## 1. Introduction



The immune system is typically represented as a system of defense that
protects the organism from pathogens. However, this system is known to
play other functions in the organism that include 


1. regeneration and repair of damaged tissues, scar formation, and
wound healing (Forbes and Rosenthal 2014);
2. surveillance against malignancies (Swann and Smyth 2007);
3. regulation of ontogenetic transformations (Ramos 2012);
4. modulation of nutrient metabolism (Zmora et al. 2017);
5. establishment of mutualistic relationships with commensals
(Kurashima and Kiyono 2017);
6. regulation of sexual partner selection and prevention of fusion
between genetically discordant individuals (Davis 2014);
7. modulation of neuro-functions by affecting mood, memory,
cognition, social behavior and spatial learning (Derecki et al. 2010;
Filiano et al. 2016); and
8. participation in a bidirectional crosstalk with other bodily
cells by means of a variety of growth factors and metabolic regulatory
signals (Burzyn, Benoist, and Mathis 2013; Davies et al. 2013).



Thus, by responding to the inner and outer environments of the
organism, the immune system participates in many capacities to
coordinate diverse physiological functions and to provide
communication between them. Immunity thus relies upon cognitive
functions coupled to an array of effector mechanisms that have
wide-ranging regulative, reparative, and defensive capabilities.
Beyond the philosophical significance of these immune-mediated
functions, studies of immunity are uniquely positioned to address
central problems in
 philosophy of biology (see entry)
 and, more broadly, philosophy of science. These include the
reductionism/holism debate, the characterization of the goals and
methods of systems biology, the organization of cognition and
information, and the challenge of integrating complexity theory with
big data studies.



Despite the multifaceted role of the immune system and its importance
in promoting survival and persistence of all forms of life (Pradeu
2012: 22-32), immunology has traditionally been of minor
interest to philosophers of biology (cf. Hull and Ruse 2007; Sarkar
and Plutynski 2010). However, increased attention has recently been
directed to address a range of ontological and epistemological
problems related to immune phenomena. These studies have focused upon
the "immune self", the central motif of biological
identity in the context of immunity (Tauber 1994; Pradeu 2012).
Ranging over diverse topics, including personal identity (Howes 1999),
ethical and anthropological concerns with human self-image (Sontag
1990; E. Martin 1994), and poststructuralist, constructivist and
feminist notions of identity (Derrida 2003; Haraway 1989; Weasel
2001), philosophers have invoked immunological conceptions of
selfhood. Moreover, the examination of immunology has proven
increasingly useful in addressing philosophical problems pertaining to
other fields of study such as ecology (Tauber 2017), neuro- and
cognitive sciences (Varela et al. 1988), developmental biology (Fagan
2007), microbiology (Methot and Alizon 2014) and evolutionary
biology (Hull, Langman, and Glenn 2001). This increased recognition of
immunology in philosophy of biology not only reflects a growing trend
towards more inclusive approaches, more generally, but also
contributes to the intensifying effort to understand ecological
dynamics that range from microbial interactions to climate change
(O'Malley and Dupre 2007; O'Malley 2014).



Immunologists have long applied philosophy to elaborate conceptual
frameworks for understanding the immune system and to shed light on
the character of experimental conduct in this biomedical field
(Anderson 2014). To highlight the common culture of immunology and
philosophy, a prominent Australian immunologist, Macfarlane Burnet,
wrote in 1965: "Immunology has always seemed to me more a
problem in philosophy than in practical science" (Burnet 1965).
He was inspired by Whitehead in elaborating his notion of immune
selfhood and by his attempts to apply cybernetics and information
theory to immunology (Anderson and Mackay 2014). Another influential,
philosophically-oriented immunologist, Niels Jerne, admitted to having
been influenced by Kierkegaard's discussion of Plato's
*Meno* when elaborating his key conceptual ideas (i.e., the
selection theory of antibody production) (Jerne 1966, Soderqvist
2003: 186). And perhaps most prominently, Ludwik Fleck's
immunological and bacteriological research served as the case example
of a "thought collective" that has served as the founding
study of the social character of scientific change in biology and
science (Lowy 1986; Fagan 2009; see the entry on
 Ludwik Fleck).
 Many other prominent immunological researchers, including
Metchnikoff, Zinsser, Medawar, Edelman and Salk, were also humanist
thinkers who, in addition to active laboratory research, conspicuously
expounded philosophical ideas on the nature of reality, the character
of cognition, the limits of science, the condition of humankind, and
the like. Thus, a rich bidirectional exchange between philosophy and
immunology has been established over a long tradition.


## 2. Organism-Level Functions of the Immune System



The basic schema of vertebrate immunity consists of two evolutionary
distinct ways to perceive the organism's external environment
and to monitor its inner state. The first modality, more primitive and
less refined in its perceptive mechanisms, is referred to as the
"innate" or "natural" immune system. This arm
of immunity is composed of a variety of primordial
phagocytes--"eating cells"--possessing
distinctive characteristics based on their tissue distribution. They
ingest particulate microbes and destroy effete, cancerous, and damaged
host cells. These immunocytes constitute the first line of the immune
encounter and comprise the "resting" state of
physiological immunity as they "police" on-going processes
of surveillance and restoration. This system has autonomous functions,
but the incorporation of antigen (a substance that stimulates an
immune response) may also lead to integration with the second mode of
immunity, the so called, "acquired" immune system. This
second arm of immunity has evolved mechanisms that are highly specific
in their recognition capabilities and exhibit immune
"memory" of previous sensitization. Acquired immunity is
mediated by several classes of lymphocytes that may be stimulated by
phagocyte first-encounters or as primary responders under certain
pathological conditions. The B-lymphocytes produce antibody that
recognizes antigens by structural homology and, correspondingly,
T-cells have specific antigen-matching receptors on their cell
surface. The initial recognition event leads to activation of a
variety of effector reactions that destroy the immune target. However,
the decision not to respond is also a recognition event and results in
immune "tolerance". Both the innate and acquired immune
cellular elements are regulated by a vast array of soluble molecular
factors that serve to either activate or dampen immune responses. The
complexity of diverse cell types, the mediators of their interactions,
the contextual determinants that determine immune reactivity, and the
wide range of physiological functions in which immunity participates,
has defied comprehensive modeling. Consequently, immunology offers a
fecund example of biological organizational complexity, which, in
turn, leads to the fundamental philosophical question: On what basis
is organismal identity established and maintained?



Immunology, from its earliest inception, has been concerned with
biological *identity*--its establishment and maintenance.
In its original iteration, immunity was conceived as that function
that preserved the *integrity* of the organism in terms of
protecting and restoring its *individuality*. Thus, immune
functions testified to the persistence of a stable, core identity
defined in terms of its insularity and autonomy. Indeed,
*individuality* undergirded the science from its inception, for
the defense against pathogens was framed by an attacked patient
(individual) pitted against alien others, the invaders. In this
scenario, distinct borders mark individual identity, and immunity is
the response to the violation of those boundaries. However, challenges
to this conception of immunity have recently appeared. Emphasizing the
contextual placement of the organism, notions of demarcated boundaries
that have characterized traditional definitions of the organism are
being revised.



Generally understood, an individual replicates itself and possesses
anatomic borders, a harmonious communication between its parts, a
division of labor for the benefit of the whole, and a system of
hierarchical dominance and control. By these criteria, the immune
system is responsible for establishing and maintaining the integrity
of such an individual (Pradeu 2016). However, symbiosis challenges
this entrenched definition of the individual organism: shared
physiologies govern homeostasis; anatomic margins lose clear
definition; development is intertwined among several phylogenetically
defined entities; and the unit of evolutionary selection becomes a
multiplex genome (see the entry on
 the biological notion of individual).
 On this consortium view, notions of individuality are replaced with
c*omplexes* of organisms that defy any singular definition of
organismal identity as independent agents (Lowy 1991; S. Gilbert,
Sapp, and Tauber 2012). In terms of commensal relationships,
symbiosis, mediated by immune tolerance, signifies stabilized
adaptation to the complex of diverse living elements that live in a
cohesive ecology, both within and external to the traditional borders
of the organism. When oriented by ecological relationships, immunology
moves from its dominant concern with autonomous individuality to
include the science of cooperative assemblies of organisms. The
ontological implications of this re-formulation are highly significant
for philosophical considerations of identity as discussed below (see
the entry on
 identity).


### 2.1 Diachronic identity



The diachronic identity of an organism, its capacity to remain the
same despite transformations, has puzzled philosophers since ancient
Greece. Aristotle postulated the existence of immutable forms, that,
being distinct from fluctuating matter, ensure the continued identity
of living creatures (*Categories*,
3b22-33; *Metaphysics*, Book D). Dissatisfied with this
solution, Locke proposed that temporal identity of animals and plants
is not ensured by their unvarying forms, but rather by the continuity
of their lived life (Locke 1689, II.27.4 and II.27.8; Kaufman
2016). In the context of contemporary philosophy of biology, the
importance of continuous identity was emphasized by Hull who argued
that species lack essences and thus should be considered historical
individuals with their own inner coherence and persistence conditions
not unlike those of other living creatures (Hull 1978). He assumed
that these persistence conditions are provided by continuity of
changes in biological organization of these individuals so that only
an abrupt disruption could cause a loss or change of identity (Hull
1992; Hull 1978: 355). This latter perspective has recently been
adopted by advocates of animalism, who argue that continuity of
physiological processes (organic animalism) or maintenance of
characteristic structural organization (somatic animalism) are
necessary for diachronic identity (Olson 1997; van Inwagen 1990;
Mackie 1999; see the entry on
 animalism).



Immunology steps into the diachronic identity debate with
Burnet's hypothesis that during embryonic development, the
immune system learns to tolerate a defined set of molecules as
"self" (Burnet 1959: 59). He proposed that autoreactive
immune cells (lymphocytes) were purged during embryonic development to
leave only those lymphocytes that ignore specific antigens encountered
during this early stage (Burnet 1957). Defined negatively by a gap in
the lymphocyte repertoire, immunological selfhood was assumed to
persist in the adult as an invariant molecular 'essence'
of the organism, analogous to an unwavering psychological ego (Burnet
1959; Tauber 1994: 194). As observed by Pradeu and Carosella, this
self/nonself model supported a substantialist view of identity in so
far as it presupposed that the immune system ensures integrity of a
preserved metaphysical core (Pradeu and Carosella 2006a: 246).



To provide a distinct view of the immune system's role in
diachronic identity, Pradeu advocates the so-called
"genidentity" view (Pradeu 2018). On this view, two
objects are identical if their states are continuously connected over
time (Lewin 1922). To specify which continuous states ensure temporal
identity of an organism, Pradeu refers to those "immune
interactions [that] isolate some continuous biochemical interactions,
which in turn individuate the organism" (Pradeu 2012:
248-249). Accordingly, the immune system reacts to rapid
molecular alterations in the pattern of biochemical interactions and
thus helps to ensure that these interactions are continuous and
unperturbed. Of note, which continuous process should be followed to
define diachronic identity is not observer independent and must be
adjusted to a particular theoretical perspective (Guay and Pradeu
2016: 318; Pradeu 2018).



However, the idea that the immune system contributes to organismal
identity *maintenance* has to be weighed against evidence
suggesting that immunity contributes to the accommodation of
*change*. At the end of the nineteenth century, Metchnikoff
proposed that phagocytes (primitive immune cells) were agents of
organismal transformation, driving metamorphic and developmental
alterations (Metchnikoff 1901 [1905]; Tauber and Chernyak 1991). This
early view has been supported by recent evidence that the immune
system actively participates in mediating transformations in
organismal identity by constantly redefining and modulating immune
reactivity towards endogenous and exogenous molecules (Tauber 2017).
This is most apparent during development as illustrated by the
activity of brain-resident macrophages (microglia), which, by
impacting angiogenesis/vascularization, as well as the migration,
proliferation and apoptosis of neurons, influence social behavioral
and sexual identity (Wynn, Chawla, and Pollard.2013; Lenz and Nelson
2018).



Tolerance of newly encountered antigens demonstrates the
"fluid" state of the reactive immune repertoire that
undergoes alteration over the lifespan of the organism (Grignolio et
al. 2014). And with a changing "immune biography",
biological identity no longer conforms to the simple binary division
of self and nonself that has hitherto characterized immune
theorizing. Accordingly, animals have no immutable molecular essence
that would ensure persistence of identity, at least as determined by
immune tolerance or rejection (Leon-Letelier, Bonifaz, and
Fuentes-Panana 2019). Identity then becomes an ever-changing
process of accepted transformations and rejected entries. From this
vantage point, the animalist definitions of diachronic identity as a
mere persistence of life or even an underlying constancy fails to
account for the dynamic quality of immune-mediated identity
transitions (van Inwagen 1990: 148-149; Olson 1997; Mackie 1999;
Roy and Hebrok 2015; Dupre 2017). Consequently, the immune
processual point of view defines organismal persistence as "a
*coordinated* group of changes" rather than as an
invariant state or a continuous connection between such states. This
understanding has important implications for philosophy of biology and
ontology, more generally (Dupre 2014; Nicholson and Dupre 2018;
Meincke 2018).


### 2.2 Synchronic identity



While *diachronic* identity of an organism is understood as its
persistence though time, *synchronic* identity is defined in
terms of its individuality or distinctiveness (Sober 2000: 154).
Attempts have been made to identify distinguishing characteristics
such as functional autonomy, possession of mutually interdependent
parts, genetic homogeneity and spatial boundaries (Clarke 2010).
Others, pointing to the heterogeneous character of biological
individuals, have argued that no sole feature can serve as a universal
determinant of individuality (see the entry on
 the biological notion of individual).
 Part of the contention resides in differing frames of reference of
study: Most considerations of synchronic individuality focus upon
*evolutionary* individuals as units of selection (Gould and
Lloyd 1999) that differs from how *physiological* individuals
might be distinguished (Pradeu 2016). Regardless of their involvement
in evolution, organisms exhibit various levels of physiological and
morphological integration that makes their indivisibility problematic
(Godfrey-Smith 2009). Immunology contributes to discussions of
individuality in this latter sense by considering the role of the
immune system in defining the boundaries of the organism by the
functional measures of rejection or assimilation.



Pradeu formulated such criteria and proposed that the immune system
plays the central role in determining what is included in the organism
and what is not (Pradeu 2012). The differentiation is based on his
continuity/discontinuity model, which depicts the immune system
reacting to transient alterations in the pattern of antigen receptor
interactions and tolerates long-lasting modifications (Pradeu, Jaeger,
& Vivier 2013; Pradeu & Carosella 2006a: 241, 2006b). Such a
mechanism is based on recognizing that autoimmunity is a normal
function of immunity (Tauber 2015). Because host antigens do not evoke
an immune response, a stable, "continuity" of immune
interactions establishes an activation threshold that initiates an
immune response only upon a rapid increase in antigenic load. The
immune system thus distinguishes the stable state of tolerant
recognition of tonic signals arising from normal physiological process
in contrast to the appearance of novel antigens, for example, arising
from pathogen invasion or tissue injury (Grossman and Paul 1992;
Myers, Zikherman and Roose 2017; Pradeu 2012: 246; Grossman 2019).
Thus the development of tolerance to frequently encountered antigens,
commensals, tissue grafts and anastomosed animals results in the
establishment of stable, integrated associations mediated by low-grade
immune interactions (Pradeu and Carosella 2006a, 2006b; Pradeu 2012:
251-252). In this formulation, the immune system plays a central
role in defining an individual by permitting beneficial physiological
inclusion of heterologous components.



Others refer to these stable immune interactions with microbiota to
*deny* that organisms are individuals (S. Gilbert, Sapp, and
Tauber 2012). Appreciating the ubiquity of symbiosis, the immune
system from this point of view becomes a key mediator of the holobiont
by tolerating and coordinating microbial-host relationships. On this
basis, these critics highlight that most of these interactions fall on
a dynamic spectrum of rejection and acceptance making it impossible,
*in principle*, to determine the boundaries of individuality.
Symbiotic interactions do not conform to a simple acceptance-rejection
model. Rather, to attune its responses to microbial signals the immune
system launches a broad spectrum of T-cell reactions in combination
with a variety of innate immune and tissue cell-derived signals
(cytokines, hormones, neurotransmitters) in combination with complex
regulatory controls (Eberl 2016). As suggested by Cohen, immunity is
the product of an active computational state that constantly assesses
the state of the organism's internal state and the surroundings
in which it lives (Cohen 2007a, 2007b). In the context of such fluid
activity, transitioning from one unique activation state to another
does not allow definitive delineation of organismal borders. Instead,
the immune system acts as gatekeeper that controls the apparent
boundary between the organism and its environment (Tauber 2008: 231; Tauber 2017; S. Gilbert, Sapp, and Tauber 2012). From this perspective, the view of immunity as protecting insularity shifts to recognizing its role in establishing and maintaining communal
relationships that blur the distinction of an atomistic
*insular* individuality (Skillings 2016).



The self/nonself, tolerance/response dichotomies collapse altogether,
when considered in the context of mammalian pregnancy, where various
modalities are employed to preserve the temporary immune sanctuary of
the 'foreign' fetus (Howes 2007; A. Martin 2010). Studies
of immune-mediated exchanges between the mother and the fetus not only
challenge our view of immunity as concerned with rejection and
defense, but also transform our understanding of biological
individuality (Erlebacher 2013; Howes 2008). More specifically, recent
studies undermine the vision of the maternal immune system as
antagonistic to the fetus and rather point to active immune
participation in the formation of an amalgamated maternal-fetal
individual, whose ontological status lies at the continuum between
unification and distinctiveness (Howes 2008). Delineation of the role
of inflammation during blastocyst implantation further supports this
interactive vision, demonstrating that instead of acting as a
rejection response, inflammation promotes a mutually tolerant fusion
between the embryo and the mother (Griffith et al. 2017; Mor, Aldo,
and Alvero 2017). Indeed, the transformation of an
inflammation-induced reaction pathway into a cell differentiation
pathway in decidual stromal cells exhibits the intimate connection of
the immune and reproductive systems in eutherians (G. Wagner,
Erkenbrack, and Love 2019; Nuno de la Rosa, Pavlicev, and
Etxeberria 2019, in Other Internet Resources).



In conclusion, despite significant contributions of philosophy of
immunology to debates about identity, no straightforward answer to the
question of how the immune system contributes to biological
individuality has been offered. Considering the actual
individualization practices in various fields of biology, it may well
be concluded that no single account of the biological individual
suffices and that the question of whether particular criteria are
valid or not depends on the research perspective adopted. Part of the
conundrum may lie in the efforts to consider the issue at the
metaphysical, rather than at the epistemological level (Love 2018,
Love and Brigandt 2017). As discussed below, the status of the
"immune self" is a fecund case in point.


###  2.3 The immune self



Wide use of the self/nonself distinction in different clinical and
research traditions (provided by the relaxed and varied meanings
associated with its use) has established such discrimination as the
governing construct of the science (e.g., Howes 2010; Hoffman 2012;
Cohn 2015). Indeed, the "immune self" has served as
immunology's foundational concept to order immune theorizing for
the past 70 years (Burnet and Fenner 1949; Tauber 1994). However,
despite the paradigm's established standing, definition of
immune identity has proven elusive. As discussed above (section 2.1),
because of fluctuations of immune activity over the lifespan of the
organism, conceptualizing and modeling active tolerance have yet to
yield criteria for defining stable identity (Bilate and LaFaille
2012). Moreover, a consensus definition of selfhood has remained
elusive inasmuch as different investigative frameworks promote
differing characteristics of immune identity based on their respective
structural and functional criteria (Matzinger 1994). Critics have
therefore questioned the immune self's standing and utility
(e.g., Matzinger 1994; Tauber 2000; Pradeu 2012). The latter position
argues that the "self" might be better regarded as only a
metaphor for a "figure" outlined by the immune
system's silence, i.e., its non-reactivity. Such a functionally
flexible definition has been resisted. Defenders argue that the notion
of stabilized discrimination correctly depicts the immune
system's organizing functions (which converge on defending a
well-demarcated organism), and that efforts to eliminate or modify
this metaphor are misguided attempts to "police" borders
between science and culture (Anderson 2014; Hoffman 2012). Drawing
from the philosophical canon, Howes referred to Hume to argue that
realism about self (immune or otherwise) can be saved despite the
dependency of context and the ever-changing character of the
postulated ego (Howes 1998). She suggested that the efforts to deny
the reality of the self are based on its non-substantial character and
thus reflects entrenched substantialist assumptions. She proposed that
a middle ground exists between substantial self and no-self by
adopting a processual, understanding of selfhood (Howes 1999).



While the standing of the immune self has remained contentious,
epistemological ambiguity and flexible polysemy has proven effective
in sustaining the term's powerful heuristic value as an
*idiom* with many uses and meanings (Crist and Tauber 2000).
Its versatility and pragmatic utility have effectively integrated
clinical immune phenomena by highlighting the essential similarity or
interconnectedness of diverse immune-mediated processes in response to
various clinical challenges. Thus nutrition, allergy, infection,
autoimmune disease, various phenomena of tolerance, natural or
experimentally created chimeras (transplantation), and autoimmunity
all become conceived as a network of interlinked or interrelated
functions subject to evolutionary transformation and adaption. As
these topics mirror and play off one another under the rubric of
selfhood, immunologists have a ready means by which to represent
states or processes that arise in the various interactions between the
organism and its environment at different evolutionary stages and
development.



Finally, the self's appearance in immunology served as a readily
understood shorthand reference to personal identity, and the efforts
to substantiate that extrapolation on its own terms guided the
discipline for the latter half of the twentieth century (for
historical case studies see Lowy 1991). After all, beyond the
experimental science, the interpretative context of immune selfhood
draws from wider social meanings of individuality and insularity
(Tauber 2016; see below, section 5.0). The autonomous construction of
identity resonates with Western civic ideals and in turn supports them
by melding laboratory findings with various extrapolated or borrowed
philosophical, political and psychological formulations of human
agency. And conversely, immunology has been studied as a source of
important metaphors and other tropes feeding back on the
science's supporting culture to transform understanding of
agency and communal relationships (discussed below, section 5.0).


## 3. Immune Ecology and Evolution



Immunology's basic conceptual orientation is undergoing
expansion from an individuality-based biology to include communal
ecological perspectives. Similar shifts in perspective have also taken
place in other fields of biology (Nathan 2014; van Baalen and Huneman
2014), and thus immunology joins a proliferation of
"sub-organismal" environmental studies that would
integrate ecology with developmental biology, physiology, cancer
biology, molecular eco-systems, and eco-immunology (S. Gilbert and
Epel 2015; Karasov, Martinez del Rio, and Caviedes-Vidal 2011;
Maley et al. 2017; Tauber 2017). This emerging perspective is
accompanied by an increasing interest in somatic evolution occurring
during carcinogenesis, neurogenesis, microbiota development, and the
adaptive immune responses. This shift has led to an abandonment of the
classical vision of the immune system directed at defense to now
include tolerant mechanisms that permit assimilation and co-habitation
that reflect stabilized microbial-host relationships. In that
re-orientation, concepts of pathogenicity and individuality have been
re-defined.



So, although the concepts of immunity were developed primarily in the
context of disease ecology, attention is shifting to symbiotic
ecosystems. The exchanges the immune system mediates highlight context
sensitivity of parasitism, commensalism and mutualism, and further
demonstrates the bidirectional dialogue between bacteria and the host
in the mutual construction of their respective ecological niches. The
problem of immune evolution and clonal selection of lymphocytes is
considered, in turn, to provide the most general account of natural
selection. An important new issue concerns a set of problems
associated with the recently discovered adaptive immune system of
bacteria, the CRISPR system, whose role in evolution poses novel
challenges to basic Darwinian principles (see section 3.2).


### 3.1 Ecological approaches to immunity



The ideas underpinning somatic ecology originate in the early view of
somatic cells behaving as social organisms forming stable associations
(Reynolds 2018: 12-58). Assuming that such interactions serve
the welfare of the organism, Virchow and other authors described a
"cell state" (or a "cell republic)", a
metaphoric expression of what became a sociological model of cellular
communication (Virchow 1858 [1863]; R. Wagner 1999; Reynolds 2018:
86-113). And pathologically, such a consortium becomes a
"civil war" of competing cell lines. The model then led to
a general Darwinian formulation of an *internal* struggle for
existence throughout the life of an individual (Roux 1881; Metchnikoff
1901 [1905]; Tauber and Chernyak 1991; see Buss 1987; Queller and Strassmann 2009;
Godfrey-Smith 2009 for the contemporary standing of this proposal of
evolutionary change). Metchnikoff, a key advocate of this theory,
assumed that cells operate on Darwinian principles similar to those
governing the adaptation of organisms in changing environmental
conditions. He thus introduced a common framework in which to
understand dynamic biological communities--whether internal cell
lines or organisms adjusting to their environment. This ecological
orientation altered basic conceptions of immunity and identity by
displacing static notions of individuality with dialectical constructs
(Levins and Lewontin 1985; Tauber 2008).



This ecological viewpoint serves to depict somatic and microbial cell
populations as systems of communication and information exchange. With
the change in focus from individuals to ecosystems, the classical
dichotomies governing immunology's theory, i.e.,
tolerance/responsiveness, immune/non-immune, self/nonself, has been
revised. How these oppositions collapse in an information-based
ecological format is illustrated by the phenomenon of inter-kingdom
signaling, a form of communication that not only bridges an
evolutionary gap between microbes and host, but also helps to overcome
putative boundaries between immune, epithelial, and neural systems
(cf. Hughes and Sperandio 2008). When considered from the
environmental perspective, the transition site between the genetic
body and its resident microbes is no longer a frontline of defense but
rather an ecological ecotone, an interactive zone at which cellular
communities engage in a dialogue to explore new adaptive opportunities
(Tauber 2008). The importance of such interfaces is well illustrated
by mutual scaffolding and niche construction strategies that are
utilized by microbial symbionts and their hosts to direct development
of larger ecological units (i.e., holobionts) (Chiu and S. Gilbert
2015).



Struggle and cooperation in the immune context were assumed since Koch
to depend on intrinsic characteristics of invading microbes that, due
to their virulence factors and other gene-encoded characteristics, act
as pathogens, commensals or mutualists (Methot and Alizon
2014). By accounting for a larger context of the immune encounter, the
ecological position challenges this vision by offering a view in which
"there are no pathogens, no commensals, and no opportunists;
instead there are only microbes and hosts that interact"
unpredictably (Casadevall and Pirofski 2015). In this scenario,
microbial virulence becomes an emergent property, dependent on host
and microbial factors, whose interactions cannot be derived from first
principles (Casadevall, Fang, and Pirofski 2011).



In sum, the ecological view has led to the view that boundaries
between parasitism, commensalism and mutualism are changeable and
fluid, dependent on host factors, the full microbiota, and the broader
environmental context (temperature, nutrients, etc.) (Methot
and Alizon 2014). Current views of plasticity, pathogenicity, and
virulence revitalizes the nineteenth-century concept of microbial-host
equilibrium (Methot 2012). In the context of disease ecology,
long-lasting associations between hosts and parasites leads to a
climax state in which the respective populations remain stable (Burnet
and White 1972; Anderson 2004). The immune equilibrium model then
depicts persistent viral colonization as a product of a "dynamic
but metastable equilibrium between the virome and the host"
(Virgin, Wherry, and Ahmed 2009; Eberl 2010). Thus, the modern idea of
*balance* highlights a stable state in which offensive and
defensive forces neutralize one another to form stable associations
between parasites and the host with little damage to either partner
(Swiatczak 2014).


### 3.2 Immunity and evolution



The environmental perspective not only refers to the application of
ecological and evolutionary knowledge to immune modeling, but also
includes lessons learned from studies of immunity that reciprocally
inform current understanding of evolution. How these findings shed
light on the character of evolutionary change is well illustrated by
the research of inheritable immune variation. The origin of variation
has been subject to much debate in philosophy of biology. Advocates of
the view that nonrandom, environmentally induced factors are involved
in the generation of inheritable variation cite evidence of
stress-induced mutagenesis, horizontal gene transfer, and non-genetic
systems of inheritance (Koonin 2012: 257-291). Such discoveries
suggest that organisms may enhance their own adaptation to altered
environmental conditions epigenetically (Jablonka and Lamb 2014; J.
Shapiro 2011). Specialized diversification and recombination
mechanisms that are used by organisms to enhance their own adaptation
are considered Lamarckian in so far as the response to specific
environmental cues leads to alterations of phenotypic features, and
these adaptive characteristics may be transmitted to succeeding
generations (Sarkar 1991; Depew and Weber 1996). Notwithstanding
evidence for such mechanisms, postulated non-random mechanisms of
evolution have been disputed by those who claim that appeals to
Lamarckism are misguided and stem from mis-interpreting the
Neo-Darwinian synthesis or from overlooking genes as the basic units
of selection (Merlin 2010; Weiss 2015). With a focus on rapidly
adapting and evolving cell populations, immunological studies provide
a unique opportunity to investigate evolution in real time and to
understand the role of non-random, inheritable alterations of the
phenotype.



Examination of adaptive immunity in prokaryotes provides a major
breakthrough in this controversy. Many bacteria and most Archaea
undergo non-random changes directed at devising protection from
invasive bacteriophages and mobile genetic elements (Horvath and
Barrangou 2010). These microbes use specialized methods of defense,
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-Cas
(CRISPR-associated protein) systems to incorporate foreign DNA
fragments into their genomes (Koonin 2019). These become templates for
the formation of RNA molecules, which when associated with
endonuclease enzymes, mediate destruction of the complementary,
foreign DNA fragments. These acquired adaptive changes are a direct
consequence of the organism's interactions with the environment,
and, because these modifications can be passed on to succeeding
generations, the CRISPR-Cas system has been suggested to operate on
Lamarckian principles, an interpretation that has been contested
(Koonin 2012: 265; Koonin 2019; Pradeu 2019). Although not conforming to the neo-Darwinian model, this system lacks the teleological character postulated by Lamarck, and thus should be considered, at most, a model of directed mutagenesis (Wideman et al. 2019; Woolley et al. 2019; Weiss 2015).
Others counter that a continuum of Lamarckian-Darwinian mechanisms
exists in nature and that CRISPR-Cas represents a genuine case of
Lamarckinism (Jablonka 2019; Koonin and Wolf 2016). Advocates of this latter interpretation place CRISPR-Cas systems among other apparently Lamarckian mechanisms like those mediating epigenetic inheritance
(Gissis and Jablonka 2011).



Highlighting the importance of directed mutagenesis and programmed
gene rearrangements in evolution, these studies potentially revise
dominant theories of adaptation. Indeed, such genetic changes operate
in the vertebrate adaptive immune system: The first exposure of
antigen leads to selection of a diverse population of lymphocytes,
each carrying antigen receptors of a single specificity with varying
degrees of affinity for the newly introduced antigen; the stochastic
but coordinated assembly of gene segments determines receptor binding
fitness (Tonegawa, et al. 1974; Podolsky and Tauber 1997). Higher
degrees of specificity arise through a class of lymphocytes (B cells),
whose activation by a specific antigen induces further variation and
selection. This mechanism exhibits hypermutation, in which rearranged
antigen receptor genes are subjected to scattered, random point
mutations to permit rapid selection of a cell variant with an enhanced
binding fitness. As the process of hypermutation acts on pre-selected
cells to improve adaptive fit of their receptors, its outcomes are
partially biased, failing to exactly fit into the Neo-Darwinian scheme
(cf. Dobzhansky 1970). Thus, in the course of antigenic exposure, the
population of lymphocytes that recognize a newly introduced antigen
collectively generates an increasingly effective pool of responsive
cells by fine-tuning the specificity of immune receptors, a process
that exemplifies non-random selection and adaptation (Simon,
Hollander, and McMichael 2015).



Further revising our understanding of adaptation is the observation that maternal antibodies may be passed on to descendants, allowing progeny to inherit some of the acquired immune characteristics of their parents. An example of such vertical immune transfer has been found in
studies of the composition of the microbiota mothers pass on to the
infant through vaginal and breastfeeding routes that program the
newborn's immune system and metabolism (Mueller et al. 2015;
Gomez de Aguero et al. 2016). By molding the composition of its
microbiota during pregnancy, the mother's immune system
engineers its environment by constructing a microbial model for her
offspring (Chiu and S. Gilbert 2015; Mueller et al. 2015). When dysbiotic
microbial populations are transmitted by obese mothers, their
metabolic abnormalities and associated pro-inflammatory phenotype are
imprinted upon their children (Soderborg et al. 2018; Ley et al.
2005). Due to the reliance on microbial niche construction, the
acquisition of an infant's immune characteristics is an instance
of ecological inheritance, where transmission of selective pressures
from one generation to another pre-sets the process of the
progeny's adaptation to the environment (Odling-Smee, Laland,
and Feldman 2003; Odling-Smee et al. 2013; Chiu and S. Gilbert 2015).
Alterations in this ecological mode of immune transmission in humans
by C-section or administration of antibiotics may compromise the
health of the child and thus predispose them to a variety of
immune-related disorders (e.g., allergy and autoimmunity) (Bokulich et
al. 2016). Thus, adaptive immunity exhibits various modalities in which variation may be generated and transferred from one generation to another. These findings challenge traditional Darwinian and Lamarckian categories, with wide-ranging ramifications.



Finally, immunology contributes to a general account of selection
(Darden and Cain 1989; Hull, Langman, and Glenn 2001). The clonal
selection theory (CST), the foundational framework of modern
immunology, states that the immune system relies on a Darwinian-like
process of selection to permit differential expansion of lymphocytes,
whose receptors are fitted to bind an antigen (Burnet 1959). Analogies
between CST, natural selection theory, and selective theories in
neuroscience have been generally regarded as examples of "a
selection type theory" (Darden and Cain 1989). CST has also been
compared to other selective theories to elaborate a general vision
of selection as cycles of replication, variation and environmental
interaction (Hull, Langman, and Glenn 2001). Such a general account of
selection would not only elucidate the most fundamental principles of
evolution, but would also serve as a guide for future selective
theories, e.g., neural group selection (cf. Edelman 1974, 1987).
Differences between selection theories have also been recognized and
suggest that unlike evolution of species, selection in somatic systems
(in particular the neural system) does not fully account for the
adaptation of the developing populations (Dumouchel 1996). More
generally, Piattelli-Palmarini suggested that such a general scheme
could be of use in cognitive science and linguistics, as well as in
other disciplinary domains outside of biology (Piattelli-Palmarini
1986).


## 4. The Character of Immunological Knowledge



Case studies of immunology have contributed to understanding the role
of models and the structure of theory in the biomedical sciences (see
the entry on
 models in science).
 For example, Schaffner provided detailed analysis of the clonal
selection theory and the two-component theory of the immune response
to elaborate his criticism of the classical view of scientific
theories and to provide an account in which middle range theories,
consisting of interrelated theoretical models, organize subject areas
in biology (Schaffner 1980). A taxonomy of immune models (both
conceptual and experimental) exhibit a mosaic of methodologies and
theoretical ways in which information is obtained and integrated in
this field (Baetu 2014). Furthermore, high throughput sequencing
techniques and other "omics" approaches in immunology,
like those of microbial ecology, are increasingly utilizing new
analytical tools (cf. Huss 2014). In conjunction with systems biology
approaches, these tools inspire engineering orientations, in which
biological systems achieve robustness and stability through the same
principles with which machines are built, namely using system controls
(e.g., feedback), redundancy (e.g., gene duplication, alternative
metabolic pathways), modular design (to minimize damage to local
units), and structural stability (Kitano 2001: 18). Apart from serving
as an exemplar of systems-based theories and models, immunology has
also been employed to develop cognitivist models, elucidate conceptual
and theoretical change in biology, and elaborate on contentious issues
about reductionism and anti-reductionism.


### 4.1. Cognitivist models



The rise of the cognitive paradigm in immunology originated in
conceiving the immune system as a faculty of perception. Immunologists
explicitly describe macrophages "seeing" antigen;
antibodies "recognizing" epitopes; T cell possessing
"memory"; and adaptive immunity comprising a
"learning" process. Such extensions from human psychology
have been widely utilized in evolutionary history (Margulis,
Asikainen, and Krumbein 2011), wherein basic categories of human
cognition have been extrapolated to animals (Bekoff, Allen, and
Burghardt 2002), bacteria (Ben Jacob et al. 2004; Ben Jacob, Shapira,
and Tauber 2005), cancer cells (Ben Jacob, Coffey, and Levine 2012)
and the immune system (Cohen 1992a, 1992b). The influence of the
cognitive metaphor (where intention plays an incipient role) appears
throughout immune theory with extrapolations to cognitive science more
generally (Varela 1994: 36; Varela et al. 1988; Varela and Coutinho
1991; Vaz 2011b).



Models of cognition in immune theorizing have been extended from human
cognitive science and linguistics, where representational and
anti-representationalist orientations have vied for dominance (Tauber
2013). The dominant model regards the immune response integrating two
steps: First, the immune system perceives molecular targets and then
"decides" how to react (Cohen 1992a). Accordingly,
"perception" is primary and effector functions (activation
or tolerance) follow along a spectrum of responses. This understanding
of immune cognition construes immunity as an information-processing
faculty, where immune activity becomes a computational process
involving algorithmic transformation of an antigenic input into an
effector output (Cohen 2007b).



This cognitivist orientation is of special interest to philosophers,
in so far as such an examination provokes questions concerning the
ontological status of intentionality, the role of representation, and
the character of cognitive processing in general. Indeed,
immunology's cognitive models carry the promise of revitalizing
some of the key issues prevalent in cognitive science by placing them
into the context of a system whose circulating components interact in
a probabilistic manner (Varela et al. 1988; Tauber 2017:
129-161; Cohen 2000: 57-99). Such a "fluid
brain" carries wide-ranging theoretical implications (Fridman
1991).



Shared nervous-immune system organizational characteristics have been
proposed (Nataf 2016). As in the visual processing areas of the brain,
where distinct features of a visual object (shape, color, motion) are
perceived separately by distinct neuronal populations (C. Gilbert
2013), the immune system utilizes dedicated cells and receptors to
process fragmentary signals that discern distinct features of its
environment (Swiatczak, Rescigno, and Cohen 2011). These signals are
then integrated by higher-level processing, which, by computing
information from their respective "receptive fields",
produce a unified representation of the antigen. Such a distributed
image parallels activities of higher cortical areas. So, analogous to
the nervous system, the immune system perceives immune objects by
assembling discrete signals (immunogens, cytokines, chemokines, etc.)
obtained as informational elements derived from various cell types,
which, in an ascending integration, generate a multitude of T-cell and
B-cell responses (Nataf 2016). In this schema, the integrative process
occurring in lymphoid aggregates is the functional equivalent to the
brain that employs an analogous hierarchal structure to process
information. Indeed, the nervous and immune systems are highly
integrated, both physiologically and anatomically. They share many of
the same messenger molecules, have close developmental histories both
in phylogeny and ontogeny, and intersect biochemically (Ader
2006).



The so-called "psycho-neuro-endocrine system" has a
well-established fourth partner in the immune system showing that its
activity cannot be understood in isolation from these other systems.
The models employed in one cognitive system are readily shared by the
other and thus propagate underlying theoretical approaches and
implicit directives. Postulating molecular-level and systems-level
recognition states carries notions of "intentionality"
(see the entry on
 intentionality).
 Alternatively, instrumentalist and eliminativist approaches argue
that intentional descriptions are either only constructs of a useful
idiom or that they should be dropped altogether (Dennett 1987;
Churchland 1989). Intentional assignments reflect an ordering
mechanism for phenomena otherwise difficult to characterize and thus
susceptible to error (Matthen and Levy 1984). Errors must be
understood in terms of reference to what end a system actually
seemingly *intends* versus what it achieves in given
circumstances. In the immune setting, autoimmunity signifies a
dysregulated state that, in this context, signifies mis-directed
intentionality of normal immune function (Matthen and Levy 1984: 361).
Any attempt to frame this process in non-intentional terms would fail,
as such descriptions do not invoke goals, expectations, unfulfilled
intentions and the like. Accordingly, immunology cannot dispense with
the intentional idiom and the associated psychological metaphors used
in its descriptive language, if even only as a heuristic device
(Rosenberg 1989: 38; Melander 1993: 239; Howes 2000). Strong arguments
have been made that metaphors in the life sciences act as
indispensable instruments of cognition and explanation in addition to
providing a useful perspective on a research subject (Reynolds 2018).
Indeed, despite neo-positivistic efforts to rid science of nonliteral
meanings to permit an objective (neutral) description of nature,
analogical thinking in science plays a variety of crucial epistemic
functions (Hesse 1966; Fox Keller 2002).


#### 4.1.1 Representational models



Advocates of representationalist approaches to immune cognition accept
the subject-object dichotomy that portrays the immune system as a
"knower", an agent, who can represent the state of its
inner and other environments (Tauber 2013). This has become a
well-entrenched orientation inasmuch as the ontological understanding
of key concepts in immunology--*self, individuality*, and
*organism*--revolves around the status of *agency*
in immune theorizing. As already mentioned, from the very inception of
the discipline, immunologists have either assumed an implicit identity
that grounds the distinction between self and foreign, or that
identity is explicitly described as an agent at the heart of immune
defense. Traditionally associated with the capacity of an intentional,
conscious being to act (see the entry on
 agency),
 agency has been redefined in philosophy of immunology to refer to the
source of immune activity.



The capacity of the immune system to create representative images
(through ligand-receptor structural homology) and to act on them does
not mean that this system hosts a centralized control unit. Rather, as
advocates of these information-based accounts suggest, immune agency
emerges from collective behavior of individual immune cells, each of
which acts as a "cellular computing machine" (Cohen and Efroni 2019). From this point of view, the apparent complex
"intelligence" of the immune system is a product of multiple cues originating from individual immune cells that function analogously to
joint decisions made by a school of fish. From this cognitive point
view, immunity arises from shared collective information.


#### 4.1.2 Non-representational models



A distinct group of philosophical problems stems from
anti-representationalist approaches to immune cognition. Advocates of
the so-called immune *network theory* challenge the classical
subject-object epistemology as a relationship between the knower and
the known that heretofore has dominated immune theory (Varela 1994:
39). Heralding a shift "from an antigen-centered immunology to
an organism-centered immunology", this view maintains that
immune agency requires neither representation nor unified control
(Varela 1991). Instead of a hierarchical organizational format, this
de-centered orientation rests on the architecture of the network
theory proposed by Niels Jerne (Jerne 1974). He theorized that if
antibodies of an individual are diverse enough to bind *any*
antigen, they also are capable of recognizing one another. Simply,
their mutual interactions must precede any exogenous antigen encounter. Thus, a binding site of one antibody could serve as an antigen to another antibody, which in turn may become the target to still another antibody to create a self-contained, inter-locking
lattice-like network (Jerne 1985). He further proposed that excitatory
and inhibitory forces resulting from antibody interactions establish
an equilibrium state, which, unless upset by an intruding antigen,
ensures stable immune dynamics. Thus, according to Jerne's
hypothesis, the immune system is a self-referential network made up of
molecules that represent one another and whose reactions against
invasive pathogens were only the *incidental* result of
equilibrating mechanisms that restore stable network dynamics.



In the network schema, cognition is not *of* something;
perception is entirely within the system itself; the agent has
vanished, and with that vacancy, representations are discarded (Vaz
and Varela 1978: 238; Mingers 1991; Coutinho 2003; Palacios and
Bacigalupo 2003; Vaz 2011a). After all, *what* requires a
*re*-presentation? In Jerne's system, no hierarchy
exists, and no cognitive center corresponding to company headquarters.
Instead, what heretofore was referred to as activation resulting from
a subject-object predicate structured cognitive event (described by
stimulus-response language) now refers to increased dynamic activity
that is due to the disruption of the network's equilibrium.
Accordingly, immune "knowledge" shifts from a
signifier-signified relationship to one in which meaning is
firmly lodged *within* the system itself. Simply, the
subject-object epistemological structure of cognition has been
radically revamped.



Jerne's provocative hypothesis, although elegant in conception
and effective in inspiring new avenues of research, did not withstand
critical evaluation (Eichmann 2008; Vaz 2011a, 2011b). Despite
confirming the presence of idiotypic antibodies (i.e., mutually
interacting immunoglobulin molecules), their role and overall
contribution to immune functions remained uncertain. Furthermore, the
idea of autonomy and closure contradicted empirical evidence
(Hershberg and Efroni 2001; Coutinho 2003). However, notions of
cognition without agency remained plausible. Pradeu and colleagues
similarly proposed that the state of the immune system is structured
by inter-connected elements, where activation results from
perturbations of the stable linkages of the resting state (Pradeu and
Carosella 2006a, 2006b; Pradeu, Jaeger, and Vivier 2013). The original
"network" theory focused upon the inter-actions of the
immune system's constituents, (Jerne 1974), while the
"continuity" theory employs an architecture of
antigenic-immune interactions (Pradeu 2012, 2018; Grossman and Paul
2015). When the immune system is regarded from this
"connected" perspective, tolerance is the result of a
stable continuity of interactions between an antigen and its
receptors. Thus, integrated states are quiescent and disrupted ones,
whether "foreign" or endogenous, generate immune
activation by breaking stabilized associations.



In addition to antigen/receptor dynamics, other factors are also
involved in delineating the scope of tolerable changes in the
organism. These include a self-regulated system of diverse
interactions among several immune components comprising a complex system of antigen-presenting cells, effector T and B lymphocytes, regulatory cells and a diverse soup of molecular signals
(Kim, Levy, and Lee 2009; Kidd et al. 2014). So, the functional
difference that determines recognition of the foreign results not only
from an aggregate of quantitative ligand-receptor affinity
differences, but also from the context in which the antigen is seen
and the degree of interruption in network dynamics induced by such an
immunogen (Cohen 2000a; Cohen and Efroni 2019). Accordingly, the
overall function of the immune system may be defined as maintenance of
molecular (antigenic) homeostasis (Poletaev, Stepanyuk, and Gershwin
2008). On this general view, a systems-wide collective
response--not the discriminatory power of individual lymphocytes
or their receptors--determines identity and immune
specificity.


#### 4.1.3 Presentational cognition



The so-called "ecological" perspective offers still another
model of cognition, where the immune system does not employ
representations of the world, but rather "sees" the world
directly (Tauber 2017: 151-156, 219-228). In this
'presentational' schema, the capacity to extract
information about the environment depends on pre-programmed systems of
perception, whose organizational structures "resonate"
with environmental inputs (Gibson 1966; 1979). Accordingly, the
environment's informational content results from the stimulation
of the system that already has the ability to acknowledge inputs of a
recognizable character. Simply, information is only that which is
*already* meaningful (Ben-Ze'ev 1993: 70-71; Gibson
1979). This scheme would reconfigure the subject-object epistemology
dominating current immune theory with an information-processing
faculty that dispenses with some knowing entity, who sits in a
"Cartesian theater" to observe the world (Dennett
1991). Drawing an analogy from collective colony behaviors of insects
(Gordon 2001; Bonabeau 2001) and bacteria (Ben Jacob, Becker, Shapira,
and Levine 2004; Ben Jacob, Shapira, and Tauber 2005), the immune
system may then be modeled without centralized control or directives
by simply following its "rules" of regulation. Such a
model of "embedded" cognition holds that perception may be
explained independently of computational processes or representations
altogether (L. Shapiro 2011). Simply, presentational cognition
substitutes an agent, who employs representations, for a process in
which the immediacy of perception removes any such intermediary.
Accordingly, cognition is not *of* something, for perception is
entirely within the system itself; the agent has disappeared, and with
that vacancy, representations are discarded.



As with Jerne's system, in presentational cognition, no
hierarchy exists, and no cognitive center is posited. The
stimulus-response model has been discarded and activation
heretofore understood as resulting from a predicate-structured
cognitive event now refers to increased dynamic activity that results
from the disruption of the network's equilibrium. Immune
"knowledge" accordingly shifts from a
signifier-signified relationship to one in which meaning is
firmly lodged *within* the system itself, i.e., a system that "knows" only itself.
To the extent immunology would fashion itself along these lines, the
conception of the self partitioned from the world would be replaced by
an agent-free information-forming and information-processing faculty
(Orosz 2001; Forrest and Hofmeyr 2001). Such a distributed information
processing system has two key features: 


1. There is no central immunological processor (as found in a
computer's central processing unit). Immune specificity has
collective properties, and tolerance, as well as activation
distinctions are distributed and cannot be "reduced" to
isolated components (Coutinho 1989; Daeron 2014).
2. The dynamical patterns of interactions among the diverse parts of
the immune system function strictly in terms of their own processes in
the absence of a mediator or witness, and thereby dispense with the
traditional features of agency and accompanying autonomy that have
traditionally dominated immune theorizing.



Thus, paralleling current trends in other philosophical disciplines,
philosophy of immunology draws from, and contributes to, parallel
studies in the cognitive sciences that address the general problems of
agency, cognition, and behavior.


### 4.2 Reductionism versus holism in immunology



Apart from elucidating issues pertaining to identity, individuality
and agency of an organism in its broader ecological and evolutionary
history, philosophy of immunology also contributes to discussions
about the origin, organization, and methods of biological knowledge.
Reflecting on explanatory practices of immunology, the epistemic
modality has an important practical dimension that contributes to
developing methodological strategies and conceptual tools to handle
the complexity of the immune system. Genomic, proteomic and
transcriptomic studies are producing vast amounts of immune data with
little understanding of the basic organization and regulation that
must integrate systems-level and molecular-level approaches (Ohno
1990; Schatz and Langmead 2013; see the entry on
 genomics and postgenomics).



The shift from a focus on the insularity and autonomy of the organism
to its integration within a complex consortium of species carries a
contrasting holistic orientation to the reductivism characterizing the
molecularization of immunology (Ulvestad 2007: 65-67). The
theoretical implications and practical methodological re-direction
indicate a re-alignment of research strategies for immunology and,
more generally, an important contribution to the larger debates
concerning the character and feasibility of non-reductionist research
programs in the life sciences (Kitcher 1984; Sarkar 1998; Wimsatt
2007). Initially focused on the question of the relationship between
classical genetics and molecular biology, these debates have turned to
explanatory strategies in distinct biological subdisciplines, such as
neuroscience (Craver 2005), ecology (Dupre 1993), systems
biology (Wolkenhauer and Green 2013) and developmental biology (Love
2008; see the entry on
 developmental biology).
 Still awaiting broader recognition as an exemplar of explanatory
practices in life sciences, immunology already serves as a case study
to approach the problem of reduction and holism in biology and
medicine.



Different models of epistemic reduction have been considered with
little consensus about the applicability of this type of explanation
(Sarkar 1998). Dissatisfaction with models of theory reduction led to
various models of explanatory reduction that, unlike
deductive-nomological accounts, consider relationships between
epistemic units other than theories containing laws, while relying on
an intuitive sense of reduction as an explanation of higher level
features in terms of their parts (see the entry on
 reductionism in biology).
 A dominant concern about reduction is the so called
"many-many" relationships between levels of analysis,
where biological features are context dependent and may vary due to
heterogeneous lower level features (Hull 1974; Fodor 1974; S. Gilbert
and Sarkar 2000). One approach maintains that non-reductionist
explanations should focus on gross "cytological" features
of the studied phenomena rather than on lower level molecular
processes (Kitcher 1984). In contrast to this approach, immunologists
assume that reduction is an attempt to explain complex immune
phenomena in terms of *isolated* parts and interactions without
taking into consideration the entirety of structural and functional
complexities (Van Regenmortel 2002). Thus, instead of assuming that
non-reductionist explanations must ignore lower level molecular
details, holistic immunologists attempt to understand the multilevel
complexity of the immune phenomena they study (Rivas et al. 2017).
Accordingly, non-reductionist descriptions do not attempt to remain on
a descriptive, biological level of understanding, but rather adapt
pluralistic approaches that integrate distinct dimensions and frames
of reference, i.e., both molecular and higher orders of analysis. This
perspective aligns with recent approaches in philosophy of biology
that move beyond the division of lower- and higher-level explanatory
strategies and highlight the importance of interdisciplinary
integration exhibited by current scientific practice (Brigandt 2010;
Love and Lugar 2013).



Both reductive and holistic immunological research agendas have vied
for dominance (Silverstein 2009: 25-42). The immune-chemical
program, championed by Ehrlich and other immunochemists of the first
half of the twentieth century, examined immune reactions in terms of
chemical and physical forces between immune receptors and their
ligands (Silverstein 2009: 456). These immunochemists were adopting a
"unifactoralism" strategy that endeavors to explain
complex biological processes in terms of single factors (Powell and
Dupre 2008). That program was modified and renewed by the
elucidation of the genetics of antibody diversification, a series of
discoveries that placed immunology well within the molecular biology
revolution (Podolsky and Tauber 1997).



Studies of immunity coupled to developmental biology, ecology, and
evolutionary biology have balanced the molecularization of immunology
with an organism-based orientation. Early advocates of such
approaches, like Metchnikoff, described immunity in terms of cells and
cellular interactions, a "biological" perspective extended
by Burnet, who eclectically endeavored to include underlying molecular
processes (Crist and Tauber 2000; Baxter 2006: 38). He presented
immunity in terms of adaptation, selection, and population-level cell
behavior, rather than solely in terms of chemical and physical
molecular reactions. As already discussed, this broadened perspective
introduced the 'self' into the immune lexicon and brought
new figurative language associated with agency and a host of meanings
borrowed from other human experience. And, complementing these
holistic explanatory and narrative strategies, he also postulated the
existence of molecular signatures of self and considered lymphocyte
receptors as independent decision-makers mediating immune reactions
based on their physical fit with cognate antigens (Burnet 1969). Thus,
by representing cases of theoretical integration and explanatory
heterogeneity, epistemic strategies adopted by Burnet and other
organism-oriented immunologists fit into the inclusion of of plurality
and unification increasingly regarded as necessary to capture the
complexity of immune functions (cf. Dupre 1993; Mitchell 2003;
Plutynski 2013).



More recently, attempts to integrate molecular biology with systems
analysis challenge the apparent conflict between reductionist and
holist strategies (Green et al. 2017; Mazzocchi 2012). After all,
attempts to explain complex immunological phenomena in terms of
isolated parts and interactions without taking into consideration the
entirety of structural and functional complexity that these phenomena
exhibit have been ineffective. For example, vaccine development
studies, when limited to investigation of the structural correlates of
antigen-antibody interaction without deeper understanding of the
dynamic features of a host-pathogen encounter, often prove
unsuccessful (Van Regenmortel 2002). So, instead of assuming that
non-reductionist explanations must ignore lower level molecular
details, system-oriented immunologists attempt to understand the
multilevel complexity of the immune reactions they study (Rivas et al.
2017). Dynamical systems theory and a variety of network-based
approaches are used in systems biology to integrate distinct levels of
analysis and elucidate the complexity of the biological phenomena in question
(Green et al. 2017). Accordingly, a pluralistic approach that attends
to distinct dimensions and frames of reference, i.e., both molecular
and higher orders of analysis, has directed recent efforts to
integrate the complexity immunity (Lowy 2008: 172; see entry on
 philosophy of systems and synthetic biology).
 However, the program of melding the reductionist and holistic methods
as complementary to each other has been slowed by both technical and
conceptual hurdles (Fang and Casadevall 2011). How to model the system
as a *system* requires the collection of information about the
totality of interactions to explain causal mechanisms with multiple
inputs and stochastic outcomes. No approach has achieved dominance
and, consequently, the question of how massive data might be
incorporated into a systems-wide comprehensive model comprises a key
challenge of contemporary immunology.


## 5. Immunology's Social Dimensions



Anti-foreign imagery in immunology provides an excellent case study of
bidirectional links between science and society (Tauber 1994, 2016;
Howes 1999). The wide acceptance of the self-nonself discrimination
model derived from the paradigmatic host-pathogen struggle that
exemplified the nineteenth century conceptualization of the body as
isolated from the environment. As developed by Claude Bernard, this
insular construct provided biology a theoretical foundation for
organismal biology that complemented Malthusian economics, liberal
political philosophy, and Comtian sociology to instantiate the
autonomous body as a political, social, economic and medical entity
(Foucault 1963 [1973]; Agamben 1998). Notwithstanding that
"independence" is a political term, Bernard's notion
of autonomy fails to fairly represent the dialectical relationships of
the organism and its environment (Levins and Lewontin 1985), nor the
evolutionary peculiarities of individuality itself (Buss 1987).



The depiction of the immune self as disconnecting the organism from
its surroundings harmonized with a particular Western cultural
experience of seeing "ourselves as entities, separate from the
rest of the world--as containers with insides and outsides"
(Lakoff and Johnson 1980: 58; Fleck 1935 [1979: 174-175]).
However, this extrapolation of a particular Western notion of
subjectivity may well be regarded a social construct (Mead 1962)
inasmuch as cross-cultural analysis reveals how the ancient Chinese
sensed self more like a fluid interface than as an enclosed entity
(Geaney 2011). And contemporary anthropological studies re-confirm how
notions of selfhood vary between cultures (e.g., Roland 1988). From
this perspective, social connotations and subjective experiences go
hand in hand with creating meaningful images of immunity and
biological identity. Finding its fertile soil in the fifties, the idea
of the demarcated organism squarely fit the valorization of
individualism that had diffused into Western arts, politics and
science during this period (Barbour 1995). An insular understanding of
"the self" at the core of these atomistic
characterizations lies at the foundation of immune theory and
practice, where contemporary psychological and philosophical
constructions of identity based on autonomous individuality prevail
(Tauber 1994).



However, culture critics have seized on immunology's notions of
autonomy as exemplifying modern notions of identity, where boundaries
are contested, and the body becomes the localized site of battle
between self and other (Sontag 1990; Haraway 1989; E. Martin 1994).
These commentators cite the recognized permeability of living
creatures, their symbiotic exchanges, and tolerance of myriad
assimilated foreign materials to challenge the origin and cultural
resonance of the atomistic framework. David Napier has characterized
our "age of immunology" as an individualism marked by a
preoccupation with the self and by an absence of transforming efforts
to incorporate the foreign (Napier 2003). Active rejection enunciated
with warfare metaphors so prevalent in immunology's
lexicon--"attack", "defense",
"invaders"--dramatically illustrate this formulation,
both in terms of the self/other dichotomy, as well as the privileged
regard of individuality over community. On this view, the
"immune self" appears as a metaphor to model Western
culture, by invoking "immunization" as an explanatory
model for understanding the core dynamics of post-industrial societies
(Esposito 2011; Sloterdijk 2011). The metaphor's wide
application--from religion and metaphysics to housing and
cities--invokes the dialectics of borders and exchange,
individuality and communes, where the balance of intrusion and defense
is invoked to characterize the "bubble" in which humans
live. Note, these interpretations closely resonate with the dynamics
of immunity regarded ecologically, as discussed above. 



These contrasting applications of social descriptions to immunology
reveal the ease by which the science may be employed for culture
criticism. But the exchange need not end with such contributions.
Having been implemented in the discourse of science, the imagery
borrowed from the culture-at-large becomes transformed and then
returns to the social domain, impacting on portrayals of persons and
their relationship with others (E. Martin 1994). On this view, the
science-culture exchange broadens the implications of understanding
the development of immune theory. For example, the political resonance
of the self/nonself framework was evident in the context of a debate
on tissue incompatibility, whose depiction as innate and unchangeable
harmonized with Burnet and Medawar's elitist sympathies and
opposition towards social Lamarckism (Lafferty 1995). The vision of
personhood that stood behind the self/nonself discrimination concept,
can be further traced back to Burnet's self-confessed
"harmless terror of strangers" and his
Darwinist vision of human relationships as defined by primordial
selfishness and incessant drives towards domination and power (Burnet
1971: 12). Along with ongoing cultural and political transformations, our
understanding of immune identity has also changed in the transition
from a modernist vision of delineated selfhood towards a more complex view
that dispenses with the self altogether. Thus, the imagery that is
used to represent the activity of the immune system has deep roots in
the broader culture that reflect dominant values and tensions defining the dialectics of the individual and her society. In sum, while immunology provides metaphors for characterizing human societies, the science in turn, draws from its supporting culture to model its
biology. Here we see an explicit demonstration of the
bi-directionality of social and scientific discourses, and to draw the
line separating the laboratory from its supporting culture again
proves problematic (Gieryn 1995).


## 6. Conclusion



Two conceptual shifts that have marked contemporary research in
immunology have influenced philosophical comment on various topics in
biology. The first is a major revision in how the mechanics of
immunity are conceived. Taking account of the context in which the
immune reaction is regulated, the earlier conception of immune
specificity as arising from some simple mechanical lock and key
matching between selected antibodies binding to noxious antigens has
been replaced with collectivist models of molecular interactions. In
accounting for the frequency and intensity of an immune encounter,
this dynamic orientation portrays the immune system as a sensor of
change rather than structure. The sensitivity of such a
cognitive system that must mediate multifarious immune reactions
requires a co-ordination of *collective* molecular ensembles,
in which diverse elements together determine the extent of the immune
response (Daeron 2014). Indeed, only through modulated responses
can immunity fulfill its diverse functions, some of which require
tolerance of recognized substances and others full blown activation of
rejection. Accordingly, immune theory has departed from the classical,
self/nonself framework that depicts the immune response as a simple
"on" and "off" binary switch, to multifaceted
models that account for a spectrum of reactivities.



The second conceptual shift addresses how immunity mediates the
interactions of the organism with its environment. That ecological
orientation has inflected immunology from its earlier insular
conceptions of the organism to a dynamic interactive view that
highlights how life experience alters the immune response to external
challenges and opportunities. With this broadened perspective, the
idea of *immunity* extends beyond defense of an atomistic
individual, to include the mediation of the organism's
ecological economy, both defensive and assimilative. This includes the
internal environment as well, inasmuch as the microbiome, established
through immune niche formation, has increasingly focused attention on
the prevalence of immune tolerance, symbiosis, and the biology
characterized by cooperative relationships of various sorts (Eberl
2010; Bilate and LaFaille 2012).



In short, the philosophical challenge of defining immune identity is
framed by differing orientations, namely, autonomous individuality
versus collective ensemble (both applicable to the regulation of the
immune response and contextual placement in the environment). Which
version chosen then leads to strikingly different answers to
immunology's key questions: 


1. What is immunity;
2. what are the defining characteristics of individuality as
determined immunologically;
3. what are the epistemological standing of immune selfhood and the
rhetorical uses of agency in its various forms (literal, metaphoric,
and idiomatic);
4. how has the cognitive paradigm framed immune processes as an
information processing system; and
5. how might biological causation of the immune system studied as a
whole be modeled?



Each of these issues directly pertains to philosophical considerations
about the character of the organism, the relationships of parts to the
whole, principles of biological organization and regulation, the
construction of cognitive schemas, and the ability of models to
capture complex organic functions.



In conclusion, although firmly embedded in philosophy of biology and
engaging in closely related concerns, the philosophy of immunology has
become an established discipline with distinctive interests and
contributions. The immunological matters of interest to philosophers
do not always overlap with those that dominate immunology's
contemporary research program. This divergence highlights how
philosophy of immunology has emerged as an autonomous field with its
own subjects of attention and methods of inquiry that complement
rather than mimic or replicate the pursuits in related areas of
theoretical and experimental immunology. Moreover, philosophical
studies of immunology have contributed to a wide range of pivotal
topics engaged by philosophers of biology--organismal identity;
individuality; dynamic causation in complex systems (integrating
complexity theory with big data studies); the characterization of the
goals and methods of systems biology; the organization of information;
the characterization of the normative and deviant; and personal
ontology (self). Each of these areas of research impact other
biological disciplines of interest to philosophers, i.e., development,
ecology, genetics, evolution and cognition. And beyond the purview of
philosophy of biology, studies of immunology contribute to the more
general discussions of reductionism/anti-reductionism, theory change
and conceptual modeling, and social and cultural studies of science
(i.e., the function of metaphors in science, the role of a scientific
discourse). In sum, a rich two-way traffic between philosophers of
immunology and philosophers of science has emerged that allows the
former to use tried-and-tested conceptual tools developed by their
colleagues, while providing a unique outlook for the latter. Given the
centrality of immunology in modern biology and the unique perspective
offered by this science on crucial philosophical problems, further
engagement not only seems likely, but an imperative for philosophy of
science writ large.