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 > 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 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 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 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 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 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 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) 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 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 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 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 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 >CD4 TH1, CD4 TH2 and CD8 –Directed by cytokines IL-12 and IFN-gamma (TH1) IL-4 and IL-6 (TH2) Continues with B cell activation in secondary lymphoid tissue >Cognate interaction with CD4 TH2 specific for same Ag Begins with T cell activation and differentiation in secondary lymphoid tissue >CD4 TH1, CD4 TH2 and CD8 –Directed by cytokines IL-12 and IFN-gamma (TH1) IL-4 and IL-6 (TH2) Continues with B cell activation in secondary lymphoid tissue >Cognate interaction with CD4 TH2 specific for same Ag

Role of T Cells in Primary Immune Response Effector TH1 cells >Leave 2nd lymphoid tissue for infected tissue >Activate destruction of extracellular pathogens by macrophages Effector CD8 cells >Leave 2nd lymphoid tissue for infected tissue >Kill infected cells Effector TH2 cells >Remain in 2nd lymphoid tissue >Stimulates B cell differentiation into plasma cells Effector TH1 cells >Leave 2nd lymphoid tissue for infected tissue >Activate destruction of extracellular pathogens by macrophages Effector CD8 cells >Leave 2nd lymphoid tissue for infected tissue >Kill infected cells Effector TH2 cells >Remain in 2nd 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 CD4 TH2 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 Differentiation into plasma cells and antibody production Locations for differentiation following CD4 TH2 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 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 IgG IC’s bind to naive B cell >Receptor >Inhibitory Fc receptor (Fc-gammaRIIB1) 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 IgG IC’s bind to naive B cell >Receptor >Inhibitory Fc receptor (Fc-gammaRIIB1)

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, IgG (Rhogam) –No maternal antibody against fetal RBC 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, IgG (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 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 Ubiquitous response of innate immunity Induced response of innate immunity Adaptive response Protective immunity Immunological memory