Immune Response: Healthy Animals Block 7 Exam

Two categories of immune response

1. innate immunity

2. adaptive immunity

Innate immunity

• sees via PAMPS

• evolutionarily older

• simple

• mucosal and skin surfaces

• fast reaction - always on

• less specific

• no adaptation

• same as primary response

Adaptive immunity

• sees via antigen

• evolutionarily newer

• complex

• lymphoid tissue

• slow reaction - days to weeks

• antigen specific

• adapts

• memory response

How are pathogens detected in innate immunity?

• self vs non self

• Pathogen Recognition Receptors (ex: TLRs)

• Pathogen-associated molecular patterns (ex: LPS)

How are pathogens detected in adaptive immunity?

• antigen

  • T cell bind peptides

  • B cell bind proteins

Pattern Recognition Receptors

• part of innate immune system

• recognize microbial PAMPs

• inside and outside of cells

Types of Patter Recognition Receptors

• Toll-like Receptors (TLRs)

• NOD-like Receptors (NLRs)

• Peptidoglycan-recognition proteins (PGRPs)

• Retinoic acid inducible gene (RIG)-like receptors (RLRs)

Pathway for PRRs

1. PAMPs (agonist)

2. PRRs (receptor)

3. Signal Transduction (messaging)

4. Gene Transcription (on switch)

Outside TLRs

• For bacterial infections

• ex: TLR1, TLR2, TLR4, TLR5, TLR6, TLR9

Inside TLRs

• for viral infections

• ex: TLR3, TLR7, TLR8, TLR9

TLR4

• senses lipopolysaccharide

• gram negative bacteria

TLR5

• senses flagellin

• bacteria

TLR7

• senses viral ss and ds RNA

• viruses

TLR9

• senses unmethylated CpG DNA

• bacteria and viruses

TLR activation

• activation of different combinations of PRRs result in different combination of gene expression and response

• different pathogens induce different inflammatory response

Acute phase response

• immediate molecular response following pathogen sensing

• secrete IL-1, IL-6, TNF-⍺ (cytokines)

What do cytokines act on?

• hypothalamus

  • sickness response = fever, anorexia, sleepiness, depression

• liver

  • production of acute phase proteins and iron sequestration

• bone marrow

  • induce white blood cell production

• immune cells

  • induce cytokine production, trafficking, and activation

Complement System

Family of proteins that interact sequentially to generate biologically active molecules that mediate numerous inflammatory functions

What does the complement system initiate?

enzyme cascade

What are the three complement pathway types?

• classical

• lectin

• alternative

Classical complement pathway

• triggered by antigen-antibody complexes

• requires time to induce adaptive immunity

Lectin complement pathway

• triggered by lectin binding to pathogen

  • lectin = protein that binds sugars, marks as non-self

Alternative complement pathway

• triggered directly by pathogen surfaces

End effect of complement pathway

• classical, lectin, and alternative pathways activate C3b (innate response)

  • cell lysis

  • inflammation

  • opsonization

  • activate other pathways

antigen

• substance that binds to lymphocyte receptor

• antibody generating molecule

• substance recognized by antibodies

• foreign material

  • infectious agent

  • environmental substances

  • chemicals

epitope

• part of antigen recognized by antibody

• if antigen is sentence, epitope is word

What happens when immune system recognizes self antigens as foreign

autoimmune disease

What makes a good antigen?

• foreign

• relatively higher does

• bigger

  • >10 kilo Dalton

• complex structure

  • tertiary

• biologically active

Why is unmethylated CpG recognized as foreign?

almost all self DNA is methylated CpG and microbial DNA is unmethylated CpG

How do T cells see antigens?

see pepride fragments of antigen presented with MHC molecule

How do B cells see antigens

recognize conformational epitopes (3-D shape)

Immune recognition of foreign

• innate immunity

  • recognize patterns

• adaptive immunity

  • antibody (B cell receptor)

  • T cell recoptor

Examples of bacteria antigens

• nucleic acid

• pili

• capsule

• cytosol, enzymes

• cell wall

• flagellum

• exotoxins

haptens

• small molecules that are too small to be recognized as foreign

• molecules bind to other larger molecules (carrier proteins)

  • recognized as foreign and elicit immune response this way

  • is how autoimmune drug reactions occur

Antibodies

• immunoglobulin (Ig)

• antigen-recognizing protein produced by B cells

• surface-bound or free in circulation

  • antibody = secreted by B cells, free

  • B cell receptor = surface bound to B cell

Structure of immunoglobulin

• chains

  • heavy chain (inner chain)

  • light chain (outer chain)

• region

  • constant

  • variable (on antigen binding sites)

• hinge

• two antigen binding sites

Heavy chains on antibody

• five distinct heavy chain types that are structurally and functionally different

• determine the Ig class (isotype)

  • can switch class by switching heavy chain

Ig classes

• IgA (alpha)

• IgG (gamma)

• IgM (mu)

• IgD (delta)

• IgE (epsilon)

Structure of Immunoglobulin

• hypervariable regions of Ig recognize contact regions on antigen

• on infectious organisms, contact regions are hypervariable

Fc region

• fragment crystallizable region

• tail portion of antibody

• interacts with Fc receptor present on innate immune cells

What are the effects of binding to Fc Region?

• opsonization

• cell lysis

• degranulation of mast cells

What are examples of innate immune cells?

• macrophages

• neutrophils

• eosinophils

• mast cells

Functions of antibody

• neutralization

• agglutination

• complement activation

• opsonization

neutralization

• antibodies coat organism’s surface or toxins and prevent binding

• major mechanism at mucosal surfaces

agglutination

antibodies bind to and form clumps of organisms which are opsonized and more appealing to phagocytes

complement activation

killing via formation of membrane attack complex

professional antigen presenting cells

• dendritic cells

• macrophages

• B cells

What makes antigen-presenting cells professional?

• readily present antigen using MHC II (and MHC I)

• loaded with PRRs

• great at eating external antigen and processing

• effective at processing/breaking down and presenting antigen

antigen processing

large antigen broken down into pieces that can be recognized by adaptive immune response (T cell = peptide and B cell = small protein)

Antigen presentation

For T cells to recognize antigen, it must be presented by MHC

MHC I

• endogenous antigen

• bound to MHC I molecules

MHC II

• exogenous antigen

• bound to MHC II molecules

effector cells

• >95% of lymphocytes produced during an infection

• short-lived

memory cells

• small percentage of lymphocytes produced during an infection

• long-lived

What do T cells split into?

• effector T cells

• memory T cells

What do B cells split into?

• effector B cell

• memory B cell

repertoire of animals B and T cells

• every T and B cell has its own unique specific antigen target in an animal

• determined by genetics of T cell receptor and B cell receptor

What happens after a T or B cell recognizes an antigen?

proliferation and differentiation of that specific cell

T cell differentiaiton

• CD8+

• CD4+

  • Th1

  • Th2

CD4+ cell

• helper T cells

• organizer cell via cytokine signals

• respond to MHC II

CD8+ cell

• cytotoxic T cells

• respond to MHC I

• attackers

What are the mechanisms of cytotoxic T cells?

• granzyme/perforin cell lysis

• cytokines (TNF-a and IFN-y)

• FasL/Fas interactions

Th1 cell

• cell-mediated immunity and production of limited IgG. profile

• best for viruses and intracellular bacteria

• produces IL-2 and IFNy

Th2 cell

• humoral immunity

  • IgG

  • IgA

  • IgE

• best for extracellular organisms

• produces IL-4, IL-5, IL-9, IL-13

IgG

• highest Ig concentration in blood

• primary component of secondary immune response

• major roles in opsonization, toxin neutralization, and antigen agglutination

IgE

• major role in hypersensitivity (allergic) responses and immunity to parasites

IgM

• second highest concentration in blood

• primary component of primary immune response

IgA

• secreted across epithelial barriers

adaptive immune response trends

• first exposure has IgM produced first with shift to IgG

• once pathogen is cleared IgG and IgM decrease but IgG remains higher due to memory B cells

• second exposure has IgG peaking higher and sooner because of memory cells

What happens after pathogen is cleared?

• 99% of T cells and B cells die by apoptosis = contraction

• small population of long-lived antigen-specific T and B cells remain = memory T cells

IL-8 response

neutrophil recruitment (chemotaxis)

IL-12 response

• activate T cells (Th1)

• induces NK cell IFNy production

IL-1, IL-6, TNFa response

• acute phase response (inflammatory cell activation)

• vasodilation and leakage (hyperemia and edema)