Oral tolerance is a long recognized method to induce peripheral immune tolerance. The primary mechanisms by which orally administered antigen induces tolerance are via the generation of active suppression or clonal anergy. Low doses of orally administered antigen favor active suppression whereas higher doses favor clonal anergy. The regulatory cells that mediate active suppression act via the secretion of suppressive cytokines such as TGF beta and IL-4 after being triggered by the oral tolerogen. Furthermore, antigen that stimulates the gut-associated lymphoid tissue preferentially generates a Th2 type response. Because the regulatory cells generated following oral tolerization are triggered in an antigen-specific fashion but suppress in an antigen nonspecific fashion, they mediate "bystander suppression" when they encounter the fed autoantigen at the target organ. Thus it may not be necessary to identify the target autoantigen to suppress an organ-specific autoimmune disease via oral tolerance; it is necessary only to administer orally a protein capable of inducing regulatory cells that secrete suppressive cytokines. Orally administered autoantigens suppress several experimental autoimmune models in a disease- and antigen-specific fashion; the diseases include experimental autoimmune encephalomyelitis (EAE), uveitis, and myasthenia, collagen- and adjuvant-induced arthritis, and diabetes in the NOD mouse. In addition, orally administered alloantigen suppresses alloreactivity and prolongs graft survival. Initial clinical trials of oral tolerance in multiple sclerosis, rheumatoid arthritis, and uveitis have demonstrated positive clinical effects with no apparent toxicity and decreases in T cell autoreactivity.

These mechanisms contribute actively to the generation of a microenvironment in the lymph nodes that suppresses the activation of encephalitogenic T cells, resulting in the downregulation of the inflammatory response in the central nervous system.

BackgroundThe modulation of inflammatory processes is a necessary step, mostly orchestrated by regulatory T (Treg) cells and suppressive Dendritic Cells (DCs), to prevent the development of deleterious responses and autoimmune diseases. Therapies that focused on adoptive transfer of Treg cells or their expansion in vivo achieved great success in controlling inflammation in several experimental models. Chloroquine (CQ), an anti-malarial drug, was shown to reduce inflammation, although the mechanisms are still obscure. In this context, we aimed to access whether chloroquine treatment alters the frequency of Treg cells and DCs in normal mice. In addition, the effects of the prophylactic and therapeutic treatment with CQ on Experimental Autoimmune Encephalomyelitis (EAE), an experimental model for human Multiple Sclerosis, was investigated as well.Methodology/Principal FindingsEAE was induced in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein (MOG35–55) peptide. C57BL/6 mice were intraperitoneally treated with chloroquine. Results show that the CQ treatment provoked an increase in Treg cells frequency as well as a decrease in DCs. We next evaluated whether prophylactic CQ administration is capable of reducing the clinical and histopathological signs of EAE. Our results demonstrated that CQ-treated mice developed mild EAE compared to controls that was associated with lower infiltration of inflammatory cells in the central nervous system CNS) and increased frequency of Treg cells. Also, proliferation of MOG35–55-reactive T cells was significantly inhibited by chloroquine treatment. Similar results were observed when chloroquine was administrated after disease onset.ConclusionWe show for the first time that CQ treatment promotes the expansion of Treg cells, corroborating previous reports indicating that chloroquine has immunomodulatory properties. Our results also show that CQ treatment suppress the inflammation in the CNS of EAE-inflicted mice, both in prophylactic and therapeutic approaches. We hypothesized that the increased number of regulatory T cells induced by the CQ treatment is involved in the reduction of the clinical signs of EAE.

Our findings indicate a role for retrograde and anterograde neurodegeneration in GM atrophy in NMOSD. However, the presence atrophy encompassing almost all lobes suggests that additional pathomechanisms might also be involved.

Immunomodulatory treatment paradigms have been applied to animal models of T cell-mediated autoimmune diseases in an attempt to develop an immunospecific and non-toxic form of therapy which can be applied to humans. These treatment paradigms are often directed to T cells with a restricted T cell receptor repertoire or that react with dominant peptide determinants. Experimental data, however, suggests that even if the initial T cell response is restricted to a specific self-protein in the target organ, spreading autoimmunity may develop with broadening of T cell autoreactivity to additional epitopes of the same autoantigen or to different autoantigens in the target organ. Thus, multiple autoantigens may become targets of the autoimmune response. This makes immunotherapeutic strategies based on suppressing responses to restricted proteins or clones of cells problematic. We have previously shown that suppression of experimental autoimmune encephalomyelitis (EAE) in the Lewis rat by oral myelin basic protein (MBP) is mediated by the release of transforming growth factor-beta after triggering by the oral tolerogen. Here, we report that in the SJL model of EAE oral administration of an autoantigen from the target tissue suppresses disease independent of whether it is or is not the inciting antigen. Thus, orally administered MBP or MBP peptides suppress proteolipid protein (PLP)-induced EAE, whereas intravenously administered MBP does not. Both oral and intravenous PLP, however, suppressed PLP disease. These findings have important implications for the use of oral tolerance as a therapeutic approach for the treatment of T cell-mediated inflammatory autoimmune diseases in man in which the inciting autoantigen is unknown or in which there is autoreactivity to multiple autoantigens in the target tissue.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent of a major global outbreak of respiratory tract disease known as coronavirus disease-2019 (COVID-19). SARS-CoV-2 infects the lungs and may cause several immune-related complications such as lymphocytopenia and cytokine storm which are associated with the severity of the disease and predict mortality . The mechanism by which SARS-CoV-2 infection may result in immune system dysfunction is not fully understood. Here we show that SARS-CoV-2 infects human CD4+ T helper cells, but not CD8+ T cells, and is present in blood and bronchoalveolar lavage T helper cells of severe COVID-19 patients. We demonstrated that SARS-CoV-2 spike glycoprotein (S) directly binds to the CD4 molecule, which in turn mediates the entry of SARS- CoV-2 in T helper cells in a mechanism that also requires ACE2 and TMPRSS2. Once inside T helper cells, SARS-CoV-2 assembles viral factories, impairs cell function and may cause cell death. SARS-CoV-2 infected T helper cells express higher amounts of IL-10, which is associated with viral persistence and disease severity. Thus, CD4-mediated SARS-CoV-2 infection of T helper cells may explain the poor adaptive immune response of many COVID- 19 patients.

The plasmacytoid dendritic cells (pDCs) express a high level of Toll-like receptor 9 (TLR-9), which recognizes viral DNA. Activated via TLR-9, pDCs also secrete large amounts of type I interferon which are involved either in stimulation or down regulation of immune response in multiple sclerosis (MS). In the present study, we determinate pDCs levels by flow cytometry in Cerebrospinal Fluid (CSF) and Peripheral Blood from MS patients in relapsing and in remitting phases of the disease, comparing with other non-inflammatory diseases (OND). We provide evidence that MS patients in relapse without any treatment have a significantly (p < 0.01) higher percentage of pDCs in CSF than do patients in remission or those with OND. No change in the percentage of pDCs was observed in the peripheral blood of any of these patients. The increase of pDCs in central nervous system during relapse may be explained either by a virus infection or a down regulatory process.

Multiple sclerosis, which is the most common cause of chronic neurological disability in young adults, is an inflammatory, demyelinating, and neurodegenerative disease of the CNS, which leads to the formation of multiple foci of demyelinated lesions in the white matter. The diagnosis is based currently on magnetic resonance image and evidence of dissemination in time and space. However, this could be facilitated if biomarkers were available to rule out other disorders with similar symptoms as well as to avoid cerebrospinal fluid analysis, which requires an invasive collection. Additionally, the molecular mechanisms of the disease are not completely elucidated, especially those related to the neurodegenerative aspects of the disease. The identification of biomarker candidates and molecular mechanisms of multiple sclerosis may be approached by proteomics. In the last 10 years, proteomic techniques have been applied in different biological samples (CNS tissue, cerebrospinal fluid, and blood) from multiple sclerosis patients and in its experimental model. In this review, we summarize these data, presenting their value to the current knowledge of the disease mechanisms, as well as their importance in identifying biomarkers or treatment targets.