Pregnancy and the post-partum period regulate experimental autoimmune encephalomyelitis through immunoregulatory cytokine production.

摘要

Women with multiple sclerosis (MS) experience a decrease in relapse rate over the course of pregnancy, with the sharpest decline occurring during the third trimester. Abruptly following parturition, however, disease activity flares before returning to its baseline level three to six months later. As a result of these dramatic changes in disease, pregnancy and the post-partum period offer a unique opportunity to study both disease amelioration and disease exacerbation. We examined the effect of pregnancy on experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Our investigations focused on the effect of the different gestational stages on both the induction of disease as well as progression of pre-existing disease. We found that when EAE was induced in pregnant animals the clinical signs of disease were prevented while immunization with neuroantigen during the post-partum period led to increased relapse severity. These effects were not associated with alterations in lymphocyte activation or with changes in Th2 cytokine (IL-4 and IL-5) production. Instead, we observed a decrease in TNF-alpha and an increase in the immunoregulatory cytokine, IL-10, when animals were immunized during pregnancy, while a decrease in IL-10 occurred when the mice were immunized post-partum.; Similar effects were observed when pregnancy was induced during pre-existing EAE. When pregnancy was induced prior to the onset of EAE clinical signs, disease was delayed until after parturition. When pregnancy was induced after the onset of clinical signs, the severity of disease was decreased. Thus, regardless of when pregnancy was induced, suppression of pre-existing EAE was observed. Similarly, this protection from disease was associated with an increase in IL-10.; We extended these studies into a transgenic mouse model in order to determine the effect of the different gestational stages on autoreactive lymphocytes in an adjuvant free system. Each gestational stage was characterized by its own unique immunological environment, including a Th2 bias during mid pregnancy and lymphocyte hyperactivation in the post-partum period. The number of autoreactive cells present in the lymphoid organs, however, did not change. Together these investigations reveal that each gestational stage has its own distinctive effect on autoimmunity and demyelinating disease.