Defining Early Life Stress as a Precursor for Autoimmune Disease.

As previously discussed, etiology and pathogenesis of ADs are considered to be multifactorial and involve a combination of environmental and genetic variables. Psoriasis is an example of an AD that has been strongly linked to stress-mediated exacerbation. 86 On the basis of retrospective studies 29 , 31 that have shown associations between ELS and psoriatic disease, we introduce psoriasis as an AD model for understanding how ELS may contribute to the development of ADs in adulthood. Psoriasis is a chronic, recurrent inflammatory skin condition that is characterized by abnormal keratinocyte differentiation, hyperproliferation of the epidermis, and potential systemic manifestations. Several variants of clinically distinct forms of psoriasis exist, including guttate psoriasis, inverse psoriasis, nail psoriasis, and psoriatic arthritis. 87 Although the most common variants of psoriasis are characterized as nonpustular, based on the characterization of observed skin lesions, pustular forms of psoriasis can be severe and occasionally life threatening. 88 Psoriasis vulgaris (also called plaque psoriasis), the most common variant overall, is characterized by erythematous plaques on the skin covered with pearlescent squamae, often described as having a silvery scale-like appearance. Primary lesions of psoriasis vulgaris are most commonly observed on extensor surfaces, such as knees and elbows, although virtually any region of the body can be affected. As seen with many disfiguring dermatologic disorders, plaque psoriasis can have a detrimental effect on quality of life by adversely affecting self-esteem, contributing to emotional stress, and increasing the risk to develop comorbid psychological disorders. 89 Although the current understanding of mechanisms that drive an individual’s susceptibility to psoriasis is complex, a strong immunogenetic basis is supported by the literature. For example, studies have associated psoriasis with single-nucleotide polymorphisms, 90 – 92 several human leukocyte antigen class I genotypes, 93 and autoantigens such as keratin 17 and antimicrobial peptide LL37, 94 , 95 which support the involvement of immune dysregulation in the pathogenesis of psoriatic disease. 96 , 97 Several findings support that perceived stress provides a higher risk of exacerbating these autoimmune pathologies. Walker et al. suggested that the type of stressor and individual differences in stress appraisal and reactivity may prove to be important prognostic factors in disease onset and/or progression in rheumatoid arthritis patients. 98 Liu et al. suggested that psychosocial factors are closely linked to the pathogenesis, pathophysiology, and clinical symptoms of multiple sclerosis. 99 In support, Brown et al. demonstrated that multiple stressors rather than severity of stressors are most important in relation to multiple sclerosis relapse risk. 100 In addition, Maunder and Levenstein provided evidence that psychological stress contributes to the inflammatory process in ulcerative colitis and Crohn’s disease. 101 Patients afflicted with AD, such as psoriasis, have reported stress as a major trigger or precedent event leading to flares, a term used to describe the episodic, relapsing-remitting pattern of clinical symptoms that is characteristic of many ADs. 28 , 86 , 102 , 103 However, not all studies support a clear relationship between stress and AD. 104 – 106 Furthermore, a lack currently exists in adequate basic science literature to support causal relationships between psychological stress and exacerbation of symptoms. It is important to note that the diagnosis of psoriasis itself may cause inherent stress in patients, thereby propagating the vicious cycle of stress-mediated flares as a function of the disease itself. Our understanding of the mechanisms and immune cells involved in the pathogenesis of psoriasis has evolved over the years. Although originally thought to be primarily a T-helper (Th)1-mediated disease, more recent evidence supports considerable involvement of the Th17 subset of CD4 + T lymphocytes for initiation and maintenance of psoriatic disease phenotypes. 97 , 107 – 110 The Th17 lineage of CD4 + T cells was named for their ability to produce interleukin (IL)-17A, although they can also produce IL-17F, IL-21, and IL-22. 111 – 113 Animal studies have provided evidence for the critical role of Th17 cells and the IL-23/IL-17 axis in psoriasis. For example, injections in mice of recombinant IL-23 and topical application of imiquimod, a toll-like receptor 7/8 agonist, have both been shown to induce and exacerbate psoriasiform lesions through mechanisms dependent on the IL-23/IL-17 axis of inflammation. 114 – 116 Rizzo et al. showed the importance of IL-22 and IL-17A in IL-23–mediated induction of psoriasis in a murine model that used injections of recombinant murine IL-23 into wild-type IL-22 and IL-17A knockout mice. 117 Their results showed that recombinant murine IL-23 injections induced epidermal hyperplasia (characteristic of psoriasis) through mechanisms that were dependent on both IL-22 and IL-17A, further supporting the involvement of Th17 cells in pathogenesis of cutaneous lesions in psoriasis. The importance of the IL-23/IL-17 axis has further been confirmed through the clinical efficacy of various new therapies that target components of this signaling pathway. 118 , 119 The glucocorticoid response has a central role in regulating immune responses and, in turn, impacts health. Most notable is the known pharmacological benefit of its use in the control of inflammatory responses. 120 Glucocorticoids regulate immune function through cellular mechanisms that result in immune suppression. 121 , 122 Intracellular glucocorticoid receptors (GRs) control glucocorticoid-mediated suppression of cellular immune function. The glucocorticoid intracellular receptor system represents two receptors: GR and the mineralocorticoid receptor. GRs are expressed on various innate and adaptive immune cell types. 123 Cortisol (corticosterone in rodents) has the greatest affinity for the GR, the dominant receptor expressed by immune cells. 124 At ligation, inactivated GRs found in the cytoplasm translocate into the nucleus, where they bind glucocorticoid response elements that regulate transcription of key gene transcription factors, including activator protein–1 and nuclear factor-κB, which regulate cytokine production. 123 , 125 – 127 In general, glucocorticoids suppress all aspects of immune response including cellular trafficking, 128 , 129 apoptosis, 130 – 133 maturation, and proliferation, 127 , 134 among other specialized functions (e.g., adhesion, cytokine production, antigenic recognition, antigen presentation). 135 , 136 Endogenous and synthetic glucocorticoids influence normal skin development and pathologic inflammatory conditions and disease. 137 As a known anti-inflammatory agent, glucocorticoid treatment has been exploited therapeutically in inflammatory skin diseases. 138 Specifically, the use of glucocorticoids as well as novel anti-IL-17 agents have been shown to reduce inflammatory psoriatic flares. 139 , 140 Yet, their use, particularly as a topical agent, has drawn some debate due to studies demonstrating that GR expression can be dysfunctional in nonlesional and lesional psoriatic skins. 141 In addition, research suggests that deficiencies in glucocorticoid expression exacerbate psoriatic conditions through mechanisms resulting in discoordination of GR signaling. 141 Given the tight regulation of glucocorticoids from higher CNS centers and in peripheral tissues (see Hannen et al. 141 ), stress-induced activation of the CNS could be considered a potential determinant of glucocorticoid treatment efficacy. Further investigation demonstrating the diversity of GR-mediated molecular signaling that causes preferences in T-cell cytokine production will greatly advance our understanding of T-cell–mediated disease pathologies, including ADs. SNS innervation is found in several tissues, including blood vessels, liver, kidney, intestines, lung, heart, and brain. 142 The SNS innervates almost all major lymphoid tissues such as thymus, spleen, bone marrow, and regional lymph nodes. 143 Autocrine production of epinephrine and norepinephrine as catecholaminergic neurotransmitters mediate SNS response through ligation of adrenergic receptors (α2 A , α2 C , β1, and β2) that are expressed in immune cells, including natural killer cells, T cells, and macrophages. 61 , 144 – 146 Specifically, in vivo administration of β2-adrenergic antagonists regulates production of Th1 cytokines IL-2 and interferon-γ in lymph nodes. 147 , 148 Panina-Bordignon et al. showed that β-adrenergic agonists can preferentially prevent IL-12 production and promote Th2 development. 134 Recent findings also highlight the potential impact of adrenergic stimulation on Th17 responsiveness that is associated with IL-23 expression in effector immune cells, such as macrophages. 149 Thus, the ability of adrenergic stimulation to facilitate activation and effector function of CD4 + T cells could be a determinant in disease pathogenesis under conditions of stress that impact risk, onset, and progression of ADs.

In this review, we described the current gap in knowledge regarding implications of ELS in development of a child’s innate and adaptive immune systems within the context of ADs. On the basis of anecdotal evidence and community-based studies, ELS may have a role in priming those who are genetically predisposed to ADs to be even more susceptible to developing certain immunogenetic diseases during adulthood, through mechanisms that are presently unknown. To address this knowledge gap, future studies must focus on investigating mechanisms that mediate long-term effects of ELS—particularly from the perspective of persistent downstream implications of severe cross talk between the CNS and immune system during perinatal period. However, investigating responsiveness, function, and regulation of the hypothalamus–pituitary–adrenal axis as a function of stress and disease has been shown to be laced with challenges due to the influence of confounders that are linked to intraindividual and interindividual variability. 150 In the future, basic science research must be performed using neonatal and adolescent animal models to deepen our understanding of how exposure to environmental factors, such as stress, during specific phases of development contributes to mechanisms involved in AD pathogenesis. For example, a particular interest in defining how ELS impacts the lymphocyte repertoire from an early stage of immune maturation could be relevant for understanding mechanisms of immune dysfunction later in life ( Fig. 2 ). Future research must also focus on identifying opportunities for AD prevention rather than remain fixated on investigating therapies and treatments alone. The significance of such studies will be to establish causal relationships between early life events, such as toxic psychosocial stress, and increased subsequent risk for ADs, thereby validating a role for preventive medicine in the management of patients with known family histories of AD. Finally, although beyond the scope of this review, it is important to recognize other sources of stress, such as those related to nutrition or infectious disease, and the development of AD as important areas of research that will further address the complex etiology of ADs.

Both anecdotal and experimental evidence supports a link between stress and disease susceptibility, particularly in the case of chronic inflammatory conditions. 48 – 55 A PubMed search using key the words “psychological stress” and “autoimmune disease” resulted in 1871 citations spanning 1949 to 2019 ( Fig. 1 ). For years, researchers have considered this link to result from biological interactions between the CNS and immune system. Yet, the mechanisms of action that define the relationship remain unresolved. Stress-derived dysregulation is mediated by two major nervous pathways: the hypothalamus–pituitary–adrenal axis in the CNS and the SNS. 56 , 57 In response to stressful experiences (e.g., psychological or physical), activation of the CNS leads to neuronal activation and neuropeptide release of stress factors, such as catecholamines (norepinephrine and epinephrine), corticosteroids (e.g., cortisol) via the corticotropin-releasing hormone and adrenocorticotropic hormone pathways in CNS, and parasympathetic-mediated acetylcholine activation. 28 , 58 Furthermore, through nervous innervations of lymphoid tissue and/or neuroendocrine receptor expression, immune cells receive nervous system stimuli, resulting in altered functions. 59 , 60 Such neuroendocrine-mediated influences on immune function have since been shown to impact disease susceptibility by facilitating hyperactivity or suppression of immune responses. 59 – 61 Much of our understanding regarding the mechanisms behind AD stem from the use of animal models. Although several animal models are spontaneous 62 , 63 and induced, 64 engineered 65 animal models through specific mutations are becoming available to better replicate human conditions in ADs. In addition, ADs in animals are quite variable and demonstrate a multitude of factors, such as sex traits, neuroendocrine conditions, microflora, and other environmental factors that are significant contributors of ADs. 64 , 66 Current basic science research investigating the mechanisms for ADs in animal models has focused attention on identifying and testing potential therapeutic targets using adult-aged animals. 67 – 71 In addition, in the context of investigating stress as a modifier of disease, human studies have mainly focused on the ways in which stress affects management of ADs after disease onset. 72 , 73 Harpaz et al. used a murine model for experimental autoimmune encephalomyelitis to show that exposure to chronic stress is associated with increased risk of developing ADs. 74 In this study, the authors used animals aged 8 wk (consistent with late adolescence to adulthood in the mouse life span) and a chronic variable stress model that emulates the multitude of chronic stressors that are more likely to be encountered in adult life (e.g., a model for chronic daily stress contributing to AL). 75 Stressors that are more likely to be encountered in early life, such as neglect, and result in toxic stress effects that are cited in the ELS literature (discussed above in Progressive Allostatic Load: ELS as a Contributor to Early Onset AD) are thought to be more psychosocial in nature and strongly tied to the quality of interaction between children and their caregivers. 76 A more natural animal model of ELS has been demonstrated on the basis of maternal separation during infancy, which is popularly used in rodent models. For example, the scheduled separation of pups from the mother/dam within the first 2 wk of postnatal life is a well-accepted in vivo model for emulating the psychological nature of early life neglect or abuse in children. 77 – 79 Many animal studies using this ELS model have done so to study effects on patterns of behavior and evaluate susceptibility to psychiatric disorders in adulthood. 80 – 85 The application of animal models for ELS to study AD susceptibility is still largely unexplored.

Stress is a natural and ubiquitous part of the human experience and may begin to impact an individual’s health at any and all stages of life. Allostatic load (AL) describes how chronic stressors may lead to repeated activation of physiological stress responses, collectively contributing to overall stress-induced wear and tear on the body. 17 In comparison, the concept of allostasis (stability through change) describes how the body maintains physiological stability, and thereby health, by adjusting parameters of its internal milieu to match environmental demands. 18 The idea behind AL contributing to stress-related disease is best explained as a domino effect. Once AL reaches a certain threshold, the body can no longer adapt because it has maxed out its capacity to maintain balance through allostasis. At this point, allostatic overload is reached and may lead to states of pathology. Chronic adulthood stress and increasing AL with age have been key areas of focus for investigating relationships among long-term stress, sympathetic nervous system (SNS)-mediated immune dysregulation, and subsequent susceptibility to disease. In adult medicine, patients are often encouraged to be mindful regarding adverse effects of stress over time and are advised to find healthy ways to manage stress from jobs, relationships, family, etc., that are all normal and inevitable parts of life. Emphasis is placed not on avoiding stress altogether but rather on improving the way patients manage and respond to stressful situations. This is an effective and valuable approach for preventive medicine, given the evidence-based support for how chronic stress contributes to a myriad of infectious and noninfectious diseases. 19 , 20 To date, much of the focus in basic science stress research has been placed on understanding mechanisms of psychosocial stress in the context of mental illness and psychiatric disorders, such as major depressive disorder, as well as mechanisms related to neuroinflammation, neurocognitive dysfunction, and cardiovascular disease. 21 – 27 Nevertheless, clinical investigation into anecdotal associations between psychological stress and autoimmunity has garnered interest in recent decades. 28 – 31 Although the retrospective nature of many of the published studies (e.g., survey-based assessments in adult patients for history of childhood trauma) lends itself to inherent, well-known limitations regarding validity and reliability, the research serves as a springboard for generating hypotheses and validates the need for further investigation through future basic science research (see the section, Current Research on Understanding Stress and Autoimmunity, below). Associations between stressful life events and psychological disorders in adults have also been under investigation for their link to AD exacerbation and pathogenesis. 32 A recent review article by Jeppesen and Benros describes a potential crossover among mechanisms of autoimmune and psychiatric disorders in humans. 33 Another recently published retrospective Swedish cohort study by Song et al. reported that adults diagnosed with stress-related disorders are at significantly higher risk to develop subsequent AD. 34 Although these recent additions to the literature provide interesting and compelling evidence for clinically significant cross talk between immune and autonomic nervous systems in the context of autoimmune pathology, their discussions and findings are centered on the adult population. When discussing psychosocial stress and its impact on pediatric health, it is important to distinguish among three different types of stress responses: positive, tolerable, and toxic. Both positive (also referred to as “eustress”) and tolerable stressors are essential for healthy human development, because they help children build a foundation of resiliency. This is understood to be both a necessary and healthy experience in the progression to maturity, because children learn important skills for adapting to social challenge and adversity. Conversely, toxic stress is defined as severe, prolonged, or repetitive adversity that is accompanied by a lack of nurturance or support from a caregiver, thereby leading to an abnormal stress response. 35 In adulthood, individuals have already encountered and overcome eustress (positive stress) that is associated with progressing through coming-of-age events. On the other hand, infants and young children are at vulnerable stages of development, during which they depend on caretakers and require external sources of comfort, protection, and validation. When the toxic stress response is continuous or triggered repeatedly by multiple sources, its effects become cumulative and may contribute to an individual’s AL from as early as childhood. 36 On the basis of human epidemiological and community-based studies, childhood trauma and early toxic stressors are now recognized as a source of long-term negative effects on adult health. 37 – 42 The strongest evidence in the literature for correlations between ELS and adult-onset pathology is demonstrated in studies that investigate psychiatric, cardiovascular, and metabolic disorders. 40 , 41 , 43 , 44 However, the sustained, long-term consequences of ELS on an individual’s health may not be realized or observed until decades later into adulthood. The literature supports an association between traumatic childhood events and increased risk to develop subsequent disorders later in life as well as differences between the effects of chronic versus acute stress on the immune system. 45 – 47 ELS is a subset of severe chronic stress, with “severe” referring to stressors that are beyond the normative range of what children in developed countries would be expected to encounter (e.g., abuse or maltreatment). Chronic stressors (such as recurrent hostility/conflict in the home environment or lack of material resources, neglect, or instability as a result of low socioeconomic status) are more likely to reflect an individual’s overall childhood experience and bring about lasting impressions on the developing body’s psyche and physiology. In the context of this review, “chronic” is used to describe stress stimuli that are present in a child’s life during a period of time (as opposed to a single, acute stress event). Several retrospective observational studies provide support for a relationship between early stressful events and relapses in increased severity of several ADs, referred to as a flare. 29 However, the paucity of basic science literature that addresses ELS and ADs in relation to one another has resulted in insufficient evidence to support definitive causal relationships. Filling the gaps in current knowledge and research could help to define those mechanisms related to stress in early life that are consequential or predictive of AD later. Little evidence from human and animal studies has been published that elucidates mechanisms linking ELS to immune dysregulation, leading to ADs (e.g., the way in which ELS would impact developmental immunity).

Autoimmune diseases (ADs) are classified as a heterogeneous group of chronic diseases with prevalence and incidence rates that vary among the 80 or more AD types ( Table 1 ). 1 , 2 AD occurs due to the immune system’s inability to distinguish self (autologous tissues) from nonself, resulting in aberrant production of autoantibodies and immune-mediated destruction of the body’s own tissues. The immune system acquires self-tolerance through the maturation of T lymphocytes that are initially generated from hematopoietic lineage cells in the bone marrow and migrate to the thymus as immature thymocytes. Through a mechanism called central tolerance, selection and/or deletion of maturing T lymphocytes is based on affinity of T-cell receptor recognition of a self-peptide that is complexed with major histocompatibility complex class I molecule expression on antigen-presenting cells and thymic epithelial tissues within specialized thymic compartments. 3 , 4 Depending on the receipt of proper signaling, T lymphocytes exit into the peripheral circulation as mature T lymphocytes or undergo cellular deletion through regulatory immune checkpoints within the thymus and throughout their life span in peripheral tissues. Such mechanisms involve anergy of self-reactive lymphocytes through a failure in activation due to the absence of costimulatory signaling and molecular events including self and nonself receptor recognition events, intracellular signaling, and release of regulatory effector molecules (e.g., cytokines, antibodies). 5 , 6 Similar mechanisms are initiated to ensure proper control and maturation of B-lymphocyte lineages that are derived from bone marrow. 7 – 9 Breakdown of one or more of these central or peripheral checkpoint strategies does not present homogenously. Rather, varying degrees of self-provocation of cell-mediated inflammatory reactions occur, causing mild reactions to more serious tissue and organ damage. Such variation in immune tolerance (both T- and B-cell based) is common due to small numbers of primed/functional autoreactive T and B cells and autoantibodies that reside in the normal pool of immune cells in healthy individuals. 10 The mere existence of self-reactive species is believed to be insufficient to produce overt autoimmunity. Rather, researchers believe that additional events act in concert to trigger, propagate, and/or sustain autoimmune status. 11 – 13 To date, exact causes and triggers are not well understood. The current paradigm for understanding AD etiology describes a multifaceted, multifactorial process that necessitates interplay between predisposing genetic and environmental factors including stress (e.g., anxiety). With respect to stress, epidemiological and survey-based studies have reported higher stress levels and increased prevalence of generalized anxiety disorder among industrialized countries, 14 , 15 with the United States ranking in the top ten most stressed countries in the world. 16 In recent years, an area of growing interest has been the link involving stress and autoimmunity, whereby mechanisms of disease are influenced by complex interactions between the central nervous system (CNS) and the immune system. In this review, we highlight the intersection between stress and immune function, with a focus on early life stress (ELS) as consequential for increased AD risks later in life.