Stroke-Induced Immunodepression and Clinical Consequences

Introduction

Infections are common complications in the acute phase after stroke affecting about one-third of all patients with stroke . The most frequent poststroke infections are urinary tract infections and stroke-associated pneumonia (SAP), the latter showing consistent association with poor outcome . Initial concepts on the etiology of SAP focused on stroke-facilitated aspiration. In fact, dysphagic patients have an increased risk for SAP. However, dysphagia alone is not sufficient for the development of SAP and therapeutic measures to prevent aspiration do not effectively protect against SAP. Moreover, even silent cerebral infarctions are related to a higher incidence of SAP . Accumulating experimental and clinical evidence suggests that stroke induces a rapid, temporary immunodepression mainly mediated by the autonomic nervous system . Stroke-induced immunodepression syndrome (SIDS) is characterized by a downregulation of systemic cellular immune responses, i.e., rapid numerical decrease in peripheral blood lymphocyte subpopulations and functional shift or deactivation of lymphocyte subpopulations as well as monocytes, lung macrophages, and epithelial cells resulting in an increased susceptibility for SAP ( Fig. 125.1 ). Alterations in markers for SIDS develop within 24 h after stroke onset and thereby precede SAP, which usually occurs between day 2–7 after stroke onset . Within weeks, signs of SIDS as well as risk of pneumonia abate.

Figure 125.1, Stroke might impair swallowing (dysphagia) and thus cause aspiration. Moreover, stroke might activate the hypothalamic-pituitary-adrenal axis, the sympathetic nervous system including the adrenal-medullary axis, and cholinergic signaling via the vagus nerve (parasympathetic nervous system). Subsequently, released glucocorticoids, epinephrine, norepinephrine, and acetylcholine bind cells of the adaptive and innate immunity via their cognate receptors inducing an immunodepressive state. Stroke-induced immunodepression syndrome (SIDS) is characterized by a rapid but temporary numerical decrease in peripheral blood lymphocyte subpopulations caused by apoptosis and lymphocytic dysfunction in secondary lymphoid organs and blood switching from a pro- to an antiinflammatory mode of action. Moreover, monocytes as well as lung macrophages and epithelial cells are suppressed. Thereby, SIDS impairs the antibacterial host defense facilitating the development of pneumonia after aspiration of an otherwise harmless bacterial colonization. ACTH , adrenocorticotropic hormone; EC , epithelial cells; IFN-γ , interferon-γ; IL , interleukin; iNKT , invariant natural killer cells; MΦ , macrophages; TNF-α , tumor necrosis factor-α.

Pathways of Stroke-Induced Immunodepression Syndrome

The nervous system and the immune system are engaged in intense bidirectional communication via complex humoral and neural pathways. Stroke disturbs this normally well-balanced interplay leading to brain inflammation and immunodepression . Three major pathways of the autonomic nervous system (ANS) are identified for being involved in the mediation of neuroimmunomodulation ( Fig. 125.1 ): the hypothalamic-pituitary-adrenal (HPA) axis, the sympathetic-adrenal-medullary axis, and the parasympathetic cholinergic nervous system (mainly the vagus nerve) . Overactivation of these signaling cascades might be caused directly by damaging or affecting the control centers of the ANS due to stroke. Furthermore, cerebral ischemia activates inflammatory pathways in the brain parenchyma causing the release of proinflammatory cytokines, which might indirectly activate control centers of the ANS . For example, clinical and experimental evidence indicate that proinflammatory cytokines produced by damaged brain tissue might activate the HPA axis . Glucocorticoids produced as a result of HPA axis activation have well known antiinflammatory and immunosuppressive effects. They prevent inflammation by suppressing the production of many proinflammatory mediators including cytokines, prostaglandins, and nitric oxide and by enhancing the release of antiinflammatory mediators such as interleukin (IL)-10 and transforming growth factor . Moreover, glucocorticoids decrease the capacity of monocytes/macrophages and dendritic cells to present antigen to T lymphocytes and to elicit immune responses by downregulating the expression of major histocompatibility complex (MHC) class II and costimulatory molecules . The hypothalamus is functionally linked with other autonomic centers allowing for a synchronization of glucocorticoid responses with the cholinergic pathway . The vagal “cholinergic antiinflammatory pathway” might reduce the production of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, IL-1β, and IL-18 by activated macrophages in inflamed peripheral organs and tissues . The sympathetic nervous system innervates primary and secondary lymphoid organs and thereby regulates immunity. Hence, overactivation of cholinergic as well as sympathetic pathways might cause immune dysfunction . For example, the cholinergic pathway suppresses pulmonary macrophages and epithelial cells of the innate immunity thereby facilitating pneumonia after stroke . Moreover, secondary lymphatic organs like spleen and thymus exhibit an atrophy after focal cerebral ischemia . The extensive sympathetic innervation of immune organs and the presence of adrenergic receptors on almost all leukocytes indicate the strong influence of sympathetic activity on immune function . Stroke induces an overactivation of the adrenergic system causing the release of catecholamines from sympathetic nerve terminals and the adrenal medulla . This results in a pronounced antiinflammatory phenotype in lymphocytes, monocytes, and macrophages . Interestingly, sympathetic activation can also result in gastrointestinal dysmotility which increases the risk of aspiration pneumonia thereby increasing the susceptibility for SAP via facilitating the two currently pathophysiologically postulated concepts on the development of SAP, aspiration pneumonia and SIDS.

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