Michels Immunity in Pulmonary Flashcards
Pulmonary Defense Mechanisms
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
Upper airways and bronchi
defense mechanisms
Anatomic barriers Cough Mucociliary apparatus Airway epithelium Secretory IgA Dendritic cells, lymphocytes, neutrophils
Host defenses in alveolar spaces
defense mechanisms
Alveolar macrophages
Immunoglobulins, opsonins, and surfactants
Lymphocyte-mediated immunity
Neutrophils and eosinophils
immune cells in the pulmonary immune system
dendritic cell, alveolar macrophage, red blood cell, lymph node dendritic cell, naive T cells and B cells, memory T cells, virus-specific B cell
Findings in BAL fluids
Normal:
Primarily alveolar
macrophages
Smoker with interstitial lung disease: many carbonaceous macrophages
Sarcoidosis:
increased numbers
of lymphocytes: CD4
alveolitis
BAL from a scleroderma patient
neutrophils and eosinophils
Neutrophils in the BAL look like
Polymorphonuclear
Anatomy: Larger than erythrocytes Nucleus - 2-4 lobes - Heterochromatin located at the periphery Cytoplasm - weakly staining Production is driven by G-CSF, GM-CSF, IL-3, and IL-5
Eosinophils in the BAL look like
Larger than erythrocytes
Nucleus
- Bilobed [mnemonic: E-O- 2-Lobe]
- Heterochromatin located at the periphery
Cytoplasm
- Eosinophilic staining due to presence of
– Specific granules
– Azurophilic granules
Production controlled by Il-5 and to some extent Il-3
Monocytes look like… and have a lifespan of
Mononuclear Phagocytes
Anatomy: Largest of the WBCs Nucleus- Indentation site at center Cytoplasm - Golgi apparatus and centrioles located at indentation - Small dense azurophilic granules-greyish-blue - Smooth and rough ER - Mitochondria
Lifespan
- Circulate in blood for 3 days
- Differentiate in local tissue
- — Macrophages
- ———Organ specific or connective tissue
- — Osteoclasts
Lymphocytes (Lymphoid Cells) look like …
Histologically distinguishable by size
- Small lymphocytes
—-90% of lymphocytes in blood stream
—-Nucleus (Slightly indented, Intensely staining)
Cytoplasm: Thin pale blue rim, Some granules, golgi, mitochondria and free ribosomes
Large lymphocytes
- Activated lymphocytes and natural killer cells
- Nucleus
Idiopathic Interstitial Pneumonias
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
- In idiopathic pulmonary fibrosis (IPF) use of corticosteroids is not indicated
- Nonspecific interstitial pneumonia (NSIP) has a more favorable response to corticosteroids
Events in the Development of IPF
genetic predisposition
Injury, environmental factors
–> vasodilation, coagulation, xidative stress, vascular remodeling –> TYPE II AEC
–> Increased expression of TGF-beta***, TNF-alpha, PDGF –> TYPE II AEC
Type II AEC: injury, failed repair, fibrosis with activated myofibroblasts and fibroblastic foci
Evidence for the Role of Cellular and Humoral Immunity in IPF
Involvement of CD4+ T cells (activated phenotype)
Biased T cell receptor Vβ repertories (BAL and peripheral)
Presence of autoantibodies in some studies with IPF patients
Evidence of lymphoid neogenesis without organized structure
Genetic Contribution to IPF
- defects in surfactant protein A2
- mutation in the surfactant protein C gene
- Telomerase mutations (IPF)
- MUC5B promotor polymorphism and pulmonary fibrosis
Connective Tissue Diseases
Rheumatoid arthritis (RA)
Systemic lupus erythematosus (SLE)
Sjögren syndrome
Systemic sclerosis (SSc)
Pulmonary manifestations include ILD
Systemic Sarcoidosis
Multisystem granulomatous
Noncaseating epithelioid granulomas
Depression of DTH responses
Bilateral hilar lymphadenopathy or lung involvement is common
Interstitial pneumonitis and granulomatous formation can progress to fibrosis with loss of alveolar and bronchial tissue and vascular surface area
Inflammatory Response in Sarcoidosis- Relevant proteins
TNF-alpha
IL-7
MMP-12
Persistent Granulomatous Inflammation
Persistence of antigen
Failure of the immune system to halt inflammatory processes
Systemic immunologic abnormalities
- Failure to mount DTH responses
- Polyclonal hypergammaglobulinemia
Hypersensitivity Pneumonitis (HP)- causes and syndromes
Group of lung diseases caused by inhalation of exogenous antigenic molecules (usually organic)
- Spores of thermophilic bacteria
- Fungi
- Animal proteins
- Bacterial products
Syndromes are often named after the occupation
- Framer’s lung
- Pigeon breeder’s lung
- Humidifier or air-conditioner lung
Hypersensitivity Pneumonitis (HP)- symptoms
Affected individuals have a heightened response to the causative agents and, in contrast to asthma, the immune response is centered in the alveolar walls (extrinsic allergic alveolitis)
Transient fever, hypoxemia, myalgias, arthralgias, dyspnea, cough 2-9 hr after exposure
Symptoms resolve without treatment provided there is no re-exposure to antigen
Immunology Associated with HP
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- IL-8 present in BAL
Cell-mediated immune process
- TGF-β, IL-1, IL-12, TNF-α
- IL-2, IFN-gamma
- IL-6, TH-17, IL-22
Tx with corticosteroids aids recovery initially, long-term outcome is unaffected
Additional Immunologic Findings- HP
Presence of specific antibodies to the causative antigen
Presence of complement and immunoglobulins in the vessel wall
Two thirds of patients have noncaseating granulomas
Proposed mechanism for the pathogenesis of HP
antigen + genetic/ evironmental promoting factors –> alveolitis –> granulomatous inflammation -> + progressing factors –> fibrosis
Eosinophilic Lung Disease
Pulmonary infiltrates with eosinophilia (PIE)
Eosinophilic infiltration into airways, alveoli, or interstitium
