Immunology Comprehensive Study

• 1. No secreted form
• 2. detects antigens from within cells using MHC Class molecules
• 3. Matures in thymus
• 4. No affinity maturation
• 5. CD4 = TH1 and TH2; MHC Class II
• 6. CD8 = cytotoxic; MHC Class I

• MHC class II-like molecule
• Catalyzes MHC class II CLIP removal
• Catalyzes MHC class II peptide binding
• Peptide editing
• Does not bind peptide
• Increased by IFN-γ

• Does not bind peptides
• Negative regulator of HLA-DM
• Not increased by IFN- γ

• Polygenic
• Polymorphic

• Human Leukocyte Antigen genes
• MHC class I and class II genes in humans

Within species variation at a gene locus

Sequence of one gene replaced by sequence of a different gene

• Replacement substitutions that change an amino acid
• Silent substitutions change codon but not amino acid

Set of anchor residues that allow binding to a given MHC class I or class II allele

Allogeneic T-cells that react to non-self MHC molecules

• Cause excessive production of T-cells
• Bind MHC class II already bound to antigen
• Bind TCR
• Creates systemic shock
• Suppresses adaptive immune response

• SE - Staphylococcal enterotoxins
• TSST - Toxic Shock Syndrome Toxins

• Immunological recognition
• Immune effector functions
• Immune regulation
• Immunological memory

• Common myeloid progenitor
• Macrophages
• Granulocytes
• Mast Cells
• Dendritic Cells

• Macrophages
• Granulocytes
• Mast Cells
• Dendritic Cells

• Innate system phagocyte
• In most tissue
• Mature form of monocytes
• Induce inflammation
• Secrete signal proteins
• General scavengers

• Neutrophils - innate system phagocytes
• eosinophils - involved in allergic inflammation reactions
• basophils - involved in allergic inflammation reactions

• Differentiate inside tissues
• Protect internal surfaces of body
• respond to parasitic worms
• cause allergic responses

• Antigen presenting cells (APC)
• Phagocytic
• Macropinocytosis
• activate T-cells

• Both adaptive and innate immune systems
• Common lymphoid progenitor
• NK
• Lymphocytes
• B-cells
• T-cells

• in bone marrow
• creates antigen specific lymphocytes and NK cells

• recognize and kill abnormal cells
• innate immunity

• Naive lymphocytes
• effector lymphocytes differentiate into B- and T- cells

• Mature in bone marrow
• enter bloodstream as naive mature B-cells
• BCR
• proliferate and differentiate into plasma cells
• produce antibodies and immunoglobulins
• can make memory cells

• TCR
• activated by antigen
• proliferate/differentiate into effector T-lymphocytes
• functions = cytotoxic, helper, regulatory
• can make memory cells

• bone marrow
• thymus
• generate lymphocytes

• lymph nodes
• spleen
• mucosal lymphoid tissues
• maintains mature lymphocytes and initiate adaptive responses

• periarteriolar lymphoid sheath
• b-cells along follicles of spleen

mucosa-associated lymphoid tissue

• Gut-associated lymphoid tissue
• M cells - microfold epithelia of Peyer's Patches in small intestines

Nasal-associated lympohoid tissue

• Bronchus-associated lymphoid tissue
• overlaid by M cells

• 1. Physical/chemical first defense barriers
• 2. innate response cells
• 3. macrophage secrete cytokines/ chemokines
• 4. cytokines affect nearby cells
• 5. chemokines attract cells out of blood
• 6. inflammation
• 7. Complement
• 8. inflammation

• Classical
• Lectin
• Alternative

• Initiated by binding of C1q to pathogen surface
• C1q binds c-reactive protein
• Binds antigen:antibody complexes
• Natural antibodies can bind C1q and activate
• C3 convertase = C4b2a

• Initiates by binding carbohydrate binding proteins (CBPs) to carbohydrate arrays on pathogen surface
• Homologous to classical pathway
• Mannose binding Lectin (MBL) acts like C1q
• C3 convertase = C2aC4b

• Initiated by binding spontaneously initiated C3 component to surface
• C3 convertase = C3bBb
• Does not depend on pathogen binding
• Tickover
• Acts as amplification loop for all three complement activation pathways

• Pattern recognition receptors
• recognize PAMPs
• includes: MBL, MMR, fMLP

• Pathogen associated molecular patterns
• Include: lipoteichoic acid, lipopolysaccharides, unmethylated DNA

• Mannose binding lectin
• free in plasma
• initiates lectin complement pathway
• binds phaogcytes

• Macrophage Mannose receptor
• similar to MBL

• Toll-like receptors
• 10 TLR genes
• produce protein for PAMPs
• limited repertoire
• cell surface receptors
• intracellular acting on endosome membranes (sense pathogen uptake)

• Detects common bacterial infections
• on Macrophages
• signal bacterial lypopolysaccharides (LPS)
• Represents Toll pathway

Signals microbial constituents: lipoteichoic acid (LTS) (Gram +) and Lipoproteins (Gram -)

• signals DS - RNA
• produces cytokine interferon

• Initiates with TLR-4
• CD-14 binds LPS
• TLR-4:MD-2 complex targets binds CD-14:LPS complex
• Causes transcript of factor NFκB

• Present in cytosol
• Similar to TLRs
• NOD-1
• NOD-2
• Acts in addition to TLR if both present
• Recognize bacterial cell-wall proteoglycans
• Activates NFκB

• Binds breakdown of (-) bacteria: iE-DAP
• Activates innate immunity
• encoded in CARD 4 gene

• Binds muramyl dipeptide of (-) and (+) bacteria
• induces α-defensins
• CARD 15 gene

• produces cytokines/chemokines
• cell surface expression of co-stimulatory molecules
• activates CD4 T-cells via MHC class II molecules
• Initiates adaptive immune response
• causes migration of APCs to lymph notes by cytokines (TNF- α)

• vehicle used to enhance antigenicity
• LPS co-injected with antigen to initiate co-stimulatory molecules necessary for adaptive memory response

• Secreted by activated macrophages
• induce responses by autocrine, paracrine, endocrine receptor binding
• hematopoietin family of groth homormones and innate and adaptive interleukins (IL)
• TNF family of adaptive and innate
• includes: IL-6, IL-1, IL-12, TNF- α

• chemoattractant cytokines recruit cells to infection
• produced by phagocytes/dendritic cells
• G-protein coupled receptors
• CXCL8 typical of family
• CC chemokines
• CXC chemokines

• Change conformation of leukocyte integrins adhesion molecules (extravasation)
• Direct leukocyte by chemokine gradient in extracellular matrix (increases toward infection site)

• promote migration of monocytes, lymphocytes, others
• 9 CC receptors (CCR 1-9)
• Example: CCL 2 induces monocyte migration to tissues for maturation to macrophages

• expressed on different cell types
• 6 CXC receptors (CXCR 1-6)
• Example: CXCL 8 promotes migration of neutorphils

• bacterial product
• acts like chemoattractant for neutrophils

• Selectins
• Integrins
• ICAMs

• cell adhsion molecule
• leukocyte recruitment
• membrane glycoprotein
• lectin-like domain binds carbohydrates
• binds fucosylated oligosaccharide ligands of leukocytes

• cell adhesion molecule
• binds ICAMs on endothelium to leukocytes
• causes tighter binding
• extravastion integrins: LFA-1, CR3

• intracellular adhesion molecules on endothelial tissue
• binds to integrins on leukocytes

Exude from a vessel into tissues

• 1. Selectins
• 2. ICAMs
• 3. Extravasation
• 4. Leukocyte migration via chemokine gradient

• P-selectin appears via cytokines, histamines, LPS produces E-selctin
• recognizes leukocyte moiety allowing reversible vessel wall adhesion

• leukocyte integrins LFA-1 and CR3
• increases adhesion of neutorphil
• bind proteoglycans to CXCL8 or chemokines causes conformational change

• leukocyte crosses endothelial wall
• diapedesis

• matrix associated chemokine gradient
• CXCL8: recruits neutrophils first
• CCL2: recruits monocytes second

• stimulated by endogenous pyrogens (TNF-α, IL-1B, IL-6) and exogenous pyrogens (via TLR-4 signaling E2)
• acts on hepatocytes
• induces 2 acute-phase proteins: C-reactive, MBL
• provides host with antibody like proteins with wide range pathogen specificity
• increases circulating neutrophils = leukocytosis

• cytokine acute phase protein
• binds phosphocholine of LPS
• Opsonizes
• activates classical pathway via C1q binding

• increased production during acute-phase repsonse
• opsonin for monocytes which do not express MMR

• proteins that interfere with viral replication
• IFN- α
• IFN- β
• IFN- γ (indirectly induced by virus)
• DS-RNA PAMPs recognized via TLR-3
• Activate RIG-1, MDA-5

• Janus-family tyrosine kinase induces transcription
• Oligoadenylated synthetase
• PKR kinase
• Mx

IL-12 + TNF-α stimulate NK cells to produce

immunoreceptor tyrosine-based activation motifs

• innate-like lymphocytes
• adaptive but act like innate
• no clonal expansion
• antigen receptors have decreased diversity due to few gene rearrangements
• not via MHC molecules - recognize antigens as consequence of infections

• IgM
• no somatic hypermutation
• Low pathogen affinity
• highly cross-reactive
• binds some self molecules
• not a consequence of infection

• antigen recognition molecules of B-cells
• each B-cell produces 1 specific Ig
• Secreted form = antibody

• B-cell receptors
• membrane-bound Ig on B-cell surface

• secreted Ig
• V-region = variable region antigen binds to
• C-region = constant region (inserted into B-cell membrane in membrane form) defines Ig effector function

• T-cell receptors
• V- and C-regions
• bind pathogenic peptide fragments associated with MHC class I & II molecules on cell surfaces

• IgM
• IgD
• IgG
• IgA
• IgE

• 2 x heavy chains (H chains) both the same
• 2 x light chains (L chains) both the same
• H chain defines class
• both H and L chains have V and C regions
• Fab fragments
• Fc fragments

• λ
• κ
• *given antibody has one or the other - not both*
• 2 Ig domains

• denoted by lowercase Greek letter of each type (α, γ, δ , μ, ε)
• defines Ig class
• four Ig domains

• Fragment Antigen Binding
• corresponds to 2 identical arms of antibody: complete light chain, V_H, C_H1
• antigen binding fragment of Ig

• Fragment crystallizable
• Ig fragment with no antigen binding activity
• functional differences
• C_H2 & C_H3

• Fragment Variable
• genetically engineered truncated Fab (V of H linked to V of L)
• small size allows easy tissue penetration
• potential tumor therapy

partial antigen that cannot alone elicit antibody response but can combine with anti-hapten molecules to produce antibodies

• Hv1
• Hv2
• Hv3 - most variable
• * outer loops for antigen binding

• complementarity determining regions
• composed of combination of VH and VL region for specificity

generating different combinations of H and L-chains

• Structure recognized by antibody
• conformational/discontinuous epitopes
• continuous/linear epitopes

• TCRα
• TCR β
• form heterodimers similar to Ig Fab

• polypeptide chains (α1 and α2) form peptide binding cleft/groove
• α3 + β2-microglobulin resemble Ig-like domain
• Bind preferentially to CD8 T-cells
• displays peptides from intervesicular pathogens
• binds peptide at endoplasmic reticulum
• on most cells except non-nucleated cells

• α1 +β1 = binding cleft
• preferentially binds CD4 T-cells
• displays peptide fragments from cystolic pathogens
• normally on b-cells, dendritic cells, macrophages
• stimulate b-cells, macrophages

• Recombination Signal Sequences
• noncoding DNA adjacent to points of recombination that guide Ig gene rearrangement

segment flanked by RSS with 12 bp spacer joins with one flanked by RSS with 23 bp spacer

• 1. combinatorial diversity
• 2. Junctional diversity
• 3. Different H- & L-chain combinations
• 4. Somatic hypermutation

palindromic sequences added to ends of gene segments

• non-template encoded
• added by TdT at SS-ends of coding DNA following hairpin cleavage

• 1. Recognized by Fc receptors on immune effector cells
• 2. binds complement and initiates compliment cascade
• 3. delivers antibodies to places unreachable without using active transport

• only in activated B-cells
• driven by antigen
• 3 mechanisms

• 1. Somatic hypermutation
• 2. Gene conversion
• 3. Class switching (recombination)
• all initiated by activation-induced cytidine deaminase (AID)

• induced by AID
• introduces point mutations into V region of both chains
• alters antigen affinity
• causes affinity maturation

• replaces blocks of gene sequence from V region with blocks from pseudogenes
• induced by AID

• induced by AID
• involves C region only
• replaces C μ with alternate isotype
• also called isotype switching
• irreversible DNA recombination
• stimulated by Tcell cytokines or pahtogenic mitogenic signals

• clones have increased affinity for antigen than original BCR
• selected preferentially for secretion

bubbles formed when RNA displaces non-template strand DNA

generation of peptides from intact antigen via modification of native protein

display of peptide at cell surface by MHCs

• ATP-binding Cassette
• mediates ATP-dependent transport
• TAP 1
• TAP 2

• viral interference of antigen presentation of MHC I molecules
• Targets TAP
• Retains MHCI:Peptide complex in E.R.
• dislocation by catalyzing degradation of newly formed MHC I molecules