Effects and inducers of autoantibodies against N-methyl-D-aspartate (NMDA) receptors

Autoantibodies against the IgG class of N-methy-D-aspartate-receptor subunit GluN1 (NMDAR1-AB) were believed to cause anti-NMDAR encephalitis. However, the view was chanllenged by the finding of age-dependent seroprevalance (up to 20%) of functional NMDAR1-AB (IgA, IgG or IgM) in both healthy and diseased human subjects (N>5000). There are a few key questions addressed in the current thesis on this topic. In project I: (i) We showed that the functional NMDAR1-AB belong to the mammalian autoimmune repertoire by screening the seroprevelence in dogs, cats, rats, mice, baboons, and rhesus macaques. The age-dependency was lost in the baboons and rehesus macaques that were kept in captivity, as well as in human migrants, which raised the hypothesis that chronic life stress may induce the production of NMDAR1-AB, predominatly IgA class; (ii) We established a novel active immunization mouse model by immunizing ApoE-/- (with compromised blood-brain barrier) and ApoE+/+ mice with a mixture of four peptides against the extracellular GluN1 domain or ovalbumin (control). 4 weeks after immunization, the edogenously formed high level of NMDAR1-AB (IgG) induced increased locomotion upon MK801 (NMDAR antagonist) treatment in ApoE-/- mice compared with the ApoE+/+ mice that were immunized with GluN1 peptides. Importantly, the NMDAR1-AB do not induce inflammation in the mouse brains, as the immunohistochemical staining for microglia and T cells in the hippocampus showed comparable resutls in the 4 groups: ApoE-/- and ApoE+/+ mice, with or without GluN1 immunization. Thus, our data suggested the IgG class of NMDAR1-AB do not cause brain inflammation directly but shape the behaviroal phenotype upon access to the brain. In project II: (i) We observed serum NMDAR1-AB flctuate upon time in both mice and humans, independent of blood-brain barrier intergrity; (ii) We showed that a standardized brain cryolesion in juvenile mice leads to increased NMDAR1-AB (IgG+IgM); (iii) We found that CTLA4 genotype predispose to serum NMDAR1-AB (IgG+IgM) in humans; (iv) Following our hypothesis that chronic life stress may induce the formation of NMDAR1-AB, we designed the chronic stress paradigm for mice, and observed increased NMDAR1-AB (IgA) in the stressed group. Strinkingly, stress induced depressed like behavior in mice and depression/anxiety rating in humans are reduced in NMDA1-AB carriers with compromised blood-brain barrier, from which we concluded that the NMDAR1-AB may serve as endogenous antidepressant. These data suggested that the NMDAR1-AB induced from variety origins under different circumastances, increasing over lifetime, may have a specturm of possible effects, including benefical ones