Ultimately, often after decades, most MS patients change from a relapsing– remitting disease course to ‘secondary progressive’ MS. In this phase patients begin to undergo a steady neurologic decline without overt periods of remission, and for many patients their disease becomes less responsive to the therapies that effectively target the adaptive immune system in relapsing–remitting MS. The reasons for this are unclear, though it has been suggested that the long-term relapsing–remitting course ultimately exhausts the central nervous system’s regenerative capacity, leading to chronic neurodegeneration. Further, prolonged disease may allow immune cells and activated microglia to remain behind the blood–brain barrier, continuing to promote neuronal damage without the need for continuous recruitment of large numbers of inflammatory cells from the periphery.
Rheumatoid arthritis (RA) is a chronic disease characterized by inflammation of the synovium (the thin lining of a joint). As disease progresses, the inflamed synovium invades and damages the cartilage; this is followed by bone erosion (Fig. 15.29), leading to chronic pain, loss of function, and disability. RA was first considered an autoimmune disease driven by B cells producing anti-IgG autoantibodies called rheumatoid factor (see Section 15-4). However, the identification of rheumatoid factor in some healthy individuals, and its absence in some patients with rheumatoid arthritis, suggested that more complex mechanisms orchestrate this pathology. The discovery that RA has an association with particular class II HLA-DR genes of the MHC suggested that T cells are also involved in the pathogenesis of this disease. In RA, as in MS, most data from humans and mouse models indicate that, at least early in disease development, autoreactive TH17 cells become activated. Autoreactive T cells provide help to B cells to produce arthritogenic antibodies. The activated TH17 cells also produce cytokines that recruit neutrophils and monocytes/macrophages, which, along with endothelial cells and synovial fibroblasts, are stimulated to produce more pro-inflammatory cytokines such as TNF-α, IL-1, or chemokines (CXCL8, CCL2), and finally matrix metalloproteinases, which are responsible for tissue destruction. IL-17A, which has been found in high concentrations in the synovium and synovial fluid of RA patients, can induce expression of the ligand for receptor activator of NFκB (RANKL), which stimulates the differentiation of osteoclast precursors into mature osteoclasts that resorb bone in affected joints. Although we do not yet know how RA starts, mouse models have shown that both T cells and B cells are needed to initiate disease. Interestingly, interrupting
Fig. 15.28 The pathogenesis of multiple sclerosis. At sites of inflammation, activated T cells autoreactive for brain antigens can cross the blood–brain barrier and enter the brain, where they reencounter their antigens on microglial cells and secrete cytokines such as IFN‑γ. The production of T‑cell and macrophage cytokines exacerbates the inflammation and induces a further influx of blood cells (including macrophages, dendritic cells, and B cells) and blood proteins (such as complement) into the affected site. Mast cells also become activated. The individual roles of these components in demyelination and loss of neuronal function are still not well understood. CNS, central nervous system.
osteoclast joint cartilage MMPs attack tissues. Activation of bone-destroying osteoclasts by RANK ligand results in joint destruction cytokines fbroblasts IL-6 RANK ligandMMP TNF-˜Cytokines induce production of MMP and RANK ligand by fbroblasts Unknown trigger sets up initial focus of infammation in synovial membrane, attracting leukocytes into the tissue Autoreactive CD4 T cells activate macrophages, resulting in production of pro-infammatory cytokines and sustained infammation