Pathophysiology

Pathophysiology of rheumatic heart disease

Micrograph showing an Aschoff body (right of image), as seen in rheumatic heart disease. H&E stain.

Rheumatic fever is a systemic disease affecting the peri-arteriolar connective tissue and can occur after
an untreated Group A Beta hemolytic streptococcal pharyngeal 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 presenting cells such as B cells present the
bacterial antigen to CD4-T cells which differentiate into helper T2 cells. Helper T2 cells subsequently
activate the B cells to become plasma cells and induce the production of antibodies against the cell wall
of Streptococcus. However the antibodies may also react against the myocardium and joints,[10]
producing the symptoms of rheumatic fever.

Group A streptococcus pyogenes has a cell wall composed of branched polymers which sometimes
contain M protein that are highly antigenic. The antibodies which the immune system generates against
the M protein may cross react with cardiac myofiber protein myosin,[11] heart muscle glycogen and
smooth muscle cells of arteries, inducing cytokine release and tissue destruction. However, the only
proven cross reaction is with perivascular connective tissue.[citation needed] This inflammation occurs
through direct attachment of complement and Fc receptor-mediated recruitment of neutrophils and
macrophages. Characteristic Aschoff bodies, composed of swollen eosinophilic collagen surrounded by
lymphocytes and macrophages 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-helper cells and macrophages.[12]

In acute rheumatic fever, these lesions can be found in any layer of the heart and is hence called
pancarditis. The inflammation may cause a serofibrinous pericardial exudate described as "bread-and-
butter" pericarditis, which usually resolves without sequelae. Involvement of the endocardium typically
results in fibrinoid 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

Chronic rheumatic heart disease (RHD) is characterized by repeated inflammation with fibrinous
resolution. The cardinal anatomic changes of the valve include leaflet thickening, commissural fusion,
and shortening and thickening of the tendinous cords.[12] It is caused by an autoimmune reaction to
Group A -hemolytic streptococci (GAS) that results in valvular damage.[13] Fibrosis and scarring of
valve leaflets, commissures and cusps leads to abnormalities that can result in valve stenosis or
regurgitation.[14] The inflammation caused by rheumatic fever, usually during childhood, is referred to
as rheumatic valvulitis. About half of patients with acute rheumatic fever develop inflammation
involving valvular endothelium.[15] The majority of morbidity and mortality associated with rheumatic
fever is caused by its destructive effects on cardiac valve tissue.[14] The pathogenesis of RHD is complex
and not fully understood, but it is known to involve molecular mimicry and genetic predisposition that
lead to autoimmune reactions.

Molecular mimicry occurs when epitopes are shared between host antigens and GAS antigens.[16] This
causes an autoimmune reaction against native tissues in the heart that are incorrectly recognized as
"foreign" due to the cross-reactivity of antibodies generated as a result of epitope sharing. The valvular
endothelium is a prominent site of lymphocyte-induced damage. CD4+ T cells are the major effectors of
heart tissue autoimmune reactions in RHD.[17] Normally, T cell activation is triggered by the
presentation of GAS antigens. In RHD, molecular mimicry results in incorrect T cell activation, and these
T lymphocytes can go on to activate B cells, which will begin to produce self-antigen-specific antibodies.
This leads to an immune response attack mounted against tissues in the heart that have been
misidentified as pathogens. Rheumatic valves display increased expression of VCAM-1, a protein that
mediates the adhesion of lymphocytes.[18] Self-antigen-specific antibodies generated via molecular
mimicry between human proteins and GAS antigens up-regulate VCAM-1 after binding to the valvular
endothelium. This leads to the inflammation and valve scarring observed in rheumatic valvulitis, mainly
due to CD4+ T cell infiltration.[18]

While the mechanisms of genetic predisposition remain unclear, a few genetic factors have been found
to increase susceptibility to autoimmune reactions in RHD. The dominant contributors are a component
of MHC class II molecules, found on lymphocytes and antigen-presenting cells, specifically the DR and
DQ alleles on human chromosome 6.[19] Certain allele combinations appear to increase RHD
autoimmune susceptibility. Human leukocyte antigen (HLA) class II allele DR7 (HLA-DR7) is most often
associated with RHD, and its combination with certain DQ alleles is seemingly associated with the
development of valvular lesions.[19] The mechanism by which MHC class II molecules increase a host's
susceptibility to autoimmune reactions in RHD is unknown, but it is likely related to the role HLA
molecules play in presenting antigens to T cell receptors, thus triggering an immune response. Also
found on human chromosome 6 is the cytokine TNF- which is also associated with RHD.[19] High
expression levels of TNF- may exacerbate valvular tissue inflammation, contributing to RHD
pathogenesis. Mannose-binding lectin (MBL) is an inflammatory protein involved in pathogen
recognition. Different variants of MBL2 gene regions are associated in RHD. RHD-induced mitral valve
stenosis has been associated with MBL2 alleles encoding for high production of MBL.[20] Aortic valve
regurgitation in RHD patients has been associated with different MBL2 alleles that encode for low
production of MBL.[21] Other genes are also being investigated to better understand the complexity of
autoimmune reactions that occur in

Pathophysiology

The pathogenic mechanisms of ARF are not completely understood. Studies of the pathogenesis of ARF
have been constrained by the lack of a highly suitable animal model, although a Lewis rat model of
valvulitis and chorea has been used for some time (Quinn, Kosanke, Fischetti, Factor, & Cunningham,
2001; Brimberg, et al., 2012). In order for ARF to occur, it appears that a pharyngeal infection caused by
S. pyogenes must occur in a host with a genetic susceptibility to the disease (Denny, Wannamaker,
Brink, Rammelkamp, & Custer, 1950; Bryant, Robins-Browne, Carapetis, & Curtis, 2009).
Activation of the innate immune system begins with a pharyngeal infection that leads to the
presentation of S. pyogenes antigens to T and B cells. CD4+ T cells are activated and production of
specific IgG and IgM antibody by B cells ensues (Cunningham, Pathogenesis of group A streptococcal
infections, 2000). Tissue injury is mediated through an immune-mediated mechanism that is initiated via
molecular mimicry (Guilherme, Kalil, & Cunningham, 2006). Structural similarity between the infectious
agent and human proteins leads to the cross-activation of antibodies and/or T cells directed against
human proteins (Cunningham, 2000)..In ARF, this cross-reactive immune response results in the clinical
features of rheumatic fever, including carditis, due to antibody binding and infiltration of T cells;
transient arthritis, due to the formation of immune complexes; chorea, due to the binding of antibodies
to basal ganglia; and skin manifestations, due to a delayed hypersensitivity reaction (Figure 1; Carapetis,
et al., 2016).

Figure 1. . Overview of the pathogenesis of acute rheumatic fever (GAS: group A Streptococcus; BCR: B
cell receptor; TCR: T cell receptor) Figure reproduced with permission from (Carapetis, et al.

Figure 1.

Overview of the pathogenesis of acute rheumatic fever (GAS: group A Streptococcus; BCR: B cell
receptor; TCR: T cell receptor) Figure reproduced with permission from (Carapetis, et al., 2016).

Molecular mimicry

There are a number of lines of evidence that suggest molecular mimicry plays a role in the development
of carditis by stimulating both humoral and cellular cross-reactive immune responses (Cunningham,
2000; Guilherme, Kalil, & Cunningham, 2006; Cunningham, et al., 1992). The alpha-helical protein
structures found in M protein and N-acetyl-beta-D-glucosamine (the carbohydrate antigen of S.
pyogenes) share epitopes with myosin, and antibodies against both of these antigens cross-react against
human tissues (Galvin, Hemric, & Cunningham, 2000). Monoclonal antibodies generated from tonsillar
or peripheral blood lymphocytes of patients infected with S. pyogenes cross-react with myosin
(Cunningham, 2000; Cunningham, et al., 1988). Monoclonal antibodies directed against myosin and N-
acetyl-beta-D-glucosamine isolated react against human valvular endothelium in patients with
rheumatic fever (Cunningham, et al., 1988). In a Lewis rat model, immunization with recombinant
streptococcal M protein type 6 led to development valvulitis (Quinn, Kosanke, Fischetti, Factor, &
Cunningham, 2001).

Human heart intralesional T cell clones react against cardiac tissues, including myosin and valve-derived
proteins (Fa, et al., 2006). Autoreactive T cells appear to play an important role in granulomatous
inflammation in cardiac valves. Vascular cell adhesion molecule 1 may be the link between humoral and
cellular immunity at the valve surface (Figure 2; Roberts, Kosanke, Terrence Dunn, Jankelow, Duran, &
Cunningham, 2001). Vascular cell adhesion molecule 1 is upregulated at the valve endothelium surface
as a result of binding of cross-reactive antibodies. This leads to adherence of CD4+ T cells to the
endothelium, with subsequent infiltration of these cells into the valve. The T-cells initiate a
predominantly TH1 response with the release of -IFN. Inflammation leads to neovascularization, which
allows further recruitment of T-cells. Epitope spreading may occur in the valve, where T-cells respond
against other cardiac proteins such as vimentin and tropomyosin and lead to the formation of
granulomatous lesions underneath the endocardium