The history of autoimmune disease and animal models (part three)

  1. Rheumatoid arthritis 

Rheumatoid arthritis is considered to be a clinical syndrome spanning several disease subsets. These different subsets entail several inflammatory cascades, which all lead to a final common pathway in which persistent synovial inflammation and associated damage to articular cartilage and underlying bone are present. One key inflammatory cascade involves overproduction and overexpression of TNF. This pathway drives both synovial inflammation and joint destruction. TNF overproduction has several causes, including interactions between T and B lymphocytes, synovial-like fibroblasts, and macrophages. This process leads to overproduction of many cytokines such as interleukin, which also drives persistent inflammation and joint destruction. Overproduction of other pro-inflammatory cytokines (eg, interleukin 1) differs from the interleukin production in that the production is either less pronounced or is specific to one or more disease subsets. This is best illustrated by the blockage of interleukin 1 in sub-forms of juvenile idiopathic arthritis or adult-onset Still’s disease. The dominant local cell populations in joints affected by rheumatoid arthritis are synovial and cartilage cells. Synovial cells can be divided into fibroblast-like and macrophage-like synoviocytes. Overproduction of pro-inflammatory cytokines is believed to be caused predominantly by macrophage-like synoviocytes. Fibroblast-like synoviocytes show abnormal behaviour in rheumatoid arthritis. In experimental models, co-implantation of fibroblast-like synoviocytes with cartilage causes fibroblasts to invade cartilage, and this behaviour is associated with joint destruction. Considerable information has been accumulated about the joint destruction and the role of osteoclast activation as a key process leading to bone erosion. It has been proven that specific inhibition of osteoclast activation can reduce joint destruction but does not affect joint inflammation. It is unclear whether arthritis starts primarily in the bones and subsequently moves to the joints, or the other way around. One argument for rheumatoid arthritis starting in the joint is the observation that fibroblast-like synoviocytes showing altered behaviour can spread between joints, suggesting how polyarthritis might develop. Regulation of immune inflammation depends on the balance between the number and strength of different cells. Control of arthritogenic immune-responses has been studied in mice known to have specific antigen. Infusion of a small number of T cells with specific characteristics can ameliorate arthritis in a rodent model of the disease, showing that T cells have protective effects. Ongoing research should translate these experimental findings into clinical practice.

Rheumatoid arthritis antibodies are classic autoantibodies in rheumatoid arthritis. IgM and IgA rheumatoid factors are key pathogenic markers for the Fc fragment of IgG. Additional (and increasingly important) types of antibodies are those against citrullinated peptides (ACPA). Although most, but not all, ACPA-positive patients are also positive for rheumatoid factor, ACPA appear to be more specific and sensitive to diagnosis and seem to be better predictor of poor prognostic features such as progressive joint destruction. Ongoing research aims to identify antibody specificities associated with different patients’ subsets and disease stages. Composition of the antibody response varies over time. In early rheumatoid arthritis, there is limited specificity, and in late disease, there is a mature response, in which more epitopes are recognised and more isotypes used. Evidence from animal models and in-vivo data suggests that ACPA are pathogenic on the basis of induction of arthritis in rodent models because immunological responses are present in ACPA-positive patients in a citrulline specific manner. Findings of clinical studies have shown that patients with rheumatoid arthritis, rheumatoid factor and ACPA (autoantibody-positive disease) differ from individuals with so-called autoantibody-negative disease. For example, histologically, people with ACPA-positive disease have more lymphocytes in synovial tissue, whereas those with ACPA-negative rheumatoid arthritis have more fibrosis and ynovial lining layers with increased thickness. ACPA-positive disease is associated with increased joint damage and low rates of remission.

50% of risk of developing rheumatoid arthritis can be attributed to genetic factors. Much progress has been made in identification of genetic regions tagged by structural variation (single nucleotide polymorphisms). Rheumatoid arthritis is associated with more than one genetic region. At present, apart from PTPN and HLA genes, no major pathogenic insights have come from these genetic associations. However, progress has been demonstrated by the realisation that from a putative 2 mm of DNA harbouring candidate variants, these regions are all contained within 2 mm of DNA. Using current sequencing methodology, 2 mm of DNA can be sequenced in large cohorts. So, we can reasonably expect that new mechanisms can be identified in the next few years. The existence of many risk alleles discovered in recent years is fairly common in the population as a whole, and individually they have modest effects on the risk of rheumatoid arthritis. However, ongoing research suggests that several risk loci are linked to other autoimmune diseases, and some genes fall within discrete biological pathways that drive inflammation. Findings of genetic studies have found that differences in ACPA status of patients with rheumatoid arthritis are related to the number of specific HLA-DRB1 alleles. These HLA alleles share a common motivation, which is known as shared epitope. Currently, antigens are believed to be modified by a process called citrullination, which entails post-translational modification of the aminoacid arginine to citrulline. This modification is thought to allow antigens to fit in the HLA alleles that harbour this shared epitope. The end result is disruption of tolerance that allows antibody formation against these antigens. Genetic risk factors associated with rheumatoid arthritis are primarily thought to be specifically associated with either ACPA-positive or ACPA-negative disease. The most studied environmental factor for rheumatoid arthritis—smoking—seems to be a risk factor for ACPA-positive disease, especially when the shared epitope of HLA-DRB1 is positive. Genetic research supports the idea that rheumatoid arthritis is a heterogeneous group of overlapping syndromes.

Reference

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