Seeking balance: Potentiation and inhibition of multiple sclerosis autoimmune responses by IL-6 and IL-10

Abstract

The cytokines IL-6 and IL-10 are produced by cells of the adaptive and innate arms of the immune system and they appear to play key roles in genetically diverse autoimmune diseases such as relapsing remitting multiple sclerosis (MS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Whereas previous intense investigations focused on the generation of autoantibodies and their contribution to immune-mediated pathogenesis in these diseases more recent attention has focused on the roles of cytokines such as IL-6 and IL-10. In response to pathogens, antigen presenting cells (APC), including B cells, produce IL-6 and IL-10 in order to up- or down-regulate immune cell activation and effector responses. Evidence of elevated levels of the proinflammatory cytokine IL-6 has been routinely observed during inflammatory responses and in a number of autoimmune diseases. Our recent studies suggest that MS peripheral blood B cells secrete higher quantities of IL-6 and less IL-10 than B cells from healthy controls. Persistent production of IL-6, in turn, contributes to T cell expansion and the functional hyperactivity of APC such as MS B cells. Altered B cell activity can have a profound impact on resultant T cell effector functions. Enhanced signaling through the IL-6 receptor can effectively inhibit cytolytic activity, induce T cell resistance to IL-10-mediated immunosuppression and increase skewing of autoreactive T cells to a pathogenic Th17 phenotype. Our recent findings and studies by others support a role for the indirect attenuation of B cell responses by Glatiramer acetate (GA) therapy. Our studies suggest that GA therapy temporarily permits homeostatic regulatory mechanisms to be reinstated. Future studies of mechanisms underlying dysregulated B cell cytokine production could lead to the identification of novel targets for improved immunoregulatory therapies for autoimmune diseases.

Bronchoalveolar lavage fluid microbiota dysbiosis in infants with protracted bacterial bronchitis

“…Significant enrichment of the core node Haemophilus was observed in infants with PBB, and it was negatively correlated with other microbial colonizers, including Lactococcus, Bacillus and Clostridium. Previous reports have shown that Bacillus affect the secretion of IL-17 indirectly (27), and Clostridium could promote T regulatory (Treg) cell differentiation, which were crucial for inflammation reactions (22,28). In infants with PBB, the relative abundances of aforementioned genera decreased as Haemophilus increased, and this was found to aggravate microbial imbalance and expand the immune response in the respiratory mucosa.…”

Effects of B Cell Depletion on Early Mycobacterium tuberculosis Infection in Cynomolgus Macaques

“…B cells were noted to secrete primarily IL-6 and IL-10 in granulomas from control animals and global reductions of these cytokines within the granulomas of rituximab-treated macaques could be attributed to B cell depletion. Indeed, B cells are prodigious producers of IL-6 in other immune settings, such as multiple sclerosis (48). IL-6 has multiple roles in inflammation, particularly B cell expansion (34,48) and T cell development (49).…”

“…Indeed, B cells are prodigious producers of IL-6 in other immune settings, such as multiple sclerosis (48). IL-6 has multiple roles in inflammation, particularly B cell expansion (34,48) and T cell development (49). A decrease in IL-6 suggests that the inflammatory response within the B cell-depleted granuloma may be less robust compared to control granulomas since IL-6 is involved in coordinating immune cell recruitment, particularly neutrophils and T cells during the acute phase of infection (50,51).…”

Activation of Macrophages <i>in vitro</i> by Phospholipids from Brain of <i>Katsuwonus pelamis</i> (Skipjack Tuna)

“…NO generated by inducible nitric oxides synthase endows macrophages with cytostatic or cytotoxic activity against bacteria, viruses and tumor cells 25 . The cytokines IL-6 is produced by cells of adaptive and innate arms of the immune system and appears to play a key role in genetically diverse autoimmune diseases and respond to pathogens 26 . There is mounting evidence that the cytokines are related to Tolllike receptors TLRs down-stream NF-κB pathway, which suggested M1 macrophage are activated 27,28 .…”