Autoimmune Responses to the Brain After Stroke Are Associated With Worse Outcome

Abstract

Background and Purpose Immune responses to brain antigens occur after stroke, and experimental studies show that the likelihood of developing a detrimental autoimmune response to these antigens is increased by systemic inflammation at the time of stroke. The aim of this study was to determine if patients who developed infection in the post-stroke period would be similarly predisposed to develop autoimmune responses to central nervous system (CNS) antigens. Methods We enrolled 114 patients within 72 hours of ischemic stroke. Clinical and demographic data were obtained, and cellular immune responses to a panel of CNS antigens were assessed during the initial week and again at day 90. Outcome was assessed using the modified Rankin Scale. Results Patients who developed an infection, especially pneumonia, in the 15 days after stroke were more likely to evidence a TH1(+) response to myelin basic protein (MBP) and glial fibrillary acidic protein (P=0.019 and P=0.039, respectively) at 90 days after stroke. Further, more robust TH1 responses to MBP at 90 days were associated with a decreased likelihood of good outcome, even after adjusting for baseline stroke severity and patient age (Odds Ratio = 0.477, 95% CI = 0.244–0.935; P=0.031). Conclusion This study demonstrates that immune responses to brain antigens occur after stroke. And while these responses are likely to be an epiphenomenon of ischemic brain injury, the response to MBP appears to have clinical consequences. The potential role of post-ischemic autoimmune mediated brain injury deserves further investigation.

Stroke induces specific alteration of T memory compartment controlling auto-reactive CNS antigen-specific T cell responses

“…The fact that self- MBP-specific T cell responses in patients 3 months after stroke onset were associated with unfavourable outcome. However, the inflammatory T cell response to CNS antigens in stroke patients was at no time point significantly higher than that found in healthy subjects [18].…”

Letter by Urra et al Regarding Article, “Autoimmune Responses to the Brain After Stroke Are Associated With Worse Outcome”

“…Becker et al recently described that immune responses to various brain antigens can be found in patients after stroke. 1 This study confirms previous reports suggesting the presence of such autoimmune responses in human stroke. 2,3 The study further describes that 90-day outcome was mainly associated to autoimmunity to myelin basic protein, raising the question of whether the consequences of autoimmunity vary depending on the antigen specificity, which would be an indication of a complex crosstalk between the central nervous system and the immune system after stroke.…”

Antigen Presentation After Stroke

“…The effects of infections in cerebral ischemia have often been tested in experimental models by administration of bacterial lipopolysaccharide at the moment of cerebral ischemia. Lipopolysaccharide increased the likelihood of developing a detrimental autoimmune response to brain antigens with higher presence of B7.1 co-stimulatory molecules on APCs and greater Th1 responses to MBP [123][124][125]. Becker et al [124] also showed that patients who developed an infection after stroke were more likely to show a Th1 response to MBP and glial fibrillary acidic protein, and stronger Th1 responses to MBP were associated to poor functional outcome.…”

“…Lipopolysaccharide increased the likelihood of developing a detrimental autoimmune response to brain antigens with higher presence of B7.1 co-stimulatory molecules on APCs and greater Th1 responses to MBP [123][124][125]. Becker et al [124] also showed that patients who developed an infection after stroke were more likely to show a Th1 response to MBP and glial fibrillary acidic protein, and stronger Th1 responses to MBP were associated to poor functional outcome. Nonetheless, it is possible that the induction of systemic inflammation or infection in experimental animals at the time of cerebral ischemia will mimic better the clinical scenario of infections precipitating a stroke rather than the infections occurring in the aftermath of stroke.…”

“…For instance, high mobility group box-1 release from the ischemic brain induced the proliferation of bone marrow-derived suppressor cells, inhibiting the adaptive immune responses and resulting in lymphopenia and functional exhaustion of monocytes [74]. In patients with stroke, the best established features of SAI are increased levels of stress hormones and antiinflammatory cytokines like IL-10 [124][125][126][127][128][129][130][131], decreased numbers of circulating lymphocytes [129,131,132], and monocyte deactivation with reduced expression of human leukocyte antigen-antigen D related and reduced capacity to produce inflammatory cytokines [129,131].…”