T cell and B cell responses in a rat model of rheumatic heart disease

Gorton, Davina (2009) T cell and B cell responses in a rat model of rheumatic heart disease. PhD thesis, James Cook University.

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Abstract

Rheumatic fever (RF) is an inflammatory disease following group A streptococcal (GAS) infection which affects the joints, skin, central nervous system and heart in susceptible individuals. Rheumatic heart disease (RHD) accounts for the majority of acquired heart disease in children and young adults in many parts of the world and is the most serious manifestation of RF. Rarely seen now in most developed nations, RF/RHD remains an important medical and economic public health problem in many developing countries and also in certain indigenous populations within developed nations.

It is known that permanent cardiac damage can manifest after prolonged or repeated episodes of RF or during a severe acute episode. Although all layers of the heart, that is the pericardium, myocardium and endocardium, can be affected, it is the loss of function of the heart valves that is associated with rheumatic carditis. The aetiology of RF/RHD is believed to be autoimmune, whereby an aberrant immune response against GAS cross-reacts with host tissue proteins through molecular mimicry. Studies have implicated mimicry between the GAS M protein, an alpha helical coiled-coil extending from the surface of the bacterium and host tissue proteins such as cardiac myosin. However, despite decades of intensive investigation, the exact pathogenic mechanism(s) involved in initiating disease remains elusive.

In this thesis the cellular and antibody responses elicited in the rat autoimmune valvulitis (RAV) model, were investigated. The RAV animal model may, in part, represent rheumatic carditis in humans. Rats immunised with recombinant streptococcal M5 protein (rM5) developed valvular lesions, distinguished by infiltration of CD3+, CD4+ and CD68+ cells into valve tissue but few CD8+ cells, consistent with human studies that suggest RF/RHD are mediated by inflammatory CD4+ T cells and macrophages.

It will be shown herein that rM5 elicits strong T cell and opsonic IgG antibody immune responses in rats. Immunisation experiments using peptides from the B-repeat and C-repeat regions of streptococcal M5 identified one B-repeat peptide (M5-B.6, amino acids TVKDKIAKEQENKETIGTIK) that contains a strong T cell epitope and a probable cardiac myosin cross-reactive epitope with the capacity to induce valvular lesions in rats.

Additional experiments were carried out to investigate the immune responses in rats as a result of repetitive immunisation with rM5 protein. Higher T cell and B cell responses with exacerbation of inflammatory changes in heart tissue and prolongation of P-R interval on ECG, in addition to increased IgG cardiac myosin cross-recognition, was demonstrated in rats which received additional booster immunisations with rM5 protein.

Alternative adjuvants and immunisation strategies were also investigated in the current study. A replacement for Freund’s complete adjuvant (FCA) was not found in the alternative formulations tested in this study, however in the RAV model, hock immunisation was demonstrated to be superior to the footpad route of immunisation when using FCA. Hock immunisation is shown to elicit less inflammation and pain in the animals whilst maintaining the desired immune responses.

Thus, the data demonstrate that the RAV model displays many of the characteristics of human rheumatic heart disease and thus, is an invaluable tool for studying the immunopathogenic mechanisms involved in RF/RHD.

Item ID: 10985
Item Type: Thesis (PhD)
Keywords: T-cells, B-cells, rat models, rheumatic heart disease, rheumatic fever, rheumatic pathogenesis, cardiac valve damage, rheumatic carditis, heart valves and rheumatism, autoimmunity
Date Deposited: 26 May 2010 23:54
FoR Codes: 07 AGRICULTURAL AND VETERINARY SCIENCES > 0707 Veterinary Sciences > 070705 Veterinary Immunology @ 50%
11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110201 Cardiology (incl Cardiovascular Diseases) @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%
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