Properties and Overview of Immune Responses

Abbas Chapter 1 David Robertson July 19, 2011

Immune Function
Defense against infectious
microbes

Microbial components Other proteins Vaccines, Allergy, Auto-immunity

General overview of the immune system. Primary function: 1. Defense against infectious microbes. 2. Because microbes are processed before presentation, other, non-infectious proteins can also be presented to the immune system and cause a reaction. Modulation of the immune system: variolation

Broken down into innate and adaptive in terms of immune reaction and components. Not a pure division: NK cells, macrophages. Innate immunity is more rapid on initial presentation, but also more general Adaptive takes longer to respond but is more specic. Innate immunity is in all multicellular organisms. Adaptive is only in vertebrates. Not pictured are cytokines, secretory molecules that: 1. link the two systems and 2. regulation 3. feedback and enhancement

Innate Immunity

Designed for immediate/rapid

response

Same response every time common pattern recognition.

First Line - Epithelial barrier Second Line - Cells

Innate immunity 1. 2. 3. 4. 5. Epithelial barriers (Immediate) APCs - Phagocytes, dendritic cells Complement cascade NK Cells Cytokines

Because the response is always the same, microbes have developed ways around them, necessitating the adaptive immune response. Epithelial barrier includes skin, airway, GI Antimicrobial effects, secreted oils, ciliary clearance Non-specic, Mechanical Once the epithelial border is breached there are two ways the innate immune ghts infection: #1 inammation

Innate Immunity

Inammation Anti-viral

Inammation APCs - Dendritic cells Cytokines - TNF-, IL-1, IL-6 Cells - Neutrophils, monocytes,

macrophages, NK cells, mast cells (TLRs)

Inammation = Cell recruitment APCs - Dendritic cells, macrophages. Process pathogens, recruit leukocytes through cytokines Cytokines Promote inammation, recruitment. Pyrogens. IL-6 promotes neutrophil proliferation, hepatic acute phase proteins, and B lymphocytes. Phagocytes cells - Neutrophils, Monocytes mature into macrophages. These cells have surface receptors that recognize foreign/ microbial components and produce reactive oxygen/nitrogen species. These receptors are germline encoded and do not undergo recombination.

Innate Immunity

PAMPs - Pathogen associated

molecular patterns

TLRs - Toll-like receptors Mannose Scavenger N-formyl methionyl

Pattern recognition receptors PAMPs - Same receptor recognize a antigen shared across an entire family of microbes also DAMPs - damage associated TLRs - Leucine rich hooks, cystine anking motif, TIR (Toll like IL-1 receptor) 9 kinds, each one recognize a different class of microbial components Mannose - phagocytosis, recognizes microbial sugar residues Scavenger - recognize oxidized lipoproteins including LPS and lipoteichoic acid N formyl methionyl - Structure on all bacterial but almost no mammalian proteins

Innate Immunity

Anti-Viral Functions Type I interferons - INF-, INF- Resistance, lymph sequestration,

increase NK cell activity

#2 Function: Antiviral Recognition of viral particles induces release of Type I interferons Effects: 1. Induce resistance to viral infection 2. Lymphocyte sequestration in the lymph nodes 3. Upregulate NK cell activity Used in the treatment of viral hepatitis (Hep C)

Innate Immunity

Complement Alternative Pathway Increased C3 activity Direct binding/activation Loss of C3 inhibition

LPS directly binds to C3 C3 always has some natural activity, but Mammalian cells have C3 inhibitors on cell surface Microbes dont and C3 can bind there begin cascade C3 deciency leads to severe, recurrent infections with encapsulates organisms, particularly S. pneumo and H u

Cytokines
Autocrine, Paracrine, Endocrine

IL-6 - Promotes antibody secretion by B cells IL-12 stimulates T 1 differentiation IL-15 promotes survival of memory CD8 T cells IL-1, IL-6, IL-23 stimulate T 17 effector cells
H + H
Autocrine - act on self Paracrine - Nearby Endocrine - Remote Already talked about TNF, IL-1, IL-6

Though Im presenting this linearly adaptive immunity is being stimulated while the innate system tries to hold off infection.

Adaptive Immunity
Specicity and diversity Specialization Memory Clonal expansion Contraction and homeostasis Self tolerance
Major players here are the lymphocytes, though once again cytokines will play a key role Using an army analogy, these guys are the specialists Much more active process, and failure at any one of these steps will cause disease

Adaptive Immunity
Specicity and Diversity

Epitope/Determinant Specialization Repertoire - 10 -10

7 9

Epitopes are the site on proteins that are immunologically active. Each lymphocyte recognizes 1 antigen or epitope Many proteins may have more than 1 (foods)

Adaptive Immunity

Humoral Extracellular Toxins Cell-Mediated Intracellular

Humoral vs Cell Mediated Active - Response to immune stimulus. Has memory Passive - Placental transfer, Specic antibody (tetanus), IVIG. No memory Together

Adaptive Immunity
CD19+

Cell Types
TH2 - IL-4, IL-5, IL-13 TH1 - INF-, IL-12, IL-18 TNF-

CD4+ CD8+ Multiple CD16,56+

Adaptive Immunity

Memory B cells Plasma Cells Memory T cells

Memory increased effectiveness B cells - Affinity maturation, better antibodies T cells have more vigorous and rapid response The secondary immune response is both more rapid and more vigorous

Adaptive Response
Two Signal Hypothesis

1. Capture and display of microbial antigens. APCs, same ones as in innate immunity present antigen to T cells. Most important probably dendritic cells. B cells can recognize soluble antigen directly, or have them presented to them. 2. Clonal expansion - There are subsets of lymphocytes that can recognize each antigen. A specic antigen will only be recognized by the corresponding lymphocyte. These cells then expand clonally to react to the specic agent. 2 signal hypothesis - 1st antigen in appropriate presenting molecule (MHC I) 2nd costimulators. 3. Differentiation - T cells. CD4+ T cells secrete IL-2 which supports T cell proliferation and maintenance. Recruit leukocytes, stimulate CD8 cells and B cells. CD8 cells differentiate into CTLs that destroy infected cells.

Adaptive Response
Two Signal Hypothesis

1. Capture and display of microbial antigens. APCs, same ones as in innate immunity present antigen to T cells. Most important probably dendritic cells. B cells can recognize soluble antigen directly, or have them presented to them. 2. Clonal expansion - There are subsets of lymphocytes that can recognize each antigen. A specic antigen will only be recognized by the corresponding lymphocyte. These cells then expand clonally to react to the specic agent. 2 signal hypothesis - 1st antigen in appropriate presenting molecule (MHC I) 2nd costimulators. 3. Differentiation - T cells. CD4+ T cells secrete IL-2 which supports T cell proliferation and maintenance. Recruit leukocytes, stimulate CD8 cells and B cells. CD8 cells differentiate into CTLs that destroy infected cells.

Adaptive Response
Two Signal Hypothesis

1. Capture and display of microbial antigens. APCs, same ones as in innate immunity present antigen to T cells. Most important probably dendritic cells. B cells can recognize soluble antigen directly, or have them presented to them. 2. Clonal expansion - There are subsets of lymphocytes that can recognize each antigen. A specic antigen will only be recognized by the corresponding lymphocyte. These cells then expand clonally to react to the specic agent. 2 signal hypothesis - 1st antigen in appropriate presenting molecule (MHC I) 2nd costimulators. 3. Differentiation - T cells. CD4+ T cells secrete IL-2 which supports T cell proliferation and maintenance. Recruit leukocytes, stimulate CD8 cells and B cells. CD8 cells differentiate into CTLs that destroy infected cells.

Adaptive Response
Two Signal Hypothesis

1. Capture and display of microbial antigens. APCs, same ones as in innate immunity present antigen to T cells. Most important probably dendritic cells. B cells can recognize soluble antigen directly, or have them presented to them. 2. Clonal expansion - There are subsets of lymphocytes that can recognize each antigen. A specic antigen will only be recognized by the corresponding lymphocyte. These cells then expand clonally to react to the specic agent. 2 signal hypothesis - 1st antigen in appropriate presenting molecule (MHC I) 2nd costimulators. 3. Differentiation - T cells. CD4+ T cells secrete IL-2 which supports T cell proliferation and maintenance. Recruit leukocytes, stimulate CD8 cells and B cells. CD8 cells differentiate into CTLs that destroy infected cells.

Adaptive Response
Two Signal Hypothesis IL-2 CTLs T cell dependent Class switching

3. B cells. Polysaccharides, nucleotides, glycolipds antigens are T cell independent. Protein antigens require presentation by T helper cells. Activated B cells produce antibodies. First IgM, then other types through class switching, also T helper cell dependent. 4. Elimination - Neutralization, opsonization, complement activation, phagocytosis 5. Apoptosis - Stimulatory cytokines fade and effector cells undergo apoptosis, through the FAS:FASL system. Mutations cause ALPS (autoimmune lymphoproliferative syndrome). 6. Memory cells remain.

Adaptive Response
Two Signal Hypothesis IL-2 CTLs T cell dependent Class switching Complement activation
3. B cells. Polysaccharides, nucleotides, glycolipds antigens are T cell independent. Protein antigens require presentation by T helper cells. Activated B cells produce antibodies. First IgM, then other types through class switching, also T helper cell dependent. 4. Elimination - Neutralization, opsonization, complement activation, phagocytosis 5. Apoptosis - Stimulatory cytokines fade and effector cells undergo apoptosis, through the FAS:FASL system. Mutations cause ALPS (autoimmune lymphoproliferative syndrome). 6. Memory cells remain.

Adaptive Response
Two Signal Hypothesis IL-2 CTLs T cell dependent Class switching Complement activation
3. B cells. Polysaccharides, nucleotides, glycolipds antigens are T cell independent. Protein antigens require presentation by T helper cells. Activated B cells produce antibodies. First IgM, then other types through class switching, also T helper cell dependent. 4. Elimination - Neutralization, opsonization, complement activation, phagocytosis 5. Apoptosis - Stimulatory cytokines fade and effector cells undergo apoptosis, through the FAS:FASL system. Mutations cause ALPS (autoimmune lymphoproliferative syndrome). 6. Memory cells remain.

Summary
Innate, Adaptive Specicity, diversity, memory, homeostasis, tolerance B lymphocytes, T lymphocytes Active, passive CD4 , CD8 Cytokines are the glue
+ +

Questions?