Table Of ContentRespiratory
Pharmacology and
Pharmacotherapy
Series Editors:
Dr. David Raeburn Dr. Mark A. Giernbycz
Discovery Biology Departrnent of Thoracic Medicine
Rhbne-Poulenc Rorer Ltd National Heart and Lung Institute
Dagenharn Research Centre Irnperial College of Science, Technology and Medicine
Dagenharn London SW3 6L Y
Essex RM 10 7XS England
England
Autoimmune Aspects of
Lung Disease
Edited by
D. A. Isenberg
s. G. Spiro
Springer Basel AG
Editors:
Professor David A . l:ienberg Dr. Slephen G. Spiro
Centre for Rheumatologyl University Colfege London Hospitals
Bloomsbury Rheumatology Unit Department of ThOfacK Medicine
Department of Medi<ine Middlesex Hospital
Uni-lersity College London Mortimer Street
40-50 Tottenham Court Road London Wl M SAA
London W l P 9PG UK
UK
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Au10immune aspects of lung disease ' 00. by D. A. lsenberg. S. G. Spiro -
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CI 1998 Springef Basel AG
Originalfy published by BirkMuser Verlag Basel Swil zerlandin1g98
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Contents
List of Contributors ......................... VII
I. The Lung and the Immune System
J. R. Catterall and E. A. Sheffield . I
2. The Respiratory System in Rheumatic Diseases
A. Rapti, B. S. Devi, S. G. Spiro and D. A. Isenberg ....... 23
3. Pulmonary Manifestations of Systemic Vasculitides
J. W Cohen Tervaert, T. van der Werf, C.A. Stegeman,
W Timens and C. G. M. Kallenberg . . . . . . . . . . 53
4. The Lung in Granulomatous Diseases
M.A. Spiteri and G.A. W Rook .... 87
5. The Diagnosis and Treatment of Respiratory Infections
in Autoimmune Disease, Excluding Tuberculosis
G. H. Bothamley and P. Shaw . . . . . . . . . . . . . . . III
6. Human Immunodeficiency Virus and the Lung
G. Agostini, R. Sancetta and G. Semenzato .... 141
7. Lung Cancer: Immunological Disturbances and Clinical
Implications
T. Sethi .............................. 167
8. Asthma
D S. Robinson .......................... 187
9. Cystic Fibrosis
p. D Phelan . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
10. Role of the Immune System in the Pathogenesis of Cryptogenic
Fibrosing Alveolitis
H. Booth and G. J. Laurent . . . . . . . . . . . . . . . . . . . . 233
II. Drugs and Other Factors
R. M. Bernstein ....... . . . . . . . . . . . . . . . . . . . 251
12. Overview
DA. Isenberg and S. G. Spiro .267
Index . 271
List of Contributors
Carlo Agostini, Department of Clinical and Experimental Medicine, Padua
University School of Medicine, Padua Hospital, 35128 Padua, Italy
Robert M. Bernstein, Rheumatology Department, Manchester Royal Infirmary,
Manchester M 13 NWL, UK
Helen Booth, Centre for Cardiopulmonary Biochemistry and Respiratory
Medicine, University College London Medical School and Royal Free
Hospital School of Medicine, London WCIE 6JJ, UK
Graham H. Bothamley, Department of Respiratory Medicine, Homerton
Hospital, London E9 6SR, UK
James R. Catterall, Respiratory Department, Bristol Royal Infirmary, Bristol
BS2 8HW, UK
Jan Willem Cohen Tervaert, Department of Clinical Immunology, University
Hospital, 9713 GZ Groningen, The Netherlands .
Beratha S. Devi, Centre for Rheumatology/Bloomsbury Rheumatology Unit,
Department of Medicine, University College London, London WIP 9PG, UK
David A. Isenberg, Centre for RheumatologylBloomsbury Rheumatology
Unit, Department of Medicine, University College London, London WIP
9PG, UK
Geoffrey 1. Laurent, Centre for Cardiopulmonary Biochemistry and Respira-
tory Medicine, University College London Medical School and Royal Free
Hospital School of Medicine, London WCIE 6JJ, UK
Peter D. Phelan, Department of Paediatrics, Royal Children's Hospital, Park-
ville, Victoria 3052, Australia
Angela Rapti, Department of Thoracic Medicine, University College London
Hospitals, London WClE 6AH, UK
Douglas S. Robinson, Department of Allergy and Clinical Immunology,
Imperial College School of Medicine at the National Heart and Lung
Institute, London SW3 6LY, UK
Graham A. W. Rook, Department of Bacteriology, University College London
Medical School, London WIP 6DB, UK
Rosaria Sancetta, Department of Clinical and Experimental Medicine, Padua
University School of Medicine, Padua Hospital, 35128 Padua, Italy
Gianpietro Semenzato, Department of Clinical and Experimental Medicine,
Padua University School of Medicine, Padua Hospital, 35128 Padua, Italy
Tariq Sethi, Respiratory Medicine Unit, Department of Medicine (RIE),
University of Edinburgh Royal Infirmary, Edinburgh EH3 9YW, UK
Penny Shaw, Department of Imaging, University College London Hospitals,
London WCIE 6AH, UK
Edward A. Sheffield, Respiratory Department, Bristol Royal Infirmary,
Bristol BS2 8HW, UK
Stephen G. Spiro, Department of Thoracic Medicine, University College
London Hospitals, London WClE 6AH, UK
VIII List of Contributors
MonicaA. Spiteri, Department of Respiratory Medicine, North Staffordshire
Hospital TrustlKeele University, Stoke-on-Trent, Staffordshire ST4 6QG,
UK
Coen A. Stegeman, Department of Clinical Nephrology, University Hospital,
9713 GZ Groningen, The Netherlands
Wim Timens, Department of Clinical Pathology, University Hospital, 9713
GZ Groningen, The Netherlands
Tjip van der Werf, Department of Clinical Pulmonology, University Hospital,
9713 GZ Groningen, The Netherlands
Autoimmune Aspects of lung Disease
ed. by D. A. Isenberg and S. G. Spiro
© 1998 BirkhiiuserVerlag Basel/Switzerland
CHAPTER 1
The Lung and the Immune System
James R. Catterall and Edward A. Sheffield
Respiratory Department, Bristol Royal Infirmary, Bristol, UK
1 Introduction
2 Structural Basis of the Pulmonary Immune Response
2.1 Lymph Nodes
2.2 Bronchus-Associated Lymphoid Tissue
2.3 Lung Parenchyma
3 Lymphocyte Circulation
3.1 Homing Molecules
3.2 Some Pulmonary Lymphocytes Are Derived from the Intestine
4 Sequence of Events in the Pulmonary Immune Response
4.1 Antigen-Presenting Cells
4.2 Antigen Recognition
4.3 Lymphocyte Activation
4.4 Cytokines
4.5 Th, and Th2 Lymphocytes
4.6 Effector Cells
4.6.1 B-cells
4.6.2 Cytotoxic lymphocytes
4.6.3 Pulmonary macrophages
4.6.4 Neutrophils
4.6.5 Mast cells
4.6.6 Eosinophils
5 Regulation of the Pulmonary Immune Response
5.1 Immunoregulation by Alveolar Macrophages
5.2 Immunological Tolerance
5.3 Immune Deviation
References
1. Introduction
The lungs are in a uniquely vulnerable position in that they are constantly
exposed to a wide range of inhaled foreign particles, including microbial
pathogens, allergens and environmental toxins. They also have the largest
blood supply of any organ, and this also is capable of delivering harm-
ful substances. The need to balance protection from these hazards against
the requirements for maximum surface area for gas exchange has been
achieved by a highly flexible combination of defence mechanisms. Abnor-
malities of this system contribute to the pathogenesis of many respiratory
disorders.
2 J. R. Catterall and E. A. Sheffield
Inhaled particles which pass through the larynx are initially exposed to
mechanical and physical defences such as the cough reflex and the muco-
ciliary escalator. They are also met by a range of innate phagocytic and
chemical defences, including macrophages, neutrophils, complement,
lysozyme and transferrin, some of which contribute to the inflammatory
response. However, the enormous flexibility of the immune system, both in
terms of its specificity and in the magnitude and variety of its response, lies
in the acquired, antigen-specific, response, at the heart of which lie the
lymphocytes. These cells recognise foreign antigen and store the informa-
tion in their memory. When antigen persists or reappears in the respiratory
tract, the lymphocytes home to the lungs, where they proliferate and dif-
ferentiate into effector or regulatory cells. These in turn contribute to the
removal of antigen, usually with the assistance of other cells.
Recent studies have helped to elucidate some of the basic mechanisms
involved in these responses. The mechanisms by which pulmonary lym-
phocytes are recruited from the circulation, the ways in which lymphocytes
interact with other cells in the lungs, and the processes involved in regula-
tion of the pulmonary immune response are beginning to be understood at
the molecular level. These insights into normal immune responses not only
help us to understand the pathogenesis of many respiratory diseases but
also offer the prospect of therapeutic intervention in a range of pulmonary
conditions with are associated with local or generalised abnormalities of
the immune system.
2. Structural Basis of the Pulmonary Immune Response
As in other organs, the lymphoid tissue consists of antigen-presenting
cells, memory cells (lymphocytes) and effector cells (including lympho-
cytes), which are organised into a number of separate functional compart-
ments.
2.1. Lymph Nodes
The pulmonary lymph nodes lie in the paratracheal region and adjacent to
major bronchi. They receive lymphatic drainage both from the mucosa of
the airways and from the lung parenchyma. They are similar in structure to
lymph nodes at other sites and contain antigen-presenting cells and a wide
range oflymphocytes, creating an environment that is conducive to antigen
presentation. Detailed kinetic studies involving localisation and quantita-
tion of both antigen-specific plasma cells and immunoglobulin-specific
mRNA have pinpointed lymph nodes as the sites at which antigen-
specific IgE and IgG responses to inhaled soluble protein antigen are
initiated [1, 2].
The Lung and the Immune System 3
2.2. Bronchus-Associated Lymphoid Tissue
Bronchus-associated lymphoid tissue (BALT) consists oflymphoid tissue
which appears to be an intrinsic part of the airway mucosa and of the lym-
phoid tissue in the peripheral lung [3]. It is characterised by the local pro-
duction of dimeric IgA and by its relationships with mucosal tissue in other
organs. Although there is controversy about the existence of BALT in nor-
mal human lung, it has been well studied in animals and has been found in
the human lung in abnormal conditions such as chronic pneumonia,
autoimmune disease, immunodeficiency and sudden infant death syn-
drome [4].
BALT does not develop until after birth and appears to depend on a local
mucosal response to inhaled antigen. As in lymph nodes, antigen-present-
ing cells are present, and there are T lymphocyte- and B lymphocyte-
dominant areas. Unlike in lymph nodes, however, there do not appear to be
T lymphocyte-dependent areas, since neonatal thymectomy does not alter
the overall morphology, and also BALT does not contain afferent lym-
phatics. Another difference from lymph nodes is that BALT contains a
modified epithelial cell called the M cell (microfold cell) which is particul-
arly effective at transporting insoluble antigen by endocytosis and deliver-
ing it to underlying lymphoid tissue without processing it or otherwise
behaving as an antigen-presenting cell [5, 6]. This cell has received atten-
tion because of its potential to act as a portal of entry for vaccines to the
mucosal lymphoid compartment [7].
BALT is part of a collection of similar lymphoid tissues which are found,
for example, in the gastrointestinal tract and nasopharynx. The collective
term "mucosal associated lymphoid tissue (MALT)" is used to include all
these tissues. An important feature of the concept of MALT is that there is
recirculation of lymphocytes away from and back to the mucosa of origin.
As well as this lymphocytic homing, there is also circulation of lympho-
cytes between the mucosal surfaces of different organs, for example be-
tween the lung and the gastrointestinal tract (see below).
2.3. Lung Parenchyma
In the alveoli and interstitium of the normal lung, immune cells are rela-
tively sparse. However, during invasion by micro-organisms or other foreign
antigen the numbers can increase dramatically as lymphocytes and other
cells migrate from the circulation [8, 9]. In contrast to BALT and lymph
nodes, in which the lymphocytes are a mixture of naive and memory cells,
and also in contrast to peripheral blood, the great majority of lymphocytes
in the alveoli and interstitium are of memory type [10], having already
been primed by antigen. Memory cells can be distinguished from naive
cells by monoclonal antibodies to different isoforms of the CD45 common
