Human genetic errors of immunity illuminate an adaptive arsenal model of rapid defenses

Abstract

New discoveries in the field of human monogenic immune diseases highlight critical genes and pathways governing immune responses. Here, I describe how the ~500 currently defined human inborn errors of immunity help shape what I propose is an ‘adaptive arsenal model of rapid defenses’, emphasizing the set of immunological defenses poised for rapid responses in the natural environment. This arsenal blurs the lines between innate and adaptive immunity and is established through molecular relays between cell types, often traversing from sensors (pathogen detection) to intermediates to executioners (pathogen clearance) via soluble factors. Predictions and missing information based on the adaptive arsenal model are discussed, as are emergent and outstanding questions fundamental to advances in the field.

A systems view of essential immune defenses delineated by monogenic infection susceptibilities

Many new and often unexpected insights arise from the discovery of gene variants causing novel inborn errors of immunity (IEIs) in patients with rare immune diseases. This was appreciated centuries ago with prescient descriptions by William Harvey (1578–1657) of the value of rare, extreme phenotypes for informing fundamental biological processes[1]. Although each IEI disease entity is individually very rare, collectively IEIs affect millions of people, most of whom remain undiagnosed worldwide[2]. Moreover, less deleterious single-nucleotide variants in the genes and pathways affected in IEIs are prime suspects in more common ailments with shared features and etiology such as infection and inflammation diatheses. While each individual disease entity offers a new window into mechanisms of healthy immune function at the individual level, the broader view of the entire set of genes, cell types affected, and disease manifestations across populations of patients with IEIs provides systems-level insights. Together, these illuminate patterns of highly functionally relevant aberrations not otherwise discernible.

The short life expectancy and high childhood mortality from infection in the era preceding the advent of modern medicine underscores how vital the arms race between host immunity and microbes is for the human population in the natural environment. Before monogenic ‘primary immunodeficiency’ (PID) could be recognized as a clinical entity, means of sufficiently preventing and managing infectious disease burden in the general population first had to be established so that physicians could discern outlier patients with more severe infection susceptibility. With the concepts of mass vaccination, germ theory, and antibiotic use established, the first primary immunodeficiency, Bruton’s agammaglobulinemia, was recognized in the 1950s, a time when cortisone as a therapy also came about and helped illuminate immunosuppression-induced infection susceptibility[3]. In the intervening decades, nearly 500 individual IEIs have been defined (including many in recent years - Supplemental Table 1), which provide an opportunity to contextualize basic immunology knowledge. It is not the intention to exhaustively cover all ~500 known IEIs, which are reviewed elsewhere[4, 5]. Instead, I aim to highlight how these disease entities are, in essence, phenotypes emerging through genetic screens in natura with important immunological implications. Of note, although some parasitic protozoan infections (such as Giardia, Cryptosporidium, Toxoplasma, Blastocystis) are relevant in some patients with IEIs, most infections are bacterial, fungal, or viral and therefore, are the focus here.

In this Opinion article, I describe how human inborn errors of immunity can be conceptualized into an ‘adaptive arsenal model of rapid defenses’ composed of the collection of intrinsic and rapid immune defenses available to the organism upon infection. In the natural environment, innate and adaptive immune responses blend to establish an arsenal that adapts to prior exposures by layering on new rapid defenses in the form of antigen-specific immunoglobulins and memory lymphocytes with innate-like characteristics. Collectively, human genetic errors and their mouse models map out essential molecular relays between cell types, often traversing from sensors (pathogen detection) to intermediates to executioners (pathogen clearance), that establish that organism’s adaptive arsenal. These relays help elucidate how cells and molecules are involved not only in host defense but also in protecting the host from tissue immunopathology, both of which are discussed below.

Phagocytes reign supreme as executioners of anti-bacterial and anti-fungal responses

The importance of phagocytes as immune cells originally described by Metchnikoff in the late 1800s is underscored by human diseases of phagocyte dysfunction first reported in the 1950s by Janeway Sr. and Good[6, 7] that led to recognition of “fatal granulomatous disease of childhood.” Phagocyte-mediated clearance mechanisms position these cells as executioners eliminating bacterial and fungal pathogens. Opsonins, comprising antibodies and complement, play a key role by coating the pathogen, particularly in the case of encapsulated bacteria, to facilitate clearance by splenic macrophages and other innate immune cells[8]. Indeed, many sensors (pathogen detection mechanisms) and relays (signals between cell types) feed into phagocyte recruitment, phagocytosis, and degranulation to support immune defense via phagolysosome-mediated microbe destruction and the combined action of molecules including reactive oxygen species (ROS)[9], antimicrobial peptides, and others. Moreover, susceptibility to both bacterial and fungal infections occurs in patients with genetic defects that disrupt the recruitment (e.g., leukocyte adhesion deficiency) or function (e.g., chronic granulomatous disease) of phagocytes, while more specific types of infections occur when specific circuits directing phagocyte responses are genetically disrupted. For example, defective IFNγ production (through a variety of means) results in ‘Mendelian Susceptibility to Mycobacterial Disease’ (MSMD) with susceptibility to mycobacteria and Salmonella infection[10]. Furthermore, mutations in the sensors or relays (e.g., Dectin-1, CARD9, IL12RB1, STAT3) that induce IL-17 outputs converge on a phenotype of fungal susceptibility in a group of disorders leading to ‘Chronic Mucocutaneous Candidiasis’ (CMC) with Candida and Staphylococcus aureus infection susceptibility[11]. Collectively, these underscore the vital importance of both IFNγ (e.g., from Th1 cells) and IL-17 (e.g., from Th17 cells) in directing phagocytes to clear particular bacterial and fungal pathogens. In the case of IFNγ, macrophages are instructed to kill intracellular bacteria, while in the case of IL-17, neutrophils are instructed to kill fungi[12]. Thus, defects in a range of molecular mediators result in susceptibility to broad or specific types of bacterial and fungal infections, providing a set of IEIs that lay out a roadmap to understanding the sensors, relays, and executioners in these responses (Figure 1).

Figure 1. Human inborn errors of immunity help delineate essential relays for anti-bacterial and anti-fungal immune defenses.

Shown are illustrative IEIs that highlight key immune relays and related genes governing anti-bacterial and anti-fungal responses, which converge on phagocyte-mediated pathogen clearance. MSMD: Mendelian susceptibility to mycobacterial disease; SCID: severe combined immunodeficiency; CMC: chronic mucocutaneous candidiasis; XLA: X-linked agammaglobulinemia; CVID: common variable immunodeficiency.

There are many genetic defects that result in defective IgG antibody responses, either due to B cell defects (e.g., agammaglobulinemia) or to CD4⁺ T cell helper defects (e.g., combined immunodeficiencies). The network of molecular and cellular interactions required for high-affinity, class-switched antibody responses is vast, and with more complex inputs, more potential points of failure can exist. Indeed, antibody defects are the most common type of IEI[13] and are classified as defects of adaptive immunity, leading to loss of the key neutralizing and opsonizing effector functions of antibodies. Downstream, defective opsonins result in susceptibility to encapsulated bacteria, with sinopulmonary bacterial infections resulting from low IgG (as well as asplenia – absence of spleen) or Neisserial bacterial infections resulting from complement C5–9 deficiencies[8]. These observations underscore the dependency of phagocytes on antibodies and complement to coat pathogens for clearance. Severe combined immunodeficiency (SCID) patients lack both IgG and CD4⁺ T cell-derived cytokines, such as IFNγ and IL-17 described above, that are necessary relays to direct phagocyte activity and, therefore, are particularly susceptible to bacterial and fungal infections[13]. Thus, ‘innate’ immune cells are positioned at both the initiation (as sensors and antigen-presenting cells) and the execution (as phagocytes) phases of anti-bacterial and anti-fungal responses, with pathogen clearance often requiring licensing either by constitutive factors (e.g., complement components, many produced by hepatocytes) or lymphocyte-derived factors (e.g., cytokines or IgG) (Figure 1). Such a relay of immunological signals ensures that short-lived phagocytic cells with potentially tissue-damaging capacity are only deployed when sufficient signals are sensed through intercellular communication.

A collaboration between cell death and antibody defenses protects from severe viral disease

Viruses are ancient, as are the effective cell-intrinsic responses of tissue cells that rapidly sense and respond to viruses. Cell death responses are key to anti-viral defense across plants (i.e., hypersensitive response[14, 15]) and animals. Evolution of the type I interferon (IFN) circuits in early vertebrates provided a potent molecular defense strategy via regulation of the anti-viral state (including induction of nucleases and the integrated stress response) and apoptosis to restrict viral infection[16]. Underscoring this point, patients with aberrant type I IFN signaling due to IFNAR1/2- or STAT2-deficiency suffer notably from disseminated disease from live, attenuated viral vaccines (e.g., measles or yellow fever) as well as natural viral infections[17]. Other cell-intrinsic immunity defects result in remarkably specific infection susceptibilities, such as with herpes simplex virus (e.g., mutations in TLR3, TRIF, IRF3[18]) or with human papillomavirus (e.g., mutations in EVER1, EVER2, CIB1[19]), highlighting redundancy of these genes for protection from other infection types. Viruses have evolved numerous defense mechanisms to subvert cell-intrinsic anti-viral responses, and cell-extrinsic induction of apoptosis via granule delivery by cytotoxic lymphocytes (NK cells and CD8 T cells) offers a secondary mechanism to clear virally infected cells. However, patients with IEIs characterized by defective cytotoxic cells [e.g., deficiency in MHC class I (TAP1, TAP2, TAPBP[20–22]), CD8A[20–22], or cytotoxic granule delivery (various genes including perforin[23])] surprisingly do not suffer from severe viral infections, underscoring the effective compensation by other layers of anti-viral immune functions. Of note, deep water animal species such as anglerfish have evolved to lose major adaptive immunity elements, including MHC class I and CD8 to adopt a lifestyle of sexual parasitism, which demonstrates apparent sufficiency of intrinsic immunity and innate immunity for survival of this species in its natural environment[24]. Regarding antibody-mediated anti-viral defenses, patients with agammaglobulinemia generally exhibit intact resistance to viral infections, with the exception of enteroviruses such as echovirus, coxsackie viruses, and poliovirus[25, 26]. These viruses enter through the gastrointestinal tract and can become systemic, where neutralizing antibodies against the virus are critical for their control[27]. These findings indicate that cell-intrinsic and apoptosis-related defenses are largely sufficient in these patients to prevent illness from most virus types. Select examples of inborn errors of anti-viral immunity that illustrate key defense circuits are shown in Figure 2. Taken together, findings from IEIs reveal specific host defenses for specific viruses and also emphasize the broad and crucial roles of cell-intrinsic immunity and apoptosis-related anti-viral defenses.

Figure 2: Human inborn errors of immunity affecting viral pathogen control underscore the key roles of the anti-viral state and neutralizing antibody responses.

Illustrative IEIs highlighting pivotal immune relays and related genes governing anti-viral responses, which converge on cell-intrinsic immunity, cell death, and antibody-mediated neutralization. HSV: herpes simplex virus; HSE: herpes simplex encephalitis; XLA: X-linked agammaglobulinemia; SCID: severe combined immunodeficiency; BLSII: bare lymphocyte syndrome II from MHCII defects.

Counterpoise: keepers of immune homeostasis revealed by monogenic immune regulatory disorders

The activating signals that induce and amplify immune defenses (discussed above) must be counterbalanced by negative regulatory mechanisms that restore homeostatic set points. The immune system can result in disease when responsiveness is either too low (causing infection susceptibility) or too high (causing immunopathology). Regarding the latter, I use the term primary immune regulatory disorders (PIRDs) to encompass the wide range of IEIs that predominately feature tissue immunopathology and inflammation. PIRDs were described in the early-1900s in parallel with the recognition of PIDs. Early examples included paroxysmal syndrome now known as familial Mediterranean fever (FMF)[28] and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also called autoimmune polyglandular syndrome type 1 (APS1) (reviewed in[29]). It took another several decades before the genetic cause of FMF (i.e., MEFV gene mutation)[30, 31] and APECED (i.e., AIRE gene mutation)[32, 33] were reported in 1997. This was followed by the discovery of gene mutations in many other PIRDs causing lymphoproliferation and/or immune-mediated, inflammatory tissue damage[34, 35]. These human diseases and their mouse models have provided important new insights into immune regulatory nodes. For example, the key importance of regulatory genes including AIRE, FOXP3, CTLA4, LRBA, FAS, XIAP, TNFAIP3, IL1RN, and many others is illuminated by PIRDs caused by loss-of-function mutations in these genes. Thus, PIRDs bring into focus genes with essential function as molecular peacekeepers, which prevent immune-mediated tissue destruction by enforcing immunological tolerance and/or functioning as a brake to limit inflammation and maintain homeostasis. There is no broad consensus on the best definition of a disease that is autoimmune (typically defined as involving TCR/BCR self-reactivity) versus autoinflammatory (typically considered more innate-like), and it has become clear that this dichotomy is oversimplified. Instead, the spectrum of PIRDs may best be captured as diseases of (i) failed lymphocyte homeostasis, causing excessive lymphocyte cell numbers and tissue infiltration, (ii) complement regulatory disorders, and (iii) cytokinopathies, a large category of genetic disorders including those converging on NF-κB activators, JAK/STAT/IRF activators, and what I term ‘frustrated cytotoxicity’, and (iv) defects in barrier integrity. I provide key examples of these groups of PIRDs below in the following sections and in Figure 3.

Figure 3. Spectrum of human monogenic immune regulatory disorders from loss of regulatory gene function or gain-of-function mutations that drive excessive effector responses.

Shown are illustrative inborn errors of immunity (IEIs) that depict major categories of primary immune regulatory disorders (PIRDs) characterized by immunopathology. GOF: gain of function; APECED: autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; APS1: autoimmune polyglandular syndrome type 1; IPEX: immunodysregulation, polyendocrinopathy, enteropathy, X-linked; ALPS: autoimmune lymphoproliferative syndrome; APDS: activated PI3K-delta syndrome; BENTA: B cell expansion with NF-κB and T cell anergy.

Monogenic diseases of failed lymphocyte homeostasis

Activated lymphocytes are one of the most proliferative cell types upon activation, and single-gene defects disrupting lymphocyte homeostasis are a major group of PIRDs. These include defective central T cell tolerance from deficiency in AIRE (APECED/APS1), resulting in a systemic disease driven by maturation of T cells that fail to be negatively selected against peripheral self-antigens during thymic development. In turn, a cascade of T cell-driven tissue damage is initiated[36] and autoantibody is produced[37–39], further fueling an immune imbalance that perpetuates disease processes. Other PIRDs from failed lymphocyte tolerance include those due to failed peripheral tolerance, including T regulatory cell defects (Treg-opathies)[40]. Most notable among these are FOXP3 mutations causing ‘immunodysregulation, polyendocrinopathy, enteropathy, X-linked’ (IPEX), though other gene defects including those disrupting CD25, CTLA4, LRBA, and DEF6 also lead to Treg-opathy and lymphocyte-driven tissue damage (e.g., gut, lung, brain, endocrine organs), as evidenced by clinical phenotypes of patients with these PIRDs[40, 41]. Fundamental new insights have been gleaned from these PIRDs, such as studies of human LRBA and DEF6 deficiency unveiling their function as key regulators of CTLA4 recycling biology[41]. Moreover, therapy with CTLA4-Ig in these genetically defined Treg-opathies has offered a precision medicine treatment based on the genetic etiology – a theme that repeats itself in the field of PIRDs. Other monogenic lymphocyte dysregulatory diseases primarily affect peripheral lymphocyte cell numbers by perturbing cell death or cell proliferation and, thereby, result in pathological lymphocyte expansion and tissue infiltration[34]. This category of ‘lymphoproliferative’ disorders includes diseases of failed lymphocyte apoptosis via death receptors, such as ‘autoimmune lymphoproliferative syndrome’ (ALPS)[42, 43], as well as those from heightened lymphocyte signaling and proliferation, such as ‘activated PI3K-delta syndrome’ (APDS)[44–47] and ‘B cell expansion with NF-κB and T cell anergy’ (BENTA)[48]. Together, this group of PIRDs reveals the genes and pathways most consequential for homeostasis of lymphocyte numbers and consequent immune regulation.

All roads lead to cytokines: PIRDs from cytokinopathy

Early studies of fever responses in rabbits in the 1940s led to recognition of an endogenous pyrogen in 1948[49]. The concept proposed in 1960 was that exogenous pyrogens (e.g., lipid A) induce endogenous pyrogens (termed leukocytic pyrogen)[50] and the inflammatory contributions of monocytes (beyond just neutrophils) were investigated[51]. With recognition in 1979 that ‘lymphocyte activating factor’[52] and ‘endogenous/leukocytic pyrogen’ were the same factor, the foundation for the key cytokine we now know to be IL-1 was laid[53]. With time, the number of interleukins, interferons, and TNF family members has expanded, and >100 separate genes coding for cytokine-like proteins have been described with roles as messengers relaying immune information in positive and negative feedback circuits[54]^,[55]. Dysregulation of these circuits underlies ‘cytokinopathies’ – disease states caused by aberrant production and/or signaling of cytokines that drive an imbalance in the costs versus benefits of these immune defense relays. In many immune responses, the cell that senses pathogen produces first-order cytokines that act on intermediate cells that then produce second-order cytokines and downstream effects[56] (Figures 1–2). Multistep relays such as these occur at different scales and across biological systems as a means to regulate processes with potentially deleterious endpoints. Indeed, many PIRDs are caused by either loss of negative regulators or gain-of-function in activators of these relays (Figure 3), and diseases traditionally categorized as autoinflammatory comprise the fastest growing category of IEIs over the last 4 years[4, 5]. Dissecting the biology and pathology of cytokinopathies informs our understanding of inflammatory and anti-inflammatory cytokine circuits, revealing cell types that produce and respond to cytokine signals and molecules that modulate cytokine activity.

The ‘cytokinopathies’ can largely be categorized as those primarily affecting NF-κB cytokine circuits (including inflammasome-opathies with elevated IL-1/IL-18), those affecting JAK/STAT/IRF cytokine circuits (including type I interferon-opathies[57] with elevated IFNα/β and multiple STAT gain-of-function defects), and those triggered by what can be termed ‘frustrated cytotoxicity’[58–60] (Figure 3). The latter results in hemophagocytic lymphohistiocytosis (HLH), which is associated with elevated IFNγ and macrophage activation secondary to a failure of cytotoxic lymphocytes to properly degranulate, often associated with Epstein Barr virus (EBV) as the trigger[61]. Aside from the new insights gleaned from a variety of gain-of-function PIRDs, a focus on tissue immunopathology disorders caused by loss-of-function mutations can highlight fundamentally important negative regulators of inflammation. These gene products function to suppress inflammation to maintain and/or return to homeostasis in presence of chronic and/or commensal microbes. These include genes like IL1RN, IL18BP, TNFAIP3, TREX1, ADAR1, IL10, TGFB1, and many others (Figure 3). Collectively, monogenic cytokinopathy disorders additionally provide a framework to better understand systemic cytokine storm-like syndromes that can also occur outside of IEIs in the context of extreme inflammatory episodes from infection, sepsis, and related critical illness. Indeed, the explosion in biologics targeting cytokines (e.g., TNFα, IL-1, IL-12p40) has had a significant impact on rare and common immune-related disease and promises continued advances.

As an additional category of peacekeepers in inflammatory circuits, epithelial barriers represent the first line of defense against pathogens, and their interactions with immune cells are particularly complex because they occur in the context of constant microbial exposures. At the same time, co-existence with microbes in particular niches within the host is important for beneficial host-microbe interactions, including metabolic and mutualistic symbiosis with commensal bacteria, fungi, and viruses (including endogenous retroviruses). As such, regulation of epithelial-immune homeostasis is a common point of failure in PIRDs. Epithelial barrier defects result in aberrant interactions between immune cells and microbes, indirectly causing cytokine overproduction and inflammation[62]. Gene defects identified in very early onset inflammatory bowel disease (VEOIBD) patients reveal crucial regulators of intestinal epithelial-immune homeostasis, including TTC7A, TTC37, and others[63]. Outside the gut, skin barrier breach also results in aberrant microbe-immune cell interactions driving disease, with a prime example being the genetic disruption of filaggrin which causes increased inflammatory and allergic immune responses in patients[64, 65]. As an example of loss of a negative regulatory factor, human IL36RN deficiency results in a PIRD characterized by generalized pustular psoriasis due to uncontrolled keratinocyte-associated cytokine circuits[66] (Figure 3).

Thus, taken together, PIDs and PIRDs illuminate complementary biology, underscoring essential immune defense genes and the counteracting immune regulatory genes that allow the host to benefit from pathogen defense without self-destructing inflammation and immunopathology as collateral damage.

Convergence on an adaptive arsenal model of rapid defenses

The collective insights from human IEIs in conjunction with mouse modeling studies brings into view a hierarchy of the most essential immune system components and relays. The prevailing conceptualization of immune system function generally frames innate, fast, antigen non-specific responses in contrast to adaptive, slower, antigen-specific responses, with the latter being more effective. While this concept is informative and accurate when considering an initial exposure to a given pathogen, it becomes less relevant in the context of most encounters of a human (or other mammal in the natural environment) with a pathogen in which cooperativity between these branches of immunity is nearly universal. That is, the binary categories of innate versus adaptive are oversimplified for realistic conceptualization of essential immune effectors because they inadequately capture their inseparable integration and overlap. This is especially true in light of (i) the dependence of adaptive immunity on downstream innate immune cell (often phagocyte) executioners in pathogen clearance and (ii) the rapid, innate-like response characteristics of both tissue-resident lymphocytes and circulating memory T and B cells. As immune exposures accumulate over the life of an organism, memory T and B cells boost that organism’s collection of rapid immune defenses by supplying the host with circulating antibodies and the capacity to efficiently produce cytokines or plasmablasts. The latter de novo recall effector responses can be triggered not only be antigen recognition but also by direct microbial pattern recognition or cytokine sensing, leading to features such as bystander activation[67–69] and an ability to provide heterologous immunity[70].

By re-focusing on what might be called an adaptive arsenal of rapid defenses, I propose a framework that integrates physiologically relevant features from both animal models and human immunology (Figure 4 and Box 1). With greater emphasis on the blended responses of barrier, intrinsic, and classically innate and adaptive immune cells, the adaptive arsenal model accounts for cumulative immune exposures of an organism in conceptualizing the set of rapid defense strategies available to the host that dictate the outcome of infection. PIDs emphasize key rapid defenses – circulating immunoglobulins and complement, phagocytes, and lymphocyte-mediated cytokine circuits that instruct executioner cells (often phagocytes) – as essential components of the adaptive arsenal. Additionally, innate-like lymphocytes, including γδT cells and mucosal associated invariant T (MAIT) cells, exert non-redundant functions in defense from infection, as has been recently shown by studies of IEIs in which disease results from failed IFNγ-mediated control of mycobacteria[71, 72]. As an organism faces microbes in the environment, its ‘adaptive arsenal’ is adaptive in that it becomes equipped with long-lived, circulating antibodies as well as memory lymphocytes that are tissue-resident or circulating and can respond to microbial or cytokine cues to rapidly elicit effector functions (secretion of immunoglobulin and cytokines). As such, the innate-like responses of memory B and T cells can offer advantages to host pathogen defense through rapid boosting of responses stored as immunological memory[67, 69, 73]. On the other hand, PIRDs often involve lymphocyte subset expansion and autoantibodies associated with cytokine overproduction, further supporting this paradigm and the capacity of mis-directed memory lymphocytes to perpetuate inflammation and immunopathology in common diseases with post-childhood and later age of onset. These concepts highlight cooperativity, interdependence, and overlapping characteristics of cells and products of classically innate versus adaptive immunity, thereby supporting the adaptive arsenal model.

Key Figure, Figure 4. A proposed model of the adaptive arsenal of rapid defenses.

The model highlights the combination of intrinsic, innate, and adaptive effectors that are available to an organism to effectively defend from pathogens. (A) The major rapid immune defenses and their importance in anti-bacterial, -fungal, and/or -viral defense, as revealed by inborn errors of immunity (IEIs). (B) Schematic depiction of an individual’s adaptive arsenal of rapid defenses, which is augmented over time with new immune exposures and regulated by cells and pathways governing maintenance of immune-tissue homeostasis.

Box 1. The ‘adaptive arsenal of rapid defenses’ model.

The adaptive arsenal model incorporates key observations from human IEIs that blur the lines between innate and adaptive immune responses.

Human IEIs underscore that innate cells are often both at the initiation and execution phases of immune responses to bacterial and fungal infections, while intrinsic immunity and cell death responses are critical for anti-viral immunity[80]. The adaptive arsenal model aims to better reflect the outsized role for cells of the more ancient innate immune system and recognize two major ‘adaptive’ features: (i) innate cells prime T cells in a manner tailored to the infection type, which in turn, often results in (ii) phagocytes being instructed by lymphocyte-derived cytokines to eliminate pathogen.

At the initiation stage of an immune response, innate immune cells provide not only a T cell receptor (TCR) signal via MHC:peptide presentation but also costimulatory and cytokine signals. Recognition in the 1980s that T cells require two signals and become anergic with TCR stimulation alone[81] helped prompt a new conceptual framework for how pattern recognition receptors on innate cells induce signal two for costimulation of T cells[82–85]. This ushered in a transition from concepts of ‘non-specific resistance to infection’ to those of ‘innate immunity’ providing the key link to ‘adaptive immunity’ by supplying costimulation to T cells upon sensing microbial patterns[82–85]. Since that time, the primary focus for T cell costimulation has remained on CD28 signals provided by CD80/CD86 on innate immune cells. However, the recent description of human CD28 deficiency resulting in an unexpectedly narrow range of infection susceptibility (β-human papilloma virus in skin) reveals that CD28 is not required for immunity to most infection types in humans[86]. Thus, besides CD28, there is likely an array of T cell costimulatory receptors, just as there is a variety of cytokine inputs, that can instruct T cell priming fates in accordance with the type of pathogen being sensed. These pathogen-tailored signals from innate cells ensure an overall immune response that is adapted to the specific type of infection.

The adaptive arsenal model emphasizes the key contributions of the most ancient systems (phagocytes, cytokines, antiviral state, cell death responses), while underscoring essential functions of immunoglobulins and cytokines from lymphocytes. Indeed, at least 10% of protein-coding genes in the human genome encode proteins involved in immune cell function, and of these, a sizable majority operates in support of innate (as opposed to adaptive) cells. Despite this, currently known PID causal genes are several fold more frequent in genes categorized as supporting adaptive immunity[87]. These observations are consistent with there being less redundancy in the adaptive immune system, likely because it is much younger (dating back ~500 million years ago as opposed ~1 billion years ago for the innate immune system) and because of potentially higher fitness cost of adaptive immunity[88]. However, the downstream effect of disrupting genes supporting either innate or adaptive immunity often converges on failed executioner (often phagocyte) cell function. That is, defects in ‘adaptive’ lymphocyte products, namely antibody opsonins and cytokines such as IFNγ and IL-17, ultimately result in defects in ‘innate’ cell executioner functions. Thus, infection susceptibility in the end relates to failed ‘innate’ responses secondary to failed ‘adaptive’ immunity products, further blurring these categorizations, and supporting the adaptive arsenal model for conceptualizing immune responses.

Besides rapid immune defenses in adult animals, the adaptive arsenal model can help frame important related questions beyond those informed by genetics and monogenic diseases. Dissecting effector responses and the formation of immunological memory upon primary exposure to a given pathogen in isolation is often the focus of rigorous, microbially ‘clean’ animal models. However, this biology is most relevant to humans in early life[74]. As neonates and children respond with qualitatively and quantitatively different immune responses compared to adults, this critical time window is key for establishing a robust adaptive arsenal tuned to the environmental exposures that are likely to be re-encountered (see outstanding questions). Failure to tune during this window can result in maladaptive immune responses later in life, as illustrated, for example, by the unremarkable EBV infection seen in early life versus the infectious mononucleosis that can occur in adolescence or adulthood[75]. As another example, there are clear differential clinical outcomes across the age spectrum upon initial exposure to SARS-CoV-2 as a novel pathogen, with children experiencing much less symptomatic infection compared to adults[76]. Within this framework, future efforts to better understand immune responses in infancy and childhood and their impact in shaping the organism’s adaptive arsenal are of key importance to elucidate the mechanisms of immune health and its derailment in disease contexts. Moreover, whether in early life or adulthood, the quality of an organism’s leukocyte-independent rapid defenses is highly relevant for the adaptive arsenal model. Beyond epithelial barrier biology and tissue cell-intrinsic immunity, other non-immune factors such as the metabolic state of the organism and health of other organ systems (invoking concepts of ‘disease tolerance’[77] and frailty[78]) can have a major impact on determining disease severity. As such, investigating infection outcomes independent of genetics and pathogen dose, for example by dissecting determinants of lethal dose 50 (LD50) outcomes in experimental infection of inbred mice of varied age and health status[79], offer promise for advancing our understanding of individual heterogeneity in disease outcomes.

Outstanding questions.

• How is the immune response during early life programmed differently from adults to qualitatively and quantitatively tailor to the needs of the neonate, infant, and child? Besides maternal antibodies in the infant that help protect from pathogens likely to be encountered in the environment shared by the mother-infant dyad, early-life lymphocytes are known to behave in more innate-like[89] capacities; these appear to be adapted to front-load the arsenal of rapid defenses in this vulnerable time window. There is also compelling evidence that intrinsic immune defenses during childhood are increased relative to adulthood (whether directly or indirectly), offering further survival advantage while the adaptive arsenal of rapid defenses is still being built[90, 91].

• Regarding cytotoxic lymphocytes, what are the implications of the observations that humans lacking CD8⁺ T cells[20–22], MHC class I (TAP1, TAP2, TAPBP[20–22]), or cytotoxic granule machinery[23] do not suffer from viral infection susceptibility? This set of findings provides clues to understanding the hierarchy of essential versus redundant mediators of anti-viral immunity. Relevant insights can likely be gleaned from organisms that have evolved to lose this branch of immunity[24].

• Conspicuously absent from the infection susceptibility paradigms in the field of IEIs are loss-of-function mutations in genes specifically governing type 2 immunity. This is likely because human populations that might experience the burden of helminths and other metazoan parasites generally do not have access to genomic DNA sequencing in search of gene defects. Do specific human genetic errors of type 2 immunity exist and, if so, what will they teach us about essential functions in response to infection, noxious insults, or tissue damage?

• Immunological insights can also be gleaned from peering into ‘healthy’ human genomes at the population level using impactful resources such as gnomAD, which now contains DNA sequencing data from >800,000 individuals[92]. Homo sapiens is the only species on earth sequenced in great numbers, and these data power investigations on rare disease[93, 94]. What can we learn from population genetics data about immune-related genes under purifying selection[95]? Which immune genes exhibit functional redundancy/compensation and can be found ‘knocked out’ in humans who are ostensibly healthy?

• Recent discoveries have emphasized that monogenic causes of immune disorders are not limited to extreme phenotypes in large pedigrees of often consanguineous families harboring homozygous, loss-of-function mutations. Instead, numerous genetic errors of immunity are de novo, heterozygous, and/or result in hyper-, hypo-, or neo-morphic function of the gene product. Moreover, some mutations are somatic/mosaic (e.g., UBA1[96], TLR8[97]) rather than germline, and efforts are being made to discover digenic and non-protein coding mutations in immune disorders. We also now appreciate that genetic errors of immunity can result in relatively mild/moderate disease and are not always life-threatening, lowering the bar to pursue genome sequencing of broader swaths of patients with immune-related diseases. What additional immune-related diseases will be found to be genetic and what new knowledge can we gain from the uncovered genes and pathways?

• The focus here has not been about what the immune system can do but rather about what it must do to support host survival and fitness in an outbred species living in the natural environment. An emergent and fascinating line of investigation focuses on secondary functions of immune cells unrelated to pathogen clearance, from neurobiology and behavior to organismal metabolism to organ- and body system-specific functions. These insights also have the potential to be leveraged to engineer immune cells as putative therapeutics, sensors, or modulators of non-immune host physiology[98–100] and disease tolerance mechanisms[77]. Will monogenic diseases further illuminate if and how leukocytes can fine-tune broader host physiology in humans?

Concluding remarks

Human genetic errors of immunity provide a wealth of knowledge that warrants thoughtful integration with findings from mouse modeling, cellular, biochemical, and molecular immunology. Such an integrated, systems view of immunology offers conceptual advances by layering information across species, environments, and pathologies (i.e., the spectrum of microbial infections and immunopathologies). Here, I describe an adaptive arsenal model of rapid defenses that accounts for the blurred lines between innate and adaptive immunity and centers on the suite of defenses available to an organism at the time of challenge. These defenses dictate infection outcome and rely on cellular and molecular sensors, relays, and executioners, which are adaptive and change with environmental exposures over the lifetime of the organism. Human gene mutations disrupting these circuits result in IEIs, helping piece together the mechanistic foundations for these defenses. The collection of IEIs and, therefore, the adaptive arsenal model emphasizes some key defenses, namely opsonins (including complement and antibodies), phagocytes, intrinsic immunity, and rapidly responding lymphocytes (innate-like and memory). This re-framing is heavily informed by observations from human PIDs; however, a limitation of the model is its lesser integration of immune regulation principles derived from human PIRDs. Further incorporating lessons from PIRDs to conceptualize a model of immune regulation that operates concurrently with the adaptive arsenal model of immune defenses is a worthwhile future effort (see outstanding questions). These endeavors can lead us to reassess how the costs of defenses are systematically counterbalanced.

Significance.

Dissecting the genetic basis of human immune disorders using unbiased, forward genetics offers translationally relevant insights into essential immune relays in outbred organisms living in natural environments. Layering key insights from human genetic errors of immunity on existing paradigms offers a new synthesis of the suite of rapid defenses against pathogens and the immunoregulatory circuits preventing tissue immunopathology. This proposed model of an ‘adaptive arsenal of rapid defenses’ can illuminate knowledge gaps and help reconceptualize the immune system as a system, with well-resolved cellular and molecular circuits.

Glossary:

Adaptive immunity

branch of immunity mediated by T and B cells that specifically recognize foreign antigen and can form immunological memory

Antibody

soluble protein derived from the B cell receptor of B cells activated by an antigen that, depending on the class/subclass (IgM, IgD, IgG, IgA, IgE), exerts effector functions including opsonization, complement fixation, neutralization

Autoimmunity

disease of immune-mediated tissue damage typically defined as being caused by adaptive immunity via T and/or B cells with antigen receptor reactive to self-antigens

Autoinflammation

disease of immune-mediated tissue damage typically defined as being caused by innate immunity with non-antigen-specific inflammatory responses

Bruton’s agammaglobulinemia

first primary immunodeficiency described, with loss of B cells and antibodies, which was later found to be due to mutations in Bruton’s tyrosine kinase (Btk)

Bystander activation

activation of T- or B-lineage cells that is not mediated by antigen receptor recognition

Class-switched antibody

antibody (also called immunoglobulin) of the IgG, IgA, or IgE isotype, derived from B-lineage cells that have switched from the IgM/IgD class via gene rearrangement

Complement

set of proteins whose function is to opsonize or lyse pathogens to facilitate their clearance

Costimulation

second signal provided by activated antigen-presenting cells to T cells in addition to antigen receptor stimulation and which boosts the T cell response

Cytokinopathy

disease caused by dysregulated cytokine circuits

Executioner

cell/molecule that mediates an effector function to eliminate a pathogen

First-order cytokines

early cytokines in an intercellular communication relay that are produced by a cell type sensing pathogen and which act on a secondary cell type to induce an effector function

Forward genetics

a phenotype-first approach of defining gene functions with unbiased approaches

Germ theory

concept that specific diseases can be caused by specific microbes

Germline mutation

genomic DNA mutation present in all cells of the body

Heterologous immunity

protection from one pathogen elicited by prior exposure to a different pathogen

Immunopathology

tissue damage caused by immune responses

Inborn errors of immunity

diseases caused by a monogenic defect

Inflammatory bowel disease

disease in the gastrointestinal tract associated with inflammation and epithelial barrier pathology

Innate immunity

branch of the immune system operated by cells sensing generic pathogen patterns

Innate-like response

immune response that is rapidly induced and mediated by non-myeloid cell types not traditionally considered part of the innate immune system

Inflammasome-opathy

category of cytokinopathy diseases that are driven by heightened inflammasome-derived cytokines (e.g., IL-1 and IL-18)

Integrated stress response

cellular response that downregulates protein synthesis and prepares the cell to survive cellular or environmental stresses

Intrinsic immunity

response of all cells (tissue and immune cells) to sensing viral infection, typically utilizing interferons

Lymphoproliferative disease

condition involving enlarged lymph nodes and/or spleen due to an imbalance in immune cell proliferation and cell death

Monogenic

caused by a single-gene defect

Opsonin

molecule such as an antibody or complement that binds to foreign microbes to facilitate their phagocytosis

Pattern recognition receptors

typically expressed highest in innate immune cells; recognize invariant patterns that are characteristic of microbes but not the host

Primary immunodeficiency

inborn error of immunity predominantly featuring infection susceptibility

Primary immune regulatory disorder

inborn error of immunity predominantly featuring immune-mediated tissue damage

Relay

cell/molecule that receives and transmits signals as intermediates to orchestrate pathogen clearance

Second-order cytokines

later cytokines in an intercellular communication relay that are produced by cells sensing first-order cytokines and eliciting downstream effector functions

Sensor

cell/molecule that senses pathogen and initiates signals to orchestrate pathogen clearance

Single nucleotide variant

alteration in genomic DNA at a particular nucleotide site

Somatic mutation

genomic DNA mutation present only in a subset of cells

Treg-opathy

category of immune regulatory disorder caused by defective function of regulatory T cells (Tregs)

Type I interferon-opathy

category of cytokinopathy diseases driven by heightened interferon cytokine production