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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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