˜ cell˛ cell˝ cellThe islets of Langerhans contain several cell types secreting distinct hormones. Each cell expresses different tissue-speciÿc proteins glucagoninsulinsomatostatinGlucagon and somatostatin are still produced by the ˜and °cells, but no insulin can be made In type 1 diabetes an effector T cell recognizes peptides from a ˛-cell speciÿc protein and kills the ˛cell CTL including myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG) (Fig. 15.28). MS takes its name from the hard (sclerotic) lesions, or plaques, that develop in the white matter of the central nervous system. These lesions show dissolution of the myelin sheath that normally surrounds nerve cell axons, along with inflammatory infiltrates of lymphocytes and macrophages, particularly surrounding blood vessels. Patients with MS may develop a variety of neurological symptoms, including muscle weakness, ataxia, blindness, and paralysis. Normally, few lymphocytes cross the blood–brain barrier, but if this barrier breaks down, activated CD4 T cells specific for myelin antigens and expressing α4:β1 integrin can bind vascular cell adhesion molecules (VCAMs) on activated endothelium (see Section 11-3), enabling the T cells to migrate out of the blood vessel. There they reencounter their specific autoantigen presented by MHC class II molecules on infiltrating macrophages or microglial cells (phagocytic macrophage-like cells resident in the central nervous system). Inflammation causes increased vascular permeability, and the site becomes heavily infiltrated by TH17 and TH1 effector CD4 T cells, which produce IL-17, IFN-γ, and GM-CSF. Cytokines and chemokines produced by these effector T cells in turn recruit and activate myeloid cells that exacerbate inflammation, resulting in further recruitment of T cells, B cells, and innate immune cells to the lesion. Autoreactive B cells produce autoantibodies against myelin antigens with help from T cells. These combined activities lead to demyelination and interference with neuronal function.
The clinical course of MS both mirrors what is seen in other autoimmune diseases and also displays how the tissue specificity of such conditions affects their progression. Most MS patients experience a disease course characterized by acute attacks (relapse) followed by a reduction in disease activity (remission) that may last for months or years. This relapsing–remitting course is characteristic of many autoimmune diseases (besides MS, Crohn’s disease and rheumatoid arthritis, among others), in terms of both the symptoms patients experience and the degree of immune-cell infiltration into the affected organ. Not only are the triggers of relapses not always clear, but the events leading to spontaneous disease remission—even when the autoantigen is still present
Infammatory reaction occurs in the brain due to mast-cell activation, complement activation, antibodies, and cytokines in the organ—remain to be discovered. Furthermore, the relapsing–remitting nature of diseases such as MS makes conducting clinical trials around these disorders especially difficult, as they must be performed over relatively long periods of time to ensure a therapy is effective in preventing relapses and disability.