Obsessive-compulsive spectrum disorders and rheumatic fever

Hounie A.G.; Mercadante M.T.; Alvarenga P.G.; Sampaio A.S.; Taub A.; Miguel E.C.

Obsessive-compulsive spectrum disorders and rheumatic fever

Tipo

Artigo de revisão

Data de publicação

2006

Periódico

Psychiatric Annals

Citações (Scopus)

0

Autores

Hounie A.G.
Mercadante M.T.
Alvarenga P.G.
Sampaio A.S.
Taub A.
Miguel E.C.

Resumo

We have presented evidence that OCSD and RF may be related by mechanisms other than chance encompassing genetic, immunological, phenomenological, and neuroimaging data. Based on the clinical data it has been reasonable to consider the existence of a subgroup of patients with OCSD who have their symptoms mediated by immunological mechanisms. This hypothesis has been in part supported by the studies reporting higher prevalence of OCSD in patients with active and nonactive RF with or without Sydenham's chorea, as well as in their relatives. The autoimmune theory is under investigation, and almost 100 studies have focused on this area. However, subtle differences in the technique, presence of comorbid conditions, time of the disease course, and level of "stress" can influence the immunologic methods in this complex field of research, compromising the preciseness of the association. Discrepancies between clinical and laboratorial data also suggest that the immunological response underlying these disorders might be different from the classical mechanisms reported in the well-known autoimmune diseases. It is important to consider that the subgroup of patients who fulfilled the diagnostic criteria for this hypothetical autoimmune OCSD has not shown tissue lesions as observed in classical autoimmune diseases, such as systemic lupus erytemathosus and in RF carditis. One possible explanation for the absence of an identifiable injury in the pathophysiology of autoimmune OCSD would be a T-independent B-cell mechanism. In this model, T-independent antigens would induce unspecific antibodies production. These low affinity autoantibodies do not have the capacities of activating complement cascade preventing tissue damage. In addition, in this model, the activation of B-cells tends to be turned off as soon as the antigenic stimulus has gone down, what would justify the waning and waxing course of symptoms. Furthermore, another putative mechanism to explain how GABHS would cause neuropsychiatric disorders without RF is superantigens. It is unlikely that the M protein is the sole factor required for establishing the autoimmune disease in PANDAS and or other neuropsychiatric cases. Superantigens are capable of nonspecifically stimulating vast numbers of CD4+ T cells, resulting in excessive cytokine release and host-tissue destruction. T cell proliferation results in interferon gamma, IL-2, and TNF alpha release and also the release of IL-1 and TNF alpha from macrophages. Recent genomic sequencing of some serotypes of GABHS has revealed that their genomes comprise prophages which encode for SAGs. Within a complex and multifactorial model, susceptible individuals in contact with M proteins of specific strains of GABHS plus SAG would result in the production of antineural antibodies. Beyond the mechanisms related to antibodies, researches are beginning to show the role of the cytokines. Inflammatory cytokines can easily cross the blood-brain barrier, and many of them have specific neuronal receptors. Studies have reported the abilities of cytokines to regulate some complex behaviors, such as the sickness behavior. Based on these data, it is reasonable to consider that maybe a subgroup of patients has their symptoms mediated by neuronal signaling activated by cytokines. Although it has been difficult to explore the role of cytokines in the CNS, the recent studies focusing on genetic polymorphisms of the related cytokines genes can provide understandable data to the field. Despite the speculative nature of the main hypothesis of this article - that that a relationship exists between immune response and psychopathology - we have provided data suggesting an intriguing relationship between the immune system and the CNS, As we reported, there are some consistent evidence of abnormalities in cortico-basal ganglia circuits as primary neural correlates of repetitive behaviors found in OCSD. Therefore, immune mediated reactivity against the brain could contribute to these OCSD behaviors by inducing a deregulation of the basal ganglia compartments balance. Repetitive behaviors (cleaning compulsions, tics and grooming behaviors) that occur as part of the normal repertoire can become exaggerated and behaviorally dominant in OCSD. Therefore, our group has pursued the hypothesis that a close relationship between OCSD behaviors and dysfunctional immune response to infections such as RF might be due to an adaptive process, as part of the phylogenic evolution. The health of subjects would be related to some habits (ie, assembled routines including cleaning compulsions, tics, and grooming behaviors) that are more prominent when they are exposed to infectious agents. As result of an evolutionary heritage, the immune system would have developed a pathway to control such behaviors by activating specific striatal neurons. If confirmed, these relationships between immunological mechanisms and complex behavior regulation will be one of the most relevant knowledge in the modern neuroscience. Nonetheless, more studies are necessary in order to have the possible association between OCSD and RF better elucidated.