology as a framework, will include description ofthe resetting process, and will incorporate those elementsto create a general outline of function of the immunesystem. The last part will focus on compartmentalization ofthe immune system, which this concept considers essentialfor establishment and preservation of immune competency.Finally, described is the emerging common mechanismproposed to underlie the pathogenesis of idiopathic chronicinflammatory conditions (ICIC). Concomitant with descrip-tion of the CDRc are examples of empirically and clinicallyrecognized human conditions, which are interpreted in theCDRc context.

2. Methods and Basic Premises

Human physiology and pathology is in focus as the mostrelevant element in the process of building the CDRc. Theapproach applies basic principles of living systems’ function,current concepts in immunology, and clinical data as theframe and points of reference for this concept.

2.1. Living System’s Integrity. Living organism actively resiststhe overall energy drive toward entropy and disintegrationinto the environment. Immune processes contribute to themaintenance of organism’s integrity by sensing/defining itsdistinction/individuality (self) against other organisms andthe environment. That is accomplished through continu-ous adjustments/resetting of a system to establish a steadystate/equilibrium (a) within the system and (b) with/againstthe environment. One can assume that, to reduce the loss ofresources and energy, the surface interactions with the envi-ronment and nonself would be energy sparing and simple—preferably nonspecific, passive, and neutralizing (such asprotective secretion of mucins, secretory IgA-mediated anti-gen exclusion, lactoferrin, etc.). Only when those rela-tively passive protective mechanisms fail are active innateresponses triggered, primarily originating from the surface-lining epithelial cells [3]. These basic passive mechanisms arevery important, as many elements of self and nonself are ofa common origin across all living organisms and thus arelikely to have similar molecular structure. Active reactionsagainst those common elements are undesirable, as they carrya risk of cross-reactions and subsequent collateral damage toself. With evolution deriving increasingly complex life forms,the sophistication of self/nonself discriminationmechanisms

has been increasing as well. The innate recognition (pattern-recognizing molecules and receptors, PRRs) remains evolu-tionarily preserved, predominant, and essential even in mostcomplex organisms. Development of additional, specificity-driven adaptive immunity that uses recombination and generearrangements to form unique T and B cell receptor (TCRand BCR) specificities has ensured a successful self/nonselfdiscrimination and expansion of jawed vertebrates (fish,amphibians, reptiles, birds, and mammals).

2.2. Stochasticity. Randomness of events and uncertainty ofoutcomes are intrinsic to all processes in nature. Livingsystem can be described as a deterministic chaos of interac-tions, with outcomes that are predictable only to a certaindegree. Evolutionarily successful living organism functionswith a degree of (un)certainty that makes its survival andreproduction sufficiently probable.

The complexity of processes governed by randomness ofinteractions is exemplified in noncovalent molecular inter-actions typical for immune processes. Those interactionsoccur due to attraction/repulsion forces between molecules’surface residues (affinity) and are further affected by spa-tial/structural compatibility (avidity).Those interactions pro-ceed as a continuous process that fluctuates depending onlocal parameters (temperature, pH, concentration of ligands,etc.). Such multifactorial interactions trigger multiple down-stream events whose interactions further expand the rangeof possible outcomes, all making the linearity in biologicprocesses highly improbable. As the dynamics and strength ofall interactions are influenced bymany parameters, outcomesare difficult to predict or control. Obviously, evolutionaryselection favored the systems that can function in a stablemanner and thus maintain integrity, that is, can successfullycompensate for a certain range of instability and fluctu-ations in a system. The redundancy of system-balancingmechanisms further contributes to the multitude of diverseprocesses and pathways that assure favorable outcomes—maintenance of integrity at optimal and energy-efficient equi-libriumpoints.Therefore, living systems are self-regulatory andsufficiently likely to maintain their integrity when functioningwithin a certain range of parameters.

2.3. Terminology and General Context. Human physiologyand pathology is in focus. Further discussion will often referto conventional T/B cells, whose phenotypes and functionare more thoroughly investigated. However, the proposedmechanisms are considered as generally applicable: they mayinvolve differentmolecules (innate receptors, inter- and intra-cellular signaling molecules, etc.), but the principle remainsthe same. Along those lines, immune repertoire includesboth innate and adaptive specificities and mechanisms. Term“self” will be used for distinct molecular patterns that areunique to every single living organism (including syngeneicindividuals). “Nonself ” can be an altered self or a foreign and,in either case, induces recognition—a molecular reaction orsignaling [4].

As a consequence of interactions with the environment,living organisms continuously change and, in response tothose changes, their self is also changing—resetting to reach

Journal of Immunology Research 3

a new point of inner (within the system) equilibrium, aswell as a steady state against the environment. Therefore,immune reactions reflect a state of a dynamic equilibrium ofa system whose likelihood of maintaining integrity against theenvironment continuously fluctuates.Those fluctuations couldbe within or outside the parameters considered physiologic(perception of health versus disease). As the uncertaintyof outcomes in such a complex system is intrinsic, learn-ing about the patterns of system’s function could identifyintervention points with acceptably predictable outcomes,potentially suitable for therapeutic purposes.

2.4. Expanding from the Current Concepts in Immunology

2.4.1. Polyspecificity/Cross-Reactivity. Thenotion is that poly-specificity must be a rule in immune recognition in order forclonal selection to work [5]. Polyspecificity primarily refersto TCR/BCR recognition, while it is certainly applicable toPRRs, chemokine receptors, endogenous ligands’ receptors,and so forth. It predicts that, with cross-reactive or degeneraterecognition, a smaller number of receptors are requiredto provide a competent repertoire. Strength of interactions(and thus their likelihood) fluctuates depending on the localparameters, which continuously change the affinity/avidityof interactions. As explained later, that may be crucial forregulation and resolution of the immune response, as well asreestablishment of equilibrium in a system.

Strength of integrated signaling regulates the functionalphenotype and survival of cells. It is well established thatthe T/B cell clonal selection depends on the strength ofTCR/BCR signaling from interactions with self [6]. Appliedto the peripheral immune setting, along with the notionabout integrated signaling, the constellation of various typesof signals that cells receive in the periphery (TCR/BCRengagement, costimulatory signals, innate signals, etc.) maydetermine both the functional phenotype and survival ofT/B cells. Indeed, recent reports have shown that integratedinnate, endogenous (TLRs, aryl hydrocarbon receptors), andTCR signals are involved in development of a particular Tcell phenotype and regulation of adaptive immunity [7–15].Similar mechanisms have been reported for marginal zone Bcells and NK cells as well [16, 17].

In a more general context, the entirety of interactionsbetween different cell populations, including leukocytes andstructural cells, and the matrix (through direct interac-tions, released mediators, exosomes, etc.), contributes tointegrated signals that continuously change and regulatethe phenotype, function, and fate of all cells [18, 19]. Suchinteractions modify the system’s inner and surface environ-ment and determine the outcomes that maintain system’sintegrity.

2.4.2. The Self Is Continuously Changing. Normal growthand development, maturation, chronologic aging, varioushormonal states (such as pregnancy), and inflammatoryand repair processes, as well as the continuous interac-tions of self with the environment (commensal flora, foodintake, etc.) are all associated with (or a consequence of)

immunologically recognizable molecular changes of self [20–22]. Those changes, which include permanent or temporarymodifications of glycosylation or glycation processes, alterthe molecular patterns of self [21–23]. That triggers home-ostatic readjustments in the system, including the immunerepertoire’s resetting independent of exposures to the foreign.Indeed, it has been reported that human marginal zoneB cells have molecular footprints of past proliferation andaccumulated mutations during fetal life in the absence ofgerminal centers and independently of antigenic stimulation[24, 25]. Also, memory phenotype T cells have been foundbefore birth in humans and in mice held in germ-free and inantigen-free conditions [13].

The changes of self could be inferred from age-associated differences in the immune repertoire,which is positively selected based on reactivityto self [6]. The limited repertoire for carbohy-drate antigens in early childhood (but with alreadycompetent repertoire for peptide antigens) sug-gests that self may be less glycosylated during thatearly growth/development period and it significantlychanges with age [21, 22]. The immune repertoireexpands through adolescence, reaches full compe-tence in adulthood, and then gradually decreasesto significant reduction in the elderly (reductionin repertoire diversity starts after age of ∼50) [26].Reduction of the repertoire in the elderly affectsprimarily responses to carbohydrate antigens (which,as it will be explained later, the CDRc considers aconsequence of age-related increased glycosylationand glycation and loss of specificities due to the reper-toire resetting against self). Related to differences inrepertoire and in molecular patterns of self may bethe variability in clinical presentation and outcomesof acute infectious diseases in subjectswithin differentage groups. For example, hepatitis A infection inyoung children is subclinical. However, it causessignificant morbidity in adults. Also, pregnancy-associated hormonal environment could induce ges-tational diabetes. Similarly, metabolic abnormalitiescaused by diabetes mellitus induce endothelial dam-age, and so forth. All those observations suggest thatself is continuously changing due to both physiologicand pathologic events [21–23, 26–28].

As it will be argued later, the interplay between envi-ronment-induced/extrinsic immune reactions and intrinsicchanges of self may determine individual’s immune status.

3. The Immune Repertoire ContinuousDual Resetting- (CDR-) Based Concept ofthe Immune System Function

The CDRc postulates continuous dual (two-sided) resetting ofthe immune repertoire triggered by (1) intrinsic changes of selfand (2) interactions with the environment. Considering thecontinuity of both processes and constant readjustments tomaintain a steady state/equilibrium, the resulting changes in


strength of integrated signaling determine the phenotype andsurvival of cells-effectors and thus the outcomes of immuneprocesses at any given point in time.

3.1. Self-Regulation. Polyspecificity and functional plasticityof T cells allow for a TCR-diverse population of activatedclones to acquire a range of functional phenotypes (from sup-pressive to response-amplifying), depending on the strengthand constellation of integrated signals that each of theactivated clones receives. During immune reaction, a set ofactivated clones will produce a dynamic curve of responses.On each side of the curve, the extremes of the curve will beclones either deleted or anergized due to the extremes of highor low strength of signaling (resp.) and thus permanently lostor (temporary) silenced. Among the intermediary-reactingclones will be the clones with regulatory function: the low-activated fraction of intermediaries acquiring a suppres-sive phenotype (IL-10/TGF-𝛽 realm) and the high-activatedfraction of intermediaries acquiring a reaction-amplifyingphenotype (Th17 realm). The expansion/contraction of thosesubsets may fluctuate depending on the strength of inte-grated signals (local parameters, concentrations of activatingself/nonself ligands, endogenous ligands, innate signals, etc.).If the signaling is overall decreasing (due to changed localparameters, ligand neutralization/clearance, downregulationof innate signals, etc.), the activation state of reaction-amplifying and medium-activated subsets will “downgrade”to medium-activated, suppressive, or dormant phenotypes,respectively. Gradually, inflammation will subside and enterthe resolution/repair phase, regulating itself according tothe changes in relevant parameters. The clones that werenot lost in this particular reaction can be activated in adifferent set of circumstances. Due to polyspecificity, clonescan assume roles/functional phenotypes different from theirprevious experience and become engaged and governed byelements of a new reaction. Therefore, there are no fixedphenotypes. Each clone can acquire a range of phenotypes andcontribute to self-regulation of different immune reactions.All clones-survivors will be available for activation in another(possibly unrelated, but cross-reactive) response. If activated,they will acquire a phenotype corresponding to the strengthof integrated signals at any given point during a particularreaction. It is reasonable to predict that greater repertoirediversity (and thus higher granularity of specificities) will affordgreater regulatory potential.

It has been observed that the long-term memoryin the CD4+ T cell population may not obey strictrules or be as long as previously thought [29]. Thatobservation could be explained by polyspecificity andmultifunctionality of clones, which may repeatedlyengage in a variety of not obviously related reactions,as well as in response to newly encountered anti-gens. Similar issues have been recently reviewed asrelated to vaccination responses in the elderly [30].Also, recent report suggests that long-term antibodyresponses aremaintained in part by long-lived plasmacells, but 40–50% of plasma cells are newly formedcells from clonally disparate precursors [31].

3.2.The Resetting Process in Tolerance and Repertoire Fluctua-tions. As described, adaptive immune response will engagea population of T cells consisting of clones with a rangeof TCR specificities, which will behave as a dynamic entitythat keeps changing its phenotype profile and adapting inresponse to a dynamic constellation of parameters, adjustingcells’ function/phenotype accordingly. At any point duringsuch a process, additional dormant clones can be engaged,and overly activated clones can be lost. Such a loss ofclones/specificities resulting from an adaptive reaction willeffectively reset the overall repertoire.

The observed sepsis-induced T cell loss and alter-ations within the CD4 T cell compartment are anexample of repertoire resetting and attrition after aviolent systemic adaptive response. Postsepsis alter-ations include reduced repertoire diversity, changedCD4 T cell subpopulation profiles, and suppressedimmune function, with increased susceptibility tosecondary infections [32].

Simultaneously with the resetting during an adaptiveresponse similar repertoire resetting occurs as a homeostaticmechanismof adaptation to the changes of self. Asmentionedbefore, those changes of self are intrinsic to growth, matura-tion, and aging but also are induced by stress, inflammation(injury, infection), pregnancy, metabolic abnormalities, andso forth. As with adaptive reactions, the changes of self canengage dormant cells that have been minimally self-reactive,already active clones can reach a state of inappropriateactivation, and additional signaling input can eliminate thosein a state of strong activation. In addition, dormant clonescan die out of neglect if the newly changed self no longerprovides the positive reinforcement signals. In this context,tolerance reflects a dynamic state of homeostasis maintainedby a successful resetting of the immune repertoire against bothself and nonself.

One can appreciate how continuous resetting of therepertoire can both expand (engagement of dormant and/ornaıve cells) and reduce (deletion due to hyperactivation) theavailable range of specificities.

In parallel, the innate repertoire (adhesion molecules,PRRs, innate receptors, etc.) is continuously changingthrough the degree of expression, tachyphylaxis, due to sec-ondary molecular modifications (changes in glycosylation,glycation), and so forth, thus affecting the strength/quality ofinteractions and integrated signaling.

It is important to note that the resetting processes will bemore pronounced with more frequent activations of adaptiveresponses. Adaptive reactions will keep inducing the resettingof the repertoire in addition to its continuous homeostaticresetting against self. It should be also kept in mind that theexpansion of the T cell repertoire is limited by availability ofnaıve clones and involution of the thymus. In addition, dueto glycosylation/glycation or other changes of self, the B cellrepertoire may shift/decline with age, with altered repertoireparticularly against the carbohydrate epitopes. Therefore,there is a breaking point when an overall immune declinestarts. From that point on, any future immune interactions(homeostatic or adaptive) are likely to result in repertoire


Puberty &adolescence

Adulthood Senescence

Glycation

Peptide ATGS

Carbohydrate ATGSCa

rboh

ydra

tes a

sm

odifi

ers o

f self

Repe

rtoi

reco

mpe

tenc

y

Glycosylation

10 20 50 800AGE (years)

Figure 1: Concomitance of the age-related changes in glycosylation and glycation patterns with the age-related repertoire competencyexpansion and contraction/attrition. Competency for peptide antigens develops early in life and persists throughout life. In contrast, repertoirefor carbohydrate antigens develops gradually. It parallels the growth- and maturation-induced glycosylation of self (first ∼15 years of life), towhich the prominently active thymus during that period of life respondswith an output of carbohydrate-responsive repertoire.That repertoirecontracts later in life, paralleling increased alterations of self due to potentially pathogenic glycosylation and/or glycation processes. Thosealterations may be primarily induced by environmental factors (injury, infection, nutrition-induced metabolic abnormalities, etc.) and mayresult in repertoire attrition.

attrition. Consequently, due to the reduced repertoire’s gran-ularity, the regulatory potential and the tolerance range willdecrease as well.

Taken together, the CDRc allows for regulatory mecha-nisms to emerge at all times and in response to a range ofnonself- or self-induced challenges. It predicts acquisition andmaintenance of tolerance as a continuous and dynamic process,which stems from and depends on the available immunerepertoire. Owing to the redundancy of mechanisms andpolyspecificity/degeneracy of interactions, the cells’ func-tional plasticity and resetting processes may preserve thecompetency of the system and successfully compensate forrepertoire attrition (intrinsic to this concept), with relativelyminor disturbances in the system. Those could manifestas subclinical inflammatory responses and allergic reac-tions. Significant alterations/reductions of such a redundantrepertoire can normally be expected with advanced age(involution of thymus, progressive alterations of self), but alsoas a consequence of violent or persistent adaptive responses(extensive injury, sepsis, perpetual infections, and chronicinflammatory syndromes). Those can gradually reduce therepertoire’s diversity and its regulatory potential and startengaging less appropriate mechanisms. Such a sequence ofevents may increase probability of unfavorable outcomes,cause instability in the system, and eventually lead to theirreparable loss of system’s integrity—death.

4. Carbohydrate Antigens, Glycosylation, andImmune Repertoire Resetting Associatedwith Age(ing)

Carbohydrates and their moieties are ubiquitous in nature.Virtually all living organisms (prokaryotes and eukaryotes,plants, fungi, and animals) are coated with carbohydrates orcarbohydrate residues. In mammals, glycosylation is a part of

posttranslational protein modification and lipid alterations,providing their structural stability and defining interactionswith other molecules [33, 34]. Glycosylation is differentiallyregulated during development, growth, and maturation. Inaddition, protein-glycan interactions are recognized as piv-otal in controlling innate and adaptive immune responses[35–37].

Such ubiquity of carbohydrates in nature and theirinvolvement in virtually all biologic reactions make thecross-reactivity in the process of self/nonself discriminationintrinsic and unavoidable. Therefore, immune reactions tocarbohydrate antigens present a delicate task for the immunesystem [38]. Indeed, while responses to peptide antigens arewell developed even in very young children, the repertoireof responses to carbohydrate antigens develops graduallyand may reflect a dynamic balance between the changes inglycosylation patterns of a growing/developing self and inter-actions with the sugar-coated environment (Figure 1). Theimmune competence of healthy individuals steadily increasesduring childhood (e.g., children remain susceptible to Strep-tococcus spp. and Haemophilus sp. infections up to adoles-cence), remains at similar levels by ∼50 yrs. of age, and thendeclines [26, 30]. The slow development of carbohydrate-responsive repertoire coincides with growth and maturation,the delay likely allowing for appropriate glycosylation ofself to proceed (Figure 1). The growth/maturation-associatedglycosylation gradually expands the carbohydrate “self tem-plate” for carbohydrate-responsive repertoire expansion. Theincreased susceptibility to bacterial infections again laterin life suggests that aging may include changed and/orincreased glycosylation/glycation of self [21–23]. Accordingto the CDRc, the continuous resetting processes will depletethe repertoire becoming overly reactive/cross-reactive withthe glycosylated/glycated self. Consistent with the conceptis also homeostatic (against the altered self) activation of


previously dormant and low-reactive clones, which maybecome intermediary self-reactive. That would result inreduced repertoire of conventional T/B cells, particularly tocarbohydrate antigens (leading to increased susceptibility toinfections), and also inception of chronic inflammatory con-ditions (increased self-reactivity coupled with progressivelylimited regulatory potential). In addition, due to alterationsin glycosylation/glycation patterns of self, innate immuneenvironment will change as well, including the expressionof PRRs, reportedly altered in the elderly [27]. Therefore,the mechanisms to maintain integrity/distinction against theenvironment will become less granular (due to the overallrepertoire reduction) and less specific. Progressive attritionof the repertoire may be setting different homeostatic pointsfor the immune system in the elderly as compared to youngeradults, with likely increased baseline inflammatory state—noted as “inflammaging” [39]. The self is becoming moresimilar to the environment and progressively less competentto distinguish between itself and nonself/environment orto maintain the integrity of the system, which eventuallyresults in death. Therefore, glycosylation/glycation processesmay regulate not only growth and development, but also agingand longevity.The changes expected per CDRc are consistentwith the observed immune remodeling/immunosenescenceassociated with both, chronic inflammatory conditions andaging [26–28, 30, 32].

5. Compartmentalization of the ImmuneSystem: A Necessity

Recognition and neutralization of a foreign without harm-ing the self are formidable tasks considering the commonorigin and inevitable molecular similarities among all livingorganisms. In the course of evolution, as the complexity oforganisms increased, the ever more sophisticated immunemechanisms to achieve high specificity of recognition (epit-omized in function of T and B lymphocytes) represent animportant evolutionary survival tool. But it is also a danger-ous one, as reacting indiscriminately and specifically to every-thing that is not self is unsustainable. This is where compart-mentalization (demonstrated to function in mammals), withthe mucosal immune compartment as a barrier between theenvironment and the systemic compartment (representing asequestered and isolated genuine self ), becomes an essentialsurvival strategy in highly organized megaorganisms [40].

The surface-lining mucosal compartment uses a versatileset ofmechanisms to achieve a low-maintenance homeostasisat the interface between the self and the foreign/environment.Functioning “on the edge,” it locally deals with not onlypotentially invading entities, but also innocuous antigens—all of which may have a certain degree of similarity with theself. In order to minimize inflammation, mucosal compart-ment may favor the versatility and general applicability ofinnate mechanisms over the conventional adaptive immuneresponses as a practical approach to deal with the environ-ment.More of a foreignmay be “allowed” atmucosal surfaces,without inducing major immune reactions or engaging con-ventional adaptive immune responses. To accomplish sucha delicate task, mucosal compartment is equipped with a

unique repertoire of unconventional effectors and mecha-nisms. Those ultimately define the system’s capacity to dealwith the environment and maintain integrity in the contextof self. Alongwith epithelial cells and their particular capacityto recruit innate effectors, unique populations of evolutionaryold cells reside along mucosal surfaces and are seldom foundelsewhere. Those resident populations include subsets ofunconventional T cells, mucosal B cells, and mast cells. Theadjective “unconventional” applies to both mucosal T andB cells, as their repertoire (T-independent antigens such ascarbohydrates and lipids) and efficient activation process(polyclonal/T cell-independent or neutrophil-mediatedB cellactivation, dispensable “classical” costimulatory signals for Tcell activation) enables them to develop a unique repertoireand, having prestored mediators, react without delay [41–46]. Mast cells, residing in such a setting of continuousself/nonself interactions, may be essential for regulation ofresponses necessary to maintain a sustainable equilibriumwith the environment [47, 48].

Thus, mucosal compartment can be considered a site ofa particular immune privilege, where direct interactions withnonself are “allowed” and tolerated at the level not desirable(nor sustainable) within the systemic compartment. Conse-quently, mucosal compartment’s repertoire must differ fromthe systemic repertoire. Considering the continuous resettingprocesses, the CDRc requires that the mucosal compartmentshould remain relatively isolated from the systemic, genuineself. That would enable the mucosal compartment to avoidsignificant resetting against the systemic/genuine self (andvice versa) and reset only in response to local changes of selfresulting from interactionswith the environment.Thatmakesthe mucosal self different from the sequestered and protectedgenuine self. The sequestration from the systemic compart-ment protects mucosal compartment’s unique repertoire andpreserves its specificities accumulated from early life on.

Accordingly, frequent failures of the epithelial barrierfunction will induce resetting of the mucosal reper-toire and alter the mucosal compartment’s immuneenvironment. Allergic reactions may indicate such analtered mucosal compartment and reflect activationof alternative mechanisms to maintain equilibriumalong the body surfaces, but at a less appropriate (i.e.,symptomatic) level.

The mucosal compartment’s repertoire (including innateand adaptive repertoire ofmucosal B andT cells)may developand expand primarily during early childhood, as a result ofinteractions with the environment, and continue expandingthrough adolescence. Only when growth and development(i.e., growth-induced alterations of self) are finalized, does themucosal compartment achieve its maximum competency.

Previous comments about the age-associated devel-opment of immune repertoire against respiratorypathogens support that notion. Also, children withasthma-like respiratory symptoms sometimes “out-grow” those by adolescence/adulthood, presumablyowing to the maturation and increased competencyof the mucosal compartment.


OutcomesCompetent mucosal comp. Systemic compartment (genuine self)

Envi

ronm

ent

Appropriatesequestration from thesystemic compartment

Appropriatelydeveloped innaterepertoire

Strong barrier againstthe environment

Minimal exposure tothe environment

Rare activations ofadaptive responses

Repertoire resettinglimited to homeostatic resettingagainst the physiologic changesof self

Preserved competencyand regulatory capacity

Increased longevity ofthe system (delayedaging-associatedrepertoire attrition)

Minimal repertoireattrition

(a)

Deficient mucosal comp. Systemic compartment (genuine self)Outcomes

Envi

ronm

ent

Weak barrierfunctionPoor mucosalversus systemicsequestrationEngagementof alternativemechanisms

conventional

Frequentinterventions of

effectors

Frequent systemic exposuresto the environment

Frequent activationsof adaptive responses

Increased repertoire resettingagainst the foreign and both,environment-inducedand physiologicchanges of self

Reduced immunecompetency andregulatory capacity

Premature aging and early immunosenescenceof the system

Increased rate ofrepertoire attrition

(b)

Figure 2: Compartmentalization: competent mucosal immune compartment is essential for appropriate function of the immune system.TheCDR concept indicates favorable outcomes in a systemwith strongmucosal barrier function and appropriately sequestered systemic immunecompartment (panel (a)). Panel (b) shows unfavorable outcomes in a system with deficient mucosal barrier function and poorly sequesteredsystemic immune compartment.

Therefore, the maturity and competency of the mucosalcompartment acquired early in life determine how often thesystemic exposure to the foreign may occur and, if it occurs,to which extent the foreign can be preprocessed/neutralizedbefore breaking through the mucosal barrier. On such occa-sions, the intrinsically self-damaging activation of the sys-temic adaptive responses (conventional systemic repertoireis selected and maintained due to its low self-reactivity) willtrigger the resetting process. The resetting will occur due toboth, reactions against the intruding foreign and against thereaction-altered genuine self. As both processes can engagedormant repertoire, as well as reduce the activated repertoire,high frequency of such events may increase the probabilityof significant depletion of the overall repertoire, reduce itsregulatory range (reduced granularity), and thus result ininception of chronic (intrinsically autoreactive) processes.

Consequently, the CDRc indicates that the “prime direc-tive” of immune protection is to isolate the systemic com-partment (genuine self) from exposures to the foreign.

In that way, the systemic repertoire will undergo only ahomeostatic resetting due to the intrinsic changes of self andavoid additional resetting events against both the intrudingenvironment and the alterations of self due to such intrusions.Such a state of systemic compartment’s isolationmay preservethe systemic repertoire and its diversity, provide appropriateregulatory breadth/capacity, and thus delay immunosenes-cence (Figure 2(a)).

Although immunosenescence usually occurs withadvanced age (also referred to as age-associatedimmune remodeling), immunosenescence occursalso in younger subjects as a consequence of majorpathologic events or associated with chronic inflam-matory conditions [26, 32]. Related to an alteredmucosal compartment is depleted and phenotypicallychanged mast cell population, as well as a formof immunodeficiency affecting responses to carbo-hydrate antigens that are both observed in severeasthmatics regardless of their age [48, 49].


Therefore, the CDRc indicates that appropriately devel-oped and preserved mucosal immune compartment is essentialfor optimal function and regulation of immune responsesin general. Strong and competent mucosal barrier ensuresindividual’s immunologic fitness and delays immunosenes-cence, despite the chronologic aging. As Figure 2(b) depicts,reduced immune competency along mucosal surfaces cantrigger a sequence of alterations in the entire immune system,which can eventually reduce the overall repertoire (repertoireattrition), impair the protective function and regulation ofimmune reactions (due to reduced repertoire’s granular-ity), and force the system to continue acquiring pathologicsteady states. Such a sequence of events, which reduces self-regulatory capacity of the immune system, may be involvedin the pathogenesis of chronic inflammatory conditions andautoimmune diseases. Allergic reactions in this context mayreflect engagement of alternative mechanisms (eosinophils,increased IgE, increased mast cell counts and activity, etc.)to cope with otherwise innocuous environmental exposures.That would indicate an altered competency of the mucosalcompartment and its barrier function and thus can representa prodromal stage of a progressive and potentially detrimen-tal immune deficiency.

6. Pathogenesis of Idiopathic ChronicInflammatory Conditions (ICIC)

The CDRc suggests a common mechanism related to thealtered mucosal protection underlies the pathogenesis ofICIC (Figure 2(b)). Under such circumstances, the stochasticnature of immune processes may produce a range of out-comes, resulting in variable clinical presentations. Indeed,ICIC are highly heterogeneous syndromes that, rather thanhaving pathognomonic features, are clinically defined usingsets of major andminor criteria.The overlap between varioussyndromes is very common.

For example, interstitial lung disease symptoms oftenprecede rheumatoid arthritis. Also, there can be aconsiderable overlap between asthma and COPD.Despite the obvious differences in lung pathol-ogy between those two syndromes, some asth-matics demonstrate fixed airflow obstruction or aTh1 inflammatory pattern typical for COPD, whilesome COPD patients have partially reversible airflowobstruction and a Th2 inflammatory pattern typi-cal for asthma. Nevertheless, altered lung mucosalimmunity underlies both diseases.

That suggests that various triggering mechanisms anddiverse pathways resulting in altered mucosal protectioncould lead toward similar pathology and clinical presenta-tions. As there is currently no way to predict which circum-stances or events would (or not) trigger an ICIC, the preven-tion strategy should be quite general and comprehensive: tosupport appropriate development of the mucosal compart-ment and to maintain its barrier function and competency.On the other hand, the therapy should primarily identify andreduce/block the mucosal triggers that cause worsening ofthe disease. Those may be different in each patient, which

means that therapeutic interventions will depend on theimmune status and circumstances specific for each patient.Therefore, in order to both prevent and start treating ICIC,immediate research focus should be on finding the means toreinforce mucosal barrier function. Future research may leadtoward understanding the specific pathogenic mechanismsand identification of specific therapeutic targets to control thepathology.

Figure 3 expands on the mechanisms of ICIC pathogen-esis proposed in Figure 2(b). It includes also the previouslymentioned direct exposures of the systemic compartment.Also, added are the influence of age at inception of pathologicprocesses and the role of gender. Generally, women aremore likely to develop ICIC, which could be related to theirtypically Th2-dominated immune environment. Of note,mucosal immune responses also have a strong humoral/Th2immune component. Those elements suggest the role of Bcells in development of ICIC in a setting of reduced T cell reg-ulatory potential. Noteworthily, the B cell repertoire (unlikewith T cells) continues to be replenished throughout life butinfluenced and limited by the changes of self. Depletion of Bcells with rituximab and similar biologicals, which is in facta form of B cell repertoire resetting, has been reported as aneffective intervention for several autoimmune diseases.

7. Discussion

This study proposes the CDR as a mechanism that underliesa comprehensive picture of the human immune systemfunction. Referencing and relying primarily on clinical andexperimental data, the study outlines a dynamic, continu-ously changing, and self-regulating biologic system governedby stochastic events and uncertainty of outcomes. Whenset in motion, the CDRc explains a range of immuno-logically distinct physiologic and pathologic phenomena:compartmentalization, physiologic growth and maturation-associated repertoire development, immunologic abnormal-ities, and repertoire alterations associated with idiopathicchronic inflammatory conditions and premature immunose-nescence, as well as aging-associated immunologic changes(i.e., chronologic immunosenescence). Finally, the CDRcsuccessfully tackles the unresolved issue of tolerance andregulation of immune responses [50]. It incorporates fun-damental principles of thermodynamics and the stochasticnature of biologic systems’ function to describe dynamicregulation and maintenance of tolerance. The basic principleof CDR is relatively simple, has internal logic and consistency,and incorporates much of the known in immunology.

Many of the pertinent elements of the CDRc are basedon our current understanding of immunity. In fact, theCDRc utilizes functional plasticity of cells and proposes thatfluctuating constellation of signals allows any activated cellto change its functional phenotype accordingly.The plasticityof T cells (but also NK cells, B cells, mast cells, fibroblasts,epithelial cells, etc.) by modifications of their stimulatoryenvironment has been demonstrated in numerous recentstudies [7–12]. Those experimental data were crucial inexplaining the dynamic nature of tolerance and regulation ofimmune responses.


RA

IBD

ILD

ASTH

COPD

MS

SLE

Path

olog

ic st

eady

stat

es

Age, gender

Mucosal pathway(altered barrier function)

Nonmucosal pathway

Direct systemic injury(massive exposure to theforeign, sepsis, massive

wounding, etc.)

Systemic compartment

Frequentactivation ofconventionaleffectors

Persistentself-injury/damage

Reducedregulatory potential(reduced repertoire)

Figure 3: Pathogenesis of idiopathic chronic inflammatory conditions (ICIC). Shown are some of the factors that can affect the systemicimmune compartment and contribute to the development of ICIC (only few are listed). Note the reduced regulatory function of the systemiccompartment as a commonmechanism in pathogenesis of ICIC. Also, note the influence of age and gender. ASTH= asthma; COPD= chronicobstructive pulmonary disease; ILD = interstitial lung disease; RA = rheumatoid arthritis; IBD = inflammatory bowel disease; SLE = systemiclupus erythematosus; MS = multiple sclerosis.

The CDRc expands primarily from elements of the Dan-ger Theory and continues to use the concept of self-nonself[51]. In contrast to predominant views, conventional adaptiveimmune responses are not considered the main mechanismof immune protection. The CDRc instead emphasizes theimportance of innate mechanisms, while the true conven-tional adaptive effectors are kept secludedwithin the systemiccompartment and, preferably, seldom engaged. The lack ofinnate memory could be an argument against the reliance onthe innate. However, the dogma about innate immunity that,as opposed to adaptive immunity, cannot provide memoryresponses has been challenged. Recent reports on trainedimmunity convincingly argue for the existence of innatememory. It functions in plants, invertebrates, and vertebratesand can provide both specific and cross-protection, as wellas engage in alloreactions [52, 53]. Indeed, innate recognitionof allogeneic nonself is reported as a base for alloreactivityin MHC-matched murine transplant models [4]. That arguesalso for an innate molecular imprint of self, a plausiblemechanism for “self-awareness” under the CDR conditionsand continuous changes of self.

The notion about self has been present in immunology fordecades. The self is considered an immunologically constantand unique quality that remains unchanged throughoutindividual’s life. However, the definition and what constitutesself remain unresolved [54]. The CDRc proposes a differentperception of self. The self per CDRc is a state of molec-ular congruency/compatibility that is derived from system’s

integrity/existence and keeps a system in homeostasis. Par-ticular molecular states and patterns, which are subjectedto continuous resettings, constitute the system’s selfness. Asthe self continuously changes, it cannot be precisely defined,nor does the immune system have the ability to specificallyidentify it—it can only sense a change and reset against it.

As emphasized before, the protection of system’s integrityrelies primarily on innatemechanisms. However, whatmakesthe integrity-sustaining resetting processes personal is theMHC context. The system uses adaptive effectors to com-pensate for disturbances whose characteristics and/or extentreach a threshold for triggering an MHC-focused/guidedresponse. Specificity-driven adaptive response (as opposedto less restricted innate reactions) has the ability to, mainlythrough innate effectors, neutralize (eliminate or tolerate)and repair the damage, that is, to actively regulate inflam-matory processes in the context of integrity of the system.MHC-guided responses are to limit the collateral damageby being specific (and also self-focused, determined by self)and to restrain/regulate inflammatory reaction as much asthe immune repertoire’s diversity affords it. Thus, specificreactions to nonself/foreign are balanced and regulated asrelative to self. They affect both nonself/foreign and self(damage it and/ormodify it). Consequently, self is included inthe system’s resetting processes and is (apart from its geneti-cally determined core structure) continuously modified. Aslong as the system can reset and establish a sustainablesteady state, a changed self will become a new self. In this


context, an MHC-focused adaptive immunity constitutesa sophisticated mechanism of regulation toward integrityprotection in highly organized biologic megasystems.

While the system recognizes the nonself/foreign as achange/disturbance at molecular level, there is no inher-ent and obligatory animosity (attacking and eliminating atall cost) against nonself/foreign. As the prime purpose ofimmune responses is to preserve the integrity of the system,the system can acquire even pathologic steady states if that isthe thermodynamically optimal solution that will maintainsystem’s integrity. Therefore, reactions to nonself/foreigncan eliminate it or, if thermodynamically preferable, thoseprocesses could result in asymptomatic/subclinical or chronicsymptomatic states (parasite or virus carriage, ICIC, etc.).

As previously emphasized, the fundamentals of system’sintegrity are as follows: (a) appropriate surface protectionwith sustainable equilibrium with the environment; (b) sys-tem’s inner equilibrium. From those elements stem com-partmentalization and consequences of failures in eitherof those areas (Figures 2 and 3). As a consequence ofcompartmentalization, the CDRc distinguishes between themucosal self and the systemic, genuine self. Genuine self ishidden within the systemic compartment and exposed tothe conventional immune repertoire. When protected by abarrier of the mucosal compartment, extrinsically inducedchanges of the genuine self are minimal and fluctuations inthe systemic (conventional) immune repertoire are mostlydue to intrinsic/homeostatic resettings only. As shown inFigure 2(a), that preserves the stability and longevity of thesystem. In contrast, altered barrier function of the mucosalcompartment exposes the genuine self to changes due toengagements of the conventional immunity, which eventu-ally leads to repertoire attrition and reduces the immunerepertoire’s granularity and thus its regulatory function.That may explain the observed association of the systemicinflammatory conditions and autoimmune diseases with analtered mucosal immunity. Although clinical presentationand outcomes of those conditions may differ depending onthe degree and segments of immunity affected, the commonmechanism of pathogenesis suggests that directing researchtoward finding a way to support the mucosal compartment’scompetency development and its barrier function may leadtoward effective prevention and therapy for a range of patho-logic conditions. Similar approaches may prevent a disease-induced immunosenescence, as well as delay the physiologicaging and the aging-induced immunosenescence. In thecontext of theCDRc, interventions and therapy approaches toinhibit or eliminate particular elements of the inflammatorycascade would be contraproductive.

The CDRc indicates that skipping the mucosal compart-ment and introducing antigens to the systemic compart-ment directly (such as immunization via parenteral route)may result in harsh alterations of the systemic compart-ment’s conventional repertoire and the molecular struc-ture of genuine self. Because of the potentially detrimentalimpact particularly during early childhood, a period oforgan development, growth, and maturation (appropriatemolecular interactions are of paramount importance in thoseprocesses!), the changes in immunization strategies would

be necessary. The immunization strategy should favor anonaggressive antigen introduction via mucosal surfaces,particularly for infectious agents that use mucosal route ofentrance. In addition, the timing of interventions to modifythe competency of the mucosal compartment may have to besynchronizedwith child’s age/maturation state. Of note, thereis a potential to exploit the cross-reactivity and perhaps lookfor “multifunctional” molecular patterns instead of multiplemicroorganism-specific antigens, which may provide a widerange of cross-protection.

There may be implications for transplant immunologyas well. The stochastic nature of a process determining thecontinuously changing “selfness” of every single individualexplainswhy even syngeneic individuals are immunologicallydifferent. In addition, autologous tissues obtained early (orearlier) in life and preserved for potential use later in life maynot be as compatible as expected. Furthermore, malignanciesindeed stand a good chance of remaining unharmed byimmune reactions, as long as the system resets itself againstthe rogue malignant cells (and vice versa) within acceptableparameters. In fact, the changes in intercellular commu-nication/signaling resulting in uncontrollable proliferation(as a consequence of initial injury/irritation) could havebeen part of resetting processes to adjust and establishthermodynamically optimal state(s).

Studies designed by teams of experts from various fieldsof natural sciences will be required to validate the CDRc.The currently available methodologies, particularly recentadvances in the field of glycobiology, should provide atleast initially sufficient investigative tools. Data analysesshould include mathematical modeling approaches. Of cru-cial importance would be to demonstrate physiologic (andpathology-associated) patterns of changes of self. Therefore,the hypothesis is that individual’s self is changing throughoutlife due to the growth and maturation processes, phys-iologic and pathologic events, and aging. Those changeswill be gender-distinctive. The changes will associate withpredictably different patterns of immune markers that willcorrespond to the changing states of self.

Experimental approaches to validate the CDRc shouldinclude prospective longitudinal studies of humans, withsampling at the age-related and other immunologically dis-tinct points. Similar butmore detailed studies in animalmod-els and/or in model organisms can be used for mechanisticstudies as well. The areas of interest are as follows:

(1) Glycosylation and glycation (G/G) processes asso-ciated with (a) physiologic development, growth,maturation, hormonally distinct periods of life (ado-lescence, pregnancy, and menopause), and aging;(b) acute systemic reactions (sepsis, significant sys-temic injury/wounding); (c) chronic inflammatoryconditions. Such studies will address the proposedcontinuous physiologic and pathologic changes ofself.

(2) Longitudinal assessment of changes in the sys-temic/serum immunoglobulin (Ig) response pat-terns (Ig classes, IgG and IgA subclasses, and theirglycosylation characteristics) to a standardized set


of T-dependent and T-independent antigens. Thosestudies (concomitantwithG/G sampling)will addressthe proposed changes in immune repertoire’s diver-sity associated with the previously outlined physio-logic and pathologic states.

(3) The relationship of innate and adaptive cellular andhumoral markers (changes in their molecular pat-terns and characteristics) to the previously outlinedphysiologic and pathologic states and other concomi-tantly evaluated elements.

In conclusion, this study offers a testable theoreticalscaffold for translational research based on systems biologyapproaches. It crystalizes a single CDR principle to outlinea relatively simple and somewhat dispassionate view offunction of the immune system: it is all about continuousmolecular rearrangements and resettings tomaintain system’sintegrity, without the drama of a battlefield and warfareagainst the unknowns. Dysregulation of immune reactions,which is often considered a cause of various idiopathies, maynot be applicable in its true sense: self-regulation is intrinsicin a living system, as molecular interactions are alwaysthermodynamically optimal under any given circumstance.Although it is clear that certain types of cells are specializedimmune cells, every single cell, a single entity itself, isinvolved in maintenance of megaorganism’s integrity andthus is part of the immune system.

8. Conclusions

This study, initiated to clarify the pathogenesis of chronicinflammatory conditions, confronts the most pertinent ques-tion in immunology: general picture of the immune systemfunction. The studies have crystalized the continuous dualresetting of the immune repertoire (CDR) as a basic principleof the immune system function.

The CDR process maintains continuous fluctuations inthe immune repertoire diversity, which plays a major rolein regulation of immune responses, tolerance, and immunerepertoire’s physiologic changes from early childhood tosenescence. The continuous repertoire resetting inevitablyleads to the repertoire attrition. That results in a form ofimmune deficiency, with reduced repertoire’s granularityand immune system’s regulatory capacity. Such repertoireattrition is normally expected with advanced age (aging-associated physiologic immunosenescence).However, patho-logic events can trigger a premature form of such immunedeficiency, which can result in altered immune responses,chronic inflammatory conditions, and autoimmune diseases.

Following the consequences of the CDR-induced reper-toire attrition, proposed is a common mechanism of patho-genesis of idiopathic chronic inflammatory conditions. Theirpathogenesis associates with altered mucosal immune com-partment’s barrier function and/or inappropriate sequestra-tion of the systemic immune compartment. Outcomes ofthe CDR under those circumstances are consistent with therecognized clinical heterogeneity and overlapping features ofchronic inflammatory conditions.

Several poorly understood issues in immunology areaddressed. The immunologic self is here defined as a constel-lation ofmolecular patterns thatmaintain a biologic system inequilibrium. It is unique to each individual and continuouslychanges as a result of physiologic and pathologic events.Furthermore, discussed is the importance of glycosylationand glycation processes. Also, emphasized is the essential roleof innate mechanisms in immunity. In addition, addressedis the complex regulatory role of conventional effectors andtheir MHC-focused responses in maintenance of system’sintegrity in highly organized megaorganisms that require thespecificity-driven TCR and BCR repertoire.

Finally, proposed are experimental approaches to test andvalidate the CDR concept of the immune system function.

Competing Interests

The author declares that there is no conflict of interestsregarding the publication of this paper.

Acknowledgments

Only a short list of essential references to support this conceptis cited, with deep appreciation of numerous here unlistedauthors whose work inspired it.

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