Chlamydia ¡§ Infection and Heart Disease Linked Through Antigenic Mimicry.¡¨ Kurt Bachmaier

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Chlamydia ¡§ Infection and Heart Disease Linked Through Antigenic Mimicry.¡¨ Kurt Bachmaier

Nalin Perera

MCDB 167

Cheap University Papers on Chlamydia ¡§ Infection and Heart Disease Linked Through Antigenic Mimicry.¡¨ Kurt Bachmaier

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INTRODUCTION

Evolution of microbes has provided some advance features for them to adopt to their surrounding environment. One of these features is that their ability to disguise themselves as the host to survive from possible immunological responses. Due to this mimicry, immune cells can mistakenly act on bodys own tissues. This is believed to be the way of getting inflammatory heart disease following Chlamydia infection. Chlamydia pathogen makes a peptide that mimics a portion of a heart muscle specific myosin peptide. This bacterial protein causes CD4+ T cells to recognize heart muscle specific peptide in association with MHC class II molecules and attack the heart muscle causing a severe inflammation. Eventhough the exact mechanism which this inflammation occurs is unknown, amino acid segment that causes for the disease in mice and human have been identified.

METHOD AND RESULTS

BALB/c mice were immunized with 0 amino acid peptide of the cardiac specific �myosin heavy chain molecule [��mhc (amino acid 614 to 64)] and this caused to induce a severe inflammatory heart disease in those mice. Induction of disease from first 16 amino acids of �myosin heavy chain [��mhc (614-6)] , designated as M7A��, was compared with the homologous region of �myosin heavy chain isoform, designated as M7A��, and no induction of the disease by the of �myosin heavy chain isoform was observed (See Table 1 and Fig 1A & 1B. Substitution of single amino acid into M7A�amino acid residues xxxxMAxxxSTxxxxx ( x is any amino acid) were important for the pathogenacity of M7A�in vivo. Disease was induced when homologue human M7A�was injected into BALB/c mice. This showed that the conservation of immunogenic amino acids between human and mice �myosin heavy chains. Homologous peptide sequences from the 60 kD Cysteine-rich outer membrane protein (CRP) from different serovars of Chlamydia trachomatis [designated as ChTR1(serovar E), ChTR (serovar C)and ChTR ( serovar L1,L & L)] as well as C. Pneumoniae (ChPN) and C. Psittaci (ChPS) were screened ( Table 1). There were no other conserved regions found on the primary sequences besides MAxxxST motif in all screened samples.

To test the antigenic mimicry between Chlamydia peptide and M7A�for antigen induced inflammatory heart disease, BALB/c mice were immunized with murine M7A�or homologous 60-kD CRP p11-derived peptides in Freunds complete adjuvant (FCA). This experiment showed that all of the Chlamydia derived peptides induced myocarditis comparably lower severity when compare with M7A��-immunized mice but they all occurred at a similar frequency (Table 1).

Immunohistochemical characterization showed that inflammatory infiltrate in ChTR1 peptide induced heart disease was similar to cardiac myosin and cardiac myosin induced myocarditis and consisted of about 11% CD4+ and 1% CD8+ T cells, 16% B0+ B cells and 61% CD11b+ macrophages ( Fig 1).

Possible inflammation on heart that could caused by peptide sequences which were responsible for inflammating other vital organs such as Liver, Lungs, Kidneys etc. was tested by injecting mice either with human immunodeficiency virus- [gp 160(71-8), INFIGPGKGSPDE] or parainfluenza virus 1 [HT8b hemagglutinin-neuraminidase (1-0), DLVFDILDLKGKTKSPRYK]derived peptide which shared homology with other immunogenic regions of the mouse

��mhc molecule [��mhc (75-747), GQFIDSGKGAEKL, and ��mhc (14-), DSAFDVLSFTAEEKAGVYK]. This test did not induce inflammatory heart disease.

One another experiment was conducted to test the mimicry between cardiac specific peptide and Chlamydia derived peptides which was indirectly confirmed the peptides other than M7A�did not responsible for myocarditis. BALB/c mice were immunized with M7A��, ChTR1 or another cardiac specific ��mhc-derived peptide (designated as kk�and it was restricted to I-Ak MHC class II molecules). kk�immunization induced myocarditis in A/J (I-Ak) mice but not in BALB/c (I-Ad) mice. 8 days after the immunization with M7A�or ChTR1, but not kk�alone, splenomegaly occurred and also increase the count of TCR ����+ CD4+ T cells, B0+B cells and CD11b+ macrophages. Also, splenic T cells proliferated strongly upon incubation of splenocytes with either M7A�or ChTR1 (Fig A). But this proliferation did not occur when �×-irradiated splenocytes incubated with non-pathogenic kk�peptide. This experiment was further expanded as follows

- splenic T cells were proliferated to ChTR1 and M7A�when mice immunized with ChTR1. But this proliferation did not occur when mice were immunized with FCA. This proved that ChTR1 peptide immunization can cross-primed for T cell reactivity against the endogenous M7A��.

Another experiment was conducted to identify the epitope spreading. In case of autoimmune myocarditis, T-cell dependent autoantibodies are produced against cardiac epitopes. Immunization with M7A�induced the production of serum antibodies for disease inducting M7A�peptide, ChTR1 peptide and kk�peptide. When mice immunized with ChTR1 peptide, the same response was observed. This conclude that, in both cases, it caused epitope spread at B cell level. Chlamydia infection occur in Lungs and reproductive organs. FCA was used as a potent immunoactivator in the experimental model which was design to identify how the infection on these organs induce myocarditis. A test was done find whether bacterial DNA-derived synthetic oligodeoxynucleotides (ODNs) containing unmethylated CpG islands could act as adjuvant for peptide mediated autoimmunity. ODNs containing various synthetic CpG motif has the ability to trigger autoimmune myocarditis in M7A�peptide immunized BLBA/c mice (Table and Fig 1F). Immunization of BALB/c mice with a CpG ODN derived from the C. Trachomatis CRP gene plus the M7A�autoantigen induced myocarditis in the absence of FCA (Table and Fig 1F). Immunization in which a control non-CpG ODN was used plus peptide did not induce disease ( Table ). Thus, CpG containing Chlamydia DNA can function as potent immunoactivator for autoimmunity.

Mice immunized with Chlamydia peptide, developed perivascular fibrosis (Fig A & B), fibrinous occlusions of cardiac blood vessels (Fig C & D) and thickening the arterial walls. Endothelium originated ), fibrinous occlusion in blood vessels occurred 60% (sample size )when mice immunized with Chlamydia peptides and 67% when immunized with M7A��. This situation did not observed when they were immunized only with FCA.

Activation of autoaggressive T and B cells were detected following Chlamydia infection. BALB/c mice, infected with C. trochomatis through respiratory track and reproductive organs, developed production of IgG antibodies to heart specific epitopes (Fig 4). Since the production of IgG antibodies to heart specific epitopes depend on the activation of T and B cells, this experiment provided proof for activation of autoaggressive lymphocytes in BALB/c mice caused by infection of C. Trachomatis.

SIGNIFICANCE

When carefully study these experimental results, it can be seen that Chlamydia peptides mimic the effect of ��mhc derived epitopes in heart muscle and autoaggressive T cells that were activated in respiratory tract and reproductive organs, could caused organ specific inflammation in the heart. Due to these reasons, it can be concluded that the Chlamydia DNA act as a potent adjuvant which facilitate the activation of autoaggressive T cells.

Chlamydia infection is very common in human population but not every person experience myocarditis, caused by the infection. This is due to genetic differences and other risk factors such as smocking, high blood cholesterol which influence to the body¡¦s response to Chlamydia infection.

These experimental results leads to an another conclusion which is all three Chlamydia species, that the researchers mentioned, cause infections leads to antigenic mimicry of autoaggressive myosin epitopes by peptides. Bacterial infection initiate the disease and then inflammation is maintained by epitope spreading.

Chlamydia infection leads to the production of inflammatory cytokines, bystrand activation of lymphocytes or both. This could also link to initiate the cardiovascular disease. All the in vivo and in vitro evidence of antigenic mimicry between Chlamydia peptides and heart specific peptides, provided from these experiments prove that the Chlamydia peptides has the ability cause inflammatory heart disease.

REFERENCES

1. Chlamydia ¡§ Infection and Heart Disease Linked Through Antigenic Mimicry.¡¨ Kurt Bachmaier et al. Science 8 18-, 15- (1)

. Immunology,rd ed.17, Janis Kuby

. Chlamydia as Pathogens ¡§New Species and New Issues.¡¨ Rosanna W. Peeling, www.cdc.gov/ncidod/EID/volno4

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