HUMAN DEFENSE MECHANISMS Categories of Defense Mechanisms Physical

HUMAN DEFENSE MECHANISMS

Categories of Defense Mechanisms • Physical barriers > Skin and mucous membranes – Chemical factors – Mechanical factors – Microbiological factors • Innate immunity • Adaptive immunity

Physical Barriers of Defense - Skin • Stratified squamous epithelium • Chemical factors > Sebum (fatty secretion from sebaceous glands) > Lysozymes (perspiration produced by sweat glands) • Mechanical factors > Desquamation > Perspiration • Microbiological factors > Normal flora

Physical Barriers of Defense – Mucous Membranes • Columnar to squamous epithelium • Chemical factors > Lysozyme in tears, saliva and nasal secretions > Enzymes and HCl in stomach secretions > Defensins in small intestine • Mechanical factors > Lacrimal apparatus > Mucociliary clearance mechanism • Microbiological factors > Normal flora

Normal Flora of Skin and Mucous Membranes • Population of microorganisms that may at any time be found residing on skin and mucous membranes of human host in the absence of disease • Skin > Staphylococcus epidermidis > Propionibacterium acnes > Corynebacterium species

Normal Flora of Mucous Membranes • Nasal mucosa > Staphylococcus aureus – Methicillin-susceptible (MSSA) – Methicillin-resistant (MRSA) • Nasopharyngeal mucosa > Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis • Buccal mucosa > Viridans streptococci, Neisseria species, Haemophilus species, Lactobacillus species, Prevotella species, Porphyromonas species, Fusobacterium species, Peptostreptococcus species

Normal Flora of Mucous Membranes • Colon mucosa > Bacteroides fragilis group, Clostridium species, Escherichia coli and other Enterobacteriaceae, Enterococccus species, Lactobacillus species, Candida albicans • Vaginal mucosa > Lactobacillus species, Gardnerella vaginalis, Mobiluncus species, Prevotella species, Porphyromonas species

PROBIOTICS • Definition > Food and Agriculture Organization of UN (FAO) and WHO > ‘live microorganisms which when administered in adequate amounts confer a health benefit on the host’ • Microorganisms > > Bifidobacterium species Lactobacillus bulgaricus Lactobacillus casei Streptococcus thermophilus

The Innate Response to Bacterial Pathogens • Complement activation via alternative pathway • Phagocytosis of pathogens by > Macrophages – Long-lived cells – Secrete cytokines in innate and adaptive immunity – Function as professional APC’s > Neutrophils – Historically called “microphages” – Enter infected tissues in high numbers – Short-lived cells

Activation of Tissue Macrophages • Activated macrophages initiate inflammatory response by secreting > Cytokines > Inflammatory mediators • Cytokines (chemoattractant cytokines / chemokines) > IL-1, IL-6, IL-8, IL-12 and TNF-alpha • Inflammatory mediators > Prostaglandins, leukotrienes, plasminogen activator, platelet-activating factor (PAF)

Figure 8 -15

The Innate Response to Viral Pathogens • Virus infection of healthy cells results in production of > Interferon-alpha (IFN-alpha) > Interferon-beta (IFN-beta) • IFN-alpha and IFN-beta are type 1 interferons • Type 1 interferons > Inhibit virus replication > Activate natural killer (NK) cells > Increases expression of MHC-1 molecules

Figure 8 -25

Natural Killer (NK) Cells • Large granular lymphocytes that circulate in blood • Functions > Killing infected cells (cytotoxic) > Secretion of cytokines • Activation by > Type 1 interferons – Infected cells – Stimulates cytotoxic function > IL-12 and TNF-alpha – Macrophages – Stimulates cytokine secretion

Natural Killer Cells • Activated NK cells release IFN-gamma which activates > Macrophages – Release IL-12 • Positive feedback system for NK and macrophages • Differentiate infected from uninfected cells > NK cells express receptors for MHC class I molecules > Binding of NK cells to MHC class I molecules turn off NK cells • NK cells provide innate immunity to intracellular pathogens

Adaptive Immune Response • Environment for starting provided by innate immune response • Consists of > Primary immune response – Follows initial exposure to antigen – Naive B and T cells – Establishment of memory > Secondary immune response – Follows second exposure to antigen – Memory B and T cells – Utilization of memory

Primary Immune Response • Begins with T cell activation and differentiation in secondary lymphoid tissue > CD 4 TH 1, CD 4 TH 2 and CD 8 – Directed by cytokines • • • IL-12 and IFN-gamma (TH 1) IL-4 and IL-6 (TH 2) Continues with B cell activation in secondary lymphoid tissue > Cognate interaction with CD 4 TH 2 specific for same Ag

Role of T Cells in Primary Immune Response • Effector TH 1 cells > Leave 2 nd lymphoid tissue for infected tissue > Activate destruction of extracellular pathogens by macrophages • Effector CD 8 cells > Leave 2 nd lymphoid tissue for infected tissue > Kill infected cells • Effector TH 2 cells > Remain in 2 nd lymphoid tissue > Stimulates B cell differentiation into plasma cells

Role of B Cells in Primary Immune Response • Differentiation into plasma cells and antibody production • Locations for differentiation following CD 4 TH 2 cognate interaction > Medullary chords of lymph nodes – First wave of antibody secretion > Primary lymphoid follicles – Formation of germinal centers then migration to • Medullary chords of lymph nodes • Bone marrow – Second wave of antibody secretion

Secondary Immune Response • Adaptive immune response following second antigen exposure • Response is stronger and more rapid than primary • Classification > Short term (False) – 4 months or less following primary infection – Antibodies and effector T cells from naive lymphocytes > Long term (True) – 4 months or more following primary infection – Antibody and effector T cells from memory lymphocytes

Secondary Immune Response • No activation of naive B and T lymphocytes with specificity for pathogen • Mechanism for naive B cells > Suppression by – Immune complex (IC) of pathogen and Ig. G • IC’s bind to naive B cell > Receptor > Inhibitory Fc receptor (Fc-gamma. RIIB 1)

Clinical Application of Memory B Cell Activation • Prevention of > Hemolytic disease (anemia) of newborn • Hemolytic disease of newborn > Rh- mother with Rh+ fetus > Fetal RBC enter maternal circulation > No intervention – Maternal antibody against fetal RBC > Intervention with Anti-Rh, Ig. G (Rhogam) – No maternal antibody against fetal RBC

Immunological Memory and a Variant Pathogen • Infection with Influenza viruses > Influenza A and B viruses mutate surface antigens – Antigenic drift (A and B) – Antigenic shift (A) • Viral strategy > Erosion of protective immunity • Strategy of immune system > Respond to strains with epitopes previously encountered > IM limited to epitopes shared by infecting and original strain

Summary of the Immune Response • Ubiquitous response of innate immunity • Induced response of innate immunity • Adaptive response • Protective immunity • Immunological memory