IMMUNOLOGY MODULE 1-2

What is innate immunity?

Initial defense against infections

what is adaptive immunity?

develops later and are mediated by lymphocytes and their products

• learned response after you encounter so it will be faster to respond next time it invades

what cells are part of adaptive system?

• lymphocytes

  • B lymphocytes

  • T lymphocytes

  • NK cells

• antigen presenting cells

  • dendritic cells

what are antigens?

foreign pathogens

what are the type of adaptive immunity?

• humoral immunity

  • B lymphocytes secrete antibodies that eliminate extracellular microbes

• cell mediated immunity

  • different types of T lymphocytes recruit and activate phagocytes to destroy ingested microbes and kill infected cells

what is the difference between primary and secondary immune responses?

• primary

  • 1st exposure

  • mediated by lymphocytes called naive lymphocytes that are seeing antigens for the 1st time

• secondary

  • rapid, larger, and better at eliminating antigen than the primary

  • result in activation of memory lymphocytes

Difference between IgG and IgM

• IgG is not a specific antigen

• IgM is a specific antigen

what are different types of lymphocytes

• B lymphocytes

  • recognize soluble or cell surface antigens and differentiate into antibody-secreting cells

• helper T- lymphocyte

  • recognize antigens on the surfaces of APC and secrete cytokinesis

• cytotoxic T lymphocyte

  • recognize antigens in infected cells and kill those cells

• Regulatory T cells

  • limit activation of other lymphocytes- prevent autoimmunity

• NK cells

  • recognize changes on the surface of infected cells and kill these cells

What are CD3, CD4, CD8?

• surface markers (used to identify specific cells) on each lymphocytes

How does the immune system respond to an antigen?

• antibody binds an antigen directly, whereas a T receptor binds a complex of: an antigen fragment and a self molecule

• cells inside holding virus protein- then it won’t know so they pish them outside in order to alert

Differences between MHC I and MHC II

• MHC I

  • collect peptides derived from and synthesized in the cytosol and are this able to display fragments of viral and on the cell surface

  • present antigens derived from proteins in the cytosol

• MHC II

  • peptides derived from bacteria and transported to the cell surface

  • bind and transport peptides derived from antigen has been bound and internalized by B cells antigen receptors

what are cytokines?

• proteins released by cells that affect the behavior of other cells that bear receptors from them

• affect behavior of other cells

  • cells release message —> trigger response

what are chemokines?

• proteins that attract cells with specific chemokines receptors such as neutrophils and monocytes from the blood stream

• chemical molecule to recruit help

why do macrophages express a variety of receptors?

allows to recognize different pathogens

What are the significance of TLR2 and TlR4?

• TLR-pattern recognition receptor present on macrophages and other immune cells, and they are able to bind different microbial component

  • TLR 2-

    • cell wall components of gram positive

  • TLR 4-

    • cell wall components of gram negative

what type of immune system does macrophages have?

innate immunity—→ have many different type of antigen receptors

What are antigen presenting cells?

• capture antigens, transport them to peripheral lymphoid tissues, and display them to lymphocytes

What do antibodies do?

• antibodies

  • come from plasma cells

  • protect against pathogens or their products by binding to them blocking their accel to cells

What are neutralization, opsonization, and complement activation?

• neutralization

  • cite is bind and block access to cells

• opsonization

  • an immune process which use opsonin to tag foreign pathogens for elimination by phagocytes

  • coats the bacterium and foreign particles in order to mark

• complement activation

  • pathogen is lysed and then in activates through a triggered-enzyme cascade

What leukocytes are derived from the common myeloid progenitor cell and the common lymphoid progenitor cells?

• myeloid progenitor us the precursor of the

  • granulocytes, macrophages, dendric cells, and mast cells of the innate immune system

• the common lymphoid progenitor cells

  • lymphocytes (T &B) and to NK (innate immunity)

Describe the activated function of each leukocyte

• Neutrophils

  • direct actions against bacteria

    • release lysozyme which destroy bacteria

    • release defensin proteins that act like antibiotics poking holes in bacterial cell walls destroying them

      release strong oxidants (bleach-like, strong chemicals ) that destroy bacteria

• eosinophils

  • combat the effects of histamine in allergic reactions, phagocytize antigen-antibody complexes, and combat parasitic worms.

• basophils and mast cells

  • liberate heparin, histamine, and serotonin in allergic reactions that intensify the inflammatory response.

• B-lymphocytes

  • response to the presence of foreign substances called antigens, differentiate into tissue plasma cells that produce antibodies

  • memory cells

• T-lymphocytes

  • destroy foreign invaders directly

    • cd 8

• dendritic cells

  • mature antigen presenting cells

How do dendritic cells form a link between innate immune system and the adaptive immune system?

• adaptive immune response

  • pathogen ingested by an immature dendritic cell in the infected tissue

• Once absorbed travel through the lymph to the regional lymp nodes where they mature and interact with recirculating naive lymphocyte

• dendritic

  • behave as an innate system

What are PAMPS? What effect do Pamps have on the immune system?

• derived from microorganisms and recognized by pattern recognition receptor (PRR)-bearing cells of the innate immune system

difference between PAMPS and antigen

• PAMPs

  • evoke an innate response

• antigens

  • evoke an adaptive response if the innate response is not sufficient to eliminate the threat

describe the chain of events that occur during inflammation

• Infection Stimulates Macrophages to Release Cytokines and Chemokines that Initiate an Inflammatory Response

  • Cytokines cause the dilation of local small blood vessels and changes in the endothelial cells of their walls.

  • These changes lead to the movement of leukocytes, such as neutrophils and monocytes, out of the blood vessel (extravasation) and into the infected tissue, guided by chemokines produced by the activated macrophages.

  • The blood vessels also become more permeable, allowing plasma proteins and fluid to leak into the tissues.

  • Together, these changes cause the characteristic inflammatory signs of heat, pain, redness, and swelling at the site of infection

why increase blood flow where is pain coming from

• bring more leukocyte

• when the buildup of fluid leads to swelling, and the swollen tissues push against sensitive nerve endings

Reason behind fluid in inflammation site

• Interstitial fluid- lymphatic vessels (fluid drained)

  • Drainage of fluid to macrophages to “police/ t cells/ b cells”

  • Make plans for intruder

    • Designing “weapon” (DNA rearrangement)

  • Mass production

  • Attack (pathogens)

• To make the pathogens move to the leukocytes

Function of lymphatic system

• It keeps body fluid levels in balance and defends the body against infections

• Lymph- vessels, tissues, organs, and glands work together to drain a watery fluid called lymph from throughout the body

What are interferons and what do they do?

• INF:

  • Antiviral proteins produced by cells in response to viral infections

• 3 major functions:

  • Induce resistance to viral replication in uninfected cells

  • Induce MHC class 1 expression - more susceptible to be killed by CD8

  • Activate NK cells

Describe the complement system

• Complement proteins- Synthesized by the liver

• 3 pathways

  • Classical

    • initiated by the binding of C1q to the pathogen surface.

  • Lectin

    • initiated by the binding of carbohydrates binding proteins to arrays of carbohydrates on the surface of pathogens.

  • Alternative

    • initiated by the binding of spontaneously activated C3 in plasma to the surface of pathogens

Describe how terminal complement proteins form the membrane-attack complex?

• C5b triggers the assembly of a complex of one molecule each of C6, C7, and C8, in that order.

• C7 and C8 undergo conformational changes, exposing hydrophobic domains that insert into the membrane. \

  • causes moderate membrane damage

  • serves to induce the polymerization of C9, again with the exposure of a hydrophobic site.

Draw an antibody molecule structure

What are the 5 classes of immunoglobulin

• IgM

  • Produced after initial exposure to antigen

  • Promotes neutralization and agglutination of antigen

  • 5-6 days

• IgG

  • Crosses placenta- conferring passive immunity to fetus

  • Promotes opsonization, realization, agglutination of antigen

• IgA

  • Present in tears, saliva, mucus, and breast milk

  • Provides localization defense of mucous membrane by agglutination and neutralization of antigens

  • Presence in breast confers passive immunity

• IgE

  • Triggers release from mast cells and basophils of histamine and other chemicals that cause allergic reaction

• IgD

  • Present primary of surface of naive B-cells that have not been exposed to antigen

Which ones are monomers?

• IgG

• IgE

• IgD

Passive vs active immunity

• Active

  • Immune system responding to antigen 

• Passive 

  • Immune provided from someone else (

  • Antibodies not provided from the person 

    • Vaccines 

    • Mother’s

Explain what are hypervariable regions are on the body

Explain what complementary -determining region and variable framework regions are

• Hypervariable region

  • Form the antigen binding site

  • Sequence variability concentrated in certain segment of the v region

  • HYPER- why?

    • There are many variables

      • Variation

        • Because there are many variants to recognize many antigens

  • 3 regions

    • HV1, HV2, HV3

• Complementary-determining region (complementary to the antigen surface)

  • hypervariable immunoglobin (Ig) domains that confine specific antibody binding

  • CDR1, CDR2, CDR3

  • Where antibody binding site at

• Variable framework region

  • Fr1, Fr2, Fr3, fr4

  • Supporting part of antibody

  • Not part determining what antigen can bind

What is an epitope?

Structure (segment of antigen)  recognized by an antibody 

Draw and explain the structure of a t-cell receptor

• T-cell receptor

  • Composed of 2 transmembrane glycoprotein alpha and beta chains

  • extracellular portion of each chain consists of two domains

Draw and label various components of MHC molecules (class I and class II)

Describe the function of MHC molecules

Function:

• to bind peptide fragments derived from pathogens and display them on the cell surface for recognition by the appropriate T cells

• MHC class I

  • The T-cell receptor binds to the top of the: peptide: MHC class I complex.

    • Cytotoxic

      • Cd 8

• MHC class II

  • Recognized by Cd 4

What MHC properties made it difficult for pathogens to evade immune response?

• The function of MHC molecules is to bind peptide fragment derived from pathogens and display them on the cell surface for recognition by the appropriate T-cells

• Two separate properties of the MHC make it difficult for pathogens to evade immune responses:

  • Polygenic: it contains several different MHC class I and class II genes

    • That alone adds variation

  • Highly polymorphic: there are multiple variants of each gene within the population as whole.

Describe the different distribution of MHC class I and class II

• MHC I

  • present peptides from pathogens commonly viruses, to CD8 cytotoxic T-cells.

  • T-cells, B cells, macrophages, dendritic cells, epithelial cells of the thymus, neutrophils, hepatocytes

  • Kidney, brain

• MHC II

  • found on B lymphocytes, dendritic cells and macrophages (APC: Antigen presenting Cells)

  • T-cells, B-cells, macrophages, dendritic cells, epithelial cells of thymus

    • Mainly found on antigen presenting cells

Describe the different cellular locations that MHC class I and II obtain peptides

• Peptides from the cytosol are bound to MHC class I molecules and are recognized by CD8 T-cells, whereas

• Peptides generated in intracellular vesicles are bound to MHC class II molecules and recognized by CD4 T-cells.

What are ABC proteins and what do they do?

• ABC proteins mediate the ATP-dependent transport of ions, sugars, amino acids and peptides across membranes in many types of cells, including bacteria.

• The two ABC proteins normally associated with the Endoplasmic Reticulum Membrane are called:

  • Transporters Associated with Antigen Processing-1 and 2 (TAP-1 and TAP-2)

    • TAP1 and TAP2 form a peptide transporter in the Endoplasmic Reticulum Membrane

Why is sending peptides to the ER?

• MHC I is at 

• MHC can’t leave until bind to peptide

How does protein get degraded in cytosol?

• degraded are introduced into the core of the proteasome. and there are broken down into short peptides, which are then released

• The PA28 proteasome activator binds to either end of the proteasome

  • Proteasome found in cytosol

What are the immunoevasin produced by virus?

• Immune Evasion- process of blocking peptide from entering ER

  • Through TAP or MHC

  • From activating

    • Not have response for MHC class I

  • Dislocate MHC

• Overall- blockage

• Result of blockage

  • By blocking entrance to going to er

    • Interfere with binding = no presentation of peptide

  • Infected cells won’t be able to present to lymphocyte= won’t know about it

    • Infection will continue

• E19, us6, icp47

Describe the generation of MHC II bound peptide

• Generated in Acidified Endocytic Vesicles

• Antigen is taken to the apc cell then takes endosome activates ….

• Steps

  • Antigen is taken up form the extracellular space into intracellular vesicles

  • In early endosome of neutral ph, endosomal proteases are infective

  • Acidification of vesicles activates protease to degrade antigen into peptide fragments

  • Vesicles containing peptide fuse with vesicles containing MHC class II molecules

• pH= activates protease

Describe what invariant chain protein is and its function on MHC II is?

• The Invariant Chain Directs newly synthesized MHC class II Molecules to Acidified intracellular Vesicles

• forms trimers, with each subunit binding noncovalently to an MHC class II : heterodimer

• The Invariant Chain is cleaved to leave a peptide fragment, CLIP, bound to the MHC class II molecule

  • Cleaved so it can’t bind other peptides=

What is HLA-DM and what is its function?

• What it is:

  • HLA-DM is vital to the proper loading and presentation of peptides in macrophages, immature dendritic cells, B cells, and other antigen presenting cells(APC).

• Function

  • Facilitates the Loading of Antigenic Peptides onto MHC class II molecules

  • The class II molecule, HLA-DM, binds to MHC class II: CLIP complexes, catalyzing the release of CLIP and the binding of antigenic peptides

    • Make binding site available

  • Its in the endoplasm ER

Explain why t-cell recognition of antigen is MHC restricted?

• The co-recognition of a foreign peptide and MHC molecule is known as MHC restriction because the MHC molecule is said to restrict the ability of the T-cell to recognize antigen

• The antigen-specific T-cell receptor (TCR) recognizes a complex of an antigenic peptide and a self MHC molecule.

• T cell receptors binds to peptide + MHC

• Peptide MHC needs to be specific for T cell receptors- can’t bind to just any

  • Different variant of MHC

    • Expressed in many versions - able to recognize wide

Describe what superantigens are

• bind independently to MHC class II molecules and to T-cell receptors, binding to the V domain of the T-cell receptor (TCR), away from the complementarity-determining regions, and to the outer faces of the MHC class II molecule, outside the peptide-binding site

  • Binds to the side

• This mode of stimulation DOES NOT prime an adaptive immune response specific for the pathogen.

• It causes a massive production of cytokines by CD4 T-cells

• The cytokines have two effects on the host:

  • 1. Systemic toxicity

  • 2. Suppression of the adaptive immune response

Describe the various functional classes of effector cells

• CD4TH1 and CD4TH2 cells 

  • contribute to humoral immunity by stimulating the production of Antibodies and inducing class switching. All classes of Antibodies contribute to humoral immunity, which is directed at extracellular pathogens.

    • Stimulate production of antibodies + induce class switching 

• CD4TH17

  •  recruit neutrophils to sites of infection 

• TFH 

  • cells contribute to humoral immunity by stimulating the production of Antibodies by B-cells, induce class switching and produce cytokines characteristics of either TH1 or TH2.

    • Suppress 

• CD4 regulatory T-cells

  •  tend to suppress the adaptive immune response and are important in preventing immune responses from becoming uncontrolled and in preventing autoimmunity.

How do lymphocytes gain entrance to lymph node from blood?

• 3 distinct stages:

  • Adhesion molecules

    • Involved:

      • selectins, integrins, members of the immunoglobulin superfamily and some mucin-like molecules

    • After adhesion, the T-cells follow gradients of chemokines to pass through the HEV wall into the paracortical region of the lymph node

    • initial Rolling of lymphocytes along the endothelial surface, Activation of integrins, firm Adhesion and transmigration (Diapedesis) across the endothelial layer into the paracortical areas, the T-cell zones.

      • Chemokines

      • Chemokines receptors

        

Describe the mechanisms that dendritic cells uptake antigens into their endocytic system

• Uptake of Antigens into the endocytic system, either by receptor-mediated phagocytosis or by macropinocytosis, is considered to be the major route for delivering peptides to MHC class II molecules for presentation to CD4 T-cells

• Phagocytosis

• Macropinocytosis

  • Small amount of

Describe the T-cell mediated cytotoxicity.

• cytotoxic T-cells can recycle to kill multiple targets, but each killing require the same series of steps, including receptor binding and the directed release of cytotoxic proteins stored in granules.

• Early in apoptosis the chromatin becomes condensed (red) and there is a necrotic cell.

• In the late stages of apoptosis, panel c: the cell nucleus is very condensed and the cell has lost much of its cytoplasm and membrane

what is the mechanism of cytotoxic T cell?

The principal mechanism of cytotoxic T-cell action is the calcium-dependent release of specialized cytotoxic granules upon recognition of antigen on the surface of a target cell.

Cytotoxic granules are modified lysosomes that contain at least three distinct classes of cytotoxic effector proteinsthat are expressed specifically in cytotoxic T-cells

What signals do APCs have for clonal expansion and differentiation for naïve T-cells?

1) Binding of the foreign-peptide: self-MHC complex by the T-cell receptor and in this example, a CD4 co-receptor, transmits a signal to the T-cell that an antigen has been encounter.

2) Effective activation of naïve T-cells requires a second signal, the co-stimulatory signal, to be delivered by the same antigen-presenting cell (APC) in this example CD28 on the T-cell encountering B7 molecules on the antigen presenting cell, whose net effect is the increase survival and proliferation of the T-cell that has received signal 1.

3) Cytokines in general are involved in directing this signal, differentiation