To understand the role of autoimmunity in psychiatric disease, we will elucidate the role neural autoantibodies play in psychiatric disease. Neural autoantibodies are increasingly detected in association with different psychiatric disorders, ranging from dementia to psychotic disorders [6,19,20,21,22]. The meaning of these neural autoantibodies is still enigmatic, although several models have postulated functions in aberrant synaptic transmission [23] and networking [24], as well as inducing specific psychiatric symptoms such as psychosis [25]. An autoimmune basis of psychiatric syndromes is fulfilled if specific criteria are present, such as (1) CNS inflammation measured by CSF pleocytosis, intrathecal IgG synthesis or other signs of brain inflammation in neuroimaging, in conjunction with (2) detecting autoantibodies in the serum and/or blood, (3) specific neuropsychiatric constellations termed as “autoimmune indicators”, such as seizures, motor abnormalities such as catatonia, fever, altered consciousness, severe cognitive dysfunction, or an adverse response to psychopharmacologic drugs [7]. By applying these criteria, clinicians can diagnose an autoimmune origin as being possible or definitive [7]. Autoantibody-mediated psychiatric disease can, on the other hand, originate from an organic autoimmune encephalitis when mainly relying on the Graus criteria [5]. Their criteria were slightly modified in a recent case series in which patients presenting primarily psychiatric symptoms were classified as psychiatric autoimmune encephalitis patients [21]. What is common to both classifications is the required occurrence of neural autoantibodies [5,7]. However, in the Hansen et al. [7] classification, the formulated criteria require signs of brain damage or inflammation via specific additional diagnostics to diagnose an autoimmune-originating psychiatric syndrome. In contrast, the presence in a recent case series of well-characterized autoantibodies such as LGI1, NMDAR or MOG antibodies [21] was regarded as a sufficient criterion to assume a probable psychiatric autoimmune encephalitis. Thus, there is substantial controversy at the moment about which diagnostic evidence must be present to classify a psychiatric disease as being autoimmune-based. We favor a more conservative approach to classifying a psychiatric syndrome as autoimmune-mediated. Several autoantibodies, such as those that are paraneoplastic, are not believed to contribute to the pathogenesis of the disease on their own, but rather in conjunction with T cells. The concept of autoimmunity in psychiatric disease probably encompasses two different mechanisms: (1) an autoantibody-mediated autoimmunity mechanism, mainly detected in patients with antibodies against membrane-surface autoantibodies, and (2), a T cell-mediated mechanism of autoimmunity detected in patients with antibodies against intracellular target antigens. Both mechanisms share an immunity process requiring the ability to have previously made a distinction between the group property “self” and its counterpart “non-self” or “foreign”. Disease states such as autoantibody-associated psychiatric disease incorporate the recognition of the “foreign” either as one’s own tissue or as microorganisms. This process is active and dynamic, so that the borders between the self and of identifying the “foreign” are not constant. The immune system is activated when “foreign” elements are recognized within the body. This recognition of the “foreign” involves a prior process of self-tolerance. The breakdown of self-tolerance induces an immune-system activation, enabling the self and non-self dichotomy, but it also leads to the continuous recognition of antigen epitopes. Such an immune-system activation can be “protective” or “aggressive”. The term protective autoimmunity refers to the autoantibodies and B cells responsible for autoantibody production in psychiatric autoimmune encephalitis or autoimmune-mediated psychiatric syndromes, but also to T cell pathology, as seen in patients with probable autoimmune-mediated psychiatric syndromes associated with intracellular autoantibodies, as described below. In our model presented in Section 3.3, Section 3.4 and Section 3.5, we establish a biological basis for psychiatric disorders that links neuronal systems to autoimmune processes. Autoinflammation in autoimmune states in organic psychiatric disorders implies minimal changes, such as mild encephalitis, and in brain tissue changes such as inflammation or brain injury.