Chlamydia pneumoniae infection, inflammation and heat shock protein 60 immunity in asthma and coronary heart disease

Tiina Sävykoski (née Huittinen)

National Public Health Institute, Department of Microbiology
Department of Medical Microbiology, University of Oulu

Abstract

Chlamydia pneumoniae is a common respiratory pathogen worldwide. It does not only cause acute respiratory infections, but is also associated with chronic inflammatory diseases, such as asthma and coronary heart disease (CHD). Chlamydial heat shock protein 60 (Hsp60) is associated with the development of immunopathological damage following C. trachomatis infections, but the role of Hsp60 in C. pneumoniae infections is unclear. A slightly elevated level of C-reactive protein (CRP), as a marker of systemic inflammation, predicts cardiovascular events, but its role in asthma has not been studied. The aim of this study was to develop an EIA method for the measurement of Hsp60 antibodies and for studying the host immune responses to C. pneumoniae and chlamydial and human Hsp60 proteins, CRP levels and their interactions in asthma and CHD.

Elevated levels of serum IgA antibodies to the Hsp60 protein of C. pneumoniae were associated with asthma and decreased pulmonary function. CRP levels were also higher in the asthma patients than in the controls. The patients with moderate asthma had higher CRP levels than those with mild asthma. The patients with a CRP level over 2 mg/l had higher levels of serum IgA antibodies to C. pneumoniae and chlamydial Hsp60 than the patients with lower CRP levels.

A prospective nested case-control study was carried out, to study the role of Hsp60 antibodies as coronary risk predictors, and their association with C. pneumoniae infection and inflammation. The participants were obtained from the Helsinki Heart Study: 241 myocardial infarctions or coronary deaths occurred during the 8.5-year period among dyslipidemic middle-aged men. An elevated level of human Hsp60 IgA antibodies in baseline serum predicted the occurrence of a coronary event several years later, especially when present simultaneously with a high C. pneumoniae IgA antibody level and an elevated CRP level. Further studies showed that only persistently, not transiently, elevated levels predicted coronary events. The risk associated with elevated antibody levels increased markedly in the presence of an elevated CRP level, and vice versa.

In conclusion, these results suggest that chlamydial Hsp60 is involved in the association between C. pneumoniae infection and asthma, while autoimmunity to human Hsp60 is implicated in the association between C. pneumoniae infection and CHD. Inflammation evidently plays an important role in these associations. It can also be concluded that IgA antibodies, compared to IgG antibodies, against C. pneumoniae and Hsp60 are better markers of chronicity, especially when they are persistently elevated.

Dedication

To my beloved ones

Table of Contents

Acknowledgements

Abbreviations

List of original publications

1. Introduction

2. Review of the literature

2.1. Heat shock proteins

2.1.1. History
2.1.2. Heat shock response
2.1.3. Heat shock protein families
2.1.4. Physiological functions
2.1.5. Immunology

2.2. Chlamydia pneumoniae

2.2.1. Taxonomy
2.2.2. History
2.2.3. Developmental cycle
2.2.4. Structure
2.2.5. Pathogenesis
2.2.6. Epidemiology
2.2.7. Clinical manifestations
2.2.8. Diagnosis
2.2.9. Treatment

2.3. Asthma

2.3.1. Definition
2.3.2. Risk factors
2.3.3. Asthma and respiratory infections
2.3.4. Diagnosis and treatment
2.3.5. Epidemiology

2.4. Atherosclerosis

2.4.1. Definition
2.4.2. Risk factors
2.4.3. Atherosclerosis — an inflammatory disease
2.4.4. Atherosclerosis as an autoimmune disease
2.4.5. Atherosclerosis as an infectious disease
2.4.6. Diagnosis and treatment
2.4.7. Epidemiology

3. Aims of the study

4. Materials and methods

4.1. Study populations

4.1.1. Asthma studies (I, II)
4.1.2. Helsinki Heart Study (III, IV)

4.2. Laboratory methods

4.2.1. Sputum induction (II)
4.2.2. Isolation of C. pneumoniae immune complexes (IV)
4.2.3. Measurement of C. pneumoniae antibodies (I–IV)
4.2.4. Hsp60 preparations and measurement of Hsp60 antibodies (I–IV)
4.2.5. Measurement of C-reactive protein concentration (II–IV)

4.3. Statistical analyses

5.1. Association of antibodies to Hsp60 and C. pneumoniae and CRP level with asthma

5.1.1. Correlation between Hsp60 and C. pneumoniae antibodies (I, II)
5.1.2. Association between C. pneumoniae infection and asthma (I, II)
5.1.3. Association between Hsp60 antibodies and asthma (I, II)
5.1.4. Hsp60 antibodies and pulmonary function (I)
5.1.5. Role of C-reactive protein (II)

5.2. Association of antibodies to Hsp60 and C. pneumoniae and CRP level with CHD

5.2.1. Associations between the risk factors at baseline (III)
5.2.2. Univariate and joint effects on coronary risk at baseline (III)
5.2.3. Role of smoking (III)
5.2.4. Prevalence of persistent risk factors (IV)
5.2.5. Univariate and joint effects of persistence of risk factors on coronary risk (IV)

6. Discussion

6.1. Methods

6.2. Study populations

6.3. Major findings

6.3.1. Immune response to chlamydial Hsp60, C. pneumoniae infection and inflammation in adults with asthma
6.3.2. Immune response to human Hsp60, C. pneumoniae infection and inflammation in predicting coronary risk

7. Conclusions

List of Tables
1. Immune response to Hsp in infectious diseases
2. Immune response to Hsp in human autoimmune diseases
3. The family Chlamydiaceae as proposed by Everett et al. (1999)
4. Acute and chronic diseases associated with C. pneumoniae
5. Laboratory methods for diagnosing C. pneumoniae infection
6. Characteristics of asthma patients and controls
7. Characteristics of asthma patients and controls
8. Characteristics of the Helsinki Heart Study cases and controls
9. Levels of IgA and IgG antibodies to C. pneumoniae and chlamydial Hsp60 among asthma and control participants with and without CRP level 2 mg/l
10. Associations between the levels of a) C. pneumoniae IgA antibodies and human Hsp60 IgA antibodies and b) human Hsp60 IgA antibodies and CRP concentration
11. ORs for coronary events by quartiles of IgA antibodies to human Hsp60, C. pneumoniae Hsp60 and C. pneumoniae and concentration of CRP
12. ORs for coronary events by combined levels of CRP concentration and IgA antibodies to C. pneumoniae and human Hsp60
13. ORs for coronary events by combined levels of smoking and IgA antibodies to human Hsp60
14. Effect of persistently elevated levels of C. pneumoniae IC/IgA and human Hsp60 IgA antibodies and CRP concentration on the ORs of coronary events
15. Importance of persistence of the combined risk factors (C. pneumoniae IC/IgA and human Hsp60 IgA antibodies and CRP concentration) measured in terms of ORs of coronary events
16. Role of CRP in the association between persistently elevated levels of C. pneumoniae IC/IgA and human Hsp60 IgA antibodies and the coronary risk

List of Figures
1. A model of the heat shock response (modified after: Morimoto 1993)
2. Developmental cycle of Chlamydia (modified after: Beatty et al. 1994b)
3. Mechanisms underlying the definition of asthma (National Heart, Lung, and Blood Institute 2002)
4. The response to injury hypothesis of atherosclerosis (modified after: Ross 1999; Encyclopedia of Medical Images).
5. Pathogenetic mechanisms through which C. pneumoniae could affect the development of atherosclerosis (modified after: Leinonen & Saikku 2002, Summersgill et al. 2000).
6. Percentage distributions of asthma patients, bronchitis controls, and asymptomatic controls in each tertile of IgA antibodies to C. pneumoniae Hsp60 presented as EIUs (optical density multiplied by 1000).
7. Prevalence (%) of participants with persistently and temporarily elevated levels of C. pneumoniae IC/IgA antibodies (top), human Hsp60 IgA antibodies (middle) and CRP concentration (bottom) among cases (left) and controls (right).
8. Prevalence (%) of participants with persistent C. pneumoniae IC/IgA antibodies together with persistent human Hsp60 IgA antibodies and/or persistent CRP concentration among cases (left) and controls (right).

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