Immune System Intro

Innate Immune Response

-Inflammatory response
-detection and clearance of pathogens by complement and macrophages
-activation of complement system and macrophages triggers local
inflammatory response leading to recruitment of more effector cells
-activation of dendritic cells leads to initiation of adaptive immune response
-mediated by proinflammatory molecules (eg. Cytokines) that cause
increased vascular permeability and extravasation of leukocytes
Adaptive Immune Response
-complements the ongoing innate immune response
-selection of pathogen-specific lymphocytes
-involves the interaction with innate immune response (DC cells)
-involves the selection and expansion of lymphocytes (T + B Cells) with
specific receptors
Major components of the immune system
-cellular components
-all derived from hematopoietic stem cells
-Neutrophil (40-75% - acute bacterial infection), eosinophil (1-6% parasite/allergy), Basophil (<1%), Monocyte (2-10% - chronic infection/viral
infection), Lymphocyte (20-50%)
-Phagocytic Cells
-Macrophages
-Resident (extravascular), matured, and long-lived monocytes
-first phagocyte to sense the invading microorganism
-orchestrating the local response to infection
-engulfing pathogens and dead cell remains
-Neutrophils
-circulating in the blood; most numerous and most lethal
-recruited to sites of infection and engulf macrophage-pathogen
complex
-Eat and then die (pus = dead neutrophils, tissue cells, and
pathogens)
-Dendritic Cells
-antigen presentation cells that are not involved in killing, but
detect signals of infection and activation of adaptive immune
response
-present in tissues in contact with external environment (skin,
nose and lungs, stomach and intestine)
-migrates from sites of infection to draining lymph nodes and
acts as a bridge between innate and adaptive immune systems
(activated during the innate immune response)
-Granulocytes
-Basophils and Mast Cells
-Basophils circulate in the blood, mast cells reside in tissues
(connective tissue, mucosa, near blood vessels)
-Surface receptor for IgE
-Activated after antigen binds to a specific type of antibody (IgE)

-Activated mast cells release inflammation substance (ig.

Histamine)
-Mast cells are also important to innate response to protect from
infection (in addition to allergic response)
-Lymphocytes
-T + B Cells: major cells involved in adaptive immunity
-B cells: antibodies
-T cells: CD4 (Helper) and CD8 (cytotoxic) T cells
-Involved in adaptive immune response
-Have specific receptor that recognize specific antigen
-Largely localized in lymphoid tissues
-Primary lymphoid tissues
-bone marrow (B+T development; B cell maturation) and thymus
(T cell maturation)
-Secondary lymphoid tissues
-spleen, adenoids, tonsils, appendix, lymph nodes, and peyers
patches
-sites where adaptive immune response is developed
-Adaptive Immunity initiated in Secondary Lymphoid Tissues
-Skin draining lymph nodes prevents entry of pathogen
into circulation
-Blood spleen (no lymph circulation) removes pathogen
that gains entry to circulation
-Oral gut-associated lymphoid tissue (GALT)
-NK Cells
-large granular lymphocyte
-involved in INNATE immunity and kill of virus-infected and
mutated cells
-non-cellular components
-complements
-cytokines: proteins made by immune cells that affect the behavior of other
cells
-chemokines: small proteins involved in guiding white blood cells to sites
where their functions are needed
Acquired Immunity
-Natural Immunity
-Active Immunity
-Developing immunity through pathogen/microbe exposure
-Passive Immunity
-Receiving immunity made by another person (motherchild)
-Artificial Immunity
-Active Immunity
-immunization
-Passive Immunity
-IVIG immunity made by another person

B-Cells and Antibody

Acquired/Adaptive Immunity
-Specific resistance to certain pathogens/antigens
-slow starting needs nonspecific defenses to be engaged
-immune memory faster response on repeat exposure
-Types: B-cell immunity (antibody, humoral) and T cell immunity (cellular immunity)
Terms
-Antibody: anti-foreign body is a protein produced by a white cell (B lymphocyte)
-Antigen: antibody generating substance is any agent, such as a chemical or
microorganism that is recognized by the antibody. Not all Antigens are
immunogens (eg. Hapten)
-Immunogen: any substance to which an animal responds by making antibodies. All
immunogens are antigens.
-Hapten: low molecular weight compounds (such as plant hormones) that typically
do not elicit a spontaneous immune response but can be recognized by antibodies.
Typically attached to a carrier molecule (eg. Albumin).
Membrane Bound Immunoglobulin
-Antigen specific proteins produced by B lymphocytes
-Belong to immunoglobulin super family
-proteins with structural feature first defined in immunoglobulins
-characteristic structural feature
-sequence of domains providing stable conformation
-Doman ppt chain folded into sandwich held together by
disulfide bond
-Superfamily members Antibodies, B cell receptors, T cell receptors, MHC
molecules and others
-Bound to surface of B lymphocytes
-function as binding/receptor sites for specific antigens
-IgM and IgD antigen receptor sites are on mature B lymphocytes
-Membrane bound form of immunoglobulin
Antibodies
-Structure
-glycoproteins composed of PPT chains and carbohydrate
-Monomeric structure
-ppt chains
-2 identical HEAVY chains
-2 identical LIGHT chains
-joined by disulfide bonds
-carbohydrate
-Variable and Constant Regions
-Variable: N-terminal of ppt chain
-antigen binding site formed by hypervariable regions
-heavy and light chain V domain
-not variable to the same degree

-Hypervariable regions (Complementarity-determining

Regions/CDR)
-amino acid sequence differences concentrated
-flanked by less variable framework regions
-three hypervarible regions in each variable domain
-Constant: C-terminal of ppt chain
-binding site for cell surface receptors and complement
-Y-shaped molecule cleaved by protease papain into Fab and Fc
Classes/Isotypes of Immunoglobulins
-Classes based on constant region of heavy chains
-IgA,D,E,G,M
-differentiation of heavy chains
-length of C region, location of disulfide bonds, hinge region,
distribution of carbohydrate
-classes have different effector functions
-Variable regions: determines specificity/what to bind
-Constant regions: determines how it works/effector functions
-Additional classification based on light chains
-kappa and lambda
-each Ig has either or, not both
-no functional differences b/t light chains
Affinity and Avidity
-Affinity: strength of binding b/t a singl binding site and single ligand
-Avidity: strength of binding b/t a molecule and a complex ligand (eg. Multiple
binding sites increases avidity)
Generation of Ig Diversity
-Germline Ig gene organization joining of gene segments to form a Ig gene
-heavy chain
-heavy-chain locus on chromosome 14
-diversity (D) gene segments that lies between arrays of V and J gene
segments
-light chain
-kappa light chain locus on chromosome 2
-gamma light-chain locus on 22
-gene segments that encode light-chain V region
-variable (V) and joining (J) gene segments
-Ig gene rearrangement/somatic recombination
-during B cell development, VDJ segments are recombined
-Junctional Diversity
-when D and J are joined together, the DNA is excised and random
sequences are added in between the D and J gene sequences to
increase diversity
-allelic exclusion
-in developing B cell, process of immunoglobulin-gene rearrangement
is tightly controlled so that only one heavy chain and one light chain
are finally expressed
-Mechanism of Ig diversity after encountering Ag
-Membrane bound Ig vs. secreted AB

-during B-cell differentiation, RNA splicing accounts for secreted Ab to

not have the hydrophobic anchoring sequence that Membrane Bound
Ig has to insert into the membrane
-does not involve any DNA rearrangement
-Somatic hypermutation
-introduction of random single nucleotide substitutions (point
mutations) throughout V regions of H and L chains
-mechanism poorly understood
-more common in hypervariable regions (CDRs)
-another form of diversification occurring in V domain following antigen
activation of B-cells
-Isotype Switching
-process by which B cell changes class of Ig produced while preserving
antigenic specificity
-involves somatic recombination which attaches different heavy chain
constant region to variable region
-occurs only during active immune response
-mechanisms involves recombination b/t specific switch regions
-switch sequences (regions)
T Cell Development and Cellular Immunity
Development In Thymus
-Majority are and minority are
-develop from a common T-cell precursor
- is further distinguished into CD4 and CD8 co-receptors that recognized
MHC II and I respectively
Positive and Negative Selection
-Positive selection occurs when T cells recognize self-MHC molecules in the thymus
- receptor of thymocyte with self-peptide:self-MHC complex on epithelial
cells are tests and if peptide:MHC complex is bound within 3-4 days, then
positive signal is delivered to the thymocyte to permite maturation
-whichever interacting complex is present (MHCI/II), then the cell
becomes either CD8/CD4
-Negative selection occurs when T cells are specific for self antigens
-moderate or strong bonding cell lives
-TIGHT bonding apoptosis
-not all are killed of regulatory CD4 T cells
-distinguished from other CD4 T cells by expression of CD25 cells
on surface and FoxP3 (transcriptional repressor protein)
-when in contact with self-antigens by MHC II, regulatory T cells
do no proliferate, but respond by suppressing the proliferation of
nave T cells responding to self-antigens presented on the same
antigen-presenting cell
T Cell Mediated Immune Response
-Dendritic cells carry the antigen from infection site to the secondary lymphoid
tissue
-Immature Dendritic Cells = dendritic cells in skin and peripherial tissues
-Mature/Activated Dendritic Cells = In lymph nodes
-congregate in the outermost part of cortex where nave T cells are
(dendritic cells activate)
-Activation of nave T Cells

-requires minding with a peptide:MHC complex as well as a co-stimulatory

signal
-co-stimulatory signal is delivered to CD28 receptor on T cell from B7
molecule on dendritic cell
-B7: Co-stimulatory molecule
-CD28: Co-stimulatory receptor
-Proliferation and Differentiation By IL-2
-cytokine IL2 genes are activated when T cells are activated and are
synthesized by activated T cells and act on itself
-production of IL2 requires signals from CD28 co-receptor and co-stimulatory
-nave cells express a IL2 receptor that weakly binds, once the cell is
activated, an is added and strongly binds to IL2
-once IL2 binds, T cells progress through cell division
-Cyclosporin and tacrolimus inhibit IL2 production by disrupting
signals from T cell receptor
-rapamycin/sirolimus inhibits signaling from IL2 receptor
-T-Cell Anergy
-state where T cell cannot respond to any external signals as a result of only
the peptide:MHC binding and no B7/co-stimulation
-results in no IL2 production and no cell proliferation
-adjuvants from bacteria are microbial components that can have costimulatory activity
T Cell activation and differentiation
-CD4 Helper Cells
-TH1 help macrophages respond to intracellular bacterial infections and viral
infections
-differentiation is controlled by the T-bet transcription factor
-increase inflammation within infected tissues
-stimulated by IL12 and IFN-y
-first made during the innate immune response
-IL12 by dendritic cells and macrophages; IFN-y by NK cells
-TH17 help neutrophils respond to extracellular bacterial and fungal infections
-Differentiation controlled by transcription factor RORyT
-induced by IL1,6 or 23
-secrete IL17 that binds to the receptor on epithelial and stromal cells,
inducing the secretion of G-CSF and other chemo that recruit
neutrophils to infected tissue
-pts w/o IL17 candida infections
-IL22 induces bacterial proteins
-inhibited by IL2,4 and IFN-y
-TH2 help eosinophils, basophils, mast cells, and B cells respond to parasite
infection
-GATA3 transcription factor
-TFH responsible for activation of nave B cells and their differentiation into
antibody-producing cells
-Bcl6 transcription factor
-Treg control and limit the activities of other types of effector CD4 and CD8 T
cells
-FoxP3 transcription factor