LUNG IMMUNOLOGY

PULMONARY DEFENSE MECHANISMS AGAINST INFECTIONS

Eddy Mart Salim, Masdianto Musai

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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Introduction Specialized regional defenses Nose and oropharynx Conducting airways The alveolar spaces Lymphocytes in the alveolar spaces Defects in host defenses that can be associated with respiratory infections Host defenses in the approach to patients with pulmonary disease

Eosinofil

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 and eliminate these unwanted elements This is accomplished by the complex and multifaceted defenses that protect the respiratory tract

 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

 Alveolar macrophages are the principal

phagocytic and scavenger cells on alveolar surfaces When further assistance is required, an inflammatory reaction can be initiated, which attracts PMNs and other vasomediators and humoral immune elements

 Specific and nonspecific defense

mechanisms exist to protect respiratory sructures The nonspecific mechanisms include the mechanical barriers, mucociliary elevator, and macrophage phagocytosis The antigen-specific cellular or humoral immune responses include s IgA which prevents mucosal adherence, and IgG opsonins that facilitate phagocytosis

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 requirements for exertion, mouth breathing occurs Inhaled air then passes into the trachea without optimal filtering and climatic conditioning

 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

 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

 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 of SIgA, secreted by the parotid glands and probably by the submandibular salivary gland Ig G is barely detectable (under 1 percent)

 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 successful treatment of illness in the lower respiratory tract

Conducting airways
Mucociliary clearance and coughing are the

principal means of cleansing the mucosal surfaces of these airways s IgA antibodies also prevent epithelial attachment 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

 The airway mucosa is coated with viscous

fluid, which has a low pH and is secreted by bronchial glands, goblet cells, and probably Clara cells Fluid is also derived from the intravascular space by diffusion through the blood-air barrier Special proteins, such as sIgA and secretory cmponents (SC), can be added locally along airways

 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 provide a 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

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, disrupt the anatomy of epithelial junctions and enhance the passage of airway substances Some bacteria, elaborate proteolytic enzymes that may break down IgA, promoting selective colonization

 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)

 Loosely organized collections of lymphocytes

(lymphoid aggregates) are concentrated in the distal airways These aggregates provide an opportunity for close 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

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 other antigenic material from alveoli depend on cellular and humoral factors Lipoprotein, Ig, complement factors, phagocytic cells such as alveolar macrophages and PMNs

 The lipoproteins are secreted by type II

pneumocytes and may have opsonic effects and antibacterial activity Ig, principally IgG class, have specific opsonic 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

 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

 The alveolar macrophage has a dual role- one as a

phagocyte and a second as an effector cell to initiate immune 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 virulent microorganisms are inhaled, the macrophage system can be overwhelmed By the secretion of proinflammatory chemotactic factors, macrophages then recruit PMNs and other cells to the lung, and pneumonitis develops

 The bacterial endotoxin can directly activate

the alternative complement pathway, formation of C5a, potent stimulus for PMN chemotaxis Also, the inflammatory response may activate the kinin system; generation of kallikreinchemotactic- and bradykinin- increasing vascular permeability Several substances with chemotactic activity produced by alveolar macrophages include IL8, MIP-1alpha, MCP-1, TNF and leukotriene

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 the kallikrein and bradykinin pathways From the effector cell function of macrophages

 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

 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

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

 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

 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 that synthesize Ig

 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

 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

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 increased incidence ob bacterial superinfection; the cause appears to be multifactorial

 Ultrastructural defects in the cilia cause

mucociliary dysfunction The constellation of multiple upper and lower respiratory infections and bronchiectasis should raise the possibility of a ciliary dyskinesis syndrome A variety of gamma globulin abnormalities are associated with recurrent infection; hypogammaglobulinemia

 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 are associated with chronic inflammation and bronchiectasis Cytotoxic antineoplastic chemotherapy and other forms of immunosuppression also compromises host defenses in a major way

Host defenses in the approach to patients with pulmonary disease

Normal hosts can develop respiratory infections or

inflammation as a result of exposure to virulent agents or a large inoculum In others, respiratory infections are associated with obvious clinical features that compromise pulmonary defenses Occasionally, a relatively young person who has an unexpected number of respiratory problems that seem inappropriate The illness can manifest as recurrent infection or poorly controlled allergic rhinitis, asthma, sinusitis, nasal polyps and or bouts of otitis media

Differential diagnosis
Cystic fibrosis

Absence of IgG subclass immunoglobulins

Structural ciliary defects IgA deficiency

 A detailed history about affected siblings,

infertility or a striking change in respiratory health Premilinary screening tests include microbial culture of respiratory secretions and analysis of electrolytes in a sample of sweat Other tests are quantitative serum Ig, s IgA, subtyping of blood lymphocytes, ciliary clearance, nasal mucosal biopsy, sperm motility, chest ct scan, otolaryngologic evaluation

 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 of bacteria, improving host defenses

 AIDS: human host is infected with HIV virus

that destroys CD4 Th lymphocytes These patients experience rerurrent respiratory infections with diverse organisms, including viruses, P carinii, M tuberculosis, fungi From subjects with AIDS, lymphocytes decrease in the CD4 Th cells, offset by an increase in suppresser-cytotoxic species of T lymphocytes

IMMUNE RESPONSES
I. Normal subject Amount 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