Pathophysiology

Rheumatic fever is a systemic disease affecting the peri-arteriolar connective t

issue and can occur after an untreated Group A Beta hemolytic streptococcal phar
yngeal infection. It is believed to be caused by antibody cross-reactivity. This
cross-reactivity is a Type II hypersensitivity reaction and is termed molecular
mimicry. Usually, self reactive B cells remain anergic in the periphery without
T cell co-stimulation. During a Streptococcus infection, mature antigen present
ing cells such as B cells present the bacterial antigen to CD4+T cells which dif
ferentiate into helper T2 cells. Helper T2 cells subsequently activate the B cel
ls to become plasma cells and induce the production of antibodies against the ce
ll wall of Streptococcus. However the antibodies may also react against the myoc
ardium and joints,[10] producing the symptoms of rheumatic fever.
Group A Streptococcus pyogenes has a cell wall composed of branched polymers whi
ch sometimes contain M protein that are highly antigenic. The antibodies which t
he immune system generates against the M protein may cross react with cardiac my
ofiber protein myosin,[11] heart muscle glycogen and smooth muscle cells of arte
ries, inducing cytokine release and tissue destruction. However, the only proven
cross reaction is with perivascular connective tissue.[citation needed] This in
flammation occurs through direct attachment of complement and Fc receptor-mediat
ed recruitment of neutrophils and macrophages. Characteristic Aschoff bodies, co
mposed of swollen eosinophilic collagen surrounded by lymphocytes and macrophage
s can be seen on light microscopy. The larger macrophages may become Anitschkow
cells or Aschoff giant cells. Acute rheumatic valvular lesions may also involve
a cell-mediated immunity reaction as these lesions predominantly contain T-helpe
r cells and macrophages.[12]
In acute rheumatic fever, these lesions can be found in any layer of the heart a
nd is hence called pancarditis. The inflammation may cause a serofibrinous peric
ardial exudate described as "bread-and-butter" pericarditis, which usually resol
ves without sequelae. Involvement of the endocardium typically results in fibrin
oid necrosis and verrucae formation along the lines of closure of the left-sided
heart valves. Warty projections arise from the deposition, while subendocardial
lesions may induce irregular thickenings called MacCallum plaques.
Rheumatic heart disease
Pathophysiology of rheumatic heart disease
Micrograph showing an Aschoff body (right of image), as seen in rheumatic heart
disease. H&E stain.
Chronic rheumatic heart disease (RHD) is characterized by repeated inflammation
with fibrinous repair. The cardinal anatomic changes of the valve include leafle
t thickening, commissural fusion, and shortening and thickening of the tendinous
cords.[12] It is caused by an autoimmune reaction to Group A -hemolytic streptoc
occi (GAS) that results in valvular damage.[13] Fi rosis and scarring of valve l
eaflets, commissures and cusps leads to a normalities that can result in valve s
tenosis or regurgitation.[14] The inflammation caused y rheumatic fever, usuall
y during childhood, is referred to as rheumatic valvulitis. A out half of patien
ts with acute rheumatic fever develop inflammation involving valvular endotheliu
m.[15] The majority of mor idity and mortality associated with rheumatic fever i
s caused y its destructive effects on cardiac valve tissue.[14] The pathogenesi
s of RHD is complex and not fully understood, ut it is known to involve molecul
ar mimicry and genetic predisposition that lead to autoimmune reactions.
Molecular mimicry occurs when epitopes are shared etween host antigens and GAS
antigens.[16] This causes an autoimmune reaction against native tissues in the h
eart that are incorrectly recognized as "foreign" due to the cross-reactivity of
anti odies generated as a result of epitope sharing. The valvular endothelium i
s a prominent site of lymphocyte-induced damage. CD4+ T cells are the major effe

ctors of heart tissue autoimmune reactions in RHD.[17] Normally, T cell activati

on is triggered y the presentation of GAS antigens. In RHD, molecular mimicry r
esults in incorrect T cell activation, and these T lymphocytes can go on to acti
vate B cells, which will egin to produce self-antigen-specific anti odies. This
leads to an immune response attack mounted against tissues in the heart that ha
ve een misidentified as pathogens. Rheumatic valves display increased expressio
n of VCAM-1, a protein that mediates the adhesion of lymphocytes.[18] Self-antig
en-specific anti odies generated via molecular mimicry etween human proteins an
d GAS antigens up-regulate VCAM-1 after inding to the valvular endothelium. Thi
s leads to the inflammation and valve scarring o served in rheumatic valvulitis,
mainly due to CD4+ T cell infiltration.[18]
While the mechanisms of genetic predisposition remain unclear, a few genetic fac
tors have een found to increase suscepti ility to autoimmune reactions in RHD.
The dominant contri utors are a component of MHC class II molecules, found on ly
mphocytes and antigen-presenting cells, specifically the DR and DQ alleles on hu
man chromosome 6.[19] Certain allele com inations appear to increase RHD autoimm
une suscepti ility. Human leukocyte antigen (HLA) class II allele DR7 (HLA-DR7)
is most often associated with RHD, and its com ination with certain DQ alleles i
s seemingly associated with the development of valvular lesions.[19] The mechani
sm y which MHC class II molecules increase a host's suscepti ility to autoimmun
e reactions in RHD is unknown, ut it is likely related to the role HLA molecule
s play in presenting antigens to T cell receptors, thus triggering an immune res
ponse. Also found on human chromosome 6 is the cytokine TNF- which is
lso
ssoci

ted with RHD.[19] High expression levels of TNF- m
y ex
cerb
te v
lvul
r tissue
infl
mm
tion, contributing to RHD p
thogenesis. M
nnose-binding lectin (MBL) is

n infl
mm
tory protein involved in p
thogen recognition. Different v
ri
nts of
MBL2 gene regions
re
ssoci
ted in RHD. RHD-induced mitr
l v
lve stenosis h
s b
een
ssoci
ted with MBL2
lleles encoding for high production of MBL.[20] Aortic
v
lve regurgit
tion in RHD p
tients h
s been
ssoci
ted with different MBL2
ll
eles th
t encode for low production of MBL.[21] Other genes
re
lso being inves
tig
ted to better underst
nd the complexity of
utoimmune re
ctions th
t occur i
n RHD.
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tic_fever
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