Excessive levels of proinflammatory cytokines in the CNS are associated with reduced serotonin (5-HT) synthesis, a neurotransmitter with diverse immune effects. In this study, we evaluated the ability of exogenous 5-HT to modulate the T-cell behavior of patients with MS, a demyelinating autoimmune disease mediated by Th1 and Th17 cytokines. Here, 5-HT attenuated, in vitro, T-cell proliferation and Th1 and Th17 cytokines production in cell cultures from MS patients. Additionally, 5-HT reduced IFN-γ and IL-17 release by CD8 T cells. By contrast, 5-HT increased IL-10 production by CD4 T cells from MS patients. A more accurate analysis of these IL-10-secreting CD4 T cells revealed that 5-HT favors the expansion of FoxP3 CD39 regulatory T cells (Tregs) and type 1 regulatory T cells. Notably, this neurotransmitter also elevated the frequency of Treg17 cells, a novel regulatory T-cell subset. The effect of 5-HT in upregulating CD39 Treg and Treg17 cells was inversely correlated with the number of active brain lesions. Finally, in addition to directly reducing cytokine production by purified Th1 and Th17 cells, 5-HT enhanced in vitro Treg function. In summary, our data suggest that serotonin may play a protective role in the pathogenesis of MS.
This study examines the link between peripheral immune changes in perpetuation of the Alzheimer's disease (AD) neuropathology and cognitive deficits. Our research design using human AD patients and rodent model is supported by past evidence from genomic studies. We observed an active immune response against Aβ as indicated by the increased Aβ specific IgG antibody in the serum of AD and patients with mild cognitive impairments as compared to healthy controls. A similar increase in IgG and decrease in IgM antibody against Aβ was also confirmed in the 5xFAD mouse model of AD. More importantly, we observed a negative correlation between reduced IgM levels and cognitive dysfunction that manifested as impaired memory consolidation. Strong peripheral immune activation was supported by increased activation of microglia in the brain and macrophages in the spleen of AD mice compared to wild type control littermates. Furthermore, inflammatory cytokine IL-21 that is involved in antibody class switching was elevated in the plasma of AD patients and correlated positively with the IgG antibody levels. Concurrently, an increase in IL-21 and IL-17 was observed in spleen cells from AD mice. Further investigation revealed that proportions of T follicular helper (Tfh) cells that secrete IL-21 are increased in the spleen of AD mice. In contrast to Tfh, the frequency of B1 cells that produce IgM antibodies was reduced in AD mice. Altogether, these data indicate that in AD the immune tolerance to Aβ is compromised leading to chronic immune/inflammatory responses against Aβ that are detrimental and cause neuropathology.
Figueiredo et al.
212ARTIGO DE REVISÃO
REVIEW ARTICLE
RESUMOOs antimaláricos, como o difosfato de cloroquina, têm sido usados amplamente no tratamento não só da malária, mas também de doenças reumatológicas como a síndrome de Sjögren (SS), artrite reumatóide (AR) e lúpus eritematoso sistêmico (LES). Essas drogas são usadas cronicamente e, em conseqüência do acúmulo nos melanócitos, podem causar hiperpigmentação cutânea, retinopatia e lesão no ouvido interno. Como o protocolo do uso de antimaláricos só envolve a avaliação oftalmológica e das enzimas hepáticas, esta revisão discute a necessidade de novos estudos da avaliação periódica da audição desses pacientes.
Circulating TFH (cTFH) cells express CXCR5, PD‐1, and, when activated, ICOS, and release IL‐21. According to the production of IFN‐γ, IL‐4, and IL‐17 and expression of FoxP3, these cells are also classified as cTFH1, cTFH2, cTFH17, and cTFR cells, respectively. This CD4+T‐cell subset is pivotal to efficient humoral immunity, and pregnancy appears to favor IgG production. Here, not only pregnancy amplified the in vivo production of anti‐HBsAg IgG in HBV immunized women, but the frequency of cTFH cells was directly correlated with estradiol levels. In vitro, pregnancy‐related dose of 17‐β‐estradiol (E2) directly increased the percentage of different cTFH subsets. While E2 and progesterone (P4) increased the proportion of differentiated TFH cells derived from naïve CD4+T‐cells, only E2 amplified the release of IL‐21 in those cell cultures. In addition, E2 and P4 increased the proportion of memory B cells and plasma cells, respectively. In SEB‐activated B/TFH cell co‐cultures, E2, in the presence of P4, increased the production of total IgG. Finally, among the hormones, P4 was stronger in upregulating the percentage of IL‐10+TFR cells. Collectively, our findings suggested that E2 and P4 cooperate in the humoral immune response by favoring the expansion of different cTFH and B cell subsets.
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