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LUNG IMMUNOLOGY
PULMONARY DEFENSE MECHANISMS
AGAINST INFECTIONS
Eddy Mart Salim, Masdianto Musai
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Biodata
Nama : Eddy Mart Salim Jabatan : Guru Besar Bidang Ilmu Penyakit Dalam
Tanggal Lahir : 22 Maret 1950
Tempat Lahir : Bukit Tinggi, Sumatera Barat
Agama : Islam
Status : Menikah
Nama Istri : Heniwati Thalib Alamat : Komplek Kenten Permai Blok F No. 5
Palembang.
Pendidikan : S1 FK UNSRI 1978
: S2 PPDS1/ Spesialis Penyakit Dalam FK UNSRI 1991
: S3 Konsultan FK UI/ PB PAPDI 1996
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1. Introduction
2. Specialized regional defenses
Nose and oropharynx
Conducting airways The alveolar spaces
Lymphocytes in the alveolar spaces
3. Defects in host defenses that can be associated with
respiratory infections4. Host defenses in the approach to patients with
pulmonary disease
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Eosinofil
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Introduction
The atmosphere is a complex mixture of
gases and particulates to which virus and
bacteria containing droplets can be added
The respiratory system must recognize andeliminate these unwanted elements
This is accomplished by the complex and
multifaceted defenses that protect the
respiratory tract
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Elements of the defense system are spaced along
the entire respiratory tract
The nasal turbinates, epiglottis, larynx, other
anatomic barriers
Inhaled particulates and infectious agents also
interact with other locally produced proteins, such as
secretory IgA
Surfactant and glycoproteins such as fibronectin, IgG,
complements (proferdin factor B) are active against
particles or microorganisms
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Alveolar macrophages are the principal
phagocytic and scavenger cells on alveolar
surfaces
When further assistance is required, aninflammatory reaction can be initiated, which
attracts PMNs and other vasomediators and
humoral immune elements
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Specific and nonspecific defensemechanisms exist to protect respiratorysructures
The nonspecific mechanisms include themechanical barriers, mucociliary elevator,and macrophage phagocytosis
The antigen-specific cellular or humoral
immune responses include s IgA whichprevents mucosal adherence, and IgGopsonins that facilitate phagocytosis
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SPECIALIZED REGIONAL DEFENSES
Nose and oropharynx
Air is filtered and conditioned for humidity and
body temperature as it flows over the nasal
turbinates and mucosa of the pharynx
Nasal obstruction or ventilatory requirementsfor exertion, mouth breathing occurs
Inhaled air then passes into the trachea
without optimal filtering and climatic
conditioning
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The nasal hairs help to exclude large
particles
Sneezing or blowing provides high velocity
ejection from the mucosal surface Production of large quantities of watery
secretions helps to wash off the surface
(rhinorrhea)
Mucociliary clearance is also operant in the
nasal cavity
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Several substances in nasal secretions help
control bacteria or viruses; lysozyme, sIgA
S IgA is synthesized locally by submucosal
plasma cells Of the nasal Igs, S IgA is the major source of
antibody; IgG is present in smaller amounts
IgE probably is not secreted by normal,nonatopic people; only in people with allergic
rhinitis
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In the oral cavity, the tongue sweeps during
chewing and swallowing
A common feature of host defense in the
mouth and nose is the plentiful amount ofSIgA, secreted by the parotid glands and
probably by the submandibular salivary gland
Ig G is barely detectable (under 1 percent)
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The upper portion of the respiratory tract has
features in common with the lower part
The infections in the upper part may have
ramifications for the diagnosis or successfultreatment of illness in the lower respiratory
tract
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Conducting airways
Mucociliary clearance and coughing are the
principal means of cleansing the mucosal
surfaces of these airways
s IgA antibodies also prevent epithelialattachment of certain bacteria and viruses to
the airway epithelial cells
The branching structure also causes airborne
particulates to impact against the mucosa,
enhancing the efficiency of clearance
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The airway mucosa is coated with viscousfluid, which has a low pH and is secreted bybronchial glands, goblet cells, and probablyClara cells
Fluid is also derived from the intravascularspace by diffusion through the blood-airbarrier
Special proteins, such as sIgA and secretorycmponents (SC), can be added locally alongairways
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The mucosal epithelial cells have beating cilia
that propel secretions up the respiratory tree,
assisted by the periodic coughing
The mocosal lining and mucous layer providea protective barrier that prevents particulates
from penetrating or sticking to the surface
Tight junctions between epithelial cells also
prevent the passage of macromolecules into
the submucosa
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A number of circumstances can alter
these protective barriers
Malnutrition, affects the integrity of mucosal
epithelial cells and enhances bacterial
adherence
Cigarette smoke and noxious fumes, disruptthe anatomy of epithelial junctions and
enhance the passage of airway substances
Some bacteria, elaborate proteolytic enzymes
that may break down IgA, promoting selective
colonization
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Lymphoid tissue is present along the entire
respiratory tract
Lymphoid nodules may occur in the mucosal
surface of bronchi These bronchial-associated lymphoid tissues
(BALT) bear some resemblance to GALT
(Peyers patches)
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Loosely organized collections of lymphocytes
(lymphoid aggregates) are concentrated in
the distal airways
These aggregates provide an opportunity forclose interaction between lymphoid cells and
inhaled antigens
Also, lymphatic channels might provide these
lymphocytes with a route to draining lymph
nodes where immunologic responses develop
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The alveolar spaces
Some particles of small size and special
geometry can elude the above mechanisms
and reach the alveolar space
Microbial clearance and the removal of otherantigenic material from alveoli depend on
cellular and humoral factors
Lipoprotein, Ig, complement factors,
phagocytic cells such as alveolar
macrophages and PMNs
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The lipoproteins are secreted by type II
pneumocytes and may have opsonic effects
and antibacterial activity
Ig, principally IgG class, have specificopsonic antibody activity for the bacterium
The complement component, especially
proferdin factor B, interact with the bacterium
and can trigger the alternative pathway,
thereby lysing the microbe directly
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Phagocytosis is divided into two phases: attachment
of the particle to the cell surface and internalization
Binding is greatly enhanced by opsonization of the
particle by antibody (IgG) or a component of the
complement system, C3b
Ingestion of membrane-bound particles occurs via a
process that is energy dependent
Plasma membrane of the ingesting cell surrounds the
bound particles, enclosing it in an endocytic vesicle
This is followed by the activation of a number of well
developed mechanisms to kill internalized pathogens
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The alveolar macrophage has a dual role- one as aphagocyte and a second as an effector cell to initiateimmune and inflammatory response
Alveolar macrophages are usually successful in
inactivating inhaled microorganisms However, if a sufficiently large bacterial inoculum
reaches the lower resp. tract, or if particularly virulentmicroorganisms are inhaled, the macrophage systemcan be overwhelmed
By the secretion of proinflammatory chemotacticfactors, macrophages then recruit PMNs and othercells to the lung, and pneumonitis develops
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The bacterial endotoxin can directly activatethe alternative complement pathway,formation of C5a, potent stimulus for PMNchemotaxis
Also, the inflammatory response may activatethe kinin system; generation of kallikrein-chemotactic- and bradykinin- increasingvascular permeability
Several substances with chemotactic activityproduced by alveolar macrophages includeIL8, MIP-1alpha, MCP-1, TNF and leukotriene
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Inflammation : ultimate host response,
can be activated in several ways
Directly by microbes or substances such as
lipopolysaccharide (endotoxin), activate the
complement cascade
Generation of phlogistic factors from thekallikrein and bradykinin pathways
From the effector cell function of
macrophages
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Proinflammatory chemokines can stimulate cellular
motion (chemokinesis) and promote directed
migration of responder cells (chemotaxis)
PMNs in acute inflammatory responses
Lymphocytes, monocytes, and eosinophils in the
chronic phase
Chemokinesis involves a number of cell surface
adhesion molecules
IL1, TNF, INF gamma induce or augment the
expression of these adhesion molecules
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If the host is successful in containing the
infective microbes or particles, resolution
usually occurs
Resolution can be passive or active Cytokine such as TGF beta, IL-6, IL-10 and
IL-1 receptor antagonist are important
mediators in active resolution of inflammation
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Lymphocytes in the alveolar space
BAL : approximately 7-10% of the respiratory cells
are lymphocytes
Two major population: T cells (depend on the thymus
gland for differentiation; and B cells (differentiate
independently of the thymus in the bone marrow)
Can be differentiated by membrane surface markers
T cells play an important role in cell mediated
immunity (CMI) and CM cytotoxicity
B cells serve as precursors for cells that synthesize
immunoglobulins
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Tcells can be divided into: CD8 cells (have a
suppressor-cytotoxic phenotype); and CD4
cells (have a helper-inducer phenotype;
called T helper or Th cells) Most of the T lymphocytes in the alveoli are
CD4 positive
Two subssets of CD4 Th cells: T helper-1
(Th1) and T helper-2 (Th2) cells
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Th1 cells secrete INF gamma and IL-2, which
activate macrophages and play a major role in CMI
Th2 cells produce IL4, IL5, and IL6, which stimulate B
cells to produce Ig; and produce IL10 and IL13 that
suppress macrophage activity and CMI responses
IL-2 (formerly called TCGF) is among the most
important T cell cytokines; acts to stimulate TH1 cells
and Th2 cell precursors, activate killer T cells, and
stimulate B cells to differentiate into plasma cells thatsynthesize Ig
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Alveolar macrophages and lymphocytes
produce many mediators (cytokines) that in
turn affect each other as well as other
inflammatory, structural, immune effector cell The release of proinflammatory chemokines
attracts PMNs, lymphocytes, monocytes and
other cells into the alveoli
LTB4, IL8, TNF alpha, MIP1alpha, MCP1 and
IL1
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Th cell can produce several monokines that
affect macrophage function
MIF immobilizes macrophages engaged in
phagocytosis IFN gamma activates macrophages,
increasing their expression of membrane
receptors, enhances macrophage phagocytic
IFN gamma also promote cellular immunity
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Defects in host defenses that can be
associated with respiratory infections
Recurrent or chronic infections may point to
deficiency or malfunction of a particular component of
the host defense system
Endotracheal tubes bypass the larynx and the other
upper airway protective structures
Patients with depressed consciousness or
postoperative chest become infected because
inability to cough and clear airway secretion
Patients with viral infections have an increasedincidence ob bacterial superinfection; the cause
appears to be multifactorial
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Ultrastructural defects in the cilia cause
mucociliary dysfunction
The constellation of multiple upper and lower
respiratory infections and bronchiectasisshould raise the possibility of a ciliary
dyskinesis syndrome
A variety of gamma globulin abnormalities are
associated with recurrent infection;
hypogammaglobulinemia
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Several common bacteria can also produce a
specific IgA protease, inactivate s IgA
Deficiencies of IgG2 and IgG4 alone and in
combination with IgA deficiencies areassociated with chronic inflammation and
bronchiectasis
Cytotoxic antineoplastic chemotherapy and
other forms of immunosuppression also
compromises host defenses in a major way
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Host defenses in the approach to
patients with pulmonary disease
Normal hosts can develop respiratory infections orinflammation as a result of exposure to virulentagents or a large inoculum
In others, respiratory infections are associated with
obvious clinical features that compromise pulmonarydefenses
Occasionally, a relatively young person who has anunexpected number of respiratory problems thatseem inappropriate
The illness can manifest as recurrent infection orpoorly controlled allergic rhinitis, asthma, sinusitis,nasal polyps and or bouts of otitis media
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Differential diagnosis
Cystic fibrosis
Absence of IgG subclass immunoglobulins
Structural ciliary defects
IgA deficiency
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A detailed history about affected siblings,infertility or a striking change in respiratoryhealth
Premilinary screening tests include microbialculture of respiratory secretions and analysisof electrolytes in a sample of sweat
Other tests are quantitative serum Ig, s IgA,subtyping of blood lymphocytes, ciliaryclearance, nasal mucosal biopsy, spermmotility, chest ct scan, otolaryngologicevaluation
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Certain form of pneumonia point to possible
deficiencies in lung cells such as macrophages,
lymphocytes or PMNs
The lack of appropriate IgG antibodies may
contribute to infections with common bacteria
Other causes of pneumonia may reflect abnormal
lymphocyte function and CMI
Experimental: administration of intratracheal IFN
gamma reduced intrapulmonary replication ofbacteria, improving host defenses
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AIDS: human host is infected with HIV virusthat destroys CD4 Th lymphocytes
These patients experience rerurrentrespiratory infections with diverse organisms,including viruses, P carinii, M tuberculosis,fungi
From subjects with AIDS, lymphocytesdecrease in the CD4 Th cells, offset by anincrease in suppresser-cytotoxic species of Tlymphocytes
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IMMUNE RESPONSES
I. Normal subjectAmount of microbes
Pathogenecity / virulency of microbes
II. Immunodeficiency/Imm.compromised pts
Commensal micr.
Pathogenecity micr.
>> pathogent
III.Immunodisorder pts.Atopy : asthma, rhinitis allergic, bronch. allerg
Carcinoma: lung ca, bronch ca
Autoimmune: SLE, Good past. synd,
pneumonitis
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