Chapter 6 part 1 (Dr. Guervin) TEST 2 Flashcards
Protect from Infectious Pathogens
INNATE IMMUNITY:
- Natural, or native, immunity: Ready to react to infections even before they occur
- Specifically recognizes and combats microbes and damaged cells
ADAPTIVE IMMUNITY:
- Acquired, or Specific, immunity: consists of mechanisms that are stimulated by (“adapt to”) microbes and non-microbial substances
- Capable of recognizing microbial and non-microbial substances
Components of Innate Immunity
1) EPITHELIAL BARRIERS:
– Skin, gastrointestinal tract, and respiratory tract
– Provides mechanical barriers to the entry of microbes
– Produce antimicrobial molecules such as defensins
– Lymphocytes located in the epithelia combat microbes
2) PHAGOCYTIC CELLS:
– Monocytes and neutrophils circulate in blood and can
rapidly be recruited to any site of infection
– Macrophages (mature monocytes) are present in all tissues
a) Sense the presence of microbes and other offending agents
b) Ingest (phagocytose) invaders and destroy them
3) DENDRITIC CELLS:
- In epithelia, lymphoid organs, and most tissues
– Capture protein antigens and display peptides for recognition by T lymphocytes
– Stimulate the secretion of Cytokines
a) Mediators that play critical roles in inflammation and anti-viral
defense
4) NATURAL KILLER CELLS (NK):
– Early protection against many viruses and intracellular bacteria
5) OTHER CELLS:
– MAST Cells: produce many mediators of inflammation
– INNATE LYMPHOID Cells: look like lymphocytes but have features of innate immunity
6) PLASMA PROTEINS:
– COMPLEMENT System: Proteins that are activated by microbes using the Alternative and Lectin pathways
a) In Adaptive immunity it is activated by antibodies using the Classical pathway
– Mannose-Binding Lectin and C-reactive protein: Coat microbes and promote phagocytosis
– Lung Surfactant: Provides protection against inhaled microbes
Pattern Recognition Receptors
• Recognize microbial components that are shared among related microbes
a) Often essential for infectivity (thus cannot be mutated)
• Damage-Associated Molecular Patterns: recognize
molecules released by injured and necrotic cells
• Located in all the cellular compartments where microbes may be present
a) Plasma membrane receptors detect extracellular microbes
b) Endosomal receptors detect ingested microbes
c) Cytosolic receptors detect microbes in the cytoplasm
Toll-Like Receptors (TLRs)
- 10 TLRs in mammals - each recognizes a different set of microbial molecules
- Signal a common pathway that leads to the ACTIVATION of Transcription Factors:
a) NF-κB: stimulates Synthesis and Secretion of CYTOKINES and the Expression of ADHESION molecules
i) Critical for the Recruitment and Activation of leukocytes
b) Interferon Regulatory Factors (IRFs): stimulates production ANTIVIRAL Cytokines (type I interferons)
• Germline loss-of-function mutations affecting TLRs and their signaling pathways
a) Rare but serious immunodeficiency syndromes
NOD-like Receptors (NLRs)
- CYTOSOLIC Receptors
- Recognize a wide variety of substances
a) Products of necrotic cells (e.g., uric acid and released ATP)
b) Ion disturbances (e.g., loss of K+)
c) Some microbial products
• Several NLRs signal via the INFLAMMASOME (a cytosolic multiprotein complex)
a) Gain-of-function mutations in one of the NLRs result in a periodic fever syndrome, called AUTOINFLAMMATORY SYNDROME
i) Can treat with IL-1 Antagonists
• The NLR-Inflammasome pathway may also play a role in:
a) Gout
b) Obesity-associated type 2 diabetes
c) Atherosclerosis
d) Other
Other Receptors for Microbial Products
• C-type LECTIN Receptors:
- Plasma membrane of macrophages and dendritic cells
- Detect fungal Glycans and elicit inflammatory reactions
• RIG-like Receptors:
- Cytosol of most cell types
- Detect nucleic acids of viruses and stimulate production of antiviral cytokines
• G PROTEIN–COUPLED Receptors:
- Neutrophils, macrophages, and most leukocytes
- Recognize bacterial peptides containing N-formylmethionyl
• MANNOSE Receptors:
- Recognize microbial sugars (mannose) → phagocytosis of the microbes
Reactions of Innate Immunity
• INFLAMMATION
– Via cytokines, products of complement activation, and other mediators
• ANTIVIRAL defense
– Via Type I interferons
• Also provides STIMULUS for the Adaptive Immune response
Adaptive Immunity
- Develops later and is more powerful than innate immunity
- Consists of lymphocytes and their products (antibodies) – Highly diverse receptors recognize a vast array of foreign substances (antigens)
- 2 TYPES:
1) HUMORAL Immunity:
a) Protects against EXTRACELLULAR microbes and their toxins
b) Mediated by B Lymphocytes and Antibodies
2) CELL-MEDIATED (or cellular) immunity
a) Defense against INTRACELLULAR Microbes
b) Mediated by T lymphocytes
Cells of the Immune System: B and T Lymphocytes
• IMMUNE SURVEILLANCE:
– Constantly circulate via blood and lymphatics to lymphoid and other tissues
• LYMPHOCYTES:
– Naïve: not encountered the antigen for which they are specific
– Once they are activated by recognition of Antigens:
a) EFFECTOR Cells: eliminate microbes
b) MEMORY Cells: “remember” the antigen and can react rapidly and strongly to it in future encounters
Lymphocyte Diversity
• ~ 10^12 Lymphocytes (1 trillion) in a healthy adult
a) Recognize 107 to 109 (10 million to 1 billion) different antigens
• Lymphocytes can respond to Multiple Antigens, but once exposed to one
a) Undergoes CLONAL SELECTION (all lymph with same specificity are CLONES)
b) Number lymphs specific for any one antigen is:
i)
T Lymphocytes
• 3 types:
1) HELPER T lymphocytes stimulate B lymphocytes to make Antibodies and activate other leukocytes (e.g., phagocytes) to destroy microbes
2) CYTOTOXIC (CTLs) kill Infected Cells
3) REGULATORY T lymphocytes limit immune responses and prevent reactions against self antigens
• Majority of lymphocytes in blood and tissue are T lymphocytes
• Recognize specific cell-bound antigen via a specific TCR
a) 95% of these are Heterodimers made up of an α and a β Polypeptide chain
• αβ TCR recognizes antigens presented by Major Histocompatibility Complex (MHC) molecules on the surfaces of APC’s
a) This MHC restriction ensures that T cells see only cells-associated antigens
T Lymphocytes Cont
• Small population of mature T cells γδ TCR
a) Recognizes peptides, lipids, and small molecules, without assistance from MHC proteins
b) Aggregate at epithelial surfaces (e.g.skin,GIandurogenitaltracts)
• Small subset of NK-T cells express a very limited diversity of TCRs
a) Recognize Glycolipids that are displayed by the MHC-like Molecule CD1
• Other proteins that assist the TCR complex:
a) CD4 and CD8 (Mutually Exclusive)
i) ~60% of mature T cells are CD4+ and about 30% are CD8+
b) CD4+ T cells-CYTOKINE-Secreting helper cells that assist Macrophages and B lymphocytes
i) Bind to class II MHC molecules (coreceptor)
c) CD8+ T cells-CYTOTOXIC (killer) T lymphocytes (CTLs) that destroy host cells harboring microbes
i) Bind to class I MHC molecules (coreceptor)
B Lymphocytes
• ~10-20% of circulating lymphocytes
• Also present in:
– Lymphnodes,spleen,andmucosa-associatedlymphoidtissues
• B cells recognize antigen via the B-cell antigen receptor complex
a) Membrane-bound Antibodies of the IgM and IgD isotopes!!!!!!!!!!!!!!
b) Present on the surface of all Mature Naïve B Cells
c) After stimulation by Antigen, they develop into Plasma Cells
i) Can secrete 100s-1000s of antibody molecules per second
• Also part of the B-cell Antigen Receptor Complex:
a) Igα and Igβ proteins
• Other molecules that are essential for signaling:
a) Type 2 Complement Receptor (CR2,or CD21)
i) Also used by EPSTEIN-BARR VIRUS (EBV) to enter and infect B cells
b) CD40-receives signals from helper T Cells
Dendritic Cells
- Most Important APC for INITIATING T-cell responses
- Have numerous fine Cytoplasmic Processes
- Keys for ANTIGEN PRESENTATION:
a) Located at the right place to capture antigens
i) Under epithelia (Langerhans cells in the skin)
ii) Interstitia of all tissues where antigens may be produced
b) Express many receptors for capturing and responding to microbes
i) TLRs and lectins
c) Recruited to the T-cell zones of lymphoid organs in response to microbes
d) Express high levels of MHC and other molecules needed for presenting antigens to and activating T cells
• FOLLICULAR Dendritic Cells: GERMINAL Centers of lymphoid follicles in the Spleen and Lymph nodes
a) Trap antigens bound to antibodies or complement proteins
b) Present antigens to B cells and select the HIGHEST AFFINITY B cells
Macrophages
• MONONUCLEAR Phagocytes
• Process antigens from phagocytosed microbes and proteins
a) Present peptide fragments to T cells
• T cells can activate Macrophages and enhance
their ability to KILL ingested microbes
• PHAGOCYTOSE and DESTROY microbes that are Opsonized (coated) by IgG or C3b
Natural Killer (NK) Cells
• Function is to DESTROY Irreversibly stressed and abnormal cells:
a) E.g. VIRUS-Infected cells and TUMOR CELLS
b) Do so without prior exposure to or activation by these microbes or tumors
c) Early line of defense
- ~5-10% of peripheral blood lymphocytes
- Do not express TCRs or IG
- Surface molecules:
a) CD16 – an Fc Receptor for IgG
i) Lyse IgG- coated target cells–called Antibody-Dependent Cell- Mediated Cytotoxicity!!!!!!
b) CD56 – function not known
• Regulated by a balance between activating and inhibitory receptors
• Also secrete cytokines (IFN-γ)
a) Activates Macrophages to destroy Ingested Microbes
• NK cells are regulated by many cytokines:
a) IL-2 and IL-15 stimulate PROLIFERATION cells
b) IL-12 activates KILLING and SECRETION of IFN-γ
Innate Lymphoid Cells (ILCs)
• Recently identified (and still much to learn about them)
• Populations of Lymphocytes that LACK TCRs but PRODUCE Cytokines similar to T cells
a) NK cells are first defined ILC!!!!
b) Different subsets of ILCs produce IFN-γ, IL-5, IL-17, and IL-
22
• Functions of ILCs:
a) Early defense against infections
b) Recognize and eliminate stressed cells
c) Provide cytokines that influence the Differentiation of T lymphocytes
MHC Molecules
- Key role in Adaptive Immune system
- FUNCTION: Display Peptide Fragments of Protein Antigens
- Linked to many autoimmune diseases
• Involved in REJECTION of Transplanted Organs
a) Major Histocompatibility Complex
- MHC molecules are called HUMAN LEUKOCYTE ANTIGENS (HLA)
- Genes that encode HLA molecules are clustered on Chromosome 6
a) Highly POLYMORPHIC
b) Thousands of alleles of MHC genes
c) Individual’s HLA alleles are pretty unique
MHC Class I Molecules
- Expressed on ALL NUCLEATED CELLA and PLATELETS
- HLA-A, HLA-B and HLA-C
• Display peptides derived from proteins located in the cytoplasm
a) E.g. viral and tumor antigens
• Recognized by CD8+ T lymphocytes
b) “Class I MHC-restricted”
MHC Class II Molecules
• Mainly expressed on Macrophages, B cells, and Dendritic Cells!!!!!!!!
• Encoded by HLA-D region
– 3 subregions: HLA-DP, HLA-DQ, and HLA-DR!!!!!!
• Display Antigens that are internalized into vesicles
a) Typically from EXTRACELLULAR Microbes and SOLUBLE
Proteins
• Recognized by CD4+ T cells
a) “Class II MHC-restricted”
MHC Molecules Cont
• HLA Haplotype - Individuals inherit one set of HLA genes from each parent:
a) Typically TWO Different molecules for every locus
b) POLYMORPHISM = almost innumerable combination
c) Everyone is UNIQUE (except identical twins) – makes organ transplantation difficult
• Key roles in regulating T cell–Mediated Immune Responses
a) Determine what antigens a person reacts to
i) E.g.Ragweed Pollen
• Many AUTOIMMUNE and other diseases are associated with particular HLA alleles
Cytokines: Messenger Molecules of the Immune System
- Secreted proteins
- Mediate many cellular interactions and functions of leukocytes
• Can Act on the cells that produce them
a) Autocrine actions
• Can act on Neighboring cells
a) Paracrine
• Can act at a Distance
a) Endocrine
Cytokines contribute to different types of Immune Responses
• Innate immune responses – produced by Macrophages, Dendritic cells, NK cells and others
a) Induce inflammation and inhibit virus replication
b) TNF, IL-1, IL-12, type I IFNs, IFN-γ, and chemokines
• Adaptive Immune Responses – produced mainly by CD4+ T cells
a) Promote lymphocyte proliferation and differentiation and to activate effector cells
b) IL-2, IL-4, IL-5, IL-17, and IFN-γ
• Some Cytokines stimulate HEMATOPOIESIS
a) Called COLONY-STIMULATING FACTORS
b) Role is to INCREASE Leukocyte numbers
c) GM-CSF and IL-7!!!!!!
Cytokine and Therapy
• ANTAGONISTS:
a) Block harmful effects of Cytokines, Inflammation, and Tissue-Damaging responses
b) E.g. - Rheumatoid Arthritis
i) Dramatic responses to TNF antagonists!!!
• Administer Cytokines to BOOST Reactions:
a) E.g. - Hematopoiesis and defense against some Viruses
Tissues of the Immune System
• GENERATIVE Lymphoid Organs (Primary/central)
a) THYMUS: T cells develop
b) BONE MARROW: Production of all blood cells and where B lymphocytes mature
• PERIPHERAL Lymphoid Organs (Secondary):
a) Lymph nodes
b) Spleen
c) Mucosal and cutaneous lymphoid tissues
d) Tissues CONCENTRATE Antigens, Antigen-Presenting Cells, and Lymphocytes
i) Optimizes interactions among these cells and the DEVELOPMENT of Adaptive Immune responses
