HUMAN DEFENSE MECHANISMS

HUMAN DEFENSE MECHANISMS

Categories of Defense MechanismsCategories 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 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

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

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

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

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

PROBIOTICSPROBIOTICS

• 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

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

• 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 MacrophagesActivation 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 8-15Figure 8-15

The Innate Response to Viral Pathogens

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 8-25Figure 8-25

Natural Killer (NK) CellsNatural 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 CellsNatural 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 ResponseAdaptive 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 ResponsePrimary 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

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

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 ResponseSecondary 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 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

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

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 ResponseSummary 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