Immunology of Interstitial Lung Diseases

Question 1

Immunology of Interstitial Lung Diseases

Answer 1

• The lung is continuously exposed to the outside environment
• Defense mechanisms are necessary to ensure efficient gas exchange and prevent infection
• Removal mechanisms are aimed at minimizing inflammation

Question 2

Lung defense can be divided into two locations

•Upper airways and bronchi

Answer 2

–Anatomic barriers
–Cough
–Mucociliary apparatus
–Airway epithelium
–Secretory IgA
–Dendritic cells, lymphocytes, neutrophils

Question 3

Lung defense can be divided into two locations

•Host defenses in alveolar spaces

Answer 3

–Alveolar macrophages
–Immunoglobulins, opsonins, and surfactants
–Lymphocyte-mediated immunity
–Neutrophils and eosinophils

Question 4

Interstitial and Inflammatory Lung Diseases (ILD)

Answer 4

• Idiopathic interstitial pneumonias
• Connective tissue diseases
• Systemic sarcoidosis
• Hypersensitivity pneumonitis
• Eosinophilic lung disease

Question 5

Diagnostic morphologic changes in BAL fluids

Normal:

Answer 5

Primarily alveolar

macrophages

Question 6

Diagnostic morphologic changes in BAL fluids

Smoker with
interstitial lung
disease

Answer 6

many
carbonaceous
macrophages

Question 7

Diagnostic morphologic changes in BAL fluids

Sarcoidosis:

Answer 7

increased numbers
of lymphocytes: CD4
alveolitis

Question 8

BAL from a Scleroderma Patient

Answer 8

Typical bronchoalveolar lavage from a patient with systemic sclerosis illustrating neutrophils and eosinophils

Question 9

Classification of Idiopathic Interstitial Pneumonias

Answer 9

IPF = Idiopathic pulmonary fibrosis, NSIP = Non-specific interstitial pneumonia, COP =
Cryptogenic organizing pneumonia, AIP = Acute interstitial pneumonia, DIP =
Desquamative interstitial pneumonia, LIP = lymphoid interstitial pneumonia, RBILD =
Respiratory bronchiolitis-associated interstitial lung disease

Question 10

Idiopathic Interstitial Pneumonias

Answer 10

• Heterogeneous group with similar clinical findings and fibrosing in nature
• BAL findings are used to exclude infection, tumor, asbestosis, or other specific diseases
• Effectiveness of corticosteroids depends on the disease

Question 11

•Effectiveness of corticosteroids depends on the disease

Answer 11

–In idiopathic pulmonary fibrosis (IPF) use of corticosteroids is not indicated
–Nonspecific interstitial pneumonia (NSIP) has a more favorable response to corticosteroids

Question 12

Events in the Development of IPF

Answer 12

Vasodilation
Coagulation
Oxidative stress
Vascular remodeling

Increased
expression:
TGF-β
TNF-α
PDGF
Injury, failed repair, fibrosis with activated myofibroblasts and fibroblastic foci

Question 13

Evidence for the Role of Cellular and Humoral Immunity in IPF

Answer 13

• Involvement of CD4+ T cells (activated phenotype)
• Biased T cell receptor Vβrepertories (BAL and peripheral)
• Presence of autoantibodies in some studies with IPF patients
• Evidence of lymphoid neogenesis without organized structure

Question 14

Genetic Contribution to IPF

Answer 14

1. Wang Y, Kuan PJ, Xing C, et. al. Genetic defects in *surfactant protein A2 are associated with pulmonary fibrosis and lung caner. Am J Hum Genet 2009; 84: 52-9.
2. Nogee LM, Dunbar AE III, Wert SE, Askin F, Hamvas A, Whitsett JA. A mutation in the *surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med 2001; 344: 573-9.
3. Armanios MY, Chen JJ, Cogan JD, et al. *Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med 2007; 356: 1317-26.
4. Seibold MA, Wise AL, Speer MC, et. al. A common *MUC5Bpromoter polymorphism and pulmonary fibrosis. N Engl J Med 2011; 364: 1503-12.

Question 15

Connective Tissue Diseases

Answer 15

• Rheumatoid arthritis (RA)
• Systemic lupus erythematosus (SLE)
• Sjögren syndrome
• Systemic sclerosis (SSc)
• Pulmonary manifestations include ILD

Question 16

Systemic Sarcoidosis

Answer 16

• Multisystem granulomatous
• Noncaseating epithelioid granulomas
• Depression of DTH responses
• Interstitial pneumonitis and granulomatous formation can progress to fibrosis with loss of alveolar and bronchial tissue and vascular surface area

Question 17

Inflammatory Response in Sarcoidosis

Relevant proteins

Answer 17

TNF-α
IL-7
MMP-12

Question 18

Persistent Granulomatous Inflammation

Answer 18

• Persistence of antigen

* Failure of the immune system to halt inflammatory processes

Question 19

Hypersensitivity Pneumonitis (HP)

Answer 19

• Group of lung diseases caused by inhalation of exogenous antigenic molecules (usually organic)
• Transient fever, hypoxemia, myalgias, arthralgias, dyspnea, cough 2-9 hr after exposure
• Symptoms resolve without treatment provided there is no re-exposure to antigen

Question 20

Immunology Associated with HP

Answer 20

• Prior sensitization is necessary
• Not associated with IgE or eosinophils
• Higher prevalence in non-smokers (80-95%)
• > 40% lymphocytes suggestive of HP; higher percentage of neutrophils and degranulated macrophages
• Cell-mediated immune process
• Tx with corticosteroids aids recovery initially, long-term outcome is unaffected

Question 21

Immunology Associated with HP

•Cell-mediated immune process

Answer 21

–TGF-β, IL-1, IL-12, TNF-α
–IL-2, IFN-
–IL-6, IL-17, IL-22

Question 22

airway epithelium

Answer 22

toll like receptors when activated they secrete cytokines and defensins

Question 23

alveolar macros

Answer 23

eat

Question 24

Lymphocyte-mediated immunity

Neutrophils and eosinophils

Answer 24

eosiniphilic lung disease when they get out of control

Question 25

BALT and GALT

Answer 25

t and b cells are activated in lymph nodes dendritic cells pick up antigen and go to lymph node and then t and b cells are activated t and b cells traffic back to where they antigen was found

Question 26

Inflammatory Response in Sarcoidosis

Answer 26

predominant th1 response the dendritic cell is presentin the antigen to the cd4 th1 cell on class 2 molecules the th1 cells have cytokines as ifn y and the dendritic ell relase il2 il18, tnf a il7 and mmp 12 and ifny there is proliferation and activation of the tcells with tnf a and there is persistent inflammation in alveolar space with no resolution so you get alveolitis which leads to ild

Question 27

IL-2, IFN-gamma

Answer 27

th1 cd4

Question 28

IL-6, IL-17, IL-22

Answer 28

th17

Question 29

th1

Answer 29

inflammation

Question 30

th2

Answer 30

fibrotic

Question 31

Eosinophilic Lung Diseases

Answer 31

predominance of eosinophils

Question 32

Simple Pulmonary Eosinophilia Etiology - Duration of symptoms - Respiratory Failure - Blood Eosinophls - BAL findings - Dehst Radiographic - Pleural Effusions - Treament - Clinical Relapse -

Answer 32

Etiology - idiopathic drugs parasites Duration of symptoms - 1-2 weeks Respiratory Failure - never Blood Eosinophls - increased BAL findings - eosinophils Dehst Radiographic - transient opacities Pleural Effusions - rare Treament - unnecessary Clinical Relapse - rare

Question 33

Chronic Eosinophilic Pneumonia Etiology - Duration of symptoms - Respiratory Failure - Blood Eosinophls - BAL findings - Dehst Radiographic - Pleural Effusions - Treament - Clinical Relapse -

Answer 33

Etiology - idiopathic Duration of symptoms - several weeks to months Respiratory Failure - very rare Blood Eosinophls - increased BAL findings - eosinophils Dehst Radiographic - peripheral opacities Pleural Effusions - rare Treament - several years Clinical Relapse - frequent

Question 34

Acute Eosinophilic pneumonia Etiology - Duration of symptoms - Respiratory Failure - Blood Eosinophls - BAL findings - Dehst Radiographic - Pleural Effusions - Treament - Clinical Relapse -

Answer 34

Etiology - idiopathic tobacco smoke drugs Duration of symptoms - 1-5 days Respiratory Failure - frequent Blood Eosinophls - normal BAL findings - eosinophils lymphocytes and neutrophils Dehst Radiographic - diffuse opacities kerley b lines Pleural Effusions - frequent Treament - 2-12 weeks Clinical Relapse - rare