Preexisting Serum Autoantibodies Against the NMDAR Subunit NR1 Modulate Evolution of Lesion Size in Acute Ischemic Stroke

Abstract

Background and Purpose-Recently, we reported high seroprevalence (age-dependent up to >19%) of N-methyl-daspartate-receptor subunit NR1 (NMdAR1) autoantibodies in both healthy and neuropsychiatrically ill subjects (N=4236). Neuropsychiatric syndrome relevance was restricted to individuals with compromised blood-brain barrier, for example, apolipoprotein E4 (APOE4) carrier status, both clinically and experimentally. We now hypothesized that these autoantibodies may upon stroke be protective in individuals with hitherto intact blood-brain barrier, but harmful for subjects with chronically compromised blood-brain barrier. Methods-Of 464 patients admitted with acute ischemic stroke in the middle cerebral artery territory, blood for NMdAR1 autoantibody measurements and APOE4 carrier status as indicator of a preexisting leaky blood-brain barrier was collected within 3 to 5 hours after stroke. Evolution of lesion size (delta day 7-1) in diffusion-weighted magnetic resonance imaging was primary outcome parameter. In subgroups, NMdAR1 autoantibody measurements were repeated on days 2 and 7. Results-Of all 464 patients, 21.6% were NMdAR1 autoantibody-positive (immunoglobulin M, A, or G) and 21% were APOE4 carriers. Patients with magnetic resonance imaging data available on days 1 and 7 (N=384) were divided into 4 groups according to NMdAR1 autoantibody and APOE4 status. Groups were comparable in all stroke-relevant presenting characteristics. The autoantibody+/APOE4− group had a smaller mean delta lesion size compared with the autoantibody−/ APOE4-group, suggesting a protective effect of circulating NMdAR1 autoantibodies. In contrast, the autoantibody+/APOE4+ group had the largest mean delta lesion area. NMdAR1 autoantibody serum titers dropped on day 2 and remounted by day 7. Conclusions-dependent on blood-brain barrier integrity before an acute ischemic brain injury, preexisting NMdAR1 autoantibodies seem to be beneficial or detrimental.

Antigen Presentation After Stroke

“…Classically, brain autoimmunity is mediated by IgG autoantibodies [38], which are rarely found in acute stroke. In contrast, the most frequently reported autoantibodies are of the IgM or IgA subclass [39].…”

“…NMDAR1 autoantibodies seem to be beneficial or detrimental, depending on the BBB integrity before stroke. Using APOE4 carrier status as an indicator of a preexisting leaky BBB, Zerche et al [39] observed greater infarct growth in patients with BBB disruption and autoantibodies against NMDAR, whereas patients without previous BBB disruption that had autoantibodies showed the smallest infarct growth. Autoantibodies may also have a role in the development of poststroke cognitive impairment.…”

Response to Letter Regarding Article, “Preexisting Serum Autoantibodies Against the NMDAR Subunit NR1 Modulate Evolution of Lesion Size in Acute Ischemic Stroke”

“…We agree that the role of endothelial NMdAR1 in blood-brain barrier (BBB) permeability and monocyte transmigration is intriguing. Also, the fact that in our study the modulating effects of NMdAR1-AB were less prominent in r-tPA (recombinant tissue-type plasminogen activator) as compared with non-r-tPA treated patients, despite their higher N number (see Figure IV), 1 may support an additional modifier influence of (exogenous) r-tPA on outcome that is probably independent of its thrombolytic activity. BBB integrity before stroke, however, at least tended to have the same influence regardless of r-tPA treatment: Beneficial NMdAR1-AB effects in individuals with previously intact BBB but harmful effects in APOE4 carriers with leaky BBB before the ischemic insult.…”

“…1 The letter nicely extends the discussion on possible mechanisms of action that might contribute to the consequences of preexisting N-methyl-d-aspartate-receptor subunit NR1 (NMdAR1) autoantibodies (AB) on brain functions. We agree that the role of endothelial NMdAR1 in blood-brain barrier (BBB) permeability and monocyte transmigration is intriguing.…”

Uncoupling the widespread occurrence of anti-NMDAR1 autoantibodies from neuropsychiatric disease in a novel autoimmune model

“…The reported syndrome, reflecting typical NMDAR1 antagonistic actions, consisted of psychosis, epileptic seizures, dyskinesia, cognitive decline, reduced consciousness, and autonomic dysregulation [1][2][3][4]. However, work on >5000 individuals, healthy or affected by different diseases, consistently revealed overall comparable age-dependent seroprevalence of functional NMDAR1-AB of all Ig classes, nurturing serious doubts regarding a purely pathological role of NMDAR1-AB of any Ig class [5][6][7][8][9][10].…”