Immune abnormalities Autoantibodies

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Rheumatoid factors Rheumatoid factors are autoantibodies directed against the Fc fragment of the immunoglobulin G molecules and are found in approximately 70% of patients with rheumatoid arthritis. Rheumatoid factors produced in normal individuals, during lymphoproliferative or transitory inflammatory conditions, are structurally and functionally dissimilar from the ones produced by rheumatoid arthritis patients. They differ, in the first place, genetically. Rheumatoid factors produced during lymphoproliferative disorders are generally encoded by a set of variable region genes that are germ-line. Hence, these autoantibodies have not been developed by selective antigenic pressure. On the contrary, genes encoding rheumatoid factors derived from patients with rheumatoid arthritis show a wide range of variable region usage. These genetic discrepancies underline strong functional differences. Rheumatoid factors found in normal individuals are part of a family of natural antibodies that have low affinity for the self antigen. They are often polyspecific, reacting with self and exogenous antigens. On the contrary, rheumatoid factors isolated from rheumatoid arthritis patients are often of high affinity for their target. B cells that express high-affinity rheumatoid factors are very effective in presenting immune complexed antigens to T cells, contributing therefore to the generation of a specific secondary immune response that may be part of the etiopathogenesis of the disease.

Other autoantibodies Autoantibodies other than rheumatoid factors are frequently found in rheumatoid arthritis patients. Their presence, in most cases, can be associated with polyclonal B cell activation, one of the immune abnormalities of the disease, rather than with a specific pathogenic pathway. Anti perinuclear factors and anti-rheumatoid arthritis-associated nuclear antigen (RANA) are specifically associated with rheumatoid arthritis and have been associated with Epstein-Barr virus (EBV) infection. Anticollagen antibodies constitute another family of autoantibodies that may play a role in rheumatoid arthritis by mediating joint damage through the activation of various inflammatory pathways.

Abnormalities of the cytokine network

Proinflammatory cytokine family Interleukin 1 (IL-1) is mainly produced by activated macrophages in response to inflammatory stimuli. IL-1 has both systemic and localized effects on the immune system. For its role in septic shock and as a pyrogen, it is considered as the endogenous pyrogen. At inflammatory sites, it induces T and B cell activation and proliferation, and release of proteolytic and chemo-tactic substances from macrophages, and has a stimulatory effect on osteoclasts, with consequent cartilage reabsorption.

TNFct is another potent proinflammatory cytokine. It is produced mainly by inflammatory cells, such as activated macrophages. T cells can also produce TNFa in response to antigenic stimuli. TNFa is a stimulator of T cell activation. It upregulates expression of interferon y (IFNy) and IL-2 receptor expression in T cells. It induces B cell activation and immunoglobulin (Ig) production. It has chcmo-attractant properties. TNFa interacts with several other proinflammatory cytokines, including 1L-15. This amplifying effect may be particularly relevant in the pathogenesis of rheumatoid arthritis.

Immunomodulatory cytokines TFNy is a potent proinflammatory cytokine produced by T cells and natural killer (NK) cells. It has a stimulatory effect on many cells of the immune system. It plays a major role in controlling infection, in particular of viral origin. It is also the cytokine primarily associated with THl-type responses. The immunomodulatory cytokine which is the natural antagonist of IFN-y is IL-4. IL-4 is produced by CD4+ T cells and eosinophils and is a potent stimulator of B cell-mediated immune responses. IL-2 and IL-6 are both intermediate mediators. They modulate immune responses by acting on other immune cells and stimulating production of other cytokines. Their effects are mainly stimulatory and both cytokines are therefore implicated in the mechanisms of autoimmune inflammation.

Growth factors Transforming growth factor 3 (TGFJ3) is a cytokine produced mainly by macrophages and epithelial cells. It is a potent chemoat-tractant and a very effective inductor of wound healing and fibroblast proliferation. With the other cytokines in this group, its role in rheumatoid arthritis is probably restricted to the late pathogenic steps, when synovial hyperplasia occurs. TGF(3 also has an important role in mucosal immunity, by boosting specific IgA responses. Another cytokine of this group that has been significantly implicated in the pathogenesis of inflammation is granulocyte-macrophage colony-stimulating factor (GM-CSF). This growth factor is produced by T cells; it is a potent stimulator of inflammatory responses and is involved in processes related to hyperplasia and inflammation.

Balance between pro- and anti-inflammatory cytokines: the TH1/TH2 paradigm The control of the balance of immune response mediators secreted by differing T cell subsets is emerging as a major im-munoregulatory mechanism. T Helper (TH) cells have been subdivided into TH1, secreting mainly IFN-y and IL-2, and TH2, secreting mainly IL-4. This subdivision, originally described in the mouse, has also been applied to humans. It has an important functional significance in the physiology of immune responses. Ijj 1-type cells are generally involved in cytotoxic T cell-mediated responses, while TH2 cells are elevated in allergic and parasitic diseases. An efficient immune response rests on a balance between the two cell types. Any alteration of this equilibrium would affect the quality of the immune response toward exogenous antigens, therefore favoring a possible loss of tolerance toward self antigens. In rheumatoid arthritis a TH1 pattern is found. Proinflammatory cytokines are upregulated. IL-6, IL-1(3 and TNFa stimulate the secretion of prostaglandins, collagenase and oxygen radicals, and sustain synoviocyte proliferation. All these anomalies in the cytokine network are probably secondary to the trig gering events that elicit autoimmune inflammation, and they certainly represent an important part of the mechanism of amplification and perpetuation of the autoimmune damage.

Adhesion molecules

Any anomalous expression of adhesion molecules, or their ligands, could affect the normal pattern of migration of immune response cells to the synovium. ICAM-3, an adhesion molecule and a costimulatory signal for both resting and activated lymphocytes, is overexpressed in rheumatoid synovium. In parallel, adhesion ligands such as ELAM-1 and VCAM-1 are overexpressed on endothelial cells in rheumatoid arthritis patients. CD44, the ligand for hyaluronic acid, is also overexpressed in synovial fluid lymphocytes. These anomalies in leukocyte trafficking and homing are present in rheumatoid arthritis. They may be part of the disease pathogenesis.

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