Innate immunity: mechanism
Germline encoded
Innate immunity: resistance
Resistance persists through generations
Does not change within an organism’s lifetime
Innate immunity: response to pathogens
Nonspecific Occurs rapidly (minutes to hours)
Innate immunity: physical barriers
Epithelial tight junctions, mucus
Innate immunity: secreted proteins
Lysozyme, complement, CRP, defensins
Innate immunity: Key features in pathogen recognition
Toll-like receptors (TLRs): pattern recognition receptors that recognize pathogen associated molecular patterns (PAMPs)
Examples: LPS, flagellum, nucleic acids
Adaptive immunity: components
TCs, BC, circulating Ab
Adaptive immunity: Mechanism
Variation through V(D)J recombination during lymphocyte development
Adaptive immunity: Resistance
Microbial resistance not heritable
Adaptive immunity: response to pathogens
Highly specific, refined over time
Develops over long periods; memory response faster and more robust
Adaptive immunity: Secreted protein
Immunoglobulins
Adaptive immunity: Key features in pathogen recognition
Memory cells: activated BC and TC
Subsequent exposure to a previously encountered Ag = stronger and quicker immune response
MHC
Encoded by HLA genes
Present Ag fragments to TCs and bind TCRs
MHC I: Loci
HLA-A, HLA-B, HLA-C
MHC I: Binding
TCR & CD8
MHC I: Expression
Expressed on all nuclear end cells
Not expressed on RBCs
MHC I: function
Present endogenously synthesized Ag (eg viral or cytosolic proteins) to CD8+ CTCs
MHC I: Ag loading
Ag peptides loaded onto MHC I in RER after delivery via TAP (transporter associated with antigen processing)
MHC I: associated proteins
Beta2 microglobulin
MHC II: Loci
HLA-DP, HLA-DQ, HLA-DR
MHC II: binding
TCR and CD4
MHC II: Expression
Expressed on APCs
MHC II: function
Present exogenously synthesized Ag (eg bacterial proteins) to CD4+ ThCs
MHC II: Ag loading
Ag loaded following release of invariant chain in an acidified endosome
MHC II: associated proteins
Invariant chain
HLA subtypes & diseases: A3
Hemochromatosis
HLA subtypes & diseases: B8
Addison disease
Myasthenia gravis
HLA subtypes & diseases: B27
Psoriatic arthritis Ankylosis get spondylitis IBD-associated with arthritis Reactive arthritis (formerly Reiter syndrome) *PAIR or seronegative arthropathies*
HLA subtypes & diseases: DQ2/DQ8
Celiac disease
I ate (8) too (2) much gluten at Dairy Queen
HLA subtypes & diseases: DR2
Multiple sclerosis
Hay fever
SLE
Goodpasture syndrome
HLA subtypes & diseases: DR3
Diabetes Mellitus type I SLE Graves' disease Hashimoto thyroiditis Addison disease
HLA subtypes & diseases: DR4
Rheumatoid Arthritis
Diabetes Mellitus type 1
Addison disease
there are 4 walls in a “rheum” (room)
HLA subtypes & diseases: DR5
Pernicious anemia (vitamin B12 deficiency) Hashimoto thyroiditis
Natural Killer cells
Use perforin and granzymes to induce apoptosis of viral infected cells or tumor cells
Lymphocytic member of innate immune system
Activity enhance by IL-2, IL-12, IFN-alpha & IFN-beta
Induced to kill when expose to a nonspecific activation signal on target cell and/or to an absence of class I on MHC on target cell surface
Also kills via Ab-dependent cell-mediated cytotoxicity (CD16 binds Fc region of bound Ig, activating NK cell)
TC functions
CD4+ TCs - help BCs make Ab and produce cytokines to recruit phagocytes and activate other leukocytes
CD8+ TCs - directly kill virus-infected cells
Delayed cell mediated hypersensitivity (type IV)
Acute and chronic cellular organ rejection
BC functions
Recognize Ag - undergo somatic hypermutation to optimize Ag specificity
Produce Ab - differentiate into plasma cells to secrete specific immunoglobulins
Maintain immunologic memory - memory BCs persist and accelerate future response to Ag
Positive selection of TCs
Thymic cortex
TCs expressing TCRs capable of binding self-MHC on cortical epithelial cells survive
BINDING TO SELF = SURVIVE
Negative Selection of TCs
Thymic medulla
TCs expressing TCRs with high affinity for self-Ag undergo apoptosis
TOO HIGH OF AFFINITY FOR SELF= APOPTOSIS
Tissue restricted self Ag are expressed in thymus due to the action of autoimmune regulator (AIRE); deficiency leads to autoimmune polyendocrine syndrome-1
Helper TCs: Th1
Secretes IFN-gamma
Activates MPs & CTCs
Differentiation induced by IFN-gamma and IL-12
Inhibited by IL-4 and IL-10
Helper TCs: Th2
Secretes IL-4, IL-5, IL-10, IL-13
Recruits eosinophils for parasite defense and promotes IgE production by BCs
Differentiation induced by IL-4
Inhibited by IFN-gamma
MP-lymphocytic interaction
MPs and other APCs release IL-12 which stimulates TCs to differentiate into Th1 cells
Th1 cells release IFN-gamma to stimulate MPs
Helper cells are CD4+, which bind to MHC II on APCs
Cytotoxic TCs
Kill virus infected, neoplasticism, and donor graft cells by inducing apoptosis
Release cytotoxic granules containing preformed proteins (eg perforin, granzymes B)
CTCs have CD8 which binds MHC I on virus-infected cells
Regulatory TCs
Help maintain specific immune tolerance by suppressing CD4 and CD8 TC effector functions
Identification: CD3, CD4, CD25, FOXP3
Activated regulatory TCs produced anti-inflammatory cytokines (IL-10, TGF-beta)
Innate immunity: components
Neutrophils, MPs, monocytes, DCs, natural killer cells (lymphoid origin), complement
Naive TC activation
- DC (APC) samples and processes Ag
- DC migrates to the draining LN
- TC activation (signal 1): Ag is presented on MHC II and recognized on TCR on Th (CD4+) cell. Endogenous Ag is presented on MHC I to Th (CD8+) cell
- Proliferation and survival (signal 2): costimulatory signal via interaction of B7 proteins (CD80/86) and CD28
- Th cell activates and produces cytokines. Tc cell activates and is able to recognize and kill virus infected cells
BC activation and class switching
- Th activation as above
- BCR-mediated endocytosis; foreign Ag presented on MHC II and recognized by TCR on Th cell
- CD40 receptor on BC bind CD40 ligand (CD40L) on Th cell
- TH cell secretes cytokines that determine Ig class switching of BCs. BC activates and undergoes class switching, affinity maturation and Ab production
Ab structure and function
Fab (containing the variable/hypervariable regions) consisting of light (L) and heavy (H) chains recognizes Ag.
Fc region of IgM and IgG fixes complement
Heavy chain contributes to Fc and Fab regions
Light chain only contributes to Fab region
Fab region
Fragment, antigen binding
Determines idiotype: unique antigen-binding pocket
Only 1 antigenic specificity expressed per BC
Fc region
Constant
Carboxy terminal
Complement binding
Determines isotype- IgM, IgD, etc
Generation of Ab diversity (Ag independent)
- Random recombination of VJ (L) and VDJ (H) genes
- random addition of nucleotides by terminal deoxynucleotidyl transferase (TdT)
- Random combination of heavy and light chains
Generation of Ab diversity (Ag dependent)
- Somatic hypermutation and affinity maturation (variable regions)
- Isotype switching (constant region)
Immunoglobulin isotypes
All isotypes can exist as monomers
Mature, naive BCs prior to activation express IgM and IgD on their surfaces. They may differentiate in germinal centers of LNs by isotype switching (gene rearrangement; mediated by cytokines and CD40L) into plasma cells that secrete IgA, IgE, or IgG
IgG
Main Ab in second (delayed) response to Ag
Most abundant isotype in serum
Fixes complement, crosses placenta (provides infant with passive immunity), opsonizes bacteria, neutralizes bacterial toxins and viruses
IgA
Prevents attachment of bacteria and viruses to mucous membranes; does not fix complement
Monomer (in circulation) or dimer (with J chain) when secreted)
Crosses epithelial cells by transcytosis
Produced in the GI tract (eg Peyer patches) and protects against gut infections (eg Giardiasis)
Most produce Ab overall, but lowest serum concentrations
Released into secretions (tears, saliva, mucus) and breast milk.
Picks up secretory component from epithelial cells, which protects the Fc portion from luminal proteases
IgM
Produce in the primary (immediate) response to Ag.
Fixes complement but does not cross the placenta
Ag receptor on the surface of BCs
Monomer on the BC, pentamer with J chain when secreted (enables bid gin to Ag while humoral response evolves)
IgD
Unclear function
Found on surface of many BCs and in serum
IgE
Binds mast cells and basophils
Cross-links when exposed to allergen, mediating immediate (type 1) hypersensitivity through release of inflammatory mediators such as histamine
Mediates immunity to worms by activating eosinophils. Lowest concentration in serum
Ag type & memory: thymus-independent antigens
Ag lacking peptide component (eg LPS from gram - bacteria)
Cannot be represented by MHC to TCs
Weakly immunogenic
Vaccines often require boosters and adjuvants (eg pneumococcal polysaccharide vaccine)
Ag type & memory: thymus-dependent Ag
Ag containing a protein component (eg diptheria vaccine)
Class switching and immunologic memory occur as a result of direct contact of BCs with Th cells (CD40-CD40L interaction)