User:Pathophysiology

Rheumatic fever

Rheumatic fever is an immune infection caused by the group A-Beta hemolytic streptococcus. Primarily, it infects the pharynx and then manifests its way to the heart, serous membrane joints, blood vessels of the brain and the skin. Streptococci pyogenes, a gram postive bacteria, is the specific strain which causes the infection in humans. S. Pyogenes enters the body via through aerosol forming dust, water vapor or transmitted by infected individuals through direct or indirect contact. As the S. pyogen passes through the pharynx it collects on the mucous membranes of the throat and tonsil which then acts as a growth media for this bacteria.

From the pharynx the S. pyogen bacteria demonstrates growth by showing white or yellow spots in the back of the throat or tonsil and creates inflammation which is indicative of pharyngitis. If the bacteria is left untreated it produces two antigens, M and T-Proteins.

Rheumatic Fever is a disease complicated by an infection of group A beta- haemolytic Streptococcus bacteria. Rheumatic fever is hardly ever progressed through the skin but more prevalently distributed through the pharynx. This is due to different streptococcus strains affecting the immune response in different ways. It is most predominantly found in children and when infected by the pharynx may show signs and symptoms within a few weeks. The longer the incubation period the bacterium has in the pharynx, the greater the chance for a rheumatic fever outcome.

Rheumatic fever is first fabricated up from an infection of the pharynx or tonsils by a specific bacterium group A beta- haemolytic Streptococcus. More specifically the strain of bacterium is called Streptococcus pyogenes. This aggressive bacterium grows and initiates the activation of T -effector cells of the innate immune system which then activates plasma cells to produce streptococcal antibodies. As these antigens are identified as foreign proteins in the body, the immune system produces antibodies to bind and eliminate these foreign antigens. The problem itself doesn’t arise from bacteria itself, but from an autoimmune response which allow the created antibodies to attack similar antigens from the heart, joints, skin and nervous system. This can lead to severe complications within its respected disciplines. This is a phenomenon known as molecular mimicry.

Molecular mimicry is a failure of the immune system to recognize self antigens within the body. M protein, a virulent bacterium, known as S. pyogens is an antigen which has similarities to antigens of the certain proteins within the body. Since these proteins are similar, antibodies start to attack the antigens of those proteins instead of the M protein of the bacterium. This is a term which is reffered to as cross reactivity. Whereby, the antibody attacks antigens against a different yet similar antigen. An example of this hypersensitive cross is depicted when antibodies attacks the antigens of the myocardial protein rather than the antigens of the bacterium S. Pyogens.

Severe complications can arise from this which can affect as mentioned earlier.

Rheumatic Fever Page 1

•Rheumatic fever is an immune response to an inflammatory disease that develops as a consequence of a pharyngeal infection with group A beta-hemolytic streptococci. The disease happens with higher frequency and risk of death or impairment in poor countries and especially in the children population. However, only small percentage of children infected children with the GAS develop ARF.

•Even though most of the cases indicate that ARF occur as after the individual’s pharyngitis, further studies are indicating that individuals with skin infection caused by the same bacterial group can also lead to immune reaction.

• The ARF mainly involves the heart, nervous system, the skin, and the joints. If ARF is untreated it gives place to RHD affecting the endocardium, myocardium, or pericardium, and possibly followed later by chronic valvular disease.

•Develop as a consequence of untreated pharyngeal infection by Group A beta-haemolytic Streptococcus o The ARF is a hypersensitivity reaction in which antibodies produced to combat streptococci react and produce lesions at specific tissues sites

o The antigens of group A streptococci bind to receptors in the heart, muscle, brain, and synovial joints, causing an autoimmune response.

oBecause the antigens are similar to the body's own cells, antibodies may attack healthy body cells by mistake. -Being consider the most pathogenic member of Streptococcus, the GAS are beta- haemolytic, gram positive, and extracellular cocci that colonize the throat and skin of their host.

o The GAS is divided in 4 different groups, one of them is the pyogenic group, and its most virulence factors is the M-protein.

o The M-protein has a coiled-coil structure that is adhere in the cell membrane. After an infection the M-protein has a certain type of immunity protection that gives the organisms a greater chance of survival.

o The binding capability of the M-protein to the host protein is what make the GAS so virulent since it is this binding ability what allow GAS to anchor to human cells and to spread through the individual’s body.

-One of the main functions of M-protein is it antiphagocytic ability that results from the M-protein inhibits opsonic function, which is also associated with the ability to bind to the host proteins. Even though the binding mechanism between the M-protein and the host proteins remain unclear, it is good to mention that it plays an important role in the development of ARF.

o Some example of this binding ability is the binding of M-protein to IgA and C4b protein of the host, giving that resistance to phagocytosis to GAS. Even more, the binding between the M-protein and fibrinogen, which also lead to the plasminogen binding.

o The plasminogen forms a cell-bound complex with streptokinase, an enzyme that is produced by hemolytic streptococci that convert plasminogen to plasmin. As a product of this cell-bound complex the plasmin produce a surface that is able to degrade the barriers that limit the bacterial spread; it is this action what facilitate the bacterial spread into the host.

o Additionally to the M-protein and its particular characteristic providing survival for the bacteria, the most dangerous type of GAS also produce a capsule. This capsule provides isolation to the organism, protecting bacteria from oxygen metabolites, creating a barrier around the cell. The encapsulated strains are more associated with severe invasive infections and the delayed complication of ARF.

PAGE 3

Another complication of rheumatic fever is rheumatoid arthritis. Rheumatoid arthritis is inflammation of synovial joints as well as joint destruction. It is believed to be caused by the spreading of S. Pyrogenes to the joints. Chronic rheumatoid arthritis may be caused by the release of p38 MAP kinase from the spinal cord. P38 MAP kinase is released when signals are received in the spinal cord that indicates pain in an area of the body such as the destruction of joints. When this happens, p38 MAPK is released to the area and it creates an inflammatory response to help reduce the pain and cure the problem. But in the case of rheumatoid arthritis, this inflammation actually makes rheumatoid arthritis worse by causing the synovial membrane of the joints to swell. According to a recent article, p38 MAP kinase may be inhibited by the presence of gamma-amino butyric acid (GABA). P38 MAPK is an intermediate in prostaglandin release by activating N-methyl-D-aspartic acid receptors in the spinal cord. It is encoded by the gene known as Mitogen-Activated Protein Kinase 14 (MAPK14) which is found on chromosome 6. MAPK14 is activated by pro-inflammatory cytokines that can be found due to rheumatoid arthritis. The activation of MAPK14 also activates p38 MAPK. The release of prostaglandins causes an inflammatory response as a response to pain. The prostaglandins are up-regulated when MAPK interacts with immunomodulators which increases the inflammatory response. By inhibiting p38 MAPK, prostaglandins cannot be released which would reduce the amount of inflammation caused by pain signals sent due to rheumatoid arthritis. This inhibition can happen when gamma-amino butyric acid is present and causes p38 MAPK to be down-regulated. GABA is the main inhibitor found in the central nervous system and it can be found with p38 when there is an interaction between the immune system and the nervous system. GABA works to reduce inflammation through receptors. Specific receptors, such as GABA-b receptors, release long term inflammatory inhibitors that act on MAPK. When MAPK is inhibited, pro-inflammatory mediators, such as interleukin 1, see reduced levels and therefore due not cause an efficient response that they normally would have had their levels been normal. With this lowered inflammation response, the inflammation in joints is not as great. With the lowering of joint inflammation, rheumatoid arthritis is not as severe. When inflammation is reduced, the synovial membrane of joints does not swell. It is the swelling of the membrane that can cause severe pain and can cause the affected areas to be immobilized or reduce the range of motion. Although GABA does not cure rheumatoid arthritis, it can help in reducing pain and improve the patient’s mobility. If there is a deficiency in GABA, then p38 MAPK will proceed without any type of regulation and severe inflammation will ensue.