This essay covers all the content of lecture 10 of Immunology of Human Disease. It discusses Rheumatoid arthritis as a chronic immune-mediated inflammatory disease. It discusses that chronic inflammatory disease results from an ongoing stimulus during which innate helper cells try to resolve but th...
Rheumatoid arthritis is a chronic immune-mediated inflammatory disease, meaning that it is
self-perpetuating. A chronic inflammatory disease results from an ongoing stimulus during
which innate helper cells try to resolve but the ongoing stimulus results in more cell
recruitment, causing an increased inflammation and changes in the cells. This causes a
repetitive cycle and an increased disease. The chronic inflammation in RA is caused by many
different cell types like inflammatory cells and mediators as well as through processes like
angiogenesis.
Inflammatory mediators in RA include cellular mediators in preformed secretory granules like
histamine produced by mast cells, serotonin produced by platelets and lysosomal enzymes
produced by neutrophils. Other cellular mediators may be newly synthesised such as
cytokines produced by macrophages and lymphocytes. The liver also produces inflammatory
mediators during complement activation where C3a and C5a are anaphylatoxins. To measure
this inflammation, C-reactive proteins produced by the liver may be measured. These are
produced in response to IL-6, IL-1 and TNF. Other proteins produced are serum amyloid
proteins to inhibit fever, mannose binding protein to aid the removal of microorganism and
fibrinogen to aid clotting.
RA is a type II, III and IV immunologic disease characterised by auto-antibodies to IgG and
aCCP. It is not a type I mediated disease as there is no IgE secretion, instead mast cells are
activated by inflammation and complements. In a normal articular joint, the bones are lined
with cartilage which is made of type 2 collagen and proteoglycan chains, forming a mesh to
absorb water and allow a shock-cushioning. There is a thin layer of cells which forms the
synovial membrane which secretes synovial fluids. Muscles, tendons and nerves signal the
joint to move. In contrast, an RA joint is hugely inflamed, swollen and painful. The cartilage is
degrading as well as the underlying bone. This immune mediated chronic disease usually
starts at the peripheral joint like the fingers and the toes. Osteo-arthritic joints are often used
as controls in studies of RA joints as it is an ageing wear and tear joint damage that often
starts in the weight bearing joints, like knees and hips.
The presentation of RA includes a progressive damage leading to joint deformity and
disability, causing extra-articular manifestations like in the skin nodules, lungs and heart often
caused by vasculitis. These individuals often have a diminished life expectancy. This disease
affects 1% of the population in the UK with more than 40% of people over 65 years of age
having a form of arthritis. There is no cure for RA though diet can help with the inflammation,
like ellagic acid in fruits and red wine affects lipid metabolism and arachidonic acid pathway.
RA is associated with MHC II in Caucasians, HLA-DR1 and HLA-DR4, it is the shared epitope
theory. The shared epitope theory implicates the activation of CD4+ T cells by MHC:peptide
with HLA-DR4 positively associated with more severe disease and HLA-DR and HLA-DR4
common specific QKRAA motif. This shared epitope is on the side of the peptide binding
groove of the MHC II, possibly influencing the peptide binding. These specific peptides may
activate more arithrogenic T cells that contribute to the inflammatory process. However,
genetic contributions to RA only account for 15% of the disease risk, 30% of which is due to
the shared epitope. There are over 100 loci in the genome with RA susceptibility variants,
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