Acute rheumatic fever and rheumatic heart disease

Abstract

Acute rheumatic fever (ARF) is the result of an autoimmune response to pharyngitis caused by infection with group A Streptococcus. The long-term damage to cardiac valves caused by ARF, which can result from a single severe episode or from multiple recurrent episodes of the illness, is known as rheumatic heart disease (RHD) and is a notable cause of morbidity and mortality in resource-poor settings around the world. Although our understanding of disease pathogenesis has advanced in recent years, this has not led to dramatic improvements in diagnostic approaches, which are still reliant on clinical features using the Jones Criteria, or treatment practices. Indeed, penicillin has been the mainstay of treatment for decades and there is no other treatment that has been proven to alter the likelihood or the severity of RHD after an episode of ARF. Recent advances - including the use of echocardiographic diagnosis in those with ARF and in screening for early detection of RHD, progress in developing group A streptococcal vaccines and an increased focus on the lived experience of those with RHD and the need to improve quality of life - give cause for optimism that progress will be made in coming years against this neglected disease that affects populations around the world, but is a particular issue for those living in poverty.

Figure 1. The global burden of RHD

Number of prevalent cases of rheumatic heart disease (RHD) in 2013 by country, as well as the change in age-standardized RHD prevalence from 1990 to 2013. Data from REF. . Image courtesy of R. Seth, Telethon Kids Institute, Perth, Australia.

Figure 2. Generation of a cross-reactive immune response in ARF

Following group A Streptococcus (GAS) adhesion to and invasion of the pharyngeal epithelium, GAS antigens activate both B and T cells. Molecular mimicry between GAS group A carbohydrate or serotype-specific M protein and the host heart, brain or joint tissues can lead to an autoimmune response, which causes the major manifestations of acute rheumatic fever (ARF). BCR, B cell receptor; TCR, T cell receptor.

Figure 3. Manifestations of ARF in the joints

Arthritis might be a result of the formation of immune complexes that bind to the synovial membrane and/or collagen in joints, which leads to recruitment of inflammatory cells. ARF, acute rheumatic fever.

Figure 4. Molecular and cellular basis of Sydenham’s chorea

In Sydenham’s chorea, neurons in the basal ganglia are attacked by antibodies against the group A carbohydrate of Streptococcus spp. that react with the surface of the neuron. This reaction activates signalling through calcium/calmodulin-dependent protein kinase type II (CAMK2), which involves an increase in tyrosine hydroxylase in dopaminergic neurons. Receptors, such as the D1 and D2 dopamine receptors, and lysoganglioside might be autoantibody targets on the neuronal cell. This targeting could lead to altered cell signalling and increased levels of dopamine, in turn leading to abnormal movements and behaviours.

Figure 5. Skin manifestations of ARF

Erythema marginatum might be due to antibodies against group A carbohydrates cross-reacting with keratin and subcutaneous nodules might be caused by delayed hypersensitivity against group A streptococcal antigens.

Figure 6. The GAS cross-reactive immune response in the heart

The heart is affected by antibodies (generated by B cells) against the group A carbohydrate binding to the surface of the valve and upregulating vascular cell adhesion molecule 1 (VCAM1) on the surface of the valve endothelium. The upregulation of VCAM1 allows T cells expressing integrin α4β1 (also known as VLA4) to adhere to the endothelium and to extravasate into the valve. The inner valve becomes infiltrated by T cells, primarily CD4⁺ T cells, and Aschoff bodies or granulomatous lesions form underneath the endocardium. Damage to the endothelium and infiltration of T cells into the valve remodels the valve structure, including the chordae tendineae, with malformation of the valve leading to regurgitation or stenosis of the valve. Breakdown of the valve releases collagen and results in further immune-mediated damage to the valve.

Figure 7. Localization of Sydenham’s chorea-derived antibodies and tyrosine hydroxylase in the brains of transgenic mice

Transgenic mice are shown in which genes encoding variable segments of a human monoclonal antibody derived from a patient with Sydenham’s chorea are expressed. The resulting antibodies target the dopaminergic neurons in these mice, showing that these antibodies cross the blood–brain–barrier to target the neurons. a | Antibody penetration of basal ganglia and neurons in the substantia nigra or ventral tegumental area. Neurons are stained in green with an antibody specific for the transgenic chorea IgG1a antibody. b | Dopaminergic neurons are labelled in red using a tyrosine hydroxylase-specific antibody. c | Merged frames show the transgenic chorea antibodies target cells that express tyrosine hydroxylase. Magnification 20×. Images are reproduced, with permission, from REF. © (2014) Taylor & Francis.

Figure 8. Expression of VCAM1 by the valvular endothelium

Immunohistochemistry of the valvular endothelium in the context of acute rheumatic fever and valvulitis is shown. Vascular cell adhesion protein 1 (VCAM1) has been labelled with an VCAM1-specific monoclonal antibody (mAb) (red). The VCAM1-specifc mAb reacted with the rheumatic valvular endothelium but not with the normal valve (not shown). That is, the antibody to anti-VCAM1 is conjugated to alkaline phosphatase and developed with fast red indicated binding of the antibody to VCAM1. Original magnification 400×. Image is modified, with permission, from REF. © (2001) Oxford Journals.

Figure 9. Immunohistochemistry of infiltration of CD4⁺ T cells into the valve of the left atrium in ARF

In acute rheumatic fever (ARF), CD4⁺ T cells cross the valvular endothelium and infiltrate into the subendocardium, where they are involved in the formation of Aschoff’s bodies. a | An Aschoff body, with CD4⁺ T cells in the valve (red, indicated with arrows) labelled with a primary monoclonal antibody against CD4, secondary antibody against human IgG and fast red. b | An IgG1 isotype control did not react with the rheumatic valve. CD4⁺ T cells are stained with the CD4-specific mAb, a secondary antibody conjugated to alkaline phosphatase and development with fast red to detect antibody binding to CD4⁺ T cells. Magnification 200×. Image is modified, with permission, from REF. © (2001) American Society for Microbiology.

Figure 10. Echocardiogram from child with severe mitral regurgitation

This echocardiogram was produced as part of an echocardiography screening programme. a | Apical four-chamber view in black and white Doppler. b | Apical four-chamber view in colour Doppler. The colour jet extends to the back of the left atrium. c | A parasternal long-axis view. The mitral valve is thickened with excessive leaflet tip motion and lack of coaptation. The left atrium is severely dilated and the left ventricle is moderately dilated. d | Pan-systolic spectral Doppler of mitral regurgitation. LA, left atrium; LV, left ventricle; P, pressure; V, volume.

Figure 11. Echocardiogram from child with severe mitral stenosis

This echocardiogram was produced as part of an echocardiography screening programme. a | Apical four-chamber view in black and white Doppler. b | Apical four-chamber view in colour Doppler. The colour jet reveals turbulence in diastole. c | A parasternal long-axis view. The mitral valve is thickened with limited motion and the chordae are thickened and fused. The left atrium is severely dilated. d | Pan-diastolic spectral Doppler of with severe mitral stenosis mean gradient (mean 21 mmHg). Env. Ti, envelope time; HR, heart rate; LA, left atrium; LV, left ventricle; Pmax, maximum pressure gradient; Pmean, mean pressure gradient; Vmax, maximum velocity; VTI, velocity time integral.