Brain-Derived Antigens in Lymphoid Tissue of Patients with Acute Stroke

Abstract

In experimental animals, the presence of brain-derived constituents in cervical lymph nodes has been associated with the activation of local lymphocytes poised to minimize the inflammatory response after acute brain injury. In this study, we assessed whether this immune crosstalk also existed in stroke patients. We studied the clinical course, neuroimaging, and immunoreactivity to neuronal derived Ags (microtubule-associated protein-2 and N-methyl d-aspartate receptor subunit NR-2A), and myelin-derived Ags (myelin basic protein and myelin oligodendrocyte glycoprotein) in palatine tonsils and cervical lymph nodes of 28 acute stroke patients and 17 individuals free of neurologic disease. Stroke patients showed greater immunoreactivity to all brain Ags assessed compared with controls, predominantly in T cell zones. Most brain immunoreactive cells were CD68+ macrophages expressing MHC class II receptors. Increased reactivity to neuronal-derived Ags was correlated with smaller infarctions and better long-term outcome, whereas greater reactivity to myelin basic protein was correlated with stroke severity on admission, larger infarctions, and worse outcome at follow-up. Patients also had more CD69+ T cells than controls, indicative of T cell activation. Overall, the study showed in patients with acute stroke the presence of myelin and neuronal Ags associated with lymph node macrophages located near activated T cells. Whether the outcome of acute stroke is influenced by Ag-specific activation of immune responses mediated by CD69 lymphocytes deserves further investigation.

Antigen Presentation After Stroke

“…+ cells [22]. The way DCs are activated to present antigens could determine the initiation of immune reactions or the induction of tolerance [49].…”

“…While DCs can transport antigens to the lymph nodes, resident microglia are unlikely to traffick out of the CNS. An increased presence of brain-derived antigens in migrating DCs and macrophages at the draining lymphoid tissue was described in rodent models of EAE, experimental stroke, patients with multiple sclerosis (MS) [56], and patients with stroke [22]. Besides trafficking of migratory DCs carrying neural antigens, soluble brain peptides could access the lymph nodes (see above) and be taken up by APCs locally.…”

“…Several lines of experimental evidence suggest that this might be the case [15][16][17][18][19][20][21], but further study is needed to confirm this possibility and dissect its potential contribution to the brain tissue fate and the potential relevance to human stroke. Indeed, our group described the presence of several brain antigens in the draining lymphoid tissue of patients with acute stroke that was correlated with the functional outcome of the patients at follow-up [22]. Recently, a study of brain ischemia in mice reported increased autoreactive T and B cells to human neural antigens [20].…”

Immunopathogenetic Aspects of Ischemic Stroke

“…Впоследствии иммунный ответ Т-клеток к раз-личным мозгоспецифическим антигенам при острой церебральной ишемии был подтвержден в клинике и эксперименте и другими автора-ми [5,139]. Презентация антигенов нервной тка-ни осуществляется презентирующими клетка-ми периферической иммунной системы, на что указывает повышенное содержание мозгоспе-цифических антигенов в дендритных клетках и макрофагах в лимфоузлах, дренирующих ЦНС, у пациентов с инсультом [93].…”

“…Так, более высокая реактивность лимфоцитов Т-клеточной зоны миндалин или лимфоузлов к основному белку миелина коррелирует с исходной тяжестью ин-сульта, большими размерами инфаркта и худшим исходом. В то же время более высокая реактив-ность к нейрональным антигенам коррелирует с меньшими размерами инфаркта и лучшими от-даленными исходами [93]. Возможно, это связа-но с презентацией миелиновых и нейрональных антигенов различными типами дендритных кле-ток, как это происходит при рассеянном склеро-зе [125], и активацией соответственно различных типов Т-клеток.…”