Lecture 14 Notes

Understanding the Immune System

• Defends the host against infectious organisms• Triggered into action with any injury, in anticipation that microbes either

caused the injury or will become involved• Self vs. non-self• Foreign substances: microbes, proteins polysaccharides, synthetic

materials

1

Monday, March 3, 14

Understanding the Immune System

• Defends the host against infectious organisms• Triggered into action with any injury, in anticipation that microbes either

caused the injury or will become involved• Self vs. non-self• Foreign substances: microbes, proteins polysaccharides, synthetic

materials

1

Immune system can be divided up into innate and adaptive, which function coordinatively

Monday, March 3, 14

The Immune System

SARS virus

Parasite in red blood cell

Fungus

Bacteria

2Monday, March 3, 14

Markers of Non-Self

Non-self leukocyte

Antibody

Epitope Class I MHC protein

Epitope

Antibody

Antigen

Antigen

Bacteria

Non-self nerve cell

SARS virus

3Monday, March 3, 14

Recognition and effector pathwaysComponents of the innate system recognize structures that are characteristic of microbial

pathogens and are not present on mammalian tissues. Includes: - ! Double stranded RNA found in cells containing replicating viruses; induces cytokines

production by infected cells leading to destruction of the virus.- Unmethylated CpG DNA sequences characteristic of bacterial infections; induces

autocrine macrophage activation and more effective intracellular killing of phagocytosed organisms.

- N-formylmethionine peptides from bacterial protein synthesis. Binding to receptors on neutrophils and macrophages causes chemotaxis and activation. Can also be engendered by protein fragments released during complement activation, lipid mediators of inflammation and chemokine proteins released by stressed cells.

- Mannose rich oligosaccharides from bacterial or fungal cell walls. Engagement of receptors on macrophages will induce phagocytosis; soluble mannose-binding protein in the plasma opsonizes or enhances phagocytosis of microbes bearing mannose.

- Bacterial or fungal wall oligosaccharides directly activate complement and induce either direct microbial lysis or microbial coating with complement that enhances phagocytosis

- Phosphorylcholine in bacterial cell walls binds to circulating CRP, induces opsonization and also activates complement

- Lipopolysaccharide from certain (gram negative) bacteria binds to circulating LPS-binding protein which binds to CD14 surface molecules on macrophages. Cytokine response includes tumor necrosis factor and interleukin-12. Septic shock

- Teichoic acid from gram positive bacteria elicits responses comparable to LPS

Monday, March 3, 14

Markers of Self

Muscle cell

Nervecell

Epithelialcell

Leukocyte

Class I MHC self-marker protein

5Monday, March 3, 14

Markers of Self

Muscle cell

Nervecell

Epithelialcell

Leukocyte

Class I MHC self-marker protein

5

MHC = HLA in humans

Monday, March 3, 14

Markers of Self:Major Histocompatibility Complex

Antigenic peptide

Antigen-presenting cell uses MHC Class I or II

Cell membrane

MHC Class II

Antigenic peptide

Viral infection

Infected cell

MHC Class I

Antigenic peptide

MHC Class I

6Monday, March 3, 14

Markers of Self:Major Histocompatibility Complex

Antigenic peptide

Antigen-presenting cell uses MHC Class I or II

Cell membrane

MHC Class II

Antigenic peptide

Viral infection

Infected cell

MHC Class I

Antigenic peptide

MHC Class I

6

MHC I distinguishes self from non-self and presents fragments of intracellular proteins

Monday, March 3, 14

Markers of Self:Major Histocompatibility Complex

Antigenic peptide

Antigen-presenting cell uses MHC Class I or II

Cell membrane

MHC Class II

Antigenic peptide

Viral infection

Infected cell

MHC Class I

Antigenic peptide

MHC Class I

6

MHC I distinguishes self from non-self and presents fragments of intracellular proteins

Monday, March 3, 14

Markers of Self:Major Histocompatibility Complex

Antigenic peptide

Antigen-presenting cell uses MHC Class I or II

Cell membrane

MHC Class II

Antigenic peptide

Viral infection

Infected cell

MHC Class I

Antigenic peptide

MHC Class I

6

MHC I distinguishes self from non-self and presents fragments of intracellular proteins

MHC II are found on APCs, and presents fragments of extracellular proteins

Monday, March 3, 14

Cells of the Immune System Bone graft

Multipotentialstem cell

Hematopoieticstem cell

Platelets

Macrophage

ErythrocytesEosinophil

Neutrophil

Megakaryocyte

Mast cell

Basophil

T lymphocyte

Natural killer cell

Dendritic cell

B lymphocyte

Lymphoid progenitor cell

Myeloid progenitor

cell

Monocyte

Marrow

Bone

7Monday, March 3, 14

Cells of the Immune System Bone graft

Multipotentialstem cell

Hematopoieticstem cell

Platelets

Macrophage

ErythrocytesEosinophil

Neutrophil

Megakaryocyte

Mast cell

Basophil

T lymphocyte

Natural killer cell

Dendritic cell

B lymphocyte

Lymphoid progenitor cell

Myeloid progenitor

cell

Monocyte

Marrow

Bone

7produce ABs

Monday, March 3, 14

Cells of the Immune System Bone graft

Multipotentialstem cell

Hematopoieticstem cell

Platelets

Macrophage

ErythrocytesEosinophil

Neutrophil

Megakaryocyte

Mast cell

Basophil

T lymphocyte

Natural killer cell

Dendritic cell

B lymphocyte

Lymphoid progenitor cell

Myeloid progenitor

cell

Monocyte

Marrow

Bone

7produce ABs

some T cells kill cells with non-self markers

Monday, March 3, 14

Cells of the Immune System Bone graft

Multipotentialstem cell

Hematopoieticstem cell

Platelets

Macrophage

ErythrocytesEosinophil

Neutrophil

Megakaryocyte

Mast cell

Basophil

T lymphocyte

Natural killer cell

Dendritic cell

B lymphocyte

Lymphoid progenitor cell

Myeloid progenitor

cell

Monocyte

Marrow

Bone

7produce ABs

kill cells with no markers of self

some T cells kill cells with non-self markers

Monday, March 3, 14

Phagocytes in the Body

Brain: microglial cells

Joint:synovial A cells

Precursors in bone marrow

Lymph node: resident and recirculating

macrophages

Blood: monocytes

Kidney:mesangial phagocytes

Spleen: macrophages

Liver: Kupffer cells

Lung:alveolar

macrophages

8Monday, March 3, 14

Innate Immunity Complement System

• Will bind to biomaterial surfaces• Group of proteins in blood that must be activated by pathogens or certain

materials to exert their effect• Pathways of complement activation

– classical pathway– alternate pathway

• Mechanisms of action– enhanced inflammation(stimulates release of inflammatory chemicals)– opsonization (promotes phagocytosis)– cytolysis (membrane attack complex)

Monday, March 3, 14

Complement

C9Enzyme

C2

C5C3b

C3aC3

C4Antigen

IgG

C1 C8

C7

C6C5b

C5b

C5a

10Monday, March 3, 14

Immunity and Cancer

Antibody

Helper T cell

Natural killer cell

Cancer cell

Macrophage

Cytotoxic T cell

11

Monday, March 3, 14

Immunotherapy

Antibody

Breast cancer cell

Growth factor Herceptin blocks receptor

Growth slows

Radioisotope

Antigen

Lymphoma cell Lymphoma cell

destroyed

Herceptin

12

Monday, March 3, 14

Seven Major Classes of Cell-Surface Receptors

Receptors linked to trimeric G-proteinsReceptors with intrinsic or associated enzymatic activity

Pathways involving Proteolysis

changes in activity of existing proteins (sometimes changes in gene expression)

modulate gene expression

13

Monday, March 3, 14

Peptide Epitopes from Biomacromolecules

FibronectinRGDSLDV

REDVPHSRN

EDGIHELLIGRKK

FibrinogenRGDSRGDF

KQAGDV

Collagen IRGDTDGEA

VitronectinRGDV

LamininYIGSRPDGSRLRGDNIKVAVLREIKLLI

ElastinVGVAPG

OsteopontinSVVYGLR

Monday, March 3, 14

Monday, March 3, 14