Non-specific Host Defense Mechanisms Lecture 8 Non-specific Host Defense Mechanisms NORBEL A. TABO, RM, SM

Learning Objectives Briefly describe the three lines of defenses Differentiate non-specific from specific host defense mechanism Identify three ways by which the digestive system is protected from pathogens Name three cellular and chemical responses to microbial invasion Describe the benefits of complement activation List the cardinal signs and symptoms associated with inflammation Outline the four steps in phagocytosis. Cite ways in which pathogens escape destruction by phagocytes Categorize the disorders and conditions that affect the body’s non-specific host mechanisms

Overview of the Immune System

Anatomical Barriers - Mechanical Factors System or Organ Cell type Mechanism Skin Squamous epithelium Physical barrier Desquamation Mucous Membranes Non-ciliated epithelium (e.g. GI tract) Peristalsis Ciliated epithelium (e.g. respiratory tract) Mucociliary elevator Epithelium (e.g. nasopharynx) Flushing action of tears, saliva, mucus, urine

Anatomical Barriers - Chemical Factors System or Organ Component Mechanism Skin Sweat Anti-microbial fatty acids Mucous Membranes HCl (parietal cells) Tears and saliva Low pH Lysozyme and phospholipase A Defensins (respiratory & GI tract) Antimicrobial Sufactants (lung) Opsonin

Anatomical Barriers - Biological Factors System or Organ Component Mechanism Skin and mucous membranes Normal flora Antimicrobial substances Competition for nutrients and colonization

Microbial antagonism Inhibitory capability of normal flora Competition for colonization sites Competition for nutrients Production of substance that kill other bacteria The effectiveness of this antagonism is frequently decreased after prolonged administration of broad spectrum antibiotics

Superinfection of Candida albicans

Pseudo-membraneous colitis

Humoral Components Complement system Coagulation system Lactoferrin and transferrin Interferons Lysozymes Cytokines

Complement System The major humoral non-specific defense mechanism. Once activated, complement can lead to increased vascular permeability, recruitment of phagocytic cells, and lysis of bacteria

Coagulation system Some products of coagulation system are directly antimicrobial Example: Beta lysin Protein produced by platelets can lyse G+ bacteria by acting as a cationic detergent

Lactoferrin and Transferrin Proteins that can limit bacterial growth.

Interferons protect cells from viral attack (among other functions). alpha, beta, and gamma interferon produced by virus-infected cells and also by macrophages and some lymphocytes, which are stimulated to produce interferon via activation by antigens. the effect of interferon on healthy cells is to stimulate them to produce antiviral proteins (AVP) which protects them from viral infection.

Lysozymes Breaks down the cell wall of bacteria

Interleukin I Induces fever and production of acute phase proteins (C-reactive proteins which is a laboratory marker for inflammation)

Cytokines Chemical mediators that are released from different types of cells. They enable cells to communicate with each other.

Cellular Components Cell Functions Neutrophils Phagocytosis and intracellular killing Inflammation and tissue damage Macrophages Extracellular killing of infected or altered self targets Tissue repair Antigen presentation for specific immune response NK and LAK cells Killing of virus-infected and altered self targets Eosinophils Killing of certain parasites

Leukocytes There are typically 5,000 to 10,000 of these per cubic millimeter of human blood ( 5-10 billion per liter ). The white cell count typically increases in response to infection. Leucocytes play a role in both specific (antibody-based) and non-specific host defense mechanisms.

Types of Leukocytes about 55-70% of circulating wbc's are PMNs. Polymorphonuclear neutrophils (PMNs) about 55-70% of circulating wbc's are PMNs. These are phagocytic cells that play an important role in the defense against bacterial pathogens. Eosinophils represent about 5 % of circulating wbc's. These are capable of phagocytosis under some conditions, but are more directly concerned with the extracellular destruction of invading organisms, particularly parasites such as helminths. High eosinophil numbers are typically associated with helminth infections.

Types of Leukocytes….. Basophils constitute 1% or less of circulating wbc's. Basophils produce a variety of biologically active chemicals including histamine (involved in allergic response) and heparin (an anticoagulant). Monocytes Constitute about 5-8 % of circulating wbc's. Like, PMNs, these cells are capable of phagocytosis. In the tissues, these cells can be transformed into macrophages which phagocytize invading cells and process and "present" antigens to B-lymphocytes, stimulating them to produce antibodies.

Types of Leukocytes….. Lymphocytes about 20% of circulating wbc's are lymphocytes. These cells are largely responsible for both humoral and cellular immunity. There are two general types of lymphocytes, B cells (plasma cells) that produce soluble (humoral) antibodies, and T cells which are responsible for cellular immunity. There are 5 different types of T-cells, each with its own set of functions (discussed later): Helper cells (Th) Suppressor cells (Ts) Delayed hypersensitivity cells (Td) Cytoxic [killer] cells (Tc)

Lymphocytes Natural killer cells (Nk) - destroy tumor cells, transplanted tissue, and cells infected with intracellular bacteria such as the Rickettsia and Chlamydias. Both Tc and Nk cells produce a protein called perforin which bores a hole in the membrane of the attacked cell, much like the membrane attack complex( MAC) of complement. While lymphocytes are generally considered to be part of the "specific" immunity system (involving antigens and antibodies), the Nk cells do not require an antigen to activate them, and so are perhaps best considered to be part of the body's non-specific defense system.

Phagocytosis and Inflammatory Response

Phagocytosis able to engulf and destroy bacteria and some other invading organisms polymorphonuclear neutrophils and monocytes and other cells called macrophages (tissue cells derived from monocytes)

Phagocytosis Chemotaxis Attachment Ingestion Digestion

Inflammation a complex interwoven series of processes that increase the blood supply to an infected site. The symptoms of inflammation: swelling, warming, reddening, and pain are all the result of the increased blood supply brought about by capillary dilation. A series of chemical mediators including histamine and the prostaglandins are also involved in inflammatory processes.

Inflammatory Response Large number of phagocytes are attracted to the wound area Blood vessels dilate Phagocytes move out from the blood Phagocytes engulf the pathogen

Classical signs and symptoms Calor - heat Dolor - pain Rubor - redness Tumor – swelling Fluor - secretions

Importance of Inflammation To localize infection To prevent spread of pathogens To destroy and detoxify pathogens To aid in repair and healing

fever Creates an unfavorable thermal environment for bacteria whose thermal optimum is 37o C. Speeds-up chemical reactions that are part of the chemical defense mechanism

Mechanisms by which pathogens escape destruction by phagocytes Production of capsules Secretion of leukocidins Presence of waxes in the cell wall (M. tuberculosis) Growth within the phagocytes (Rickettsia, Legionella, Brucella, Coxiella, Listeria) Growth within the leukocytes (Ehrlichia, Anaplasma)

Disorders and conditions that adversely affect phagocytic and inflammatory processes Leukopenia Low number of circulating leukocytes Chediak-Higashi Syndrome Inability of leukocytes to migrate in response to chemotactic agents Chronic Granulomatous Disease Incapability of phagocytes to kill the pathogens

Factors that can impair host defense mechanisms Nutritional status Increased iron levels Stress Age Cancer and Cancer chemotherapy AIDS Drugs B-cell and T-cell deficiency