New in MS Research: Interplay Between IFN-beta, B-cells and Monocytes

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system (CNS), characterized by the presence of scar tissues (plaques) localized within the brain’s white matter and spinal cord. These plaques are results of myelin-degeneration (demyelination) and axonal death. Although MS has been classically considered to be a T-cell-mediated disease, the high efficacy of B cell-depleting therapies have demonstrated the critical role of B-lymphocytes and the humoral immune response in MS pathogenesis, albeit the underlying mechanisms remain unclear. In approximately 90% of MS patients, there is increased levels of intrathecally synthesized IgG in the MS-plaques as well as Cerebral Spinal Fluid (CSF), which manifests B-cell clonal expansions within the CNS.

B-cell-lineage cells differentiate into antibody-secreting plasma cells that are the source of persistent IgG, in the presence of key factors such as interleukin-6 (IL-6), B-cell-activating factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL). IL-6 promotes terminal differentiation of B cells to plasma cells and is essential for the survival and Ig secretion. In conjunction with APRIL, BAFF regulates, B-cell survival, differentiation and is essential for initiation of T-cell independent B-cell responses. 

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Type I IFNs (IFN-α, IFN-β, IFN-κ, and IFN-ω) are cytokines expressed by many cell types in response to viral or microbial infections, which bind to- and trigger specific Toll-like receptors (TLRs) that induce a large number of genes modulating and linking the innate and the adaptive immune responses.

Despite the development of other new treatments, IFN-β has been the first-line disease-modifying drug treatment for patients with relapsing-remitting multiple sclerosis (RRMS). Thus, understanding the molecular mechanisms of the anti-inflammatory effect of IFN-β in RRMS may provide insight into MS pathogenesis.  

TLRs are a family of non-catalytic pattern recognition receptors that recognize and bind to specific molecular patterns of pathogen-derived and endogenous damage-associated components. In addition to their key role in mediating innate immunity, TLRs have also been shown to play an important part in the activation of the adaptive immune system by inducing proinflammatory cytokines such as TNF-α, IL-1, IL-6, IL-12, and IFN.

Several studies have shown that of the 11 TLRs identified in humans, endosomal TLRs 7, 8 and 9 which recognize pathogen-derived and synthetic nucleic acids, also recognize endogenous immune complexes containing self-nucleic acids in certain autoimmune disorders such as MS. Interestingly, B-cells express both TLR7 and TLR9. TLR7 recognizes guanosine- and uridine-rich single-stranded RNAs (ssRNAs), whereas TLR9 recognizes hypomethylated CpG-rich double-stranded DNAs.  Upon activation by their specific ligands, these TLRs induce B cell proliferation and differentiation into Ig-secreting cells.

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In a recent study published in the European journal of Immunology, Coccia’s group has demonstrated the essential interactions between monocytes and B cells for the release of effective humoral immune response that elicits TLR7-mediated -induced B-cell differentiation into Ig secreting cells. Furthermore, they have shown a clear deficiency in this cross-talk interaction in MS patients; the peripheral blood mononuclear cell (PBMC) of MS patients exhibit substantially lowered TLR7-induced Ig production (compared to Healthy donors). However, results obtained after one-month long IFN-β therapy showed that lower humoral immune response in MS subjects was replenished, through IFN-β–induced secretion of TLR7- triggering cytokines, which mediated the selective increase in IgM and IgG to levels comparable to Healthy donors’. This data revealed that the IFN-β enhancement of TLR7-induced B-cell responses in MS patients occurs in at least two steps: 1) Regulation of TLR7 gene expression, and 2) Secretion of B-cell differentiation factors, in particular IL-6 and BAFF.

Finally, the last and perhaps the most significant finding of Coccia’s new study, is reporting, for the first time, the presence of a defect in TLR7 gene expression and signaling in monocytes of MS patients. Lack of TLR7-driven IgM and IgG production, absence of IL-6 and a significant reduction in BAFF expression in samples of MS patient-IFN-β treated PBMCs that were depleted of monocytes, evince IFN-β therapeutic mechanism by fine-tuning monocyte functions, through stimulation of TLR7 which subsequently effects B cell differentiation.

The discovery of the tight regulation of both TLR expression and TLR-induced responses in maintenance of immune environment’s homeostasis, as well as IFN-β-mediated- TLR7 function recovery are indicative of the critical changes in PBMC microenvironment induced by IFN-β therapy; within this microenvironment, leukocyte subsets establish critical immune regulatory interactions which determine the fate of the host’s immune tolerance processes.

Coccia’s new study has revealed new insights, which are not only crucial for the better understanding of the MS immunopathology, but also significant for development of new MS therapeutic strategies which target TLR expression and/or TLR-induced responses.

Further Reading:

IFN-β therapy modulates B-cell and monocyte crosstalk via TLR7 in multiple sclerosis patients.