Lecture 3 - Antigens and Cytokines (Part 1)

Lymphocytes

recognize specific pathogens (technically small parts of specific pathogens)

Some non-self molecules…

don’t stimulate B and T cell responses by themselves (but with some modification they can)

Immunogen

molecule that, by itself generates adaptive immune response

Antigen (Ag)

is a molecule that can specifically bind to an antibody OR whose fragments can be recognized by T cell

• Antigens may or may not induce response in and of itself - not all Antigens are immunogenic

Immunogen and Antigen terms are basically

interchangeable

Influences on Host Response to Antigen (Ag)

Host Factors:

• Age

• Health

• Genetics

Host factor - Age

• Neonates (Newborns) - underdeveloped response; aided by maternal response

• Elderly - wanes

Host factor - Health

Stress, fatigue, other disease states, malnourishment

Host factor - Genetics

produce our own array of BCRs, TCRs, and MHC proteins

• involved in recognizing antigens and antigen fragments

• based on genes we inherit

• structures of these proteins determine the specific antigens/fragments that can bind

  • Non-covalent forces; physical constraints

Antigen factors

• Dose of Antigens

• Route of exposure

• Size

• Foreignness

• Composition, complexity of antigen

Dose of Antigen (Small doses)

often handled by innate immunity

Dose of Antigen (Large doses)

adaptive response can occur

The more antigen…

the greater the response (usually)

Too much antigen….

immune tolerance (we “tolerate”/don’t respond to it)

Route of Exposure - Intravenous

Antigen in blood; usually to spleen

Route of Exposure - Intradermal and Subcutaneous

Antigen in/under skin; usually to LNs (local lymph nodes)

Route of Exposure - Oral

Antigen is mucosa; usually to tissues of MALT (gut)

Antigen Factors

Size Foreignness, Composition, complexity of antigen, and ability to be processed and presented on MHC molecules

Antigen factors - Size

• Greater molecular weight → greater response

• Usually at least 10 kDa for response; most typically over 100 kDa

Antigen factors - Foreignness

• Less related to self → greater the response

  • Transplant from self (e.g., skin graft): “autoantigen”

  • Transplant from other humans: “alloantigens”

    • Immediate family, other relative, unrelated people

  • Transplant from animal: “heteroantigen”/xenotransplant

Antigen factors - Composition, complexity of antigen

• Potent inducers: proteins, polysaccharides

  • Protein structures: huge variation in shapes

    • Most potent inducers

    • Amino acids; primary → quaternary structures

• Carbs

  • Smaller, less variation than proteins

    • Less potent

  • Usu. glycoproteins, glycolipids

• Lipids, DNA

  • Usu. require “carrier” molecule to be immunogenic

• Synthetic materials: little/no variation

  • Simple repeating subunits; usually no response

Antigen Factors - Ability to be processed and presented on MHC molecule

• Antigens digested into smaller peptides/fragments

• Peptides attached to MHC, presented to T cells

• T cells can help activate B cells

• If it can’t be digested and/or presented:

• T & B cell responses to that antigen aren’t induced

Epitopes

the specific parts of antigens recognized by lymphocytes

Epitopes (function)

• Antigens usually have many epitopes

  • Stimulate many unique lymphocyte responses

    • Many points of attack against overall Antigen

• T cells recognize peptide fragments 

  • Often internal portion of larger molecule; internal epitopes

• B cell receptors/Antibodies bind external parts of Antigen 

  • No protein degradation needed

Linear Epitopes

• Consecutive amino acids recognized 

• Amino acids “in a line”

Conformational Epitopes

• Non-consecutive portions recognized at once

• Based on protein structure (conformation) 

Haptens

small, non-immunogenic substances

Haptens (function)

• Induce response when linked to a carrier substance 

• Antibodies to hapten can then be produced

• Can bind to BCRs/Antibodies

  • Alone: can’t cross-link BCRs to activate B cells

    • Cross-linking stimulates activation

  • Alone: can’t cross-link antibodies to precipitate out (diagnostic tests)

  • Hapten-carrier conjugate: cross-linking can occur

• Occurs naturally, in lab setting

Antigen-Host Relationship

• If autoantigens induce response; autoimmune disease possible

• Autoantigens, alloantigens, heteroantigens

• Heterophile antigens

  • Heteroantigens with highly similar structure

    • Cross-reactive antibodies can be produces

• ABO blood group antigens

  • A and B: sugars on RBCs

  • Similarity to certain bacterial structures

• Messenger proteins

  • Secreted by cells- response to:

    • Microbes/products

    • Other chemical messengers

• Act on other cells or itself

  • Paracrine (cell close by), autocrine (itself)

  • Endocrine (systemic, longer-range)

• Bind cytokine receptors on recipient cells

  • Certain functions induced or shut down

    • Transcription of genes (→ production of proteins)

    • Growth, differentiation

    • Inflammation/anti-inflammation

    • Inhibition/regulation of immune response

Traits of Cytokines

Redundancy, Pleiotropy, Synergy, and Antagonism

Redundancy

different ones having same effect

Pleiotropy

one having multiple effects

Synergy

additive effect of multiple cytokines

Antagonism

one exerts opposing effect on another

Usually act in network with other cytokines

• Several cell types responding to infection 

• Several pathways used to clear infection 

• Cytokine cascades

Cytokine Cascades

series of cytokine-producing steps culminating in an effect

Cytokine Normal regulation

pathogen is cleared and response wanes

Cytokine Dysregulation/inability to control

• “Cytokine storm” may occur

• Massive production; harmful effects

  • Fever, hypotension, hypoperfusion; shock 

  • Organ failure; disseminated intravascular coagulation 

Innate Response Cytokines

Effect excerted early after Antigen recognized

• Main effects: inflammation, anti-viral response

• Main examples:

  • Interleukin-1 (IL-1) family

  • Tumor necrosis factor-alpha (TNF-α)

  • Interleukin-6 (IL-6)

  • Transforming growth factor-beta (TGF-β)

  • Interferon-alpha (IFN-α) and interferon-beta (IFN-β)

  • Chemokines (different than cytokines)