Neuropsychiatric illness, autoimmunity and the role of microbes

Neuropsychiatric illness often involves brain inflammation for which there may be an autoimmune origin. The authors of a paper* recently published in Current Opinion in Rheumatology set out to...

"...illustrate how microbes might participate in the pathogenesis of neuropsychiatric illness by triggering the production of autoantibodies that bind to brain targets."

They describe the science emerging on underlying mechanisms behind the observations that both exposure to infectious agents and autoantibodies without evidence of pathogens can cause brain disorders...

".......evidence accumulates to support the idea that dysregulated cross-talk between the brain and the immune system is an important contributor to the pathogenesis of conditions as diverse as schizophrenia, mood disorders, autism spectrum disorders (ASDs), obsessive-compulsive disorder (OCD), Tourette syndrome and other tic disorders, attention-deficit hyperactivity disorder (ADHD), anorexia nervosa, narcolepsy, posttraumatic stress disorder and myalgic encephalomyelitis/chronic fatigue syndrome (CFS). In addition, intriguing new evidence lends support to the possibility that not only the microbes associated with infectious episodes but also the bacteria of the gut microbiome can foster the production of brain-reactive autoantibodies, and that these microbe-induced antibodies provide the critical link between infection and neuropsychiatric disorders."

In the case of infection, it may not even matter so much what the infectious agent is...

"A complication in delineating the relationship of a particular pathogen to a particular neuropsychiatric disorder is that even if the link is real, it may nonetheless be nonspecific, both in terms of the type of infectious agent capable of inducing brain dysfunction, as well as in the neurobehavioral features that follow. An expanding body of studies using animal models of infection-related developmental disorders reports persistent effects on offspring brain development and behavior following prenatal or early postnatal exposures to noninfectious agents that mimic actual infection with influenza virus, such as polyinosinic:polycytidylic acid (poly I:C, a form of synthetic, double-stranded RNA), or a bacterium, such as lipopolysaccharide (LPS, or bacterial endotoxin), illustrating the importance of maternal immune responses as modifiers of postinfectious sequelae in the offspring. Findings from these studies suggest that CNS damage requires the presence of innate immune and inflammatory molecules that disrupt brain development."

Noting that shifts in maternal immune activation toward an autoimmune and allergic phenotype predisposed offspring to autism-like behaviors which were subsequently abolished by bone marrow transplantation to modify immune expression...

"In addition to this overlap in neurodevelopmental consequences after prenatal and postnatal virus-like and bacteria-like exposures, exposure of infant mice to environmental contaminants such as the organic compound, toluene, is associated with upregulated expression of cytokine genes in hippocampus. Thus, increasing evidence suggests that it is the presence of innate immune molecules, as opposed to direct infection of neurons and glial cells, that mediates these effects."

While breaching of the blood brain barrier (BBB) immunoreactive agents into the privileged space of the central nervous system, it may not always be necessary for the manifestation of neuropsychiatric symptoms:

"Another study that focused on GAS [group A streptococcus]-related, CNS-directed autoimmunity raised the intriguing suggestion that alternate transport systems may exist for entry of certain immunoglobulin isotypes or subclasses into the CNS. Zhang et al. injected naïve mice with anti-GAS IgM monoclonal antibodies, without the use of an adjuvant to breach the BBB, and found increased stereotypic behaviors...Transcellular mechanisms that obviated the need to compromise BBB integrity were postulated to facilitate the entry of these IgM antibodies into the CNS."

Pathogens aren't the only microbes that can incite autoimmune activity. As noted in earlier posts, the 'normal' commensal microbiota can also participate in loss of immune tolerance:

"Recent evidence suggests that both pathogenic and commensal microbes play a role in the pathogenesis of a subset of neuropsychiatric disorders through induction of brain-reactive autoantibodies. Whereas infection with certain pathogens can trigger autoantibody production through molecular mimicry, commensal bacteria that comprise the gastrointestinal microbiota probably set the stage for the development of autoimmune responses by skewing immune responses toward overproduction of Th17 cells and reduction in numbers and function of Tregs."

The authors also note the role of antioxidants and depletion of the antoxidant system, particularly glutathione:

"Failed uptake of antioxidant precursors in the terminal ileum, influenced by differences in tryptophan degradation capacity of the microbiota and related factors, may also contribute to a skew toward autoimmunity by reducing levels of Tregs and increasing levels of autoimmunity-provoking Th17 cells."

The link between schizophrenia and Toxoplasma gondii infection is illustrative:

"There is also evidence that the microbial infection itself is not likely to be as important in pathogenesis as the presence of antibodies to the microbe, as well as the isotype and binding characteristics (cross-reactivity, affinity and avidity) of these antibodies. Anti-toxoplasma antibodies may also be more prevalent in individuals with bipolar disorder, type 1."

Moreover...

"In individuals with schizophrenia, antibodies directed against food antigens, including bovine milk casein and wheat-derived gluten, are correlated with the presence of antibodies to T. gondii...In a separate study, increased levels of anti-gliadin antibodies were found in individuals with schizophrenia. Furthermore, the interactomes of nine neuropsychiatric disorders, including multiple sclerosis, Alzheimer's disease, schizophrenia, bipolar disorder, depression, childhood obesity, Parkinson's disease, ADHD and ASD, but not anorexia nervosa or myalgic encephalomyelitis/CFS, showed significant overlap with the interactome of T. gondii, and has been closely associated with a number of autoimmune diseases."

Interestingly, autoimmunity with loss of tolerance to gluten may involve reduced antioxidant capacity:

"The relationship of anti-toxoplasma antibodies to anti-gliadin antibodies in some neuropsychiatric disorders may relate to reduced antioxidant capacity in the terminal ileum. Gliadin, a major protein component of wheat that is associated with celiac disease, also appears able to dysregulate redox balance in peripheral blood mononuclear cells, triggering allergic-type responses that include specific enhancement of IL-4-mediated IgE production...A clearer understanding of these processes may uncover unique strategies for intervention with less potential for toxicity, including antioxidants, prebiotics, probiotics and transplantation of fecal microbiota."

Clinical note: Clearly practitioners must be alert to the role of autoimmunity in neuropsychiatric disorders and must discriminate between infection and loss of immune tolerance triggered by infection. It may not be so apparent that the indigenous commensal microbiota can play a role in autoimmunity, antimicrobial therapy may modify symptoms for a time but 'dig the hole deeper', and that caution must be observed in contemplating treatment for infections that expose the immune system to the lipopolysaccharides of disintegrating bacterial and fungal cells in the presence of active or latent loss of immune tolerance.The authors conclude:

"Genetically susceptible individuals may generate brain-reactive autoantibodies when exposed to certain infectious agents or commensal organisms. Under inflammatory conditions that promote BBB disruption and facilitate trafficking into the CNS, binding of autoantibodies to cross-reactive epitopes may contribute to the cognitive and behavioral disturbances associated with these disorders by altering brain activity within key circuitry. This conceptual model views altered brain–immune signaling as a product of the interaction of immune response genes and microbial exposures at key points during prenatal and postnatal development, and provides a framework within which discordant findings across studies of different neuropsychiatric disorders may be better explained and through which novel pathways for improved therapeutics may be discovered."

* The entire paper can be read in Medscape Family Medicine.