Rheumatoid arthritis immune response

In rheumatoid arthritis, immune complexes are deposited in the affected joints, causing an inflammatory response that is amplified by eicosanoids. Lymphocytes and macrophages accumulate in the synovium, whereas leukocytes localize mainly in the synovial fluid. The major eicosanoids produced by leukocytes are leukotrienes, which facilitate T-cell proliferation and act as chemoattractants. Human macrophages synthesize the COX products PGE2 and TXA2 and large amounts of leukotrienes. 

Hypersensitivity. Hypersensitivity reactions, considered to be vaccine-related based on the timing and specificity of the reactions, were reported to the United States Vaccine Adverse Event Reporting System (VAERS) following vaccination for Lyme disease and subsequently evaluated (Burmester et al., 1995 Lathrop et al., 2002). Other reported immune system-related events to vaccines included rheumatoid arthritis, immune system disorders, detection of antinuclear antibodies, lupus syndrome, and lymphocytosis (Zhou et al., 2003). These were very rare events, with each condition comprising 0.2% or fewer of the total reports. Anaphylactic responses to vaccines were also rare and were estimated at less than one case per miUion administered vaccine doses (Bohlke et al., 2003). A number of studies evaluated anaphylactic responses to the measles-mumps-rubella (MMR), hepatitis B, diphtheria or tetanus vaccines with similar findings (Dobson et al., 1995 D Souza et al., 2000 Patja et al, 2000 Pool et al., 2002). However, some of the vaccine-induced hypersensitivity reactions are attributed to components of the formulation, such as gelatin or egg, rather than the antigen itself (Patja et al., 2001 Pool et al., 2002). 

Human tumor necrosis factor (TNF) (Fig. 1) is a hormone-like proinflammatory peptide belonging to the group of cytokines. It is mainly produced by cells of the immune system in response to infection, inflammation, or cell damage. Disregulated TNF is an important factor in many pathological situations, like sqDsis, rheumatoid arthritis, inflammatory bowel disease (Crohn s disease), and Cachexia. The cytotoxic activity of TNF is of interest in development of new antitumoral strategies. 

A glucocorticoid-resistance model has been proposed to provide an explanation for how stress might influence diseases in which excessive inflammation is observed (e.g., allergies, autoimmune diseases, rheumatoid arthritis, and cardiovascular disease). In these cases, chronic stress diminishes the immune system s sensitivity to glucocorticoids that normally terminate the inflammatory response. For example, in a study of a group of 50 parents caring for a child undergoing treatment for pediatric cancer, whole blood of parents of cancer patients exhibited a lesser dexamethasone-dependent suppression of IL-6 production in vitro compared to parents of medically healthy children.94... 

Heavy Metals. Some heavy metals such as gold and platinum are used pharmacologically as immunomodulators to treat rheumatoid arthritis and as antineoplastic drugs, respectively. Most heavy metals inhibit mitogenicity, antibody responses, and host resistance to bacterial or viral challenge, and tumor growth. Platinum has been shown to suppress humoral immunity, lymphocyte proliferation, and macrophage function (Lawrence, 1985). Clinically, mild to moderate myelosuppression may also be evident with transient leukopenia and thrombocytopenia. 

The major neutrophil-activating factors within rheumatoid joints are immune complexes. These predominantly IgG-containing complexes vary considerably in size. Curiously, blood neutrophils do not generate reactive oxidants in response to soluble immune complexes, needing to be primed before they can be activated in this way (Fig. 8.4). It is therefore of interest to note that neutrophils isolated from the synovial fluid of patients with rheumatoid arthritis have been primed in vivo and can secrete substantial quantities of reactive oxidants in response to these soluble complexes. Thus, it is extremely likely that these soluble immune complexes are responsible for activation of the secretion of reactive oxygen metabolites by infiltrating synovial-fluid neutrophils. This phenomenon may contribute to the events that lead to the destructive joint processes characteristic of this disease. 

Mecfianism of Action Gold compounds that alter cellular mechanisms, collagen biosynthesis, enzyme systems, and immune responses. Therapeutic Effect Suppress synovitis in the active stage of rheumatoid arthritis. 

Mechanism of Action Aprotein that binds to tumor necrosis factor (TNF), blocking its interaction with cell surface receptors. Elevated levels of TNF, which is involved in inflammatory and immune responses, are found in the synovial fluid of rheumatoid arthritis patients. Therapeutic Effect Relieves symptoms of rheumatoid arthritis. Pharmacokinetics Well absorbed after subcutaneous administration. Half-life 115 hr. 

Mechanism of Action A heavy metal antagonist that chelates copper, iron, mercury, lead to form complexes, promoting excretion of copper. Combines with cystine-forming complex, thus reducing concentration of cystine to below levels for formation of cystine stones. Exact mechanism for rheumatoid arthritis is unknown. May decrease cell-mediated immune response. May inhibit collagen formation. Therapeutic Effect Promotes excretion of copper, prevents renal calculi, dissolves existing stones, acts as anti-inflammatory drug. 

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